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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
Showing 1 - 200 of 253 Journals sorted by number of followers
Nature Reviews Drug Discovery     Full-text available via subscription   (Followers: 332)
International Journal of Drug Policy     Hybrid Journal   (Followers: 254)
Journal of Clinical Oncology     Hybrid Journal   (Followers: 242)
Journal of Medicinal Chemistry     Hybrid Journal   (Followers: 157)
Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 155)
Drugs     Full-text available via subscription   (Followers: 146)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 98)
Pharmaceutical Research     Hybrid Journal   (Followers: 94)
European Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 86)
Drug Safety     Full-text available via subscription   (Followers: 83)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 56)
Biomaterials     Hybrid Journal   (Followers: 54)
Clinical Pharmacology & Therapeutics     Hybrid Journal   (Followers: 44)
Regulatory Toxicology and Pharmacology     Hybrid Journal   (Followers: 42)
Journal of Controlled Release     Hybrid Journal   (Followers: 38)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 38)
International Journal of Pharmaceutics     Hybrid Journal   (Followers: 37)
Clinical Therapeutics     Hybrid Journal   (Followers: 34)
European Journal of Pharmaceutics and Biopharmaceutics     Hybrid Journal   (Followers: 34)
Pharmacoepidemiology and Drug Safety     Hybrid Journal   (Followers: 33)
British Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 32)
Journal of Pharmacy and Pharmacology     Full-text available via subscription   (Followers: 31)
Drug Development and Industrial Pharmacy     Hybrid Journal   (Followers: 29)
PharmacoEconomics     Full-text available via subscription   (Followers: 27)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 27)
AAPS Journal     Hybrid Journal   (Followers: 26)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 25)
Journal of Clinical Psychopharmacology     Hybrid Journal   (Followers: 24)
International Journal of Pharmacy Practice     Full-text available via subscription   (Followers: 24)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 24)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Journal of Pharmacokinetics and Pharmacodynamics     Hybrid Journal   (Followers: 22)
Journal of Pain & Palliative Care Pharmacotherapy     Hybrid Journal   (Followers: 21)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 20)
Journal of Applied Toxicology     Hybrid Journal   (Followers: 19)
Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 19)
Pharmaceutical Development and Technology     Hybrid Journal   (Followers: 19)
American Journal of Cardiovascular Drugs     Hybrid Journal   (Followers: 19)
Clinical Trials     Hybrid Journal   (Followers: 18)
Toxicology     Hybrid Journal   (Followers: 18)
Journal of Pharmaceutical and Biomedical Analysis     Hybrid Journal   (Followers: 18)
Clinical Toxicology     Hybrid Journal   (Followers: 18)
International Journal of Toxicology     Hybrid Journal   (Followers: 17)
Critical Reviews in Clinical Laboratory Sciences     Hybrid Journal   (Followers: 16)
Journal of Clinical Pharmacy and Therapeutics     Hybrid Journal   (Followers: 16)
Journal of Natural Products     Hybrid Journal   (Followers: 16)
Pharmaceutical Statistics     Hybrid Journal   (Followers: 15)
Toxicology Letters     Hybrid Journal   (Followers: 15)
Journal of Pharmacy Practice     Hybrid Journal   (Followers: 15)
Psychopharmacology     Hybrid Journal   (Followers: 15)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 14)
Cardiovascular Drugs and Therapy     Hybrid Journal   (Followers: 14)
European Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 14)
Current Medicinal Chemistry     Hybrid Journal   (Followers: 13)
American Journal of Therapeutics     Hybrid Journal   (Followers: 13)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 13)
Journal of the American Pharmacists Association     Full-text available via subscription   (Followers: 13)
Clinical Research and Regulatory Affairs     Hybrid Journal   (Followers: 12)
Seminars in Hematology     Hybrid Journal   (Followers: 12)
Drug Discovery Today: Technologies     Full-text available via subscription   (Followers: 12)
Current Pharmaceutical Design     Hybrid Journal   (Followers: 12)
Journal of Oncology Pharmacy Practice     Hybrid Journal   (Followers: 12)
Journal of Psychopharmacology     Hybrid Journal   (Followers: 11)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 11)
Toxicology in Vitro     Hybrid Journal   (Followers: 11)
Drug Development Research     Hybrid Journal   (Followers: 11)
Drug Metabolism and Disposition     Hybrid Journal   (Followers: 11)
Seminars in Oncology Nursing     Full-text available via subscription   (Followers: 10)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Journal of Separation Science     Hybrid Journal   (Followers: 10)
CNS Drugs     Full-text available via subscription   (Followers: 10)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 10)
Journal of Medical Marketing     Hybrid Journal   (Followers: 10)
Drugs & Aging     Full-text available via subscription   (Followers: 10)
European Neuropsychopharmacology     Hybrid Journal   (Followers: 9)
Food Additives & Contaminants Part A     Hybrid Journal   (Followers: 9)
Journal of Pharmacology and Experimental Therapeutics     Hybrid Journal   (Followers: 9)
Environmental Toxicology and Pharmacology     Hybrid Journal   (Followers: 9)
Medicinal Chemistry     Hybrid Journal   (Followers: 9)
Biometrical Journal     Hybrid Journal   (Followers: 9)
Drugs & Therapy Perspectives     Full-text available via subscription   (Followers: 9)
Prescriber     Hybrid Journal   (Followers: 9)
ChemMedChem     Hybrid Journal   (Followers: 9)
Current Opinion in Pharmacology     Hybrid Journal   (Followers: 9)
European Journal of Pharmacology     Hybrid Journal   (Followers: 8)
Inhalation Toxicology     Hybrid Journal   (Followers: 8)
Antiviral Research     Hybrid Journal   (Followers: 8)
Drug Metabolism Reviews     Hybrid Journal   (Followers: 8)
Progress in Neuro-Psychopharmacology and Biological Psychiatry     Hybrid Journal   (Followers: 8)
Human & Experimental Toxicology     Hybrid Journal   (Followers: 8)
Drug Delivery     Open Access   (Followers: 8)
BioDrugs     Full-text available via subscription   (Followers: 8)
Frontiers in Drug Design & Discovery     Hybrid Journal   (Followers: 8)
Expert Review of Pharmacoeconomics & Outcomes Research     Full-text available via subscription   (Followers: 8)
Experimental and Clinical Psychopharmacology     Full-text available via subscription   (Followers: 7)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 7)
Journal of Pharmacological and Toxicological Methods     Hybrid Journal   (Followers: 7)
Clinical and Experimental Pharmacology and Physiology     Hybrid Journal   (Followers: 7)
Scandinavian Journal of Clinical and Laboratory Investigation     Hybrid Journal   (Followers: 7)
Epilepsy Research     Hybrid Journal   (Followers: 7)
Clinical Drug Investigation     Full-text available via subscription   (Followers: 7)
Journal of Veterinary Pharmacology and Therapeutics     Hybrid Journal   (Followers: 6)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 6)
Skin Pharmacology and Physiology     Full-text available via subscription   (Followers: 6)
Journal of Cardiovascular Pharmacology     Hybrid Journal   (Followers: 6)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6)
Current Drug Discovery Technologies     Hybrid Journal   (Followers: 6)
Current Drug Delivery     Hybrid Journal   (Followers: 6)
Current Therapeutic Research     Open Access   (Followers: 6)
Expert Review of Cardiovascular Therapy     Full-text available via subscription   (Followers: 6)
Neuropharmacology     Hybrid Journal   (Followers: 5)
Current Drug Metabolism     Hybrid Journal   (Followers: 5)
Fitoterapia     Hybrid Journal   (Followers: 5)
Expert Review of Molecular Diagnostics     Full-text available via subscription   (Followers: 5)
Expert Review of Anti-infective Therapy     Full-text available via subscription   (Followers: 5)
Anti-Infective Agents     Hybrid Journal   (Followers: 5)
Toxicon     Hybrid Journal   (Followers: 5)
Medicinal Research Reviews     Hybrid Journal   (Followers: 5)
Investigational New Drugs     Hybrid Journal   (Followers: 5)
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry     Hybrid Journal   (Followers: 5)
Current Cancer Therapy Reviews     Hybrid Journal   (Followers: 5)
Reviews of Physiology, Biochemistry and Pharmacology     Hybrid Journal   (Followers: 4)
Planta Medica     Hybrid Journal   (Followers: 4)
Current Vascular Pharmacology     Hybrid Journal   (Followers: 4)
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4)
Journal of Child and Adolescent Psychopharmacology     Hybrid Journal   (Followers: 4)
CNS Drug Reviews     Open Access   (Followers: 4)
Inpharma Weekly     Full-text available via subscription   (Followers: 4)
Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal   (Followers: 4)
Immunopharmacology and Immunotoxicology     Hybrid Journal   (Followers: 4)
International Journal of Pharmaceutical and Healthcare Marketing     Hybrid Journal   (Followers: 4)
Inflammation Research     Hybrid Journal   (Followers: 4)
Cancer Chemotherapy and Pharmacology     Hybrid Journal   (Followers: 4)
International Journal of Neuropsychopharmacology     Open Access   (Followers: 3)
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 3)
Physiology International     Full-text available via subscription   (Followers: 3)
Cardiovascular Therapeutics     Open Access   (Followers: 3)
ASSAY and Drug Development Technologies     Hybrid Journal   (Followers: 3)
Pharmacopsychiatry     Hybrid Journal   (Followers: 3)
Chemotherapy     Full-text available via subscription   (Followers: 3)
Therapeutic Drug Monitoring     Hybrid Journal   (Followers: 3)
Current Drug Therapy     Hybrid Journal   (Followers: 3)
Research in Social and Administrative Pharmacy     Hybrid Journal   (Followers: 3)
PharmacoEconomics & Outcomes News     Full-text available via subscription   (Followers: 3)
Journal of Aerosol Medicine and Pulmonary Drug Delivery     Hybrid Journal   (Followers: 3)
Journal of Ethnopharmacology     Hybrid Journal   (Followers: 3)
Drug Resistance Updates     Hybrid Journal   (Followers: 3)
Journal of Pain Management & Medicine     Open Access   (Followers: 3)
Journal of Infection and Chemotherapy     Hybrid Journal   (Followers: 3)
Journal of Cardiovascular Pharmacology and Therapeutics     Hybrid Journal   (Followers: 3)
Current Pharmacogenomics and Personalized Medicine     Hybrid Journal   (Followers: 3)
Acta Pharmacologica Sinica     Hybrid Journal   (Followers: 3)
Microbial Drug Resistance     Hybrid Journal   (Followers: 3)
Frontiers in Medicinal Chemistry     Hybrid Journal   (Followers: 3)
Human Psychopharmacology Clinical and Experimental     Hybrid Journal   (Followers: 3)
BMC Pharmacology     Open Access   (Followers: 2)
The Brown University Psychopharmacology Update     Hybrid Journal   (Followers: 2)
International Clinical Psychopharmacology     Hybrid Journal   (Followers: 2)
Canadian Journal of Physiology and Pharmacology     Hybrid Journal   (Followers: 2)
Journal of Drug Targeting     Hybrid Journal   (Followers: 2)
Inflammopharmacology     Hybrid Journal   (Followers: 2)
Journal of Inflammation     Open Access   (Followers: 2)
Fundamental & Clinical Pharmacology     Hybrid Journal   (Followers: 2)
Behavioural Pharmacology     Hybrid Journal   (Followers: 2)
Vascular Pharmacology     Hybrid Journal   (Followers: 2)
Pulmonary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 2)
Biomedicine & Pharmacotherapy     Full-text available via subscription   (Followers: 2)
Clinical Neuropharmacology     Hybrid Journal   (Followers: 2)
Drugs in R & D     Full-text available via subscription   (Followers: 2)
International Immunopharmacology     Hybrid Journal   (Followers: 2)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 2)
Letters in Drug Design & Discovery     Hybrid Journal   (Followers: 2)
Archiv der Pharmazie     Hybrid Journal   (Followers: 2)
Pharmacological Reviews     Hybrid Journal   (Followers: 2)
Molecular Pharmacology     Hybrid Journal   (Followers: 2)
Journal of Microencapsulation: Microcapsules, Liposomes, Nanoparticles, Microcells, Microspheres     Hybrid Journal   (Followers: 2)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 2)
Particulate Science and Technology: An International Journal     Hybrid Journal   (Followers: 1)
Pharmacological Research     Hybrid Journal   (Followers: 1)
Current Enzyme Inhibition     Hybrid Journal   (Followers: 1)
Journal of Neuroimmune Pharmacology     Hybrid Journal   (Followers: 1)
Current Pharmaceutical Analysis     Hybrid Journal   (Followers: 1)
Current Neuropharmacology     Hybrid Journal   (Followers: 1)
Pharmacogenetics and Genomics     Hybrid Journal   (Followers: 1)
Journal of Texture Studies     Hybrid Journal   (Followers: 1)
Pharmaceutical Biology     Open Access  
Journal of Liposome Research     Hybrid Journal  
Toxin Reviews     Hybrid Journal  
Kaohsiung Journal of Medical Sciences     Open Access  
Redox Report     Open Access  
Pharmacology     Full-text available via subscription  
Pharmaceutical Chemistry Journal     Hybrid Journal  
NeuroMolecular Medicine     Hybrid Journal  
Journal of Ocular Pharmacology and Therapeutics     Hybrid Journal  
Harm Reduction Journal     Open Access  
Current Nanoscience     Hybrid Journal  
Infectious Disorders - Drug Targets     Hybrid Journal  
Current Bioactive Compounds     Hybrid Journal  
Cancer Biotherapy & Radiopharmaceuticals     Hybrid Journal  
Autonomic & Autacoid Pharmacology     Hybrid Journal  

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Similar Journals
Journal Cover
Human & Experimental Toxicology
Journal Prestige (SJR): 0.559
Citation Impact (citeScore): 2
Number of Followers: 8  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-3271 - ISSN (Online) 1477-0903
Published by Sage Publications Homepage  [1175 journals]
  • The hypermethylation of FOXP3 gene as an epigenetic marker for the
           identification of arsenic poisoning risk

    • Free pre-print version: Loading...

      Authors: Lu Ma, Xiaolin Fang, Aihua Zhang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background and Purpose: Arsenic exposure can lead to skin lesions and multiple organ damage, which are not easily reversible and for which there is no effective therapeutics. Identification of reliable epigenetic markers is essential for early recognition of arsenic poisoning risk. Anomalous DNA methylation of immune homeostasis regulator FOXP3 is a critical mechanism for triggering arsenic poisoning. This study aims to explore the value of FOXP3 methylation in the identification of arsenic poisoning risk.Methods: 88 arsenic poisoning subjects and 41 references were recruited. Urinary arsenic contents and FOXP3 methylation in PBLCs was measured by ICP-MS and pyrosequencing, respectively.Results: The results showed that the elevated FOXP3 methylation in PBLCs were associated with the increased levels of urinary arsenic and were positively associated with the increased risk of arsenic poisoning and its progression. The result of mediation analysis revealed that 24.3% of the effect of arsenic exposure on the risk of arsenic poisoning was mediated by increased FOXP3 methylation. Additionally, we constructed a nomogram model with FOXP3 methylation as an epigenetic predictor to assess the probability of individual arsenic poisoning. The model showed a robust ability in the discrimination of arsenic poisoning risk, with an area under receiver operating characteristics curve of 0.897(0.845–0.949) and more than 70% accuracy. The calibration curves and the Harrell concordance index showed that the consistency rate between the probability predicted by the nomogram model and the actual probability is 89.7%.Conclusions: Taken together, we found the great potential of FOXP3 methylation for the identification of arsenic poisoning risk and provided a new approach to the application of epigenetic markers in accurately quantifying the risk of adverse outcomes.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-12-05T04:03:52Z
      DOI: 10.1177/09603271221142819
      Issue No: Vol. 41 (2022)
       
  • Overexpression of lncRNA A2M-AS1 inhibits cell growth and aggressiveness
           via regulating the miR-587/bone morphogenetic protein 3 axis in lung
           adenocarcinoma

    • Free pre-print version: Loading...

      Authors: Hongfei Guo, Tao Li, Chunlei Peng, Qinghua Mao, Biao Shen, Minxin Shi, Haimin Lu, Ting Xiao, Aimin Yang, Yupeng Liu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Lung adenocarcinoma (LUAD) is a malignant tumor that occurs in the lungs. Numerous reports have substantiated the participation of long non-coding RNAs (lncRNAs) in the tumorigenesis of LUAD. Previously, lncRNA alpha-2-macroglobulin antisense RNA 1 (A2M-AS1) was confirmed to be an important regulator in the biological processes of LUAD and dysregulation of A2M-AS1 was associated with non-small cell lung cancer (NSCLC) progression. However, the precise mechanism of A2M-AS1 in LUAD has not been elucidated. Therefore, our study was designed to investigate the detailed molecular mechanism of A2M-AS1 in LUAD. Herein, the expression of lncRNA A2M-AS1, microRNA (miRNA) miR-587, and bone morphogenetic protein 3 (BMP3) in LUAD cell lines and tissues were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. The viability, proliferation, migration and invasion of LUAD cells were tested by cell counting kit-8 (CCK-8), colony formation and Transwell assays. In vivo tumor growth was investigated by xenograft animal experiment. Interactions among A2M-AS1, miR-587 and BMP3 were measured by RNA pulldown and luciferase reporter assays. In this study, A2M-AS1 was downregulated in LUAD tissues and cells and related to poor prognosis in LUAD patients. A2M-AS1 overexpression suppressed LUAD cell proliferation, migration and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, A2M-AS1 directly bound with miR-587 to promote BMP3 expression in LUAD cells. Low expression of BMP3 was found in LUAD tissues and cells and was closely correlated with poor prognosis in LUAD patients. BMP3 deficiency reserved the inhibitory influence of A2M-AS1 overexpression on LUAD cell behaviors. Overall, A2M-AS1 inhibits cell growth and aggressiveness via regulating the miR-587/BMP3 axis in LUAD.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-12-03T05:52:44Z
      DOI: 10.1177/09603271221138971
      Issue No: Vol. 41 (2022)
       
  • Trans-resveratrol alleviates hepatic and renal injury in γ-irradiated
           rats

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      Authors: Nermeen M El Bakary, Mohamed K Abdel-Rafei, Rokaya E Maarouf, Somaya Z Mansour, Noura M Thabet
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundAlthough ionizing radiation (IR) has been of immense value to human life due to its involvement in several fields, it doesn’t eliminate that exposure to IR results in an array of biological consequences, including oxidative stress, inflammation, and death. Thus, this study aimed to explore the curative effect of trans-Resveratrol (t-Res) on hepatic and renal injury in a rat model exposed to single and fractionated doses of γ-rays.MethodsRats exposed to a single dose of IR (6 Gy, as an acute effect) or a fractionated dose of IR (2 Gy/time/3 days, day after day; to imitate a chronic impact) were treated with t-Res. Then, the radio-protective effect of t-Res was investigated via biochemical and histological estimations in the liver and kidney of rats in the different groups.ResultsThe data displayed a significant amelioration in biochemical and histological indices in the liver and kidney of rats exposed to IR doses and treated with t-Res. Particularly, t-Res reduced the oxidative stress milieu through decreasing HIF-1α, ROS, and MDA levels associated with increased CAT activity and Nrf-2 gene expression. Also, t-Res improved the inflammatory status via a decrease in TNF-α, NF-κB, SOCS-3, and HSP-70 genes expression linked with elevations in SIRT-1 and P53 genes expression.ConclusionIt could be concluded that t-Res had hepatoprotective and renoprotective effects against the deleterious consequences of γ-rays exposure due to its antioxidant and anti-inflammatory properties.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-12-02T09:07:01Z
      DOI: 10.1177/09603271221142817
      Issue No: Vol. 41 (2022)
       
  • The protective effects of red ginseng and amifostine against renal damage
           caused by ionizing radiation

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      Authors: Hamit Yilmaz, Yunus Karakoc, Levent Tumkaya, Tolga Mercantepe, Hacer Sevinc, Adnan Yilmaz, Sema Yılmaz Rakıcı
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the toxic effect of ionizing radiation (IR) on kidney tissues through changes in biochemical and histopathological parameters in addition to contributions to the use of amifostine and RG in clinical studies. Five groups were established: Group I (control, receiving only saline by gavage), Group II (IR only), and Group III (IR+AM, 200 mg/kg intraperitoneally (i.p.). Group IV (IR + RG, 200 mg/kg orally once a day for 4 weeks), and Group V (IR+RG+AM, 200 mg/kg orally once/day for 4 weeks before IR and 200 mg/kg AM administered (i.p.) 30 min before IR). All groups, except for the control group, were subject to 6-Gy whole-body IR in a single fraction. 24 h after irradiation, all animals were sacrificed under anesthesia. IR enhanced MDA, 8-OHdG, and caspase-3 expression while decreasing renal tissue GSH levels (p < .05). Significant numbers of necrotic tubules together with diffuse vacuolization in proximal and distal tubule epithelial cells were also observed. The examination also revealed substantial brush boundary loss in proximal tubules as well as relatively unusual glomerular structures. While GSH levels significantly increased in the AM, RG, and AM+RG groups, a decrease in KHDS, MDA, 8-OHdG, and caspase-3 expression was observed, compared to the group subject to IR only (p < .05). Therefore, reactive oxygen species-scavenging antioxidants may represent a promising treatment for avoiding kidney damage in patients receiving radiation.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-12-01T10:19:57Z
      DOI: 10.1177/09603271221143029
      Issue No: Vol. 41 (2022)
       
  • Clerodane diterpene induces apoptosis/anoikis and suppresses migration and
           invasion of human bladder cancer cells through the histone deacetylases,
           integrin–focal adhesion kinase, and matrix metalloproteinase 9
           signalling pathways

    • Free pre-print version: Loading...

      Authors: Yu-Chi Chen, Chih-I Chen, Chao-Yuan Chang, Bu-Miin Huang, Yung-Chia Chen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Clerodane diterpene, a class of bicyclic diterpenoids, is found in hundreds of plant species. 16-hydroxycleroda-3,13-dien-15,16-olide (CD) can be isolated from the plant Polyalthia longifolia and has been applied against oral cancer and glioma by xenograft model. In this study, we aim to explore its antitumour action by examining its histone deacetylase (HDAC) activity and integrin-associated intracellular signalling pathway on T24 human bladder cancer (BC) cells. Our results revealed that CD-inhibited colony formation, HDAC activity, HDAC (1, 2 and 3) mRNA and cell spreading on fibronectin-coated surfaces in a concentration-dependent manner. Furthermore, decreased cFLIP and increased caspase-8 cleavage accompanied CD-induced cell death. At non-toxic concentrations, CD blocked the migration and invasion of T24 cells. CD hindered migration and invasion by the downregulation of fibronectin, integrin α5β1, β-catenin, FAK, vinculin and Rho A, as well as by reduction of phosphorylated glycogen synthase kinase 3β (pGSK3β), pSrc, pstat3 and pNFκB. We observed that the MMP9 gene was closely linked with prognosis of patients with bladder cancer. MMP9 protein levels and activity were largely attenuated by CD in a concentration-dependent manner. In conclusion, CD-induced caspase-8-dependent apoptosis and suppressed migration and invasion by blocking several intracellular signalling pathways, including downregulation of HDAC activity and integrin–FAK and MMP9 pathways.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-29T11:04:04Z
      DOI: 10.1177/09603271221143040
      Issue No: Vol. 41 (2022)
       
  • Sortilin 1 regulates hepatocellular carcinoma progression by activating
           the PI3K/AKT signaling

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      Authors: S Ye, B Wang, Y Zhou, Q Sun, X Yang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundSortilin 1 (SORT1) has been reported as an oncogene in several human tumors. Nonetheless, the biological functions of SORT1 in hepatocellular carcinoma (HCC) remain poorly understood.MethodsWestern blotting was employed for the determination of protein expression. Hepatocellular carcinoma cell viability, apoptosis, migration, and invasion were measured via CCK-8, flow cytometry, wound healing, and Transwell assays.ResultsSortilin 1 was upregulated in HCC and closely associated with unsatisfactory outcomes of HCC patients. Furthermore, in vitro and in vivo assays revealed that SORT1 knockdown significantly diminished HCC cell proliferation and metastasis but accelerated HCC cell apoptosis; moreover, SORT1 depletion also restrained the growth of xenografted HCC tumors. Mechanistically, SORT1 activated PI3K/AKT signaling in HCC cells, thereby promoting the malignant behaviors of HCC cells.ConclusionThis study demonstrated that SORT1 might promote HCC progression by activating PI3K/AKT signaling, indicating that SORT1 might be a promising target and biomarker for HCC treatment and prognosis.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-29T05:57:05Z
      DOI: 10.1177/09603271221140111
      Issue No: Vol. 41 (2022)
       
  • lncRNA FGD5-AS1 acts as a ceRNA to regulate lipopolysaccharide-induced
           injury via the miR-223-3p-3p/GAS5 axis in cardiomyocytes

    • Free pre-print version: Loading...

      Authors: Xiao-ling Fang, Shu-guang Shi
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Long noncoding RNAs (lncRNAs) are abnormally expressed in numerous diseases, and they are closely associated with cardiac diseases. However, the role of lncRNAs in lipopolysaccharide (LPS)-induced cardiotoxicity as well as the potential mechanism remain largely unclear. In the present study, IncRNA microarray assays were performed to analyze differential lncRNA expression in LPS-treated cardiomyocytes, and lncRNA FGD5-AS1 was one of the downregulated lncRNAs. H9C2 cells were treated with LPS, and the expression of lncRNA FGD5-AS1 was markedly downregulated. LncRNA FGD5 overexpression decreased the LPS-induced cardiomyocyte apoptosis and inflammation. Bioinformatics analysis and a luciferase reporter assay indicated that lncRNA FGD5-AS1 directly binds to miR-223-3p. A miR-222-3p mimic partially reversed the inhibitory effect of lncRNA FGD5-AS1 on the LPS-induced H9C2 cell apoptosis and inflammatory response. Moreover, miR-223-3p directly targeted growth arrest-specific transcript 5 (GAS5). LncRNA FGD5-AS1 regulated LPS-induced H9C2 cell inflammation and apoptosis via the miR-223-3p/GAS5 axis.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-29T01:27:03Z
      DOI: 10.1177/09603271221138969
      Issue No: Vol. 41 (2022)
       
  • Evaluation of the toxic effects of thimerosal and/or aluminum hydroxide in
           SH-SY5Y cell line

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      Authors: Mehmet Evren Öztürk, Anıl Yirün, Selinay Başak Erdemli-Köse, Aylin Balcı-Özyurt, Deniz Arca Çakır, Didem Oral, Pınar Erkekoğlu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      In this study, we aimed to evaluate possible toxic effects of thimerosal, aluminum and combination of thimerosal and aluminum in SH-SY5Y cells. Inhibitory concentrations were determined by MTT assay; reactive oxygen species (ROS) were determined by a fluorometric kit and antioxidant/oxidant parameters were measured by spectrophotometric kits. Nuclear factor erythroid 2-associated factor 2 (Nrf2), norepinephrine (NE), dopamine transporter (DAT) and dopamine beta β-hydroxylase (DBH) levels were measured by sandwich ELISA kits while 8-hydroxy deoxyguanosine (8-OHdG) and dopamine levels were determined by competitive ELISA kits. Thimerosal (1.15 μM) and aluminum (362 μM) were applied to cells at inhibitory concentrations 20 (IC20s) for 24 h. ROS increased significantly in cells aluminum- and aluminum+thimerosal-treated cells. Glutathione levels decreased in aluminum group while total antioxidant capacity and protein oxidation levels increased significantly in aluminum and aluminum+thimerosal groups. Lipid peroxidation increased significantly in groups treated with aluminum and aluminum+thimerosal. Nrf2 levels and DNA damage were significantly higher in all groups while dopamine levels significantly increased in cells treated with thimerosal and aluminum+thimerosal, DAT levels were found to be higher in all experimental groups compared to the control. These findings showed that both thimerosal and aluminum can change oxidant/antioxidant status, cause DNA damage, alter dopamine and DAT levels. Changes seen in cells treated with combined exposure to aluminum and thimerosal are more pronounced. Special care should be taken while vaccinating sensitive populations and safer alternatives for aluminum and thimerosal should used.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-22T04:07:50Z
      DOI: 10.1177/09603271221136206
      Issue No: Vol. 41 (2022)
       
  • Bortezomib induces cellular senescence in A549 lung cancer cells by
           stimulating telomere shortening

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      Authors: Lei Wang, Hang Yin, Shiren Huang, Sini Huang, Congcong Huang, Zhao Zhang, Hui Liu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Bortezomib (BTZ) is a first-generation proteasome inhibitor with anti-tumor properties for multiple myeloma and mantle cell lymphoma. Increasing evidence has shown that BTZ exhibits toxic effects on diverse tumor cells, including non-small cell lung cancer (NSCLC) cells. However, the mechanism has not been fully evaluated. Here, we examined the regulatory effect of BTZ on cellular senescence, a potent tumor suppressive mechanism, in NSCLC cell lines. SA-β-gal staining assay showed that BTZ caused a significant increase in β-Gal positive A549 cells. BTZ also induced cell cycle arrest on G0/G1 phase in A549 cells. Furthermore, telomerase activity was markedly reduced in A549 cells treated with BTZ. BTZ reduced the expression levels of hTERT, and the key proteins binding to telomeric DNA, including POT1 and TIN2. It also induced the expressions of the cell cycle-associated tumor suppressors p53 and p21 in A549 cells. Moreover, hTERT overexpression abolished the effects of BTZ on A549 cells. These results show that BTZ induced cellular senescence by stimulating telomere shortening. Our results provide experimental data for the potential clinical application of BTZ in NSCLC treatment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-19T05:42:29Z
      DOI: 10.1177/09603271221124094
      Issue No: Vol. 41 (2022)
       
  • Lanzhou Lily polysaccharide fragment protects human umbilical vein
           endothelial cells from radiation-induced DNA double-strand breaks

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      Authors: S Kang, Z Guo, F Zhao, L Song, L Lu, C Wang, Z Liu, J Zhao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundRadiotherapy is widely used in the treatment of tumors. However, while killing tumor cells, radiation may also cause damage to the surrounding normal tissues. Therefore, it is very important to find safe and effective radiation protection agents.PurposeTo investgate the radiation protection effect of Lanzhou Lily polysaccharide fragments (LLP). Methods: The crude polysaccharides of Lanzhou Lily were extracted from the dried bulb powder of Lilium lilium by ultrasonic-assisted hot water method, and then five different fragments were separated from the polysaccharides by DEAE-52-cellulose column. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, neutral comet and immunofluorescent staining were used to investigate the effect of LPe fragment on Human Umbilical Vein Endothelial Cells (HUVEC) survival and the possible radioprotective mechanism.ResultsThe LPe fragment (composing of mannose and glucose, with a ratio of 5.5:2.9, and the average molecular weight is 8629.8 Da), significantly promoted the proliferation of HUVECs and protected cells from X-ray-induced double-strand breaks (DSBs) in DNA, in which pretreatment with the LPe fragment at 100 μg/mL showed the most pronounced protection. In addition, the occurrence of X-ray-induced γH2AX foci was significantly reduced by treatment with the LPe fragment at 50, 100, and 200 μg/mL. Furthermore, caffeine or wortmannin in combination with the LPe fragment at 25 μg/mL significantly reduced the number of X-ray-induced γH2AX foci, indicating phosphoinositide-3 kinases (PI3K) is involved in H2AX phosphorylation in HUVECs.Conclusion These results indicate the LPe fragment has a protective effect against radiation-induced DSBs and may be used as a natural antioxidant agent.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-15T09:48:46Z
      DOI: 10.1177/09603271221140110
      Issue No: Vol. 41 (2022)
       
  • ARL4C depletion suppresses the resistance of ovarian cancer to carboplatin
           by disrupting cholesterol transport and autophagy via
           notch-RBP-Jκ-H3K4Me3-OSBPL5

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      Authors: Juan Yang, Shuping Peng, Keqiang Zhang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Increasing studies indicate that cholesterol plays an important role in drug resistance. ARL4C is implicated in the export and import of cholesterol, therefore this study aimed to explore the effect of ARL4C on the resistance of ovarian cancer (OVC) to Carboplatin. This study collected OVC tissue samples from patients who are sensitive or resistant to carboplatin, and established Carboplatin-resistant OVC cell lines, OVCAR3(R) and SKOV3(R) using OVCAR3 and SKOV3. High throughput sequencing was conducted to find genes that regulated by ARL4C. Cholesterol esterification was performed to evaluate the transport of cholesterol from Lysosome (LY) to Endoplasmic reticulum (ER). The fluorescence of LC3-GFP-mRFP was used to evaluate the function of autophagy flux. As indicated by PCR, western blot and Immunohistochemistry, ARL4C was increased in the Carboplatin-resistant OVC tissues and cells. Knockdown of ARL4C attenuated the resistance of OVCAR3(R) and SKOV3(R) to Carboplatin. By suppressing Notch signal, ARL4C knockdown inhibited the transcriptional function of RBP-Jκ and RBP-Jκ-induced H3K4Me3, which collectively reduced OSBPL5 expression. OSBPL5 deficiency inhibited the transport of cholesterol from LYs to ER, which led to the accumulation of cholesterol in LYs and the dysfunction of autophagy. In summary, ARL4C knockdown attenuated the resistance of OVC to Carboplatin by disrupting cholesterol transport and autophagy. This study revealed a promising target to attenuate the resistance of OVC to Carboplatin and elucidated the potential mechanism.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-11T06:24:07Z
      DOI: 10.1177/09603271221135064
      Issue No: Vol. 41 (2022)
       
  • Transcriptomic and proteomic characteristics of the di(2-ethylhexyl)
           phthalate-induced sperm dna damage mouse model

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      Authors: Chenming Zhang, Zulong Wang, Rubing Chen, Shiqi Wang, Hao Zhang, Sicheng Ma, Zhong Hua
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Di(2-ethylhexyl) phthalate (DEHP) is one of the most common organic pollutants and is added to various plastic products as a plasticizer. DEHP oxidative metabolite content in the human body is associated with DNA damage in sperm and decreased testosterone levels in blood. In this study, a DEHP-induced sperm DNA damage mouse model was replicated and improved, and the transcriptomic and proteomic characteristics of the model were observed. Male mice in the two groups were exposed to DEHP 1 g/kg/d or the same amount of normal saline for 60 days, and the sperm DNA fragmentation index (DFI) was detected by a sperm chromatin structure assay (SCSA). The mRNA and protein expression profiles of the testis were detected by RNA-seq and data-independent acquisition (DIA). The sperm DFI of the DEHP group was significantly increased. Compared with the control group, 111 differentially expressed genes (DEGs) and 2147 differentially expressed proteins (DEPs), such as Lamb2, Ahnak, Tkt, Dnah8 and Tbl2, were found in the DEHP group. These genes were mainly enriched in metabolic pathways, pathways in cancer and the PI3K-Akt signaling pathway. Our results showed that DEHP 1 g/kg/d can induce sperm DNA damage in a male mouse model after 60 days of intragastric administration. The reproductive toxicity of DEHP may be related to metabolic pathways in cancer and the PI3K-Akt signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-10T11:36:56Z
      DOI: 10.1177/09603271221139444
      Issue No: Vol. 41 (2022)
       
  • Relationship between styrene exposure and prolactin secretion in human and
           animal studies: A systematic review

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      Authors: P Sadighara, A Abedini, M-R Zirak, A Salehi, S Darbandi Azar, G Mirzaei, N Vakili Saatloo
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Styrene is widely used in industrial applications. Inhalation exposure occurs in the industry. Some studies indicated that serum prolactin concentrations increased after exposure to styrene, while other studies found no change. In this systematic review, the search was done with the keywords styrene and prolactin in the PubMed, Science Direct, Web of Science and Scopus databases, regardless of the publication period. 118 studies were obtained and only seven articles were finally selected according to exclusion and inclusion criteria. The effect of styrene on prolactin secretion was selected in both human and animal studies. The increased response was seen in inhalation exposures. Subcutaneous exposure has no significant effect on prolactin levels. The observed responses were both dose-dependent and gender-dependent. Changes in serum prolactin were more frequent in women compared to exposed men. Dopamine depletion was not observed in all studies, so more tests on laboratory animals are necessary to clarify the possible mechanism.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-11-02T07:07:22Z
      DOI: 10.1177/09603271221133538
      Issue No: Vol. 41 (2022)
       
  • CCl4 inhibits the expressions of hepatic taurine biosynthetic enzymes and
           taurine synthesis in the progression of mouse liver fibrosis

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      Authors: Di Zhang, Jiaming Zheng, Guobin Qiu, Tongjuan Niu, Yuneng Gong, Sheng Cui
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Carbon tetrachloride (CCl4) is a widely used hepatotoxin for the studies of liver fibrosis and cirrhosis, and taurine has function to abate liver fibrosis induced by CCl4. But the interacting mechanisms between taurine and CCl4 in liver are still largely unknown. These made us to hypothesize that CCl4 may induce liver fibrosis by affecting the expressions of taurine biosynthetic enzymes and taurine synthesis. We thus assayed the expressions of hepatic cysteine dioxygenase (CDO), cysteine sulfonate acid decarboxylase (CSAD) and taurine transporter (TauT) in the progression of mouse liver fibrosis induced by CCl4. The results demonstrated that CCl4 treatment markedly decreased hepatic CSAD, CDO expressions, and taurine levels in hepatic tissue, although TauT expression did not exhibit significant decline. It was contrasting that hepatic α-SMA, serum AST, ALT, ALP kept increasing, which were accompanied by the pathological characters of liver, whereas taurine supplement attenuated the progression of liver fibrosis induced by CCl4. These results demonstrate that CCl4 may induce liver fibrosis by inhibiting hepatic CSAD and CDO expressions and taurine synthesis, which are crucial for our understanding the mechanisms of liver fibrosis induced by CCl4, and also potential for establishing therapeutic strategies of liver fibrosis and related diseases.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-31T07:41:49Z
      DOI: 10.1177/09603271221135033
      Issue No: Vol. 41 (2022)
       
  • Therapeutic role of nitroglycerin against copper-nitrilotriacetate induced
           hepatic and renal damage

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      Authors: Ayesha Rahman Ahmed, Senty Vun-Sang, Mohammad Iqbal
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Earlier we have shown that exposure to copper-nitrilotriacetate (Cu-NTA) manifests toxicity by generating oxidative stress and potent induction of proliferative reaction in the liver and kidney. In the study, we look at the impact of nitroglycerin (GTN) administration on Cu-NTA-induced oxidative stress and hyperproliferative response in the liver and kidney. GTN administration intraperitoneally to male Wistar rats after Cu-NTA administration intraperitoneally caused substantial protection against Cu-NTA-induced tissue injury, oxidative stress and hyperproliferative response. Cu-NTA administration at a dose of 4.5 mg/kg body weight produces significant (p < .001) elevation in biochemical parameters including aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine (CREA) with a concomitant increase in microsomal lipid peroxidation. Along with these alterations, we discovered a substantial increment in [3H]thymidine incorporation into hepatic and renal DNA synthesis (p < .001). Cu-NTA-induced tissue damage and lipid peroxidation in hepatic and renal tissues were inhibited by GTN treatment in a dose-dependent manner (p < .05–0.001). Furthermore, GTN can suppress the hyperproliferative response elicited by Cu-NTA by down-regulating the rate of [3H]thymidine incorporation into hepatic and renal DNA (p < .01–0.001). Protective effect of GTN against Cu-NTA was also confirmed by histopathological changes in liver and kidney. This result suggests that GTN may serve as a scavenger for reactive oxygen species (ROS) and reduces toxic metabolites of Cu-NTA, thereby avoiding tissue injury and oxidative stress. Further, administration of NO inhibitor, NG-Nitroarginine methyl ester (L-NAME), exacerbated Cu-NTA induced oxidative tissue damage and cell proliferation. Overall, GTN reduces Cu-NTA-induced tissue damage, oxidative stress, and proliferative response in the rat liver and kidney, according to these findings. On the basis of the above results, present study suggests that GTN may be a potential therapeutic agent for restoration of oxidative damage and proliferation to liver and kidney.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-28T09:42:22Z
      DOI: 10.1177/09603271221131312
      Issue No: Vol. 41 (2022)
       
  • Exposure to pesticides and pediatric Wilms’ tumor. A meta-analysis on
           pre-conception and pregnancy parental exposure with an IARC/WHO commentary
           

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      Authors: A Khan, J Feulefack, CM Sergi
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundThere are hereditary types of nephroblastoma or Wilms’ tumor associated with exposure of the germ cells of either parent to harmful environmental factors. Some studies have examined the exposure of compounds used pesticides and herbicides as a risk factor for Wilms’ tumor.MethodsA systematic review and meta-analysis were carried out on case-control studies to establish the potential link between exposure to these organic molecules and Wilms’ tumor occurrence in children rigorously. We examined the monographs on some organo-phosphate insecticides and herbicides issued by the International Association for the Research on Cancer (IARC) under the auspices of the World Health Organization (WHO). PUBMED, SCOPUS, and Google Scholar studies (1960–2021) were identified and systematically reviewed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Subgroup analyses were conducted after stratification for occupational versus residential exposure and before birth (prenatal) vs. after birth (postnatal) exposure. In addition, we revised the monographs on chemical compounds issued recently by the IARC/WHO.ResultsOur findings seem to consolidate that parental pesticide exposure during the preconception or pregnancy period is correlated with an increased occurrence risk for Wilms’ tumor. We confirm the validity of the WHO essays on certain organophosphate herbicides and insecticides, which support these compounds, may be highly relevant in future cancer prevention policies.ConclusionParental exposure to pesticides, particularly in household settings, is poorly emphasized in our society. There is a strong association between these organophosphate compounds and pediatric cancer. Public health agencies may need to take stronger action than in the past.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-27T02:34:33Z
      DOI: 10.1177/09603271221136211
      Issue No: Vol. 41 (2022)
       
  • [Gly14]-Humanin inhibits an angiotensin II-induced vascular smooth muscle
           cell phenotypic switch via ameliorating intracellular oxidative stress

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      Authors: Yi Xie, Jin Zhang, Min Zhang, Li Jiang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Angiotensin II (AngII) is involved in the pathogenesis of hypertensive artery remodeling by inducing a phenotypic switch in vascular smooth muscle cells [Gly14]-Humanin (HNG), a humanin analogue, exerts potent cytoprotective effects both in vitro and in vivo. This study aimed to investigate the effects of HNG on an AngII-induced phenotypic switch in VSMCs and the potential mechanisms underlying these effects. The roles of [Gly14]-Humanin in AngII-stimulated VSMCs proliferation and migration was detected by CCK-8 assay, Cell cycle analysis, wound healing assay, trsnswell assay and western blot. The mechanism by which [Gly14]-Humanin regulates VSMC phenotypic switch was determined by intracellular oxidative stress detection, transcriptomic analysis and qRT-PCR. The results showed that HNG inhibited AngII-induced VSMC proliferation and migration and maintained a stable VSMC contractile phenotype. In addition, HNG reduced the level of AngII-induced oxidative stress in vascular smooth muscle cells. This process could be accomplished by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity. In conclusion, the results suggested that HNG ameliorated intracellular oxidative stress by inhibiting NAD(P)H oxidase activity, thereby suppressing the AngII-induced VSMC phenotype switch. Thus, HNG is a potential drug to ameliorate artery remodeling in hypertension.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-27T01:45:15Z
      DOI: 10.1177/09603271221136208
      Issue No: Vol. 41 (2022)
       
  • Hepatoprotective effect of ferulic acid and/or low doses of γ-irradiation
           against cisplatin-induced liver injury in rats

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      Authors: Marwa A Esmat, Ahmed Osman, Rasha E Hassan, Sanaa A Hagag, Tarek K El-maghraby
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The therapeutic efficacy of cisplatin (CIS) is limited owing to its hepatotoxic side effects. The current study aimed to investigate the protective impact of ferulic acid (FA) and low-doses of γ-irradiation (LDR) against CIS-prompted hepatotoxicity in rats. Adult male Swiss albino rats were divided into eight groups: untreated group; FA, LDR, and CIS treated groups; and combinations of one or more of the above treatments. Post-treatment analyses included measuring redox markers like SOD and CAT activity, NO free radical content, and lipid peroxidation in liver tissue. Serum aminotransferase activities were also determined. Additionally, gene transcript levels of liver NF-ҡB-P65, caspase-1, COX-2, and IL-1β were quantified. Moreover, immunohistochemistry for caspase-3 and histopathological examinations were estimated in liver tissue. Our findings revealed increased levels of oxidative stress along with a significant reduction in anti-oxidative responses and a significant increase in serum aminotransferase activities in the CIS-intoxicated group. A similar increase was also observed in COX-2 and IL-1β transcript levels and caspase-3 enzyme activity, besides a decrease in transcript levels of NF-ҡB-p65 and caspase-1, indicating an overall inflammatory trend and an increase in the apoptotic shift. The co-administration of FA and/or treatment with LDR has ameliorated the hepatotoxic effect induced by CIS. The histopathological investigation of liver tissues confirmed this ameliorating action of these adjuvant therapies against CIS toxicity. In conclusion, it is plausible to suggest that the hepatoprotective effects of co-administration of FA and/or LDR against CIS-induced hepatotoxicity are attributed to the possession of anti-oxidative, anti-inflammatory, and anti-apoptotic capabilities.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-22T01:13:47Z
      DOI: 10.1177/09603271221136205
      Issue No: Vol. 41 (2022)
       
  • Phosphodiesterase inhibitor, Vinpocetine, guards against doxorubicin
           induced cardiotoxicity via modulation of HIF/VEGF and cGMP/cAMP/SIRT
           signaling pathways

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      Authors: Marwa M.M. Refaie, Maram El-Hussieny, Elshymaa A. Abdel-Hakeem, Michael A Fawzy, Eman Shaaban Mahmoud Abd El Rahman, Sayed Shehata
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Purpose: Doxorubicin (DOX) is a widely used chemotherapeutic agent complicated with cardiotoxic adverse effects. Up till now, there are no researches discussing the role of vinpocetine (VIN) in DOX cardiotoxicity. Thus, the aim of our work was to study this effect and explore the different involved mechanisms.Methods: 50 male Wistar albino rats were subjected to DOX toxicity via administration of single i.p. Dose (15 mg/kg) on the 4th day with or without co-administration of VIN (10, 20, 30 mg/kg/day) orally for 5 days. Results: Our data revealed that VIN succeeded in protecting the heart against DOX induced damage as manifested by significant decrease of cardiac enzymes, hypoxia inducible factor alpha (HIF-1α), vascular endothelial growth factor-A (VEGF-A), tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and caspase3 levels. Furthermore, VIN given group showed marked improvement of the histopathological changes of cardiac injury, total antioxidant capacity (TAC), elevation of reduced glutathione (GSH), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP) and sirtuin-1 (SIRT-1). Conclusion: We concluded that VIN could ameliorate DOX induced cardiac damage and this effect may be attributed to modulation of HIF/VEGF signaling pathway, up-regulation of cGMP/cAMP/SIRT pathway, inhibition of phosphodiesterase enzyme, besides its anti-apoptotic, anti-inflammatory, and anti-oxidant properties.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-21T10:42:15Z
      DOI: 10.1177/09603271221136209
      Issue No: Vol. 41 (2022)
       
  • LncRNA colorectal neoplasia differentially expressed exacerbates the
           impairments in learning and memory induced by isoflurane

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      Authors: Xiang Tian, Yawei Yuan, Long Wang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundThis observation aimed to investigate the effect of colorectal neoplasia differentially expressed (CRNDE) targeted miR-212-5p on cognitive impairment induced by isoflurane (ISO) anesthesia in rats.MethodsThe cognitive function of rats was measured by Morris water maze test. QRT-PCR detection of CRNDE and miR-212-5p expression levels in rats in each group. Double luciferase was used to verify the targeting relationship between miR-212-5p and CRNDE, and commercial kits were used to detect the level of inflammatory cytokines in hippocampus.ResultsThe concentration of CRNDE was enhanced in rats treated by ISO anesthetic. The neurological severity score was elevated, the escape latency of rats was prolonged, the stay time in the quadrant of the platform, and the number of times crossing the platform decreased in the ISO group. The above indexes of rats in ISO + si-CRNDE were improved. MiR-212-5p is a mediator in the management of CRNDE on cognition and inflammation.ConclusionCRNDE led to the deterioration of impairment on cognition induced by ISO through suppressing miR-212-5p expression and promoting neuroinflammation.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-20T06:34:14Z
      DOI: 10.1177/09603271221132152
      Issue No: Vol. 41 (2022)
       
  • Has_circ_0010220 regulates the miR-574-3p/IL-6 axis to increase
           doxorubicin resistance in osteosarcoma

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      Authors: Yanglin Gu, Guangchang Wang, Baocai Ran
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundOsteosarcoma (OS) is the most common primary bone malignancy. It has an aggressive nature and produces drug resistance in diseased patients, which in turn causes obstacles in treating cancer with chemotherapy. The objective of our investigation was to analyze the function and hsa_circ_0010220 mechanism in doxorubicin (DOX) resistance to OS.MethodsThe hsa_circ_0010220, IL-6, and miR-574-3p levels in OS diseased tissues and cell resistance towards DOX drug were elucidated by qRT-PCR and Elisa assay. The DOX half-inhibitory concentration (IC50) was quantified by Cell Counting Kit-8. For this study, we used RNA pull-down, RNA immunoprecipitation, and a dual-luciferase reporter experiment to identify the proteins that interacted with has_circ_0010220, IL-6, and miR-574-3p in OS cells that have developed resistance towards DOX.ResultsThe results indicated upregulated Hsa_circ_0010220 and IL-6 expression, However, DOX-resistant OS tissues and cells showed a downregulation of miR-574-3p. Reducing DOX resistance in vitro was achieved by silencing Has_circ_0010220. Further, by sponging miR-574-3p, increasing has_circ_0010220 boosted DOX resistance. However, miR-574-3p bound to IL-6 and inhibited DOX resistance. Additionally, it was discovered that hsa_circ_0010220 sponged miR-574-3p for upregulating IL-6 expression.ConclusionsHsa_circ_0010220 encouraged OS resistance to DOX by miR-574-3p/IL-6 axis regulation, suggesting its potency as a promising biomarker for treating OS.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-15T09:56:48Z
      DOI: 10.1177/09603271221131307
      Issue No: Vol. 41 (2022)
       
  • Acetaminophen alleviates ferroptosis in mice with sepsis-associated
           encephalopathy via the GPX4 pathway

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      Authors: Jing Chu, Yi Jiang, Wenyu Zhou, Jialei Zhang, Hong Li, Yang Yu, Yonghao Yu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Sepsis-associated encephalopathy (SAE) is a cognitive impairment caused by sepsis, associated with increased morbidity and death. And acetaminophen (APAP) is a promising therapeutic medicine for SAE treatment. This research was designed to determine whether APAP alleviates SAE by attenuating ferroptosis and mediating the glutathione peroxidase (GPX4) pathway. The cecal ligation and puncture (CLP) approach was used to establish septic mouse models. The survival rates for 7 days were determined. The Morris water maze (MWM) was utilized to assess cognitive function. Hematoxylin and eosin (HE) staining identified histopathologic alterations in hippocampal tissue. Mitochondrial damage was discovered in hippocampal tissue using transmission electron microscopy (TEM). The reactive oxygen (ROS) levels in hippocampal tissue were measured using commercial assays. Septic cell models were produced using HT22 cells grown with 1 μg/ml lipopolysaccharide (LPS). ROS were quantified using immunofluorescence. Ferroptosis-related protein expression levels in hippocampal tissue and HT22 cells were measured using western blotting. To evaluate the iron content of hippocampal tissue and HT22 cells, commercial kits were employed. According to the findings, APAP improved survival rates, lowered hippocampal and mitochondrial damage, and improve cognitive impairment. In both animal and cell studies, APAP reduced iron content, ROS, glutamate antiporter (xCT), 4-hydroxy-2-nonenal (4-HNE) levels but increased GPX4 expression. However, RSL3, a GPX4 inhibitor that acts as a ferroptosis activator, decreased the protective properties of APAP in vitro. Our findings suggest that APAP reduces sepsis-induced cognitive impairment by reducing ferroptosis, which is mediated by the GPX4 signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-10T11:45:36Z
      DOI: 10.1177/09603271221133547
      Issue No: Vol. 41 (2022)
       
  • Ameliorative effect of herbacetin against cyclophosphamide-induced
           nephrotoxicity in rats via attenuation of oxidative stress, inflammation,
           apoptosis and mitochondrial dysfunction

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      Authors: Muhammad Umar Ijaz, Shama Mustafa, Riffat Batool, Huma Naz, Hussain Ahmed, Haseeb Anwar
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Herbacetin (HBN) is a glycosylated flavonoid, which possesses numerous pharmacological properties. Cyclophosphamide (CYC) is a chemotherapeutic drug that adversely affects the kidneys. The present investigation aimed to evaluate the curative potential of HBN against CYC-induced nephrotoxicity. Sprague Dawley rats (n = 48) were randomly divided into four groups: control (0.1% DMSO + food), CYC (150 mg/kg b.wt.), CYC+HBN (150 + 40 mg/kg b.wt.), and HBN (40mg/kg b.wt.). CYC treatment significantly decreased the activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GSR) while elevating the concentration of reactive oxygen species (ROS) and malondialdehyde (MDA). Treatment with HBN significantly recovered the activity of CAT, SOD, GPx, and GSR while reducing the concentrations of ROS and MDA. Moreover, an increase in the level of renal functional markers, including Urea, creatinine, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), and a decrease in creatinine clearance after CYC administration was recovered to control values by HBN treatment. Furthermore, HBN treatment normalized the increased levels of inflammatory markers such as nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) after CYC administration. Besides, HBN administration increased the expression of anti-apoptotic markers (Bcl-2) while decreasing the apoptotic markers (Bax and Caspase-3). Furthermore, HBN decreased the activities of tricarboxylic acid (TCA) cycle enzymes (ICDH, αKGDH, SDH, and MDH) as well as renal mitochondrial respiratory-chain complexes (I-IV) and repolarized mitochondrial membrane potential (ΔΨm). Additionally, HBN administration significantly protected against renal histological damage induced by CYC. In conclusion, CYC-induced toxicity was effectively ameliorated by the HBN administration. These results indicate that HBN might be considered as a potential protective agent against nephrotoxicity. The observed protection may be due to its antioxidant, anti-inflammatory, and anti-apoptotic potential.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-10-06T01:24:32Z
      DOI: 10.1177/09603271221132140
      Issue No: Vol. 41 (2022)
       
  • Curcumin treatment attenuates cisplatin-induced gastric mucosal
           inflammation and apoptosis through the NF- κ B and MAPKs signaling
           pathway

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      Authors: Jinping Gao, Yunen Liu, Juan Chen, Changci Tong, Qian Wang, Ying Piao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      To investigate the protective effects of curcumin (Cur) on gastric mucosal injury induced by cisplatin (DDP), and explore possible molecular mechanisms. A mouse of gastric mucosal injury was established by intraperitoneal injection of DDP (27 mg/kg). Thirty mice were randomly divided into control group, DDP group and DDP + Cur group. Serum and gastric mucosal samples were collected on the 7th day after Cur treatment. The index of gastric mucosa injury was calculated, and the expression levels of inflammation, apoptosis and signaling pathway proteins were evaluated using hematoxylin and eosin staining, ELISA and western blotting analysis. These data showed that Cur treatment significantly attenuated DDP-induced decrease in body weight, food intake, fat and muscle ratios, and improved the gross gastric injury, scores of ulcer index, and histopathology changes triggered by DDP (p < .05). Meanwhile, Cur significantly decreased serum IL-23 and IL-17 proteins, reduced the expression levels of gastric mucosal IL-1β, TNF- α and MPO, and restored the level of IL-10 protein (p < .05). Moreover, Cur treatment significantly inhibited the expression levels of Caspase-3, PARP and Bax, and increased the expression of Bcl-2 protein. Furthermore, Cur treatment significantly decreased the expression levels of IL-1R, MyD88 and TAK1, and also repressed the activation of NF-κB and nuclear translocation of NF-κB p65. And more importantly, Cur treatment significantly inhibited DDP-induced gastric mucosal JNK1/2, ASK1, P38 and JUN phosphorylation, and promoted the phosphorylation of ERK1/2 and C-Myc proteins. Our data suggest that Cur treatment alleviates DDP-induced gastric mucosal inflammation and apoptosis, which may be mediated through the NF- κ B and MAPKs signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-30T11:01:14Z
      DOI: 10.1177/09603271221128738
      Issue No: Vol. 41 (2022)
       
  • Implication of microglia in ketamine-induced long-term cognitive
           impairment in murine pups

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      Authors: Y Yin, H Li, J Wang, Y Kong, J Chang, G Chu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundKetamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely applicable to anesthesia, analgesia, and sedation. However, the function and mechanisms of ketamine in the long-term learning and memory function of neonatal mice are unclear.ObjectiveThe present study aims to investigate whether long-term learning and memory function will be affected by multiple ketamine exposures in the early development period.MethodsThe mRNA and protein levels were measured by RT-qPCR and western blot, respectively. The Morris Water Maze test was performed to assess spatial learning and memory.ResultsWe identified that neonatal exposure to ketamine downsized the positive neurons for microtubule-associated protein doublecortin (DCX) and Ki67 in hippocampal dentate gyrus at the juvenile and late adolescence stages. Double-labeling tests demonstrated that the counts of Iba1+ cells and Ki67+ cells were pronouncedly diminished with exposure to ketamine. Further, qPCR assays to screen the key factors predisposing the populations and maturation of microglia exhibited remarkable decline of CX3CR1 mRNA levels in ketamine group versus the control group. The close relation of microglia to synaptic plasticity was depicted by the significantly downregulated synaptic plasticity-related proteins NR2B and PSD-95 subsequent to multiple exposures to ketamine. Finally, we found that both the protein and mRNA levels of BDNF were markedly decreased in ketamine group versus the control group.ConclusionWe found that multiple exposures to ketamine in neonatal mice lead to spatial learning and memory dysfunction. The alterations of microglial development and function are the possible mechanisms of long-term learning and memory impairment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-29T09:18:52Z
      DOI: 10.1177/09603271221128739
      Issue No: Vol. 41 (2022)
       
  • Overcoming chemoresistance in glioblastoma by fluvastatin via
           prenylation-dependent inhibition of Ras signaling

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      Authors: Cheng Long, Limei Yuan, Wei Wei, Jingwen Li
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The resistance of glioblastoma to chemotherapy remains a significant clinical problem. Targeting alternative pathways such as protein prenylation is known to be effective against many cancers. Fluvastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase, thereby inhibits prenylation. We demonstrate that fluvastatin alone effectively inhibits proliferation and induces apoptosis in multiple human glioblastoma cell lines. The combination index analysis shows that fluvastatin acts synergistically with common chemotherapy drugs for glioblastoma: temozolomide and irinotecan. We further show that fluvastatin acts on glioblastoma through inhibiting prenylation-dependent Ras activation. The combination of fluvastatin and low dose temozolomide resulted in remarkable inhibition of glioblastoma tumor in mice throughout the whole treatment duration without causing toxicity. Such combinatorial effects provide the basis for utilizing these FDA-approved drugs as a potential clinical approach in overcoming resistance and improving glioblastoma treatment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-29T02:42:49Z
      DOI: 10.1177/09603271221125934
      Issue No: Vol. 41 (2022)
       
  • Corrigendum

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      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-28T07:59:48Z
      DOI: 10.1177/09603271221130591
      Issue No: Vol. 41 (2022)
       
  • Antidiabetic effects of nerolidol through promoting insulin receptor
           signaling in high-fat diet and low dose streptozotocin-induced type 2
           diabetic rats

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      Authors: Nengmei Jiang, Yuanyuan Zhang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The present study was designed to investigate the antidiabetic effect of nerolidol on high-fat diet and streptozotocin-induced diabetic rats. Type 2 diabetes was induced in animals by feeding them a high-fat diet for 4 weeks and administering a single intraperitoneal dose of streptozotocin (35 mg/kg body weight). Diabetic rats were treated with nerolidol (25 mg/kg BW) for 28 days. Results showed that nerolidol treatment significantly reduced (p < 0.05) the level of elevated glucose, glycosylated hemoglobin and improved (p < 0.05) the body weight and insulin level. Nerolidol also considerably improved (p < 0.05) the carbohydrate metabolic enzyme activities and increased the glycogen storage in the liver of diabetic rats. Increased serum triglycerides, total cholesterol (C), low-density lipoproteins-C and very low-density lipoproteins-C levels were significantly lowered (p < 0.05), while reduction of serum high-density lipoprotein-C was alleviated after administration of nerolidol. In addition, nerolidol attenuated oxidative stress markers by significantly increasing (p < 0.05) the levels of superoxide dismutase, catalase, reduced glutathione, and lowering (p < 0.05) the level of thiobarbituric acid reactive substances, and lipid hydroperoxide. Similarly, nerolidol showed its pharmacological effects against hepatic markers via restoring (p < 0.05) the alleviated level of alanine transaminase, aspartate aminotransferase, and alkaline phosphatase. Finally, it improved insulin-dependent glucose transport in skeletal muscle by enhancing and activating glucose transporter protein-4. These findings confirmed the antidiabetic potential of nerolidol in type 2 diabetic rats. This may be related to a high antioxidant capacity, the restoration of plasma insulin and lipid levels, and the activation of insulin signaling in STZ/HFD-induced diabetic rats.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-28T02:44:08Z
      DOI: 10.1177/09603271221126487
      Issue No: Vol. 41 (2022)
       
  • A comprehensive gene expression profile analysis of prostate cancer cells
           resistant to paclitaxel and the potent target to reverse resistance

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      Authors: Ping Che, Shihao Jiang, Weiyang Zhang, Huixuan Zhu, Daorong Hu, Delin Wang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background: Paclitaxel resistance is the major clinical obstacle in the chemotherapy of prostate cancer (PCa), but the resistant mechanism is less investigated.Purpose: To establish two paclitaxel-resistant PCa cells, provide a comprehensive gene expression profile analysis of resistant cells and the potential target to reverse resistance.Methods: Two Paclitaxel-resistant PCa cells (PC3/PR, LNcap/PR) were established by gradually increasing drug concentration. MTT and transwell assays were performed to detect drug sensitivity, cell proliferation and migration abilities. RNA-Sequencing (RNA-seq) and bioinformatic analyses were performed to identify abnormally expressed genes (AEGs) in resistant cells, and annotate the biological functions of AEGs. The role of the candidate AEG, TLR-4, on the resistant phenotypes was further investigated.Results: The resistance index of resistant cells was 2-3, and they showed a slower proliferation and increased migration ability. 4741 AEGs were screened out (Log2fold change absolute: log2FC(abs)  > 1) in the resistant cells, and they were enriched in 2'-5'-oligoadenylate synthetase activity and chemical carcinogenesis. A number of AEGs, CCND2, IGFBP3, FOS, SHH, ZEB2, and members of FGF, FGFR and WNT families were also identified to be involved in cancer- and resistant phenotype-related processes. Finally, TLR-4 was validated significantly increased in resistant cells, and knockdown of TLR-4 increased drug-sensitivity, inhibited the proliferation and migration abilities.Conclusions: The study provided a comprehensive gene expression profile of paclitaxel-resistant PCa cells, and TLR-4 could be a potential target to reverse paclitaxel resistance.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-27T09:16:04Z
      DOI: 10.1177/09603271221129854
      Issue No: Vol. 41 (2022)
       
  • Melatonin Protects Against Cyclophosphamide-induced Premature Ovarian
           Failure in Rats

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      Authors: Hongxia Xu, Xiuming Bao, Hanxin Kong, Junya Yang, Yan Li, Zhiwei Sun
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      This study was designed to understand the efficacy and molecular cues of melatonin in cyclophosphamide(CTX)-induced premature ovarian failure (POF) in rats. Female SD rats were used to evaluate the potential effects of melatonin on the ovarian hormonal status, follicular development, and granulosa cells in CTX-treated rats. Here, we found that pretreatment with melatonin before CTX administration preserved the normal sex hormone levels, improved follicular morphology, and granulosa cell proliferation, and reduced apoptosis, as compared to the CTX treatment alone. Additionally, melatonin also up-regulated CYR6 and CTGF at the mRNA and protein levels. A potential mechanism is that melatonin inhibits LATS1, Mps1-One binder (MOB1), and YAP phosphorylation, thereby activating the Hippo signal pathway to promote its downstream targets, CYR61 and CTGF. In conclusion, pretreatment with melatonin effectively protected the ovaries against CTX-induced damage by activating the Hippo pathway. This study lay the foundation for the clinical application of melatonin for cancer patients with CTX treatment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-26T09:37:03Z
      DOI: 10.1177/09603271221127430
      Issue No: Vol. 41 (2022)
       
  • Aluminum chloride induces G0/G1 phase arrest via regulating the reactive
           oxygen species-depended non-canonical STAT1 pathway in hFOB1.19 cells

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      Authors: Y Zhao, F Li, S Li, J Ji, W Qiao, J Fang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Treatment with aluminum chloride (AlCl3) suppresses the growth of osteoblastic cells; however, the molecular mechanisms underlying the impact of AlCl3 on cell growth have not been fully characterized. In this study, we observed that exposure of hFOB1.19 cells to AlCl3 arrested cells at G0/G1 phase by inducing p21 expression. Further studies indicated that AlCl3 upregulated the phosphorylation level of signal transducer and activator of transcription 1 (STAT1) at serine 727 site (Ser727). By chromatin immunoprecipitation and electrophoretic mobility shift assay, we found that AlCl3 promoted STAT1/DNA binding activity to p21 promoter, thus resulting in the upregulation of p21. Moreover, siRNA-mediated knockdown of STAT1 attenuated p21 level induced by AlCl3. Notably, using hFOB1.19 cells stably expressing dominant-negative STAT1 (Ser727Ala), we demonstrated that phosphorylation of STAT1 at Ser727 site is required for p21-mediated cycle arrest induced by AlCl3. Mechanism investigation indicated that AlCl3 stimulated the phosphorylation of JNK, and administration of JNK inhibitor SP600125 prevented AlCl3-induced G0/G1 arrest through suppressing the phosphorylation of STAT1. Notably, pretreatment with N-acetyl-cysteine, a reactive oxygen species scavenger, conferred a significantly inhibitory effect on AlCl3-mediated activation of JNK/STAT1 signaling pathway. Taken together, our findings provide the molecular mechanism for G0/G1 arrest induced by AlCl3 in osteoblastic cells.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-26T06:50:05Z
      DOI: 10.1177/09603271221129846
      Issue No: Vol. 41 (2022)
       
  • The effects of acrylamide-mediated dorsal root ganglion neurons injury on
           ferroptosis

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      Authors: Shuai An, Jingfei Shi, Zheng Li, Mingli Feng, Guanglei Cao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Acrylamide (ACR) is a water-soluble chemical applied in industrial and laboratory processes. The neurotoxicity induced by acrylamide involves both peripheral and central nervous system. Hence, there is a growing urgency to investigate the mechanisms of acrylamide-induced neurotoxicity and search novel therapeutic target for the nerve repair. The effects of ACR on the proliferation, reactive oxygen species (ROS) and iron production of dorsal root ganglia (DRG) neurons and Schwann cells were determined. 5-Ethynyl-2′-deoxyuridine (EDU) staining and transwell assay were applied to detect the proliferation and migration capacity of DRG cells. Ferrostatin-1 (Fer-1) was used to suppress ferroptosis induced by ACR. RT-PCR analysis was performed to examine the expression of neurotrophic factors including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF) and glial cell line-derived neurotrophic factor (GDNF). Moreover, Iron, ROS, malondialdehyde (MDA) and glutathione (GSH) contents were measured to reveal the regulation of ferroptosis in ACR-related nerve injury. ACR inhibited the proliferation and migration of DRG neurons and the supplementation of Fer-1 reversed the effects induced by ACR. Besides, the treatment of Fer-1 effectively increased the expression of NGF, BDNF, VEGF and GDNF. Furthermore, ACR increased the iron level, MDA and ROS contents while inhibited the level of GSH. It was unveiled that ACR attenuated the proliferation, migration and neuron repair of DRG neurons through regulating ferroptosis. The modulation of ferroptosis might be a promising therapeutic strategy and provide references for future treatment of acrylamide-induced nerve damage.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-26T01:46:52Z
      DOI: 10.1177/09603271221129786
      Issue No: Vol. 41 (2022)
       
  • Gestational bisphenol A exposure impairs hepatic lipid metabolism by
           altering mTOR/CRTC2/SREBP1 in male rat offspring

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      Authors: Q Yang, Y Mao, J Wang, H Yu, X Zhang, X Pei, Z Duan, C Xiao, M Ma
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Lipid metabolism is an important biochemical process in the body. Recent studies have found that environmental endocrine disruptors play an important role in the regulation of lipid metabolism. Bisphenol A (BPA), a common environmental endocrine disruptor, has adverse effects on lipid metabolism, but the mechanism is still unclear. This study aimed to investigate the effects of gestational BPA exposure on hepatic lipid metabolism and its possible mechanism in male offspring. The pregnant Sprague-Dawley rats were exposed to BPA (0, 0.05, 0.5, 5 mg/kg/day) from day 5 to day 19 of gestation to investigate the levels of triglyceride (TG) and total cholesterol (TC), and the expression of liver lipid metabolism-related genes in male offspring rats. The results showed that compared with the control group, the TG and TC levels in serum and liver in BPA-exposed groups was increased. And the expressions of liver fatty acid oxidation related genes, such as peroxisome proliferators-activated receptor α (PPARα) and carnitine palmitoyl transferase 1α (CPT1α), were down-regulated. However, the expressions of fatty acid synthesis related genes, such as sterol regulatory element binding proteins 1 (SREBP-1), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1), were up-regulated. The increased protein levels of mTOR and p-CRTC2 suggested that CREB-regulated transcription coactivator 2 (CRTC2) might be an important mediator in the mTOR/SREBP-1 pathway. In conclusion, these results demonstrated that mTOR/CRTC2/SREBP-1 could be affected by gestational BPA exposure, which may involve in the lipid metabolic disorders in later life.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-23T01:57:59Z
      DOI: 10.1177/09603271221129852
      Issue No: Vol. 41 (2022)
       
  • Ropivacaine represses the ovarian cancer cell stemness and facilitates
           cell ferroptosis through inactivating the PI3K/AKT signaling pathway

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      Authors: Yi Lu, Jinbao Mao, Yanbing Xu, Hao Pan, Yu Wang, Wei Li
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      PurposeOvarian cancer is a malignant tumor in women all over the world. Ropivacaine is identified as a potential drug for the treatment of malignant tumors, but the role and mechanism of ropivacaine in ovarian cancer remains unknown.Materials and methodsOvarian cancer cells were treated with different doses of ropivacaine. The function of ropivacaine in ovarian cancer was assessed using Cell Counting Kit-8 assay, flow cytometry, sphere-formation assay, Western blot, Fe2+ level analysis, and immunofluorescence. Meanwhile, the mechanism of ropivacaine in ovarian cancer was investigated by multiple molecular experiments. The protective function of ropivacaine in ovarian cancer was further confirmed by in vivo assay.ResultsThe functional research data indicated that the growth and stemness of ovarian cancer cells were restrained after ropivacaine treatment, while the ferroptosis in ovarian cancer cells was facilitated. The mechanism results confirmed that ropivacaine inactivated the PI3K/AKT signaling pathway in ovarian cancer cells. Furthermore, in vivo assay demonstrated that ropivacaine repressed the proliferation of ovarian cancer cells in vivo and had a protective function in ovarian cancer.ConclusionRopivacaine restrained ovarian cancer cell stemness and accelerated cell ferroptosis by inactivating PI3K/AKT signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-20T10:34:07Z
      DOI: 10.1177/09603271221120652
      Issue No: Vol. 41 (2022)
       
  • Tricin attenuates cerebral ischemia/reperfusion injury through inhibiting
           nerve cell autophagy, apoptosis and inflammation by regulating the
           PI3K/Akt pathway

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      Authors: Ying Liu, Xiaoning Qu, Mengjun Yan, Dalei Li, Rong Zou
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      To elucidate the effect of tricin in cerebral ischemia/reperfusion (I/R) injury and examine its possible underlying mechanisms. Rats were randomly divided into Sham (exposed the right internal carotid arteries), I/R, and tricin (administered at various doses) groups. After the cerebral I/R injury model was established, a Morris water maze test and a tetrazolium chloride assay were performed. Apoptosis and autophagy were assessed in the nerve cells of hippocampus tissue, and the levels of inflammatory markers within animal serum were detected. Proteins related to apoptosis and the PI3K/Akt pathway were evaluated. To further investigate the mechanisms by which tricin affects brain damage, mouse neuroblastoma cells N2a were divided into control, oxygen-glucose deprivation and reoxygenation (OGD/R), tricin, PI3K/Akt activator, and tricin + PI3K/Akt inhibitor groups. The cell viability, apoptosis, inflammatory factors, and PI3K/Akt pathway related proteins in N2a cells were also detected. The results revealed that I/R-induced learning and memory dysfunction was improved by tricin treatment. The area of cerebral infarction, the levels of apoptosis and autophagy in nerve cells, and the serum inflammatory marker content were all decreased following tricin treatment. Additionally, the expression of Beclin-1 protein was downregulated, while the expression of Bcl-2 protein, p-PI3K/PI3K and p-Akt/Akt was upregulated after tricin treatment. Mechanistically, tricin or PI3K/Akt activator ameliorated OGD/R-induced apoptosis, autophagy, and inflammation. However, these effects were reversed following PI3K/Akt inhibitor treatment in OGD/R-induced N2a cells. In summary, this study suggested that tricin can against I/R-induced brain injury by inhibiting autophagy, apoptosis and inflammation, and activating the PI3K/Akt signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-16T04:43:04Z
      DOI: 10.1177/09603271221125928
      Issue No: Vol. 41 (2022)
       
  • Verbascoside represses malignant phenotypes of esophageal squamous cell
           carcinoma cells by inhibiting CDC42 via the HMGB1/RAGE axis

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      Authors: Mingming Ji, Jian Sun, Jun Zhao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundAs an aggressive human malignancy, esophageal squamous cell carcinoma (ESCC) is prevalent globally, especially in China. Verbascoside (VE) exerts anti-cancer effects in several human cancers. This work was to investigate the effects of VE on ESCC cells.MethodsEsophageal squamous cell carcinoma cell proliferation, apoptosis, migration, and invasion were assessed by CCK-8, TUNEL, and Transwell assays. Gene and protein levels were detected by RT-qPCR and western blotting. CDC42 activity was evaluated by G-lisa assay.ResultsVerbascoside significantly inhibited cell proliferation, migration, and invasion and induced cell apoptosis in ESCC cells. Furthermore, it was found that VE markedly inhibited HMGB1 and RAGE expression in a dose-dependent manner. Besides, HMGB1/RAGE upregulation partially reversed the anti-cancer effects of VE on ESCC cells. VE repressed HMGB1/RAGE-induced CDC42 activation in ESCC cells. In addition, ML141-mediated CDC42 inactivation further enhanced the effect of VE on ESCC cell proliferation, apoptosis, migration, and invasion.ConclusionsOur findings indicated that VE has significant anti-tumor potential in ESCC by suppressing HMGB1/RAGE-dependent CDC42 activation.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-16T03:14:18Z
      DOI: 10.1177/09603271221127429
      Issue No: Vol. 41 (2022)
       
  • Semaglutide ameliorates lipopolysaccharide-induced acute lung injury
           through inhibiting HDAC5-mediated activation of NF-κB signaling pathway

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      Authors: Zeyu Jiang, Jinyi Tan, Yan Yuan, Jiang Shen, Yan Chen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundAs a life-threatening respiratory syndrome, acute lung injury (ALI) is characterized by uncontrollable inflammatory activities. Semaglutide (SEM) has been identified as an effective anti-inflammatory drug in a variety of diseases. This study intended to explore the functional effect and potential mechanisms of SEM in ALI.MethodsLipopolysaccharide (LPS) was used to construct an in vivo ALI model based on Sprague-Dawley (SD) rats and an in vitro ALI model based on human pulmonary artery endothelial cells (HPAECs). Hematoxylin & eosin (H&E) staining and ELISA were applied to evaluate the histopathological changes in pulmonary tissues and detect TNF-α and IL-6 levels. RT-qPCR and Western blotting were used to measure gene and protein expressions in pulmonary tissues and cells. HPAEC viability and apoptosis were evaluated by CCK-8 method and flow cytometry methods.ResultsSemaglutide pretreatment significantly mitigated pulmonary injury, reduced TNF-α and IL-6 production, and led to a decrease in cleaved caspase-3 level and an increase in Bcl-2 level, suggesting SEM could ameliorate LPS-induced ALI in rats. In vitro, SEM increased the proliferative capability and mitigated inflammation and apoptosis in LPS-stimulated HPAECs. In addition, SEM inhibited HDAC5-mediated NF-κB signaling pathway in HPAECs. HDAC5 overexpression or NF-κB signaling activation could partly impair SEM-mediated protective effects against LPS-induced damage to HPAECs.ConclusionSemaglutide restrains LPS-induced ALI by inhibiting HDAC5/NF-κB signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-08T11:53:21Z
      DOI: 10.1177/09603271221125931
      Issue No: Vol. 41 (2022)
       
  • Valtrate antagonizes malignant phenotypes of lung cancer cells by reducing
           SLC7A11

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      Authors: Wei Xu, Huan Yu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectivesThis research explored the efficacy of valtrate (Val) in lung cancer (LC).MethodsA549 and H1299 cells were dealt with Val. SLC7A11 was overexpressed by cell transfection. Xenograft model was established in nude mice. Cell viability, proliferation and apoptosis were measured by CCK-8, EdU and Annexin-V and propidium iodide staining, respectively. Ferroptosis was assessed by iron assay kit. reactive oxygen species level was tested by ROS assay kit. Histopathological changes in tumor tissues were analyzed by HE staining. Protein expression was analyzed employing Immunohistochemical staining and western blot.ResultsA549 and H1299 cell viability were notably lowered by Val in a concentration-dependent way. Cell proliferation was markedly repressed by 10 and 20 μM of Val, while apoptosis and ROS generation were markedly augmented. SLC7A11 and GPX4 expression was both distinctly lowered, while Fe2+ level was remarkably improved by 10 and 20 μM of Val. However, 20 μM of Val-triggered effects were distinctly counteracted by SLC7A11 overexpression. In vivo assay revealed that both tumor volume and weight were distinctly declined by 10 mg/mL Val. The variations of proliferation, apoptosis and ferroptosis-related proteins were in line with the results in vitro assay.ConclusionVal might antagonize malignant phenotypes of LC cells by reducing SLC7A11.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-09-01T05:35:22Z
      DOI: 10.1177/09603271221124096
      Issue No: Vol. 41 (2022)
       
  • Parkinson’s disease protein 7 protected against oxidative stress of
           myocardial infarction direct through p47phox and nicotinamide adenine
           dinucleotide phosphate oxidase 4

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      Authors: Guozhong Pan, Shiwei Yang, Xiaowan Han, Xian Wang, Lanjun Kou, Jing Xie, Chunyan Li
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      In the present study, we aimed to investigate the role and mechanism of Parkinson’s disease protein 7 (Park7) in myocardial infarction (MI). The Park7 expression in the serum and tissues was down-regulated in mice with MI. Recombinant Park7 protein protected against MI-induced injury and reduced oxidative stress in mice model. Conversely, knockout Park7 increased injury of MI and promoted oxidative stress in MI mice model. In embryonic rat cardiac myoblasts H9c2 cells, over-expression of Park7 reduced reactive oxygen species (ROS)-induced oxidative stress, while down-regulation of Park7 increased ROS-induced oxidative stress. Park7 combined nicotinamide adenine dinucleotide phosphate (NADPH) oxidase cytoplasmic subunit p47phox protein had direct effect on inducing NADPH activator. The inhibition of p47phox reduced the effects of Park7 in ROS production of H2O2-treated H9c2 cells. The regulation of NADPH participated in the effects of Park7 on ROS production of in both MI mice model and H2O2-treated H9c2 cells. Our data demonstrated that Park7 protects against oxidative stress in MI model direct through p47phox and NADPH oxidase 4.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-31T04:46:18Z
      DOI: 10.1177/09603271221124099
      Issue No: Vol. 41 (2022)
       
  • Potential anticancer effect of sodium caprate on human gastric cancer
           cells

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      Authors: Nam-Hee Kim, Jung Ho Park, Dong-Hoe Koo, Taeheon Lee, Jeong-Yoon Yang, Hee-Young Lee
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The role of sodium caprate (C10) in enhancing drug absorption is well established; however, little information is available on its role as an anticancer drug. This study aimed to evaluate the anticancer effect of C10 in gastric cancer cells. The mechanism of cytotoxicity of C10 was evaluated by western blotting following treatment of the gastric cancer cells with various concentrations of C10. C10 cytotoxicity was measured via MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium), lactate dehydrogenase (LDH), cAMP, and ATP assays. Gastric cancer cells were observed by electron microscopy following treatment with C10. Then, xenograft mice that were inoculated with gastric cancer cells were treated with C10 for 4 weeks, after which the changes in tumor size were measured. C10 triggered apoptosis in the gastric cancer cells through the mitochondrial pathway at concentrations of more than 0.2 mM. However, 15 mM of C10 induced necrosis in gastric cancer cells by causing cellular swelling and the formation of holes in the cell membrane. Levels of cAMP and ATP decreased significantly following exposure to 15 mM C10 for 1 h. Additionally, the size of the xenograft tumors was significantly reduced by 24% after 4 weeks of C10 treatment (p < 0.05). This study indicates that C10 induces apoptosis and necrosis in a concentration-dependent manner and has clear anticancer effects on gastric cancer cells.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-31T04:39:43Z
      DOI: 10.1177/09603271221119182
      Issue No: Vol. 41 (2022)
       
  • Involvement of caspase-3 in apoptosis of human lymphocytes exposed to
           cadmium chloride

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      Authors: Mona Mirkamali, Hamid Reza Momeni, Tahereh Etemadi, Ghasem Mosayebi, Majid Komijani
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundLymphocytes are a group of white blood cells with a variety of roles their integrity is crucial for the body’s immune responses. Cadmium, a heavy metal and environmental pollutant, is known as a toxicant to exert its adverse effects on some sort of cells including blood cells.Research DesignIn this study, human lymphocytes were divided into 3 groups: (1) lymphocytes at 0-h, (2) lymphocytes at 24 h (control), (3) lymphocytes treated with cadmium chloride (15 μM). Lymphocyte viability and plasma membrane integrity were assessed in these groups. In addition, the occurrence of apoptosis was investigated by assessment of nucleus diameter and flow cytometry. Activation of caspase-3 was also detected by immunocytochemistry.ResultsResult showed that lymphocyte’s viability and plasma membrane integrity decreased in lymphocytes treated with cadmium as compared with the control group. Decreased nucleus diameter and result of flow cytometry demonstrated cadmium-induced apoptosis in human lymphocytes. Furthermore, lymphocytes treated with cadmium displayed intensely activated caspase-3 immunoreactivity in their cytoplasm.ConclusionIn conclusion, cadmium not only negatively effect on viability and plasma membrane, but also induces caspase-dependent apoptosis in human lymphocytes.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-28T02:16:52Z
      DOI: 10.1177/09603271221121796
      Issue No: Vol. 41 (2022)
       
  • Retraction notice

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      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-27T07:42:45Z
      DOI: 10.1177/09603271221122627
      Issue No: Vol. 41 (2022)
       
  • Effect of methamphetamine on clock genes and drug-metabolizing enzyme
           expression

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      Authors: Naoto Tani, Tomoya Ikeda, Takaki Ishikawa
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      This study examined the association between clock gene expression and the effect of methamphetamine (MA) on drug-metabolizing enzymes from the perspective of drug metabolism. The relationship between expression of the clock genes BMAL1 and PER2 and the drug-metabolizing enzymes CYP3A4 and CYP2D6 was investigated using livers from autopsy cases of MA-intoxication deaths. Additionally, the effect of MA exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. Comparisons of the expression of various genes in MA users according to blood MA concentration revealed that CYP3A4 expression was similar to that of PER2, and CYP2D6 expression was similar to that of BMAL1. In cultured cell experiments, BMAL1 and CYP2D6 expression decreased depending on the time elapsed after MA addition, and PER2 and CYP3A4 expression increased slightly in a concentration-dependent manner. These results were consistent with the findings of autopsy examinations. Expression of CYP3A4 and CYP2D6 under BMAL1 and PER2 suppression, but not CYP2D6 under PER2 suppression alone, was upregulated in response to MA. These results suggest that CYPs are regulated via the clock genes BMAL1 and PER2 during MA metabolism.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-27T02:55:18Z
      DOI: 10.1177/09603271221124092
      Issue No: Vol. 41 (2022)
       
  • Protective effect of D-(−)-quinic acid as food supplement in modulating
           AMP-activated protein kinase signalling pathway activation in HFD induced
           obesity

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      Authors: Jie Dong, HaiLong Zheng, Qiuyao Zeng, Xian Zhang, Liang Du, Souravh Bais
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundDietary quinic acid given as the nutritional supplement, which may leads to tryptophan and nicotinamide production in the intestinal tract and NAD+ precursor which can prevent from the negative consequences of high fat diet (HFD) consumption.ObjectiveThe present study was designed to assess in vivo and in vitro effect of D-(−)-Quinic acid in high-fat diet induced hyperlipidemia in mice.Material and methodsThirty six albino mice were randomly divided in six groups and each group had six mice. Group I, controlled mice given normal pellet diet, Group-II mice, administered with high fat diet (HFD), Group-III mice given standard drug, Atorvastatin (20 mg/kg, p.o.) along with HFD to mice and Group IV, V and VI mice received D-(−)-Quinic acid at a dose of 75, 150 and 300 mg/kg, respectively in separate group along with HFD to mice. After completion of trial (49 days) the animals were sacrificed and evaluated for body weight, organ fat pad weight, and changes in weight of liver, heart and kidney and also for biochemical parameters, expression of adipogenic and inflammation markers in adipose tissues, and histology examination of liver tissue.ResultsIn vitro testing results showed, D-(−)-Quinic acid potentially inhibit α-glucosidase enzyme activity as compared to acarbose. The D-(−)-Quinic acid showed significant hypolipidemic activity by decreasing the increased level of cholesterol, triglyceride level, LDL, VLDL and other hepatic parameters like SGOT and SGPT in serum. D-(−)-Quinic acid reduces the mRNA expression level of PPAR-γ2, TNF-α, IL-1β and IL-6 in adipose tissue in hyperlipidemic mice.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-25T04:10:06Z
      DOI: 10.1177/09603271221119804
      Issue No: Vol. 41 (2022)
       
  • The protective effects of ritodrine against hypoxia/reoxygenation-induced
           injury in endometrial stromal cells

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      Authors: Jing Zhu, Haiyun Liu, Lijing Mao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Endometriosis (EMS) is often observed in women of childbearing age and significantly impacts patients’ quality of life. Ritodrine is a β2 receptor agonist applied for relaxing the uterine smooth muscle. Its inhibitory effects on inflammation have recently been noted. The present study explored the protective impact of Ritodrine on hypoxia/reoxygenation (H/R)- induced injury in endometrial stromal cells (ESCs). Human ESCs (HESCs) were treated with Ritodrine (0.1, 0.5 μM) for 24 h, followed by exposure to H/R for 6 h. Ritodrine ameliorated H/R-induced higher reactive oxygen species (ROS), declined glutathione (GSH) concentration and increased production of tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1) in HESCs. Furthermore, Ritodrine ameliorated the H/R-induced higher nuclear level of nuclear factor κ-B (NF-κB) p65 expression and increased luciferase activity of the NF-κB promoter. In addition, we show that Ritodrine mitigated H/R-induced higher estrogen receptor α (ER-α) expression in HESCs. Interestingly, overexpressing ER-α abolished the regulatory effects of Ritodrine on oxidative stress and the NF-κB pathway-mediated inflammation. Collectively, our data reveal that Ritodrine alleviated H/R-induced injury in ESCs by inhibiting the ER-α/NF-κB pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-24T08:27:10Z
      DOI: 10.1177/09603271221120650
      Issue No: Vol. 41 (2022)
       
  • Effect of LncRNA OIP5-AS1/microRNA-186-5p on isoflurane-induced cognitive
           dysfunction in aged rats

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      Authors: Yujing Sun, Yawei Yuan, Long Wang, Sen Sun
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundPost-operative recognition dysfunction (POCD) is a kind of central nervous system complication that appears after operative anesthesia. Recent studies on the mechanism of long non-coding RNA (lncRNA) in neurodegenerative diseases are abundant.AimsThe study aimed to explore the expression pattern and role of lncRNA OIP5-AS1 in POCD and to investigate its underlying mechanism in old rats.MethodsThe old rats were exposed to isoflurane to mimic the POCD in the elderly, and their cognitive function was tested via Morris water maze (MWM) test. Enzyme linked immunosorbent assay was applied for the concentration detection of inflammation and oxidative stress-related factors. Luciferase reporter assay was done for the target gene analysis.ResultsDownregulation of OIP5-AS1 was accompanied by isoflurane treatment in rats, overexpression of OIP5-AS1 induced the rats to spend more time in the target quadrant, and shorten escape latency time. OIP5-AS1 inhibited the release of TNF-α, IL-6 and IL-1β, GSH and superoxide dismutase, decreased the activation of caspase-3, but promoted malondialdehyde release. miR-186-5p was a target miRNA of OIP5-AS1, and exhibited high expression in rats after isoflurane exposure. miR-186-5p can abolish the beneficial role of OIP5-AS1 against cognitive impairment, inflammatory response, oxidative stress and neuron apoptosis.ConclusionOIP5-AS1 plays a neuroprotective role in elderly POCD rats through sponging miR-186-5p, and it is related to OIP5-AS1/miR-186-5p mediated inflammatory response, oxidative stress and neuron apoptosis.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-24T08:18:11Z
      DOI: 10.1177/09603271221116276
      Issue No: Vol. 41 (2022)
       
  • RETRACTION NOTICE: Cytochrome P450 3A5 polymorphism affects the metabolism
           

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      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-23T08:31:54Z
      DOI: 10.1177/09603271221076714
      Issue No: Vol. 41 (2022)
       
  • RETRACTION NOTICE: AgNPs reduce reproductive capability of female mouse
           for their toxic effects on mouse early embryo development

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      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-19T10:21:45Z
      DOI: 10.1177/09603271221076703
      Issue No: Vol. 41 (2022)
       
  • RETRACTION NOTICE: Effect of nano zinc oxide on proliferation and toxicity
           of human gingival cells

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      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-19T10:21:25Z
      DOI: 10.1177/09603271221076704
      Issue No: Vol. 41 (2022)
       
  • Androgen receptor suppresses inflammatory response of airway epithelial
           cells in allergic asthma through MAPK1 and MAPK14

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      Authors: T Xia, J Ma, Y Sun, Y Sun
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundDysfunction of airway epithelial cells in patients with asthma is closely with the occurrence and development of allergic asthma. Finding the differences of airway epithelium between asthmatic patients and normal patients is helpful to find out new treatment strategies.MethodsFirst, three original microarray datasets (GSE89809, GSE41861, GSE104468) from the Gene Expression Omnibus (GEO) dataset were used to assess differentially expressed genes in the epithelial tissues between patients with allergic asthma and healthy controls. Then, 10 ng/mL TGF-β1 treated BEAS-2B cells and rats with ovalbumin induced allergic asthma were performed to confirm our assumption from the gene expression analysis with microarrays.ResultsTop ten hub significant difference genes were obtained by Cytohubba plug-in from GSE41861, and found that androgen receptor (AR) was closely associated with the mitogen-activated protein kinase (MAPK) pathway, especially MAPK1 and MAPK14. After treated with the TGF-β1 treated BEAS-2B cells and rats with allergic asthma, we found that 5α-dihydrotestosterone (5α-DHT), AR agonist, significantly decreased the Th2 inflammation (IL-25 and IL-33), MAPK1 and MAPK14 proteins expression in vitro and in vivo. The roles of 5α-DHT were similar with the results of chicanine (a p38 MAPK and ERK1/2 inhibitor), but the roles of 5α-DHT were masked by the C16-PAF (a MAPK and MEK/ERK activator) treatment.ConclusionAndrogen receptor limits the secretion of Th2 inflammatory factors by downregulating MAPK1 and MAPK14 in the TGF-β1 treated BEAS-2B cells and rats with ovalbumin induced allergic asthma, which plays a critical role for the therapeutics of patients with asthma.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-19T05:36:04Z
      DOI: 10.1177/09603271221121320
      Issue No: Vol. 41 (2022)
       
  • Corrigendum

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      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-19T02:52:53Z
      DOI: 10.1177/09603271221123137
      Issue No: Vol. 41 (2022)
       
  • Urinary metabolomics study of vancomycin-associated nephrotoxicity based
           on ultra-performance liquid chromatography coupled with
           quadrupole-time-of-flight mass spectrometry

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      Authors: Pei Cao, Yu Kang, Jian Liu, Xiuju Liu, Yiran Jin, Zhiqing Zhang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Drug-induced nephrotoxicity is widespread and seriously affects human health. Vancomycin is a classical glycopeptide antibiotic. Vancomycin is widely used for severe infections caused by Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus but its obvious nephrotoxicity affects the safety of its clinical application. However, the etiology of vancomycin induced kidney injury is not well understood. This study aimed to explore the potential mechanism of vancomycin-induced nephrotoxicity in rats. Vancomycin (400 mgkg−1) was used to establish kidney injury models in rats. A metabonomic approach was employed using ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) to delineate metabolic alterations. As a result, 15, 22, and 37 biomarkers were identified in urine samples from the treatment group compared to the control model on D2, D4, and D7, respectively. Changes in the levels of these metabolites indicated that amino acid metabolism and energy metabolism were disturbed in rats with vancomycin-associated nephrotoxicity. This study revealed the kidney effect of vancomycin, which may provide novel and promising research approaches to vancomycin-induced renal toxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-19T02:43:18Z
      DOI: 10.1177/09603271221119178
      Issue No: Vol. 41 (2022)
       
  • Methamphetamine exposure increases cardiac microvascular permeability by
           activating the VEGF-PI3K-Akt-eNOS signaling pathway, reversed by
           Bevacizumab

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      Authors: Rui Chen, Peng Huang, Songren Wei, Cui Zhang, Xiaoping Lai, Huijun Wang, Jianpin Tang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Methamphetamine (METH) is an illicit amphetamine-like psychostimulant that is commonly abused. However, the modulation of METH-induced cardiac microvascular permeability is still not completely known. Previously, we discovered that the vascular endothelial growth factor (VEGF) regulated the cardiotoxicity produced by METH. In this work, we looked into the effect of METH exposure on cardiac microvascular permeability via the VEGF-PI3K-Akt-eNOS signaling pathway, as well as the efficacy of Bevacizumab treatment in reducing this effect. The findings revealed that METH exposure enhanced cardiac microvascular permeability while also activating the VEGF-PI3K-Akt-eNOS signaling pathway. Furthermore, treatment with Bevacizumab has been shown to be effective in reversing the METH-induced phenomena. Briefly stated, our research may provide fresh insight into the molecular underpinnings of METH-induced cardiac microvascular permeability, and it may also provide evidence for a relationship between METH misuse and Bevacizumab medication.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-17T10:54:07Z
      DOI: 10.1177/09603271221121795
      Issue No: Vol. 41 (2022)
       
  • Phoenixin-14 Promotes the Recovery of Neurological Dysfunction After
           Spinal Cord Injury by Regulating Microglial Polarization via PTEN/Akt
           Signaling Pathway

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      Authors: Zhiyong Yu, Hao Wu, Yonghong Wang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Spinal cord injury (SCI) is a destructive event in central nervous system (CNS) with the hallmark of deficits in neuronal function. Phoenixin-14 (PNX-14) is a reproductive peptide that also has neuroprotective effects. However, the role of PNX-14 in SCI has not yet been studied. In this study, we firstly investigated the effects of PNX-14 on the recovery of neurological dysfunction and microglial polarization in a SCI mice model. We demonstrated that PNX-14 improved the recovery of neurological dysfunction with increased Basso Mouse Scale (BMS) scores, reduced lesion area volume and Evans blue (EB) dye extravasation. PNX-14 alleviated neuronal apoptosis and neuroinflammation in mice underwent SCI. In vitro co-culture assay proved that PNX-14 protected neurons injury in response to LPS- activated BV-2 cells. PNX-14 suppressed the LPS- induced microglia M1 phenotype polarization with decreased expression of M1-associated markers (CD16 and iNOS) and increased expression of M2-associated markers (CD206 and Arg1). PNX-14 also suppressed LPS- caused decrease in anti-inflammatory cytokines TGF-β, IL-10, and IL-13, as well increase in pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in BV2 cells. PNX-14 treatment caused increased PTEN expression and decreased p-Akt expression in BV2 cells against LPS induction. While inhibition of PTEN by SF1670 reversed the effects of PNX-14 on LPS- induced phenotypic transition of BV2 cells. Taken together, we found that PNX-14 exerted protective effects on neurological dysfunction and inflammation in SCI mice through modulating microglial polarization via PTEN/Akt signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-14T06:13:32Z
      DOI: 10.1177/09603271221111345
      Issue No: Vol. 41 (2022)
       
  • Potential value and mechanism of Rosa roxburghii tratt juice on
           pro-inflammatory responses in peripheral blood of patients with arsenic
           poisoning

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      Authors: Ling Dong, Shiqing Xia, Baofei Sun, Lu Ma, Xiong Chen, Shaofeng Wei, Zhonglan Zou, Aihua Zhang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Increasing evidence supports the role of arsenic in dysregulated immune and inflammation responses, while, safe and effective treatments have not been fully examined. Rosa roxburghii Tratt (RRT), a traditional Chinese edible fruit with potential immunoregulatory activities, was considered as a dietary supplement to explore its protective effects and possible mechanism in arsenic-induced dysregulated inflammation responses. We enrolled 209 arsenicosis patients and 41 controls to obtain baseline data, including the degree of arsenic poisoning prior to the RRT juice (RRTJ) intervention. Then, based on criteria of inclusion and exclusion and the principle of voluntary participation, 106 arsenicosis patients who volunteered to receive treatment were divided into RRTJ (n = 53) and placebo (n = 53) groups randomly. After three months follow-up, 89 subjects (46 and 43 of the RRTJ and placebo groups, respectively) completed the study and were examined for the effects and possible mechanisms of RRTJ on the Th17 cells-related pro-inflammatory responses in peripheral blood mononuclear cells (PBMCs). The PBMCs had higher levels of Th17 and Th17-related inflammatory cytokines IL-17, IL-6, and RORγt. Furthermore, the gene expressions of STAT3 and SOCS3 in PBMCs increased and decreased, respectively. Conversely, RRTJ decreased the number of Th17 cells, secretion of IL-17, IL-6, RORγt, and relative mRNA levels of STAT3, and increased the transcript levels of SOCS3. This study provides limited evidence that possible immunomodulatory effects of RRTJ on the critical regulators, IL-6 and STAT3, of the Th17 cells in arsenicosis patients, which indicated that IL-6/STAT3 pathway might appear as a potential therapeutic target in arsenicosis.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-14T03:31:32Z
      DOI: 10.1177/09603271221121313
      Issue No: Vol. 41 (2022)
       
  • Mycotoxin ingestion during late gestation alters placentome structure,
           cotyledon transcriptome, and fetal development in pregnant sheep

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      Authors: JL Britt, MA Greene, JL Klotz, SM Justice, RR Powell, RE Noorai, TF Bruce, SK Duckett
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Ergot alkaloids, a class of mycotoxins, induce vasoconstriction when consumed by animals and humans. Pregnant ewes (n = 16; 81.2 kg ± 7.7) were assigned fed endophyte-infected tall fescue seed (E+; 4.14 μg ergovaline + ergovalinine/g seed) or a control diet (CON; 0 μg ergovaline + ergovalinine) for increasing duration during late gestation (from gd86 to gd110 or gd133) to examine changes in placentome morphology and mRNA transcriptome, and fetal development. Exposure to E+ fescue reduced serum prolactin concentrations at gd110 and gd133 demonstrating treatment efficacy. For control ewes, cotyledon and total placentome weights decreased with advancing gestation due to remodeling of placental tissues; however, cotyledon and placentome weight did not change with advancing gestation in E+ fed ewes. Fetal brain sparing was evident in E+ exposed fetuses at gd110 and gd133 compared to CON, which demonstrates asymmetrical growth and intrauterine growth restriction. Mycotoxin exposure (E+) resulted in differential expression of 22 genes in the cotyledon tissue at gd110 but only one gene at gd133 compared to CON. These results suggest that the response to mycotoxin exposure in the pregnant sheep model has an immediate impact on placental remodeling and fetal development that persists throughout the duration of the exposure period.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-10T08:25:27Z
      DOI: 10.1177/09603271221119177
      Issue No: Vol. 41 (2022)
       
  • Corrigendum

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      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-08-04T12:22:53Z
      DOI: 10.1177/09603271221115902
      Issue No: Vol. 41 (2022)
       
  • Hsa_circ_0000285 knockdown inhibits the progression of hepatocellular
           carcinoma by sponging miR-582-3p to regulate CCNB2 expression

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      Authors: Jing Huang, Hongchi Zhou, Yun Diao, Zhiming Yang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      AimHsa_circ_0000285, a novel circular RNA, has been proven to extensively take part in the pathogenesis of numerous tumors. In hepatocellular carcinoma (HCC), very little is known about hsa_circ_0000285 until now. Hence, this research aims to determine hsa_circ_0000285’s functional role and underlying mechanisms in HCC.MethodsThe expressions of miR-582-3p, hsa_circ_000028, and cyclin B2 (CCNB2) among the HCC cells and tumor samples were determined by performing western blotting and qRT-PCR analyses. The impacts of hsa_circ_000028 on the proliferative and migratory abilities of HCC cells were examined through the execution of CCK-8 and wound-healing assays. Meanwhile, the expressions of the proteins Bcl-2 and Bax were detected via western blotting. Tumor xenograft models were established to examine how hsa_circ_000028 functions during the mediation of HCC tumor growth in vivo. RNA immunoprecipitation and luciferase reporter experiments were performed for the validation of the interactions of miR-582-3p, hsa_circ_000028, and CCNB2 with each other.ResultsElevated hsa_circ_0000285 and CCNB2 expressions, and a decreased miR-582-3p expression were observed among the HCC cell lines and tumors. Hsa_circ_0000285 bound to miR-582-3p competitively to improve CCNB2 levels. Silencing of hsa_circ_0000285 promoted apoptosis and repressed proliferation and migration among HCC cells. Moreover, silencing hsa_circ_0000285 also impeded the growth of HCC tumors in vivo. Inhibiting hsa_circ_0000285 or CCNB2 reversed the miR-582-3p-knockdown-mediated promotion of malignant HCC cell phenotypes.ConclusionOur study has demonstrated that hsa_circ_0000285 fosters the development of malignant HCC cells phenotypes through the modulation of the miR-582-3p/CCNB2 axis. Thus, these results suggest that hsa_circ_0000285 is a prospective target for HCC treatment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-07-15T09:18:16Z
      DOI: 10.1177/09603271221115400
      Issue No: Vol. 41 (2022)
       
  • Ursolic acid inhibits proliferation, migration and invasion of human
           papillary thyroid carcinoma cells via CXCL12/CXCR4/CXCR7 axis through
           cancer-associated fibroblasts

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      Authors: Xianjiao Cao, Qingqing He
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      As a pentacyclic triterpenoid compound, Ursolic acid (UA) broads range of biological effects. CXCL12 is a ligand for CXCR4 and CXCR7 proteins on thyroid cancer cells. Here we examined the effects of UA on the proliferation, migration and invasion of papillary thyroid carcinoma (PTCs) in a dose-manner. In addition, UA can reduce the expression levels of CXCR4 and CXCR7 in PTCs. In addition to this direct anticancer pathway, studies have shown that UA can play an anticancer role by affecting the secretion of CXCL12 in cancer-associated fibroblasts (CAFs). After treated with UA, normal fibroblasts and CAFs culture medium (CM) showed differential CXCL12 expression levels. We prepared fibroblast conditioned medium according to the intervention of UA, then cultured TPC-1 and B-CPAP cells with differential CM, and detected significant differences in the proliferation, migration and invasion of cancer cells. Our findings uncovered an indirect anticancer mechanism of UA. This cancer chemopreventive properties is expected to make UA a clinically useful chemopreventive agent.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-07-04T08:52:49Z
      DOI: 10.1177/09603271221111333
      Issue No: Vol. 41 (2022)
       
  • The sesquiterpenoid valerenic acid protects neuronal cells from the
           detrimental effects of the fungicide benomyl on apoptosis and DNA
           oxidation

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      Authors: Mehtap Kara, Ezgi Öztaş, Tuğçe Boran, Çiğdem Sevim, Seda Eren Keskin, Aristidis S Veskoukis, Sergei V Kuzmin, Aristides M Tsatsakis
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundValerenic acid (VA), a sesquiterpenoid of the plant Valeriana officinalis, has attracted attention of the research community due to its potential positive role against neurodegenerative diseases induced by chemicals. However, the relevant evidence in the literature is scarce. Therefore, this study aimed to examine the putative protective role of VA on the toxic effects of the fungicide benomyl on SH-SY5Y neural cells.MethodsCell viability was determined via the MTT and NRU assays, DNA damage was assessed via comet assay and apoptosis was evaluated through the expression of relevant genes.ResultsAccording to the results, exposure of the cells to benomyl enhanced viability inhibition and promoted DNA damage and apoptosis since the expression levels of the genes coding for MAPK8, NF-kB, Bax, Caspase-9 and Caspase-3 were increased. Treatment of the cells with VA ameliorated these effects in a concentration dependent manner.ConclusionIt is concluded that the molecular mechanism through which benomyl exerts its toxic action appears to depend on DNA oxidation and apoptosis induction. Furthermore, VA, a plant-derived compound is a protective antioxidant against pesticide-induced toxicity. Therefore, herbs, extracts and compounds of plant origin could be used as nutritional supplements that back up the beneficial role of medicine in neurodegenerative diseases.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-29T01:46:20Z
      DOI: 10.1177/09603271221101038
      Issue No: Vol. 41 (2022)
       
  • Simvastatin cardioprotection in cyclophosphamide-induced toxicity via the
           modulation of inflammasome/caspase1/interleukin1β pathway

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      Authors: Marwa MM Refaie, Maram El-Hussieny, Asmaa MA Bayoumi, Sayed Shehata, Nermeen N Welson, Walaa Yehia Abdelzaher
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Drug-induced cardiotoxicity is a serious adverse effect that occurs during the administration of chemotherapeutic agents such as cyclophosphamide (CYC). Therefore, there is a critical need to find cardioprotective agents to keep the heart healthy. The current study aimed to investigate the protective effect of simvastatin (SIM) against CYC-induced heart damage and evaluate different mechanisms involved in mediating this effect, including the inflammasome/caspase1/interleukin1β (IL1β) pathway and endothelial nitric oxide synthase (eNOS). 36 rats were randomly assigned to one of four groups: a control group that received only vehicles, a CYC group that received CYC (150 mg/kg/day) i.p. on the fourth and fifth days, a CYC+SIM group that received SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the fourth and fifth days, and a CYC+SIM+ Nitro- ω-L-arginine (L-NNA) group that received L-NNA (25 mg/kg/day, SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the 4th and 5th days. The CYC group revealed an obvious elevation in cardiac enzymes and heart weights with toxic histopathological changes. Moreover, there was an increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNFα) levels, and up-regulation of the NLRP3inflammasome/caspase1/IL1β pathway. In addition, total antioxidant capacity (TAC), eNOS, reduced glutathione (GSH), and superoxide dismutase (SOD) significantly decreased. CYC-induced cardiotoxicity was most properly reversed by SIM through its anti-oxidant, anti-inflammatory, and anti-apoptotic actions with the stimulation of eNOS. The co-administration of L-NNA diminished the protective effect of SIM, indicating the essential role of eNOS in mediating this effect. Therefore, SIM ameliorated CYC-induced cardiotoxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-28T07:33:27Z
      DOI: 10.1177/09603271221111440
      Issue No: Vol. 41 (2022)
       
  • Agmatine mitigates palmitate (PA)-induced mitochondrial and metabolic
           dysfunction in microvascular endothelial cells

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      Authors: Dan Zhang, Jinzhao Li, Tianzhu Li
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Agmatine is an arginine metabolite that has neuroprotective capacity. Recently, it has been found to ameliorate atherosclerosis progression in rabbits. However, further molecular mechanisms of its anti-atherosclerotic properties remain unclear. High plasma levels of free fatty acids (FFAs) are an important risk factor for atherosclerosis due to their detrimental effects on vascular endothelial cells (ECs). Here, we used palmitate (PA), a kind of FFA, to induce endothelial dysfunction in human microvascular endothelial cells (HMECs) to determine the possible biological functions of agmatine. We found that PA caused ECs dysfunction in HMEC-1 cells, decreased cell viability, and elevated lactate dehydrogenase (LDH) release which could be reversed by agmatine treatment. Agmatine also improved the nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in PA-induced HMEC-1 cells. The PA-caused mitochondrial dysfunction of HMEC-1 cells was diminished after agmatine treatment, as proven by the increased intracellular Adenosine Triphosphate (ATP) level, decreased mitochondrial reactive oxygen species (ROS) level, and increased mitochondrial oxygen consumption rate (OCR). Further, agmatine could alleviate PA-caused lipid accumulation with increased levels of Triglyceride (TG) and total cholesterol (TC) in HMEC-1 cells. Furthermore, Western blot analysis revealed that agmatine administration markedly decreased the expression levels of phosphorylated-AMP-activated protein kinase α (p-AMPKα), p-protein kinase B (p-AKT), and p-eNOS in PA-induced HMEC-1 cells. Inhibition of AMPK by compound C reversed the protective effects of agmatine on PA-induced HMEC-1 cells. Taken together, we hypothesize that agmatine mitigated PA-induced HMEC-1 cell dysfunction by alleviating mitochondrial and metabolic dysfunction via the AMPK/PI3K/Akt/eNOS signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-24T06:35:28Z
      DOI: 10.1177/09603271221110857
      Issue No: Vol. 41 (2022)
       
  • Lipid emulsion attenuates propranolol-induced early apoptosis in rat
           cardiomyoblasts

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      Authors: Seong-Ho Ok, Seung Hyun Ahn, Soo Hee Lee, Hyun-Jin Kim, Gyujin Sim, Jin Kyeong Park, Ju-Tae Sohn
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectivePropranolol is used to treat several cardiovascular diseases; however, toxic doses of propranolol cause severe myocardial depression and cardiac arrest. The aim of this study was to examine the effects of lipid emulsion (LE) on cardiotoxicity induced by toxic doses of propranolol in H9C2 rat cardiomyoblast cell line and to elucidate the underlying mechanism.MethodsThe experimental groups comprised control, propranolol alone, esmolol alone, or LE followed by propranolol or esmolol treatment, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine (NAC) followed by propranolol treatment. The effects of propranolol, esmolol, NAC, and LE, alone or in combination, on cell viability, apoptosis, and ROS production were examined. Additionally, we investigated the effect of LE on propranolol concentration.ResultsLE and NAC reversed the inhibition of cell viability induced by propranolol (p < .001). However, LE had no effect on the inhibition of cell viability caused by esmolol. The LE inhibited propranolol-induced expressions of cleaved caspase-3 (p < .001), caspase-9 (p < .001), and Bax (p < .01), but not caspase-8. NAC inhibited the propranolol-induced expression of cleaved caspase-3. LE inhibited propranolol-induced early apoptosis, but had no effect on late apoptosis. Additionally, LE inhibited the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells generated by propranolol. It attenuated propranolol-induced ROS production. However, it had no effect on propranolol concentration.ConclusionLE inhibits early apoptosis caused by a toxic dose of propranolol by suppressing the intrinsic apoptotic pathway, via direct inhibition of ROS production.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-24T01:06:45Z
      DOI: 10.1177/09603271221110852
      Issue No: Vol. 41 (2022)
       
  • Metabolic profiling of lysophosphatidylcholines in chlorpromazine
           hydrochloride- and N-acetyl-p-amino-phenoltriptolide-induced liver injured
           rats based on ultra-performance liquid chromatography quadrupole
           time-of-flight mass spectrometry

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      Authors: Cong Hu, Hong-Wei Li, Jia-Qun Ke, Xue-Chun Yu, Mei-Yu Zhao, Xin-Yue Shi, Lin-Jing Wu, Xi-Lan Tang, Yin-Hua Xiong
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Chlorpromazine hydrochloride (CH) and N-acetyl-p-amino-phenoltriptolide (APAP) are typical acentral dopamine receptor antagonists and antipyretic analgesics in clinical applications, respectively. However, it has been reported that these 2 drugs could cause liver damage. Lysophosphatidylcholines (LPCs) have multiple physiological functions and are metabolized primarily in the liver, where it undergoes significant changes when the liver is damaged. In the study, 15 LPCs in the rat serum with CH- and APAP-induced liver injury were quantified based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry, and multivariate statistical analyses including principal component analysis (PCA) and orthogonal partial least squares discriminate analysis (OPLS-DA) were combined to understand CH- and APAP-induced liver injury from the perspective of LPC metabolic profiling. The quantitative results showed that there were significant changes in 10 LPCs and 5 LPCs after CH- and APAP-administration, separately. The results of PCA and OPLS-DA indicated that CH- and APAP-induced liver injury could be well distinguished by the LPC metabolic profiling, and 7 LPCs and 1 LPC biomarkers that could characterize CH- and APAP-induced liver damage in turn had been screened. This study will not only provide a new perspective for the clinical diagnosis of CH- and APAP-induced liver injury, but also offer a reference for further study of their hepatotoxicity mechanisms.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-20T08:23:29Z
      DOI: 10.1177/09603271221108320
      Issue No: Vol. 41 (2022)
       
  • Curcumin and resveratrol inhibit chemoresistance in cisplatin-resistant
           epithelial ovarian cancer cells via targeting P13K pathway

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      Authors: Yalikun Muhanmode, Meng Ke Wen, Amina Maitinuri, Guqun Shen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background:The activation of the PI3K/AKT/mTOR pathway has been proved to be associated with survival as well as proliferation of various tumour cells in multiple cancer types, including epithelial ovarian cancer (EOC).Purpose:Moreover, the activation of the PI3K/AKT/mTOR pathway is the key mechanism responsible for higher invasiveness and migratory capacities of ovarian cancer cells. Furthermore, PI3K is crucial for activation of the PI3K/AKT/mTOR pathway; therefore, its inhibition might be an effective strategy against cancer.Research Design:The combination approach is now an established strategy against cancer. So, the present study evaluated molecular mechanics behind the synergistic effects of curcumin and resveratrol along with cisplatin treatment on inhibition of the PI3K pathway in ovarian cancer cells.Results:The present study confirmed significant inhibition of the PI3K/AKT/mTOR pathway as observed by Matrigel invasion assay, Western blot expression of important molecular markers and apoptotic markers.Conclusion: The present study concludes that the combination of curcumin and resveratrol significantly sensitized the EOC cells to cisplatin treatment, thereby inhibiting chemoresistance in ovarian cancer cells by significant inhibition of the PI3K/AKT/mTOR pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-20T07:24:33Z
      DOI: 10.1177/09603271221095929
      Issue No: Vol. 41 (2022)
       
  • Calpain-mediated cleavage of mitochondrial fusion/fission proteins in
           acetaminophen-induced mice liver injury

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      Authors: Shulin Shan, Zhaoxiong Liu, Linlin Li, Cuiqin Zhang, Ruirui Kou, Fuyong Song
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Mitochondrial dysfunction was considered to be a critical event in acetaminophen (APAP) -induced hepatotoxicity. Recent studies suggest that abnormal mitochondrial dynamics contributes to mitochondrial dysfunction in APAP-induced liver injury, yet the underlying mechanisms responsible for deregulated mitochondrial dynamics remains elusive. In this study, C57BL/6 mice were used to establish a model of acute liver injury via intraperitoneal (i.p.) injection with overdose of APAP. Furthermore, calpain intervention experiments were achieved by the inhibitors ALLN or calpeptin. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in mitochondrial dynamics and calpain degradative pathway were determined by electron microscopy, immunoblot and calpain activity kit. The results demonstrated that APAP overdose resulted in a severe liver injury, mitochondrial damage and an obvious cleavage of fusion/fission proteins. Meanwhile, the activation of calpain degradative machinery in liver were observed following APAP. By contrast, pretreatment of calpain inhibitors significantly inhibited the activation of calpains. Our further investigation found that ALLN or calpeptin administration significantly suppresses the changes of mitochondrial dynamics in APAP-treated mice and finally protected against APAP-induced hepatoxicity. Overall, these results suggest that calpain-mediated cleavage of mitochondrial dynamics proteins was involved in the pathogenic process of mitochondrial dysfunction and thus present a potential molecular coupling APAP-induced hepatotoxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-17T01:59:38Z
      DOI: 10.1177/09603271221108321
      Issue No: Vol. 41 (2022)
       
  • Circle RNA circCSPP1 promotes human osteosarcoma cell proliferation and
           increases glucose metabolism by suppressing miR-200c maturation

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      Authors: L Zhang, ST Yang, C Wang, LC Zhang, X Zhang, FC Li, SY Wang, K Ma
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      IntroductionMiR-200c plays a central role in glucose metabolism in cancer cells. However, its upstream regulators in this process are unknown. CircRNA CSPP1 (circCSPP1) was predicted to bind to premature miR-200c, an oncogenic miRNA. Therefore, we explored their interaction in osteosarcoma (OS).MethodsDifferential circCSPP1 and miR-200c expression in OS was analyzed using RT-qPCR. Glucose metabolism was analyzed by glucose uptake assay. Subcellular circCSPP1 location in OS cells was detected using cellular fractionation assay. The direct interaction between circCSPP1 and miR-200c was explored using RNA-RNA pull-down assay. The role of circCSPP1 in miR-200c maturation was investigated by analyzing both mature and premature miR-200c levels in OS cells with circCSPP1 overexpression.ResultsCircCSPP1 and premature miR-200c levels were increased while mature miR-200c level was decreased in OS. CircCSPP1 was detected in both the nuclear and cytoplasm fractions of OS cells. CircCSPP1 directly interacted with premature miR-200c. CircCSPP1 overexpression increased premature miR-200c level, glucose uptake, and cell proliferation, but decreased mature miR-200c level. MiR-200c overexpression suppressed the role of circCSPP1 in OS cells.ConclusionsCircCSPP1 promotes OS cell proliferation and increases glucose metabolism by suppressing miR-200c maturation.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-17T01:27:57Z
      DOI: 10.1177/09603271221097364
      Issue No: Vol. 41 (2022)
       
  • Pulmonary toxicity of sodium dichloroisocyanurate after intratracheal
           instillation in sprague-dawley rats

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      Authors: Jean Yoo, Haewon Kim, Yeon-Mi Lim, Byung-Il Yoon, Pilje Kim, Ig-Chun Eom, Ilseob Shim
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      In water, sodium dichloroisocyanurate (NaDCC), a source for chlorine gas generation, releases free available chlorine in the form of hypochlorous acid, a strong oxidizing agent. NaDCC has been used as a disinfectant in humidifiers; however, its inhalation toxicity is a concern. Seven-week-old rats were exposed to NaDCC doses of 100, 500, and 2500 μg·kg−1 body weight by intratracheal instillation (ITI) to investigate pulmonary toxicity. The rats were sacrificed at 1 d (exposure group) or 14 d (recovery group) after ITI. Despite a slight decrease in body weight after exposure, there was no statistically significant difference between the control and NaDCC-treated groups. A significant increase in the total protein level of the bronchoalveolar lavage fluid (BALF) was observed in the exposure groups. Lactate dehydrogenase leakage into the BALF increased significantly (p < 0.01) in the exposure groups; however, recovery was observed after 14 d. The measurement of cytokines in the BALF samples indicated a significant increase in interleukin (IL)-6 in the exposure group and IL-8 in the recovery group. Histopathological examination revealed inflammatory foci and pulmonary edema around the terminal bronchioles and alveoli. This study demonstrated that ITI of NaDCC induced reversible pulmonary edema and inflammation without hepatic involvement in rats.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-08T07:29:43Z
      DOI: 10.1177/09603271221106336
      Issue No: Vol. 41 (2022)
       
  • Dental amalgam fillings and mercury vapor safety limits in American adults

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      Authors: DA Geier, MR Geier
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveFor more than 150 years, dental amalgam fillings (50% metallic mercury (Hg0) by weight) have been used in American dentistry. The US Food and Drug Administration (FDA) acknowledged that amalgams release Hg vapor that may be harmful to certain patients. This study examined the impact of Hg vapor exposure from amalgams in American adults.MethodsAmalgam-Hg vapor exposure among 158,274,824 weighted-adult Americans was examined in the 2015–2018 National Health and Nutrition Examination Survey (NHANES). Beta (β)-coefficients were calculated for the correlation between the number of amalgam surfaces and daily micrograms (μg) of urinary Hg and daily μg of Hg vapor exposure from amalgams per kilogram (Kg) bodyweight.ResultsAbout 91 million (57.8%) adults had ≥1 amalgam surface and about 67 million (42.2%) had no amalgams. A β-coefficient = 0.041 significantly correlated the number of amalgam surfaces to daily amounts of urinary Hg. Differences were observed for gender and racial groups. Daily Hg vapor doses from amalgams were in excess of the most restrictive California’s Environmental Protection Agency (EPA) safety limit for about 86 million (54.3%) adults and in excess of the least restrictive US EPA safety limit among about 16 million (10.4%) adults. The mean allowable number of amalgam surfaces ranged from 1.28 for adult females under the California’s EPA safety limit to 16.23 for adult males under the US EPA safety limit.ConclusionGiven that American adults are receiving significant, ongoing exposure to Hg vapor from amalgams, careful evaluation of the need to reduce use of amalgams should be considered.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-04T07:54:20Z
      DOI: 10.1177/09603271221106341
      Issue No: Vol. 41 (2022)
       
  • Withania somnifera (Ashwagandha) root extract counteract acute and chronic
           impact of γ-radiation on liver and spleen of rats

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      Authors: Khaled Sh Azab, Rokaya E Maarouf, Mohamed K Abdel-Rafei, Nermeen M El Bakary, Noura M Thabet
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The exposure to ionizing radiation has become inescapably because of increased dependence on radiation to execute works in different fields and also its influences on biological systems. Thus, the current study aimed at examination of the radio-protective effect of the natural ashwagandha (Ag) against acute and chronic doses of γ-radiation on liver and spleen of rats. The impact of Ag was inspected in rats exposed to acute exposure of 8 Gy (single dose) or to chronic exposure of 8 Gy (2 Gy every other day for 4 times). The data obtained reveals significant amelioration of the redox status (MDA, GSH and ROS) in spleen and liver tissues of rats treated with Ag and exposed to the 2-different modes of γ-radiation. Besides, the changes in inflammatory responses assessed by measurements of IL-17, IL-10 and α7-nAchR are less pronounced in rats received Ag and γ-radiation compared to irradiated rats. Further, the measurements of tissues structural damage markers (MMP-2, MMP-9 and TIMP-1) pointed to benefit of Ag against γ-radiation. The histopathological investigation of spleen and liver tissues confirmed this ameliorating action of Ag counter to γ-radiation hazards. It could be suggested that Ashwagandha could exerts radio-protective influences because of its antioxidants and anti-inflammatory capabilities.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-06-03T10:15:37Z
      DOI: 10.1177/09603271221106344
      Issue No: Vol. 41 (2022)
       
  • Neuroprotective potential of nuclear factor erythroid 2-related factor 2
           (Nrf2)/antioxidant response element signaling modulator cucurbitacin I
           upon glucose and oxygen deprivation/reperfusion (OGD/RP)

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      Authors: Hu Ju, Chuanchuan Liu, Guanghua Zhang, Changlin Xu, Hu Wang, Haining Fan
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      This study aimed to investigate the inhibitory effect and mechanism of Cucurbitacin I (Cu I) on apoptosis, oxidative stress, and mitophagy in PC12 cells with glucose and oxygen deprivation/reperfusion (OGD/RP) injury. OGD/RP cell injury model was established by gas anoxic cell incubator and glucose-free medium. The cells were divided into the control group, OGD/RP group, OGD/RP + Cu I group, and OGD/RP + Cu I + 2 µM nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385 group. The results showed that apoptotic rate and reactive oxygen species (ROS) production were significantly increased in OGD/RP group, which were reversed by Cu I pretreatment. Meanwhile, western blot analysis proved that Cu I inhibited OGD/RP-induced mitophagy, manifested as the decreased expression of PTEN-induced kinase 1 (PINK1) and parkin RBR E3 ubiquitin-protein ligase (Parkin), and light chain 3 (LC3) Ⅱ∕LC3 I, as well as the increased expression of P62. Furthermore, immunofluorescence (IF) staining showed that Cu I reduced the co-localized puncta of LC3 with TOM20 in OGD/RP-induced PC12 cells. Similarly, transmission electron microscope finding is consistent with the IF results. Mechanically, after Cu I and OGD/RP treatments, nuclear Nrf2 expression and the levels of downstream target genes were significantly upregulated compared with OGD/RP alone treatment. Nrf2 inhibition reversed the protective effects of Cu I on OGD/RP-induced injury in PC12 cells. The present study provides evidence of the neuroprotective effect of Cu I unraveling its potential as a potential therapeutic candidate for the treatment of ischemic stroke.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-28T05:06:55Z
      DOI: 10.1177/09603271221104450
      Issue No: Vol. 41 (2022)
       
  • MiR-200c-3p regulates pyroptosis by targeting SLC30A7 in diabetic
           retinopathy

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      Authors: Weina Li, Sheng Yang, Guangsheng Chen, Shiping He
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Clinical relevance:MicroRNAs (miRNAs) have been reported to be involved in the progression of various diseases. Studying the regulatory mechanisms of miRNAs can help clinical treatment.Background:Diabetic retinopathy (DR) is one of the complications of diabetes. The objective of this study was to elucidate the underlying molecular mechanisms by which miR-200c-3p regulates the pyroptosis of DR cell.Methods:Human retinal microvascular endothelial cells (HRMECs) and high glucose (HG) cultures established DR cell model in vitro. RT-qPCR is used to detect the expression level of miRNAs. CCK-8 assays and flow cytometry are used to detect apoptosis of HRMECs cell. Western blotting is used to detect cleaved caspase-3, cleaved caspase-1, and N-GSDMD proteins levels in HRMECs. The ELISA assay is used to detect the expression of IL-1β and IL-18. Predict and validate potential binding sites between miR-200c-3p and SLC30A7 by dual luciferase reporter gene analysis.Results:The results showed that HG caused damage to HRMECs through the pyroptosis pathway rather than the apoptosis pathway. MiR-200c-3p is highly expressed in HG induced-HRMECs, and knockdown of miR-200c-3p mitigates HG-induced HRMECs pyroptosis. MiR-200c-3p negatively targets SLC30A7 in HRMECs, and miR-200c-3p regulates pyroptosis of HG-induced HRMECs by targeting SLC30A7.Conclusion:The results suggest that miR-200c-3p might be a promising interference target for DR prevention and treatment. The results of current study may provide new insights into development of therapeutic strategies for DR.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-24T05:43:31Z
      DOI: 10.1177/09603271221099589
      Issue No: Vol. 41 (2022)
       
  • Antagonism of G protein-coupled receptor 55 prevents
           lipopolysaccharide-induced damages in human dental pulp cells

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      Authors: Wei-Jie Li, Jie Shen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Pulpitis is a common oral inflammatory disease in dental pulp commonly associated with bacterial infection. G protein-coupled receptor 55 (GPR55) is a member of the G protein‐coupled receptors family that has been found to regulate inflammatory response. However, its roles in dental pulp inflammation have not been investigated. In this study, we used lipopolysaccharide (LPS) to induce inflammation in human dental pulp cells (hDPCs) to simulate an in vitro model of pulpitis. We found that LPS markedly induced the GPR55 expression in hDPCs. Treatment with the GPR55 antagonist ML-193 ameliorated the LPS-caused decrease in cell viability and increase in lactate dehydrogenase release. The upregulated inflammatory cytokines, interleukin-6 (IL-6) and tumour necrosis factor α, in LPS-challenged hDPCs were also attenuated by ML-193. Treatment with ML-193 ameliorated LPS-induced production of the inflammatory mediators cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2), and inducible nitric oxide synthase/nitric oxide (iNOS/NO) in hDPCs. ML-193 also inhibited the activation of Toll-like receptor 4-myeloid differentiation primary response 88-nuclear factor-κB (TLR4-Myd88-NF-κB) signaling in LPS-induced hDPCs via decreased expressions of TLR4, Myd88, and p-NF-κB 65. Our study provides evidence that the GPR55 antagonist ML-193 exhibited anti-inflammatory activity in LPS-stimulated hDPCs through inhibiting TLR4-Myd88-NF-κB signaling. The results imply that ML-193 might be a novel agent for pulpitis.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-24T02:49:24Z
      DOI: 10.1177/09603271221099598
      Issue No: Vol. 41 (2022)
       
  • Idebenone regulates sirt1/Nrf2/TNF-α pathway with inhibition of oxidative
           stress, inflammation, and apoptosis in testicular torsion/detorsion in
           juvenile rats

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      Authors: Walaa Yehia Abdelzaher, Gomaa Mostafa-Hedeab, Abdel Hamid Sayed AboBakr Ali, Michael Atef Fawzy, Amira F Ahmed, Mohamed Ahmed Bahaa El-deen, Nermeen N Welson, Dina A Aly Labib
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Testicular torsion is an emergency, mainly in newborn and adolescent males, resulting in testicular ischemia. The current study aimed to evaluate the effect of Idebenone (IDE) on testicular torsion/detorsion (T/D) in juvenile rats. Thirty-two rats were randomized into: (1) the sham group: rats received sham operations with no other interventions; (2) the IDE group: rats received idebenone (100 mg/kg, i. p) without T/D; (3) the T/D group: rats underwent torsion for 2 h and detorsion for 4 h; and (4) the IDE+ T/D group: rats received IDE 1 h before T/D. Testicular malondialdehyde (MDA), total nitrite/nitrate (NOx), total antioxidant capacity (TAC), tumor necrosis factor-α (TNF-α), caspase-3, sirtuin type 1 (Sirt1), serum interleukin-1β (IL-1β), total cholesterol, and testosterone were measured. Histological changes, nuclear factor (erythroid-derived 2)-like-2 factors (Nrf2), and proliferating cell nuclear antigen (PCNA) immuno-expressions were assessed. T/D displayed an increase in MDA, NOx, TNF-α, caspase-3, IL-1β, and total cholesterol with a significant decrease in TAC, Sirt1, and testosterone and strong positive Nrf2 and negative PCNA immuno-expressions. IDE could improve all oxidative, inflammatory, and apoptotic indicators. Therefore, IDE significantly reduced testicular ischemia-reperfusion injury in the juvenile rat testicular T/D model by limiting oxidative stress, inflammation, and apoptosis via the Sirt1/Nrf2/TNF-α pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-20T10:10:04Z
      DOI: 10.1177/09603271221102515
      Issue No: Vol. 41 (2022)
       
  • Mitochondrial dysfunction is involved in the cellular activity inhibition
           by eleutheroside B in SMMC-7721 and HeLa cells

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      Authors: Shangfan Sun, Yi Zhang, Weili Xu, Bin Wang, Jing Chen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Eleutheroside B, also known as syringin, has been shown to have various pharmacological activities such as anti-inflammatory, anti-irradiation and antidepressant, but there are few studies on its anti-cancer activity. Its anti-tumor effect on SMMC-7721 cells has not been revealed. Moreover, whether it induces autophagy is still unclear. Thus, the present study investigated whether Eleutheroside B induces apoptosis, autophagy and cellular motility in SMMC-7721 cells and HeLa cells, and explored the underlying molecular mechanisms. SMMC-7721 cells and HeLa cells treated with Eleutheroside B and cell viability measured by MTT assay and trypan blue dye exclusion assay. Apoptosis checked by flow cytometry combined, fluorescent staining. Apoptotic signal proteins and autophagy proteins were checked by Western blot. This study showed that Eleutheroside B inhibited the cell proliferation and blocked cell cycle, migration and invasion as well. Moreover, Eleutheroside B induced apoptosis in SMMC-7721 cells and HeLa cells. It upregulated Bax expression, while simultaneously decreasing Bcl-2 expression. Further elucidation of the mechanism revealed that Eleutheroside B induced mitochondrial dysfunction, with mitochondrial membrane potential collapse and cytochrome c release, suggesting that Eleutheroside B induced apoptosis by triggering mitochondrial pathway. Most importantly, Eleutheroside B could induce autophagy in SMMC-7721 cells and HeLa cells. Taken together, these results suggested Eleutheroside B is a potential therapeutic candidate for HCC and Human cervical cancer.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-18T01:41:15Z
      DOI: 10.1177/09603271221089006
      Issue No: Vol. 41 (2022)
       
  • Exosomal miR-455-3p from BMMSCs prevents cardiac ischemia-reperfusion
           injury

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      Authors: Yue Wang, Yusi Shen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveBone marrow mesenchymal stem cells (BMMSCs) exert protective effects against myocardial infarction (MI). Here, we focused on the function and mechanism of miR-455-3p from BMMSCs-derived exosomes (BMMSCs-Exo) in myocardial infarction.Materials and methodsBMMSCs were isolated from rat bone marrow, and the exosomes from the culture medium of BMMSCs were separated, and administered to H9C2 cells under hypoxia-reperfusion (H/R) stimulation. MTT and TUNEL staining analyzed cell viability and apoptosis, respectively. RT-qPCR determined miR-455-3p expression. Apoptosis-related proteins, autophagy-associated proteins, and the MEKK1-MKK4-JNK signaling pathway were detected. The interaction between miR-455-3p and MEKK1 was confirmed through dual luciferase activity and RIP assay. An in vivo ischemia reperfusion (I/R) model was established in rats. 2, 3, 5 triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, Masson staining, and TUNEL staining evaluated the infarct volume and histopathological changes.ResultsmiR-455-3p′s expression was down-regulated in BMMSCs-derived exosomes, I/R myocardial tissues, and H/R myocardial cells. miR-455-3p enriched by BMMSC exosomes reduced H/R-mediated cardiomyocyte damage and death-related autophagy. miR-455-3p upregulation suppressed MEKK1-MKK4-JNK. MEKK1 overexpression notably mitigated cell apoptosis, cramped cell viability, suppressed autophagy expansion, and attenuated Exo-miR-455-3p′s protection on H/R myocardial cells. In-vivo trials reflected that BMMSC exosomes enriched with miR-455-3p repressed ischemia reperfusion-induced myocardial damage and myocardial cell function.ConclusionmiR-455-3p, shuttled by exosomes from MSCs, targets the MEKK1-MKK4-JNK signaling pathway to guard against myocardial ischemia-reperfusion damage.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-17T01:23:02Z
      DOI: 10.1177/09603271221102508
      Issue No: Vol. 41 (2022)
       
  • Neutrophil-to-lymphocyte ratio versus platelet-to-lymphocyte ratio in
           predicting clinical outcomes in acute methanol poisoning

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      Authors: Hanan M. Abdelwahab, Ola E. Nafea, Radwa Elsherif, Amal F. Gharib, Amani A. Alrehaili, Walaa G. Abdelhamid
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Acute methanol poisoning is a global health concern. This study was designed to compare the prognostic roles of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and their combination in the prediction of clinical outcomes in methanol-intoxicated patients as well as to evaluate their associations with all initial patients’ characteristics. We conducted a cross-sectional study among methanol-intoxicated patients. A total of 109 patients were enrolled in the study. Thirty-four (31%) patients died during hospital admission while 30 (27.5%) patients developed visual loss. Most of the unfavorable findings were evident in patients with high NLR and PLR. Neutrophil-to-lymphocyte ratio and PLR can excellently differentiate between survivors and non-survivors with an area under the curve (AUC) of 0.991 vs 0.923, respectively. Platelet-to-lymphocyte ratio showed an accepted discrimination ability to differentiate between patients who developed and patients who did not develop visual loss, AUC of 0.734, however, NLR showed no discrimination, AUC of 0.558. We concluded that NLR and PLR can serve as valuable tools in risk-stratifying patients and prognosticating outcomes in acute methanol poisoning. Platelet-to-lymphocyte ratio is superior to NLR as a predictive factor in patients with permanent visual impairment. However, a combination of NLR with PLR can develop a more powerful prediction for overall clinical outcomes.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-16T06:08:04Z
      DOI: 10.1177/09603271221102504
      Issue No: Vol. 41 (2022)
       
  • Neurotoxic 18-kDa apolipoprotein E fragment production contributes to
           anesthetic sevoflurane-induced tau phosphorylation and neuroinflammation
           in vitro

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      Authors: Yang Yu, M Yang, X Zhuang, J Pan, J Feng, J Yu, Yonghao Yu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Anesthesia may induce neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its 18-kDa fragments are reported to induce neurodegeneration and neuroinflammation in Alzheimer’s disease patients. We aimed to test the hypothesis that differences in 18-kDa ApoE fragment levels, but not full-length ApoE, in primary neurons contribute to differences in tau phosphorylation and neuroinflammation with or without sevoflurane administration. Neurons extracted from wild-type (WT), ApoE knockout (ApoE-KO), and ApoE ε3-and ε2-targeted replacement (ApoE ε3, ApoE ε2) mice were divided into control and sevoflurane groups. Neurons in the sevoflurane group were treated with 21% O2, 5% CO2, and 4.1% sevoflurane, whereas those in the control group were treated with 21% O2 and 5% CO2 only on day 5 of neuronal culture. ApoE mRNA, full-length ApoE, 18-kDa ApoE fragments, Tau-PS202/PT205 (AT8), Tau-PSer396/404 (PHF1), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 and IL-1β levels were measured. The data showed that sevoflurane-induced AT8 and PHF1 increases, and TNF-α, IL-6, and IL-1β increases in WT or ApoE ε3 neurons (both expressing full-length and 18-kDa fragmented ApoE) could be mitigated in ApoE ε2 (only expressing full-length ApoE), but not in ApoE-KO neurons, indicating that differences in 18-kDa ApoE fragments, but not full-length ApoE, in primary mouse neurons contributed to differences in tau phosphorylation and neuroinflammation with or without 4.1% sevoflurane administration.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-16T02:24:34Z
      DOI: 10.1177/09603271221102519
      Issue No: Vol. 41 (2022)
       
  • Dentists, are you ready to deal with the “smokers of the future
           ”'

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      Authors: Bruna Fernandes do Carmo Carvalho, Mônica Ghislaine Oliveira Alves, Sandra Silva Marques, Márcio Ajudarte Lopes, Mário Pérez-Sayáns Garcia, Janete Dias Almeida
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.

      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-14T12:07:33Z
      DOI: 10.1177/09603271221101052
      Issue No: Vol. 41 (2022)
       
  • Curcumin alleviated lipopolysaccharide-evoked H9c2 cells damage via
           suppression of intercellular adhesion molecule 1/CD40/NF-κB signaling

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      Authors: Yi Liu, Xiaoli Li, Yan Zhao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundCurcumin has been reported to have many benefits, including anti-inflammatory, anti-cancer, and so on. In this research, we aimed to investigate the function of curcumin on lipopolysaccharide (LPS)-injured H9c2 cells.MethodsH9c2 cells stimulated by LPS mimic the in vitro model of myocarditis injury. Comparative Toxicogenomics Database (CTD) was applied to detect the genes associated with curcumin. GEO database was used to analyze Intercellular Adhesion Molecule 1 (ICAM1) and CD40 expression in myocarditis patients. KEGG enrichment analysis was employed to investigate the meaningful pathways related to differentially expressed genes. Cell proliferation, apoptosis, expression of ICAM1/CD40/P65- NF-κB, and level of TNF-α, IL-6, and IL-10 were observed by cell counting kit-8, flow cytometry and western blotting assays, ELISA assay, respectively.ResultsAfter curcumin treatment, the decreased activity of H9c2 cells evoked by LPS was improved. ICAM1 and CD40, which highly expressed in myocarditis patients, were identified as targets of curcumin and negatively regulated by curcumin. Inhibition of ICAM1 or CD40 strengthened the protective effect of curcumin on LPS-evoked H9c2 cells damage, accompanied by increased cell viability and decreased cell apoptosis and inflammation. Additionally, addition of curcumin or depletion of ICAM1/CD40 suppressed p-P65 NF-κB expression.ConclusionsCurcumin mitigated LPS-evoked H9c2 cells damage by suppression of ICAM1/CD40/NF-κB, providing a potential molecular mechanism for the clinical application of curcumin.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-13T11:03:34Z
      DOI: 10.1177/09603271211069043
      Issue No: Vol. 41 (2022)
       
  • Myrica salicifolia Hochst. ex A. Rich. suppress acetic acid-induced
           ulcerative colitis in rats by reducing TNF-alpha and interleukin-6,
           oxidative stress parameters and improving mucosal protection

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      Authors: NU Rehman, MN Ansari, AH Palla, A Karim, F Imam, M Raish, AM Hamad, M Noman
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with rising prevalence in developing countries, and limited success of current therapies, natural products have immense potential for therapy due to their “disease modifying and side-effect neutralizing” potential. Myrica salicifolia is traditionally used for gastrointestinal diseases and have reported antiinflammatory activities, but its use in IBD has not yet been studied. Therefore, in the present study, the effects of the root extract of M. salicifolia (Ms.Cr) were investigated using the acetic acid-induced UC model in rats. For 6 days, the rats were given either vehicle (10 mL/kg), lower (200 mg/kg), and higher (400 mg/kg) doses of Ms.Cr, or the positive control drug (prednisolone; 2 mg/kg) orally. A single dosage of 5% acetic acid (1.0 mL) was administered intrarectally to rats on day 6 to induce UC. Disease activity index (DAI), histological observations, the biochemical parameters related to oxidative stress, and specific cytokines such as interleukin-6 (IL-6) and the tumor necrosis factor-α (TNF-α) were determined to assess the effect of Ms.Cr. In comparison to the AA-induced colitis rats, Ms.Cr’s pretreatment significantly decreased DAI, colonic ulceration, and inflammatory score. Total glutathione levels and catalase activity were considerably recovered in the colitis group treated with Ms.Cr, whereas enhanced lipid peroxidation in colon tissues was significantly decreased. Moreover, Ms.Cr pretreatment also caused inhibition of the activation of IL-6 and TNF-α in the colonic tissues of respective groups. Based on these findings, Ms.Cr might be developed to treat UC in the future.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-13T06:27:03Z
      DOI: 10.1177/09603271221102518
      Issue No: Vol. 41 (2022)
       
  • Tanshinone IIA alleviate rifampicin-induced cholestasis by regulating the
           expression and function of bile salt export pump

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      Authors: L Liu, Y Yang, W Li, Y Li, X Jiang, L Wang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Objective: Rifampicin (RFP) induces cholestasis due to long-term tubercular therapy. Impairment of the canalicular bile acids efflux via the bile salt export pump (BSEP) is a well-recognized cause of cholestasis. Tanshinone IIA (TAN IIA) has a protective effect on the liver. However, there are limited studies on the effects of RFP and TAN IIA on BSEP. In present study, we aimed to elucidate the effects of RFP and TAN IIA on BSEP and provide evidence to support the treatment of RFP-induced cholestasis with TAN IIA. Methods: Firstly, liver histopathological examination and serum biochemical tests were evaluated in rats. Secondly, we evaluated BSEP expression by qRT-PCR and western blotting to explore whether RFP and TAN IIA influence liver function through BSEP. Thirdly, the accumulation of BSEP substrate taurocholic acid (TCA) in bile ducts was determined to investigate the effects of RFP and TAN IIA on BSEP function. Results: Apparent histopathological alterations and significantly increased serum biomarkers were observed in the RFP group (200 mg/kg), while these changes were attenuated in the combination groups. The mRNA and protein levels of BSEP were decreased by RFP. Whereas TAN IIA reversed the downward regulation of BSEP caused by RFP. And RFP primarily inhibited TCA excretion but co-administration of TAN IIA markedly induced TCA excretion mediated by BSEP. Conclusion: Our findings collectively demonstrated that RFP-induced cholestasis could be related to the inhibition of BSEP, and TAN IIA had the potential to prevent RFP-induced cholestasis by regulating BSEP.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-11T07:09:27Z
      DOI: 10.1177/09603271221097365
      Issue No: Vol. 41 (2022)
       
  • Neuroprotective effects of tannic acid against kainic acid-induced
           seizures in mice

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      Authors: Ali Hasanvand, Azam Hosseinzadeh, Morteza Saeedavi, Mehdi Goudarzi, Zahra Basir, Saeed Mehrzadi
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background Epileptic seizures are associated with the release of potentially neurotoxic amount of glutamate, which results in the over-production of free radicals and inflammatory factors, and induction of neuronal cell death. Current study evaluated the effect of tannic acid (TA) on Kainic acid (KA)-induced seizures in mice.Methods Mice were divided into the six groups. Group I was administrated with normal saline (NS; 1 mL/kg, intraperitoneally (i.p.)), Group II was injected with KA (15 mg/kg, i.p.), Groups III was treated with diazepam (DZ; 20 mg/kg, i.p.) and KA (15 mg/kg, i.p.), Groups IV-VI were treated with TA (25, 50 and 100 mg/kg, i.p.) and KA (15 mg/kg, i.p.). Animals received all treatments 30 min before injection of KA. After the injection of KA, mice were observed for seizure (latency, activity and duration) and mortality for 2 h. In the brain tissue, oxidative stress, apoptosis, and inflammatory markers were evaluated in addition to the determination of histological alterations in the CA1 molecular layer of hippocampus.ResultsTreatment with TA significantly increased seizure latency and decreased seizure duration and activity, but could not significantly decrease mice mortality. This effect was associated with the reduction of oxidative stress, inflammation, and apoptosis. Furthermore, treatment with TA significantly improved KA-induced pyramidal cell loss and change in the arrangement of CA1 molecular layer.ConclusionsTannic acid may be useful in the control of epileptic seizures through regulating oxidative stress, inflammation and apoptosis.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-11T04:39:08Z
      DOI: 10.1177/09603271221093989
      Issue No: Vol. 41 (2022)
       
  • LncRNA HOXC-AS3 overexpression inhibits TGF-β2-induced colorectal cancer
           cell migration and invasion by sponging miR-1269

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      Authors: Tong-tong Zhang, Hai-peng Chen, Su-yang Yu, Shi-peng Zhao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveLong non-coding RNA (lncRNA) HOXC-AS3 has been characterized as a cancer-related lncRNA in many types of cancer, while its role in colorectal cancer (CRC) is unknown.MethodsThe expression of HOXC-AS3 and TGF-β2 were detected by RT-qPCR. Overexpression assays were performed to explore the interaction between HOXC-AS3 and TGF-β2. A follow-up study was performed to explore the prognostic value of HOXC-AS3 for CRC. The direct interaction between HOXC-AS3 and miR-1269 was assessed with RNA-RNA pulldown assay. Transwell assays were performed to determine the role of HOXC-AS3 and TGF-β2 in regulating CRC cell invasion and migration.ResultsHOXC-AS3 was significantly downregulated in CRC tissues, while TGF-β2 was significantly upregulated in CRC tissues compared to that in adjacent non-cancer tissues of CRC patients. The follow-up study showed that low expression levels of HOXC-AS3 in CRC tissues were closely correlated with poor survival. Correlation analysis showed that HOXC-AS3 and TGF-β2 were inversely correlated across CRC tissues but not non-cancer tissues. Overexpression of HOXC-AS3 in the two cell lines resulted in downregulation of TGF-β2, while the expression of HOXC-AS3 was not affected by TGF-β2. Transwell migration and invasion assay showed that overexpression of TGF-β2 increased cell invasion and migration, while overexpression of HOXC-AS3 decreased cell migration and invasion. In addition, overexpression of HOXC-AS3 attenuated the effects of overexpression of TGF-β2. MiR-1269 increased the expression of TGF-β2. HOXC-AS3 directly interacted with miR-1269 in CRC cells.ConclusionsUpregulation of HOXC-AS3 inhibited TGF-β2-induced colorectal cancer (CRC) cell migration and invasion possibly by sponging miR-1269.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-10T09:29:08Z
      DOI: 10.1177/09603271221093630
      Issue No: Vol. 41 (2022)
       
  • Icariin inhibits gastric cancer cell growth by regulating the
           hsa_circ_0003159/miR-223-3p/NLRP3 signaling axis

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      Authors: Fengli Zhang, Yanfen Yin, Wenwen Xu, Yanan Song, Zhou Zhou, Xin Sun, Ping Li
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      This study aimed to clarify the expression and role of hsa_circ_0003159 in gastric carcinogenesis, and validate the protective effects of Icariin (ICA) against gastric cancer (GC) cell growth through the in vitro and in vivo experiments. The levels of hsa_circ_0003159, microRNA (miR)-223-3p and NLRP3 were measured by Quantitative real time Polymerase Chain Reaction or western blot. The cell counting kit (CCK)-8 was used to determine cell proliferation. The target relationship of miR-223-3p/hsa_circ_0003159 and miR-223-3p/NLRP3 was predicted by bioinformatics and validated by the dual-luciferase reporter and pull-down assays. Xenograft model was constructed to assess the roles of hsa_circ_0003159 and protective effects of ICA in GC in vivo. Results showed that hsa_circ_0003159 was downregulated in GC cell lines and its overexpression promoted GC cell viability. MiR-223-3p was identified as a target of hsa_circ_0003159. By competitively sponging miR-223-3p, hsa_circ_0003159 positively regulated NLRP3 expression. MiR-223-3p mimics reversed the suppressive effect of hsa_circ_0003159 on GC cell viability and cell pyroptosis. Importantly, ICA inhibited GC cell viability and triggered GC cell pyroptosis by regulating the hsa_circ_0003159/miR-223-3p/NLRP3 axis in vitro and in vivo. In conclusion, this study indicated ICA inhibits GC cell growth by regulating the hsa_circ_0003159/miR-223-3p/NLRP3 signaling axis. This study not only reveals the mechanism of gastric carcinogenesis but also provides potential molecular targets and therapeutic tools for its treatment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-09T12:59:17Z
      DOI: 10.1177/09603271221097363
      Issue No: Vol. 41 (2022)
       
  • Milk fat globule-epidermal growth factor-factor 8 decreased neuronal
           apoptosis and neuroinflammation to ameliorate early brain injury induced
           by subarachnoid hemorrhage through the inhibition of high mobility group
           box-1

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      Authors: Jiaoxue Qiu, Wenna Li, Rutao Mu, Lingling Wang, Lei Guo, Lili Ma
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      AimBoth MFGE8 and HMGB1 were vital players for aneurysmal subarachnoid hemorrhage. However, whether HMGB1 was served as the downstream target of MFGE8 was unknown. To test this new mechanism, we performed the SAH model in rats.MethodAll treatments were injected intraventricularly into the right lateral ventricles. SAH grade, brain water content, and neurological function scores were evaluated. HMGB1 expression was studied by double immunofluorescence staining. HE and Nissl’s staining were performed to observe the pathological change. Inflammatory factors were measured by ELISA method.ResultsHigh expression of MFGE8 could improve neurological function and reduce the brain edema and pro-inflammatory factors. Injection of rhMFGE8 inhibited HMGB1. To further verify the regulation of MFGE8 in HMGB1, we used rhHMGB1 and glycyrrhizin, and the results indicated MFGE8 produced excellent effect on SAH rats via inhibiting HMGB1.ConclusionIn a word, MFGE8 improved EBI caused by SAH, depending on HMGB1 that was the potential mechanism.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-05-03T03:58:33Z
      DOI: 10.1177/09603271221093635
      Issue No: Vol. 41 (2022)
       
  • Association of miR-9-5p and NFIC in the progression of gastric cancer

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      Authors: Shihong Lv, Lei Liu, Baijing Yang, Xiaohua Zhao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundGastric cancer is the most common malignant neoplasm of digestive system. Herein, we aim to detect the expression of nuclear factor I C (NFIC) in gastric cancer cells, and to explore the effect and mechanism of its expression on the development of gastric cancer.MethodsqPCR and Western blot assays were carried out to detect NFIC expression. Then, BGC-823 and SGC-7901 cell lines were selected to perform the following functional experiments. The function of NFIC on gastric cancer cells was analyzed by biological experiments. The associations between miR-9-5p and NFIC were searched on the bioinformatics website and identified by dual luciferase assay. The effects of miR-9-5p and NFIC on cells were verified by co-transfection experiments. The related genes expression was examined by Western blot.ResultsA marked augmentation of NFIC was observed in gastric cancer cells. Knockdown of NFIC significantly inhibited the viability, colony formation, invasion, and migration of gastric cancer cells. Overexpression of miR-9-5p obviously suppressed the viability, colony formation, invasion, and migration of gastric cancer cells, and this phenomenon was aggravated by si-NFIC. Additionally, the expression levels of PCNA, vimentin, and Snail were obviously decreased after miR-9-5p mimic or/and si-NFIC treatment.ConclusionsThese results suggested that NFIC was highly expressed in gastric cancer cells, and knockdown of NFIC suppressed the growth and mobility of gastric cancer cells; miR-9-5p was identified as an upstream regulator of NFIC and suppressed the malignant behaviors of gastric cancer cells by targeting NFIC through affecting PCNA, vimentin, and Snail expression.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-28T11:16:20Z
      DOI: 10.1177/09603271221084671
      Issue No: Vol. 41 (2022)
       
  • The effects of subconjunctival bevacizumab, ranibizumab, and aflibercept
           on corneal neovascularization

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      Authors: MT Eski, Kuddusi Teberik, Pembe Oltulu, Handan Ankaralı, Murat Kaya, Merve Alpay
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      PurposeTo investigate the effects of subconjunctival bevacizumab, ranibizumab, and aflibercept in an experimental corneal neovascularization model.Materials and methodsThe eyes of 24 rats were chemically cauterized and randomly divided into four groups: bevacizumab group (0.05 mL/1.25 mg bevacizumab), ranibizumab group (0.05 mL/0.5 mg ranibizumab), aflibercept group (0.05 mL/1.25 mg aflibercept), and control group (0.05 mL saline solution). Plasma vascular endothelial growth factor (VEGF) levels were among the major measurement outcomes to assess corneal neovascularization. The collected plasmas were analyzed using the SIGMA RAB0511 Rat VEGF Elisa kit. The PCR technique and VEGF amplification procedures were used for molecular analysis. Each cornea was removed and histologically examined on day 21. Corneal images were evaluated by image analyzer software.ResultsIn the post-injection period, the number of major corneal arteries decreased significantly in the injection groups when compared to the control group (p = 0.037), but no statistically significant differences were noted among the injection groups (p> 0.05). The aflibercept group had the lowest area of neovascularization. Immunohistochemical staining revealed substantially lower VEGF percentages in neovascularized arteries of the injection groups than the control group (p = 0.015). In TUNEL staining, the mean TUNEL value (number/1hpf) was substantially greater in the control group than in the injection groups, but the mean TUNEL values were similar between the injection groups (p = 0.019, p> 0.05, respectively). No statistically significant differences were observed between the groups in terms of corneal surface area with increased cellularity, edema, and inflammation (p = 0.263). The mean plasma VEGF concentration in the control group was statistically greater than those in the injection groups (p = 0.001).ConclusionSubconjunctival bevacizumab, ranibizumab, and aflibercept crossed the blood and seemed to be effective in inhibiting corneal neovascularization without causing epitheliopathy in an experimental rat model compared to the controls. However, no significant results were noted between these three anti-VEGF molecules.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-25T03:33:50Z
      DOI: 10.1177/09603271221084674
      Issue No: Vol. 41 (2022)
       
  • Targeting p-AKT/mTOR/MAP kinase signaling, NLRP3 inflammasome and
           apoptosis by fluvastatin with or without taxifolin mitigates gonadal
           dysfunction induced by bisphenol-A in male rats

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      Authors: Ahmed M Kabel, Samir A Salama, Hany M Borg, Dina A Ali, Maaly A Abd Elmaaboud
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Bisphenol-A (BPA) is a chemical substance that is widely used in industry for manufacturing of plastic bottles and resins. Recent reports found that BPA may mimic the effects of estrogen to a great manner that might disrupt the normal hormonal balance in the human body. Fluvastatin is an agent used for treatment of hypercholesterolemia that was proven to possess promising antioxidant ant anti-inflammatory properties. Taxifolin is a polyphenolic compound with potential antioxidant and antiestrogenic effects. The present study investigated the prospect of fluvastatin with or without taxifolin to mitigate testicular dysfunction elicited by BPA in rats. In a model of BPA-induced testicular toxicity, the hormonal profile was assessed and the testicular tissues were examined by biochemical analysis, histopathology, and immunohistochemistry. Fluvastatin with or without taxifolin improved the body weight gain, hormonal profile, testicular weight and functions, sperm characteristics, the antioxidant status, and the anti-inflammatory mechanisms together with enhancement of autophagy and suppression of the proapoptotic events induced by BPA in the testicular tissues. In addition, fluvastatin with or without taxifolin significantly mitigated the histopathological and the immunohistochemical changes induced by BPA in the testicular tissues. These desirable effects were more pronounced with fluvastatin/taxifolin combination relative to the use of each of these agents alone. In tandem, fluvastatin/taxifolin combination might counteract the pathogenic events induced by BPA in the testicular tissues which may be considered as a novel strategy for amelioration of these disorders.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-23T04:07:43Z
      DOI: 10.1177/09603271221089919
      Issue No: Vol. 41 (2022)
       
  • MicroRNA-200b-3p as a biomarker for diagnosis and survival prognosis of
           multiple organ dysfunction syndrome caused by acute paraquat poisoning

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      Authors: Minggang Ding, Yi Zhang, Weijun Xu, Chongtao Fang, Kaitai Zhang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundAcute paraquat poisoning-induced multiple organ dysfunction syndrome (MODS) leads to the high mortality. This study aimed to investigate the clinical significance of microRNA-200b-3p (miR-200b-3p), an upstream inhibitor of high-mobility group box 1 (HMGB1), in acute paraquat poisoning patients for the prediction of MODS and survival.MethodsThis study enrolled 80 patients with MODS induced by paraquat and 94 healthy volunteers. The interaction between miR-200b-3p and HMGB1 was identified by luciferase reporter assay. miR-200b-3p levels were measured by quantitative real-time (QRT) PCR. High-mobility group box 1 levels were measured by enzyme-linked immune sorbent assay (ELISA). Receiver operating characteristic analysis was used to evaluate the diagnostic value of miR-200b-3p in screening MODS patients. The relationship between miR-200b-3p and the 28-day survival of MODS patients was evaluated by Kaplan–Meier curves and log-rank test. Cox regression analysis was used to assess the prognostic value of miR-200b-3p. Correlation between miR-200b-3p and HMGB1 was confirmed by Pearson’s correlation analysis.ResultsmiR-200b-3p directly target HMGB1. miR-200b-3p, decreased in MODS patients, had high diagnostic value to screen MODS patients from healthy controls. Additionally, serum miR-200b-3p was decreased in non-survivors, and patients with low miR-200b-3p level had poor 28-day survival. Serum miR-200b-3p could independently predict the survival prognosis. Moreover, serum HMGB1 level was increased in MODS patients, and was negatively correlated with miR-200b-3p level.ConclusionDecreased miR-200b-3p may function as a biomarker for the diagnosis and survival prognosis of MODS patients, and miR-200b-3p may be involved in the progression of acute paraquat-induced MODS via regulating inflammatory responses by targeting HMGB1.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-20T12:36:05Z
      DOI: 10.1177/09603271221094008
      Issue No: Vol. 41 (2022)
       
  • Ursolic acid protects against anoxic injury in cardiac microvascular
           endothelial cells by regulating intercellular adhesion molecule-1 and
           toll-like receptor 4/MyD88/NF-κB pathway

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      Authors: Zhongrui Bian, Hui Liu, Fei Xu, Yimeng Du
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundCardiac microvascular endothelial cells (CMECs) are rapidly damaged after myocardial ischemia or hypoxia. In this study, we intend to explore whether ursolic acid (UA) can protect CMECs against hypoxia/reoxygenation (H/R) injury and to detect related molecular mechanism.MethodsCMECs were subjected to H/R condition in the absence or presence of UA. Cell behaviors were measured by Cell Counting Kit-8, transwell, ELISA and western blot assays. siRNA was applied to reduce ICAM1 expression, then the effect of co-treatment of UA and si-ICAM1 on CMECs has been detected by biological experiments.ResultsUnder H/R stimulation, the proliferation and migration of CMECs were inhibited, as well as the inflammation and oxidative stress were enhanced. UA treatment obviously reversed these H/R-induced injuries and reduced ICAM1 expression. Moreover, knockdown of ICAM1 could alleviate the H/R-induced injuries and strengthen the protective effect of UA on CMECs under H/R condition. Additionally, the protein levels of TLR4, MyD88 and p-P65 NF-κB were obviously increased after H/R stimulation, whereas the addition of UA could alter the phenomena by reducing TLR4, MyD88, and p-P65 NF-κB expression.ConclusionsOur results insinuated that UA could alleviate H/R-induced injuries in CMECs by regulating ICAM1 and TLR4/MyD88/NF-κB pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-19T01:07:28Z
      DOI: 10.1177/09603271221093626
      Issue No: Vol. 41 (2022)
       
  • Neuroprotection of chromobox 7 knockout in the mouse after cerebral
           ischemia-reperfusion injury via nuclear factor E2-related factor
           2/hemeoxygenase-1 signaling pathway

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      Authors: Hai-Tao Zhang, Xi-Zeng Wang, Qing-Mei Zhang, Han Zhao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveTo explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury.MethodsThe experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress–related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins.ResultsAt 6 h, 12 h, 24 h, 3 days, and 7 days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24 h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice.ConclusionKnockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-18T01:50:58Z
      DOI: 10.1177/09603271221094660
      Issue No: Vol. 41 (2022)
       
  • An in vitro study on anti-carcinogenic effect of remdesivir in human
           ovarian cancer cells via generation of reactive oxygen species

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      Authors: Chang Min Lee, Mi-Ae Kang, Jun Sang Bae, Kyungmoon Park, Yung-Hun Yang, Jongsung Lee, Kyu Yun Jang, See-Hyoung Park
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundRemdesivir is an anti-viral drug that inhibits RNA polymerase. In 2020, remdesivir was recognized as the most promising therapeutic agents against coronavirus disease 2019 (COVID-19). However, the effects of remdesivir on cancers have hardly been studied.PurposeHere, we reported that the anti-carcinogenic effect of remdesivir on SKOV3 cells, one of human ovarian cancer cell lines.Research designWe anlalyzed the anti-carcarcinogenic effect of remdesivir in SKOV3 cells by performing in vitro cell assay and western blotting.ResultsWST-1 showed that remdesivir decreased cell viability in SKOV3 cells. Experiments conducted by Muse Cell Analyzer showed that remdesivir-induced apoptosis in SKOV3 cells. We found that the expression level of FOXO3, Bax, and Bim increased, whereas Bcl-2, caspase-3, and caspase-7 decreased by remdesivir in SKOV3 cells. Furthermore, we observed that intracellular reactive oxygen species (ROS) level increased after treatment of remdesivir in SKOV3 cells. Interestingly, cytotoxicity of remdesivir decreased after treatment of N-Acetylcysteine.ConclusionTaken together, our results demonstrated that remdesivir has an anti-carcinogenic effect on SKOV3 cells vis up-regulation of reactive oxygen species, which suggests that remdesivir could be a promising reagent for treatment of ovarian cancer.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-13T11:38:27Z
      DOI: 10.1177/09603271221089257
      Issue No: Vol. 41 (2022)
       
  • LncRNA SNHG12 ameliorates bupivacaine-induced neurotoxicity by sponging
           miR-497–5p to upregulate NLRX1

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      Authors: Lijie Sun, Ru Yuan
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) has been reported to participate in the regulation of various nervous system disorders. Bupivacaine (BV), a commonly used local anesthetic, could generate neurotoxicity in neurons. This work intended to investigate the role and specific mechanism of SNHG12 in BV-induced neurotoxicity. In this study, we established an in vitro cell model of BV-induced neurotoxicity by exposing human neuroblastoma cells (SH-SY5Y) to BV. It was found that SNHG12 and NLRX1 levels were gradually downregulated, while miR-497–5p enrichment was upregulated accordingly with the increase of BV concentration. As indicated by functional assays, SNHG12 overexpression promoted cell viability but inhibited cell apoptosis and oxidative stress in BV-treated SH-SY5Y cells. In addition, it was identified that SNHG12 directly targeted miR-497–5p and attenuated BV-induced neurotoxicity via interaction with miR-497–5p. Besides, it was confirmed that SNHG12 could upregulate NLRX1 expression by absorbing miR-497–5p. Moreover, miR-497–5p decreased cell viability and induced cell apoptosis and oxidative stress, which was partly reversed by NLRX1 upregulation. In conclusion, our findings indicated that SNHG12 might relieve BV-associated neurotoxicity by upregulating NLRX1 via miR-497–5p in vitro, providing novel clues and biomarkers for the treatment and prevention of BV-associated neurotoxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-12T06:47:03Z
      DOI: 10.1177/09603271221089001
      Issue No: Vol. 41 (2022)
       
  • Effects of Y-27632 on the osteogenic and adipogenic potential of human
           dental pulp stem cells in vitro

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      Authors: Zhiwei Xie, Qiuping Xu, Lu Sun, Ruijing Li, Jizhou Shi, Qian Yang, Min Zong, Jianyong Qin
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundHuman dental pulp stem cells (hDPSCs) possess mesenchymal stem cell properties, originating from migrating neural crest cells. hDPSCs have received extensive attention in the field of tissue engineering and regenerative medicine due to their accessibility and ability to differentiate in several cell phenotypes. In this study, we cultured hDPSCs with Y-27632 to observe their biological behaviors changes.MethodsThe hDPSCs were separately cultured with Y-27632 (0, 0.156, 0.312, 0.625, 1.25, 2.50, 5, 10, 20, 40 μm) for 24, 48, 72 h to select the suitable concentration and time using CCK-8. Then, the hDPSCs were cultured with 2.50 μm Y-27632 for 48 h to analyzed the biological behaviors changes by 5-Ethynyl-2′-deoxyuridine (EdU), plate cloning, transwell, scratch, and Annexin V FITC/PI assays, separately. Additionally, osteogenic calcium nodules and lipid droplets were analyzed using alizarin red staining and oil red O staining, respectively. qRT-PCR was used to analyze the expression of osteogenesis, adipogenesis, stemness maintenance, and inflammation related genes.ResultsThe hDPSCs proliferation was significantly enhanced after cultured with 2.50 μm Y-27632 for 48 h, but there was no significant difference in migration and apoptosis. Observation of alkaline phosphatase (ALP) activity, osteogenic and adipogenic differentiation abilities of hDPSCs, Y-27632 treatment clearly decreased the ALP activity and osteogenic differentiation ability, increased the adipogenic differentiation ability. Furthermore, Y-27632 decreased the CD73, CD90, CD105, CD166, TLR4, and NF-κB p65 genes expression, but increased the IL-8 gene expression.ConclusionsThe biological behaviors of hDPSCs could be changed when they cultured with Y-27632.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-07T11:37:17Z
      DOI: 10.1177/09603271221089003
      Issue No: Vol. 41 (2022)
       
  • A comparative assessment of e-cigarette aerosol extracts and tobacco
           cigarette smoke extracts on in vitro endothelial cell inflammation
           response

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      Authors: Le Su, Minghan Zhao, Feifan Ma, Zaiyong An, Qiulin Yue, Chen Zhao, Xin Sun, Song Zhang, Jing Xu, Xingtao Jiang, Kunlun Li, Lin Zhao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      With the development of the times, electronic cigarettes (e-cigarettes) are being received by more and more people. We compared the different effects of e-cigarettes and tobacco cigarettes on human umbilical vein endothelial cells (HUVECs) treated with the typical e-cigarette aerosol extracts (ECA) and cigarette smoking extracts (CS) sourced from commercial retail stores. HUVECs were treated with different kinds of ECA or CS with different nicotinic concentrations (0.03125, 0.125, 0.5, 2, 8, or 32 μg/mL). Cell viability was examined by the MTT assay. The cell apoptosis was investigated by acridine orange (AO) and Hoechst 33258 staining. The RT-PCR and western blot assays were used to analyze the adhesion molecules and inflammation cytokines released by HUVECs. Furthermore, the intracellular reactive oxygen species (ROS) was observed by fluorescence microscopy. Our data showed that the CS (nicotine concentration at 0.125 μg/mL could decrease the viability of HUVECs by 71%, but not the four kinds of ECA. The apoptotic ratio was about 32.5% in the CS group. No matter the levels of adhesion molecules, inflammation cytokines or ROS, they were higher in CS groups than in ECA groups. Overall, the four kinds of e-cigarettes induced significantly less cytotoxicity than the commercially available tobacco cigarettes in HUVECs. The CS showed the most severe impact on HUVECs. ECA might provide a harm reduction measure, especially in cardiovascular risk, after people switch from tobacco cigarettes to e-cigarettes.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-06T07:40:12Z
      DOI: 10.1177/09603271221088996
      Issue No: Vol. 41 (2022)
       
  • Protective effects of apigenin on methylmercury-induced
           behavioral/neurochemical abnormalities and neurotoxicity in rats

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      Authors: Rajeshwar Kumar Yadav, Sidharth Mehan, Rakesh Sahu, Sumit Kumar, Andleeb Khan, Hafiz Antar Makeen, Mohammed Al Bratty
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Methylmercury (MeHg) is a neurotoxin that induces neurotoxicity and cell death in neurons. MeHg increases oligodendrocyte death, glial cell activation, and motor neuron demyelination in the motor cortex and spinal cord. As a result, MeHg plays an important role in developing neurocomplications similar to amyotrophic lateral sclerosis (ALS). Recent research has implicated c-JNK and p38MAPK overactivation in the pathogenesis of ALS. Apigenin (APG) is a flavonoid having anti-inflammatory, antioxidant, and c-JNK/p38MAPK inhibitory activities. The purpose of this study is to determine whether APG possesses neuroprotective effects in MeHg-induced neurotoxicity in adult rats associated with ALS-like neuropathological alterations. In the current study, the neurotoxin MeHg causes an ALS-like phenotype in Wistar rats after 21 days of oral administration at a dose of 5 mg/kg. Prolonged administration of APG (40 and 80 mg/kg) improved neurobehavioral parameters such as learning memory, cognition, motor coordination, and grip strength. This is mainly associated with the downregulation of c-JNK and p38MAPK signaling as well as the restoration of myelin basic protein within the brain. Furthermore, APG inhibited neuronal apoptotic markers (Bax, Bcl-2, and caspase-3), restored neurotransmitter imbalance, decreased inflammatory markers (TNF- and IL-1), and alleviated oxidative damage. As a result, the current study shows that APG has neuroprotective potential as a c-JNK and p38MAPK signaling inhibitor against MeHg-induced neurotoxicity in adult rats. Based on these promising findings, we suggested that APG could be a potential new therapeutic approach over other conventional therapeutic approaches for MeHg-induced neurotoxicity in neurobehavioral, molecular, and neurochemical abnormalities.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-04T05:49:33Z
      DOI: 10.1177/09603271221084276
      Issue No: Vol. 41 (2022)
       
  • Knockdown of LINC00511 decreased cisplatin resistance in non-small cell
           lung cancer by elevating miR-625 level to suppress the expression of
           leucine rich repeat containing eight volume-regulated anion channel
           subunit E

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      Authors: Benkun Liu, Fucheng Zhou, He Liu, Yanbo Wang, Junfeng Wang, Fenghai Ren, Shidong Xu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundLINC00511 has been reported as a biomarker related to the prognosis of non-small cell lung cancer (NSCLC), but the molecular mechanism and exact functions of LINC00511 in chemoresistance of NSCLC remain to be elucidated.MethodsRT-qPCR was used to evaluate the mRNA expression of LINC00511, miR-625, and leucine rich repeat containing 8 volume-regulated anion channel subunit E (LRRC8E). Western blotting detected the protein levels of Ki-67, MMP-9, cleaved-caspase-3. The interaction between miR-625 and LINC00511 or LRRC8E was verified by luciferase reporter assays. CCK-8, TUNEL, and Transwell assays were used to evaluate IC50 value, proliferation, migration, and invasion of NSCLC cells.ResultsIn our study, it was discovered that the levels of LINC00511 and LRRC8E were increased, while miR-625 expression was decreased in NSCLC tissues, DDP-resistant NSCLC cells, and non-resistant NSCLC cells. LINC00511 depletion significantly curbed cell growth, IC50 value, and metastasis in DDP-resistant NSCLC cells. In addition, the influence of LINC00511 deficiency on the DDP resistance in NSCLC was overturned by suppressing miR-625. Furthermore, LRRC8E overexpression abolished the promotive effect of miR-625 abundance on the DDP sensitivity in DDP-resistant NSCLC cells.ConclusionOur results demonstrated that LINC00511 increased DDP resistance in NSCLC by suppressing miR-625 to upregulate LRRC8E.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-04-01T01:20:04Z
      DOI: 10.1177/09603271221089000
      Issue No: Vol. 41 (2022)
       
  • Solasonine relieves sevoflurane-induced neurotoxicity via activating the
           AMP-activated protein kinase/FoxO3a pathway

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      Authors: Huifang Zhang, Lei Yan
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundSolasonine (SS), the main active ingredient of Solanumnigrum L, has been reported to boast extensive anti-tumor, anti-oxidant, and anti-inflammatory properties. This study is committed to exploring whether solasonine can alleviate neurotoxicity resulting from sevoflurane.Materials and methodsThe mouse hippocampal neuron cell line HT22 was treated with sevoflurane and/or solasonine of different doses. The proliferation, inflammation, oxidative stress response, and apoptosis of HT22 cells were examined. The AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway was ascertained through Western blot and cellular immunofluorescence. In in-vivo experiments, Morris water maze figured out the changes in learning and memory abilities of mice treated with 8 mg/kg solasonine and exposed to SEV.ResultsSevoflurane induced apoptosis and hampered proliferation in HT22 cells. It also aggravated the release of inflammatory factors and oxidative stress mediators. Solasonine weakened neuron damage mediated by sevoflurane in a concentration-dependent pattern. Mechanically, sevoflurane clogged AMPK/FoxO3a signaling pathway activation, which was strengthened by solasonine. AMPK inhibition greatly influenced solasonine’s protective effect on HT22 cells. Invivo, solasonine prominently ameliorated learning and memory disorders and nerve damage in mice exposed to sevoflurane.ConclusionsSolasonine alleviates sevoflurane-induced neurotoxicity through activating the AMPK/FoxO3a signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-30T08:11:43Z
      DOI: 10.1177/09603271211069984
      Issue No: Vol. 41 (2022)
       
  • Plantamajoside promotes metformin-induced apoptosis, autophagy and
           proliferation arrest of liver cancer cells via suppressing Akt/GSK3β
           signaling

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      Authors: Zhuo Wang, Jieliang Zuo, Linlin Zhang, Zhenghua Zhang, Yongpeng Wei
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Metformin, a well-known antidiabetic drug, exhibits anticancer effect in a variety of cancers, including liver cancer. Plantamajoside (PMS), a phenylethanoid glycoside compound isolated from Plantago asiatica, is proved to possess anticancer effects, too. In our study, we hypothesized that PMS might promote metformin mediated anticancer effects on liver cancer. The half maximal inhibitory concentration (IC50) of metformin was evaluated by cell viability assay. The influence of PMS on proliferation, migration, invasion and apoptosis of metformin-treated cells was evaluated by BrdU incorporation assay, flow cytometry, western blot, wound scratch healing assay, transwell cell migration assay and immunofluorescence. A fasting/feeding mouse model was built to evaluate the influence of PMS on metformin sensitivity in vivo. PMS (2.5, 10 or 40 μg/mL) treatment reduced the IC50 of metformin under different glucose concentrations. PMS (10 μg/mL) promoted metformin (5 mm) induced apoptosis and autophagy, and inhibition on proliferation, migration and invasion of HepG2 and HuH-7 cells. In the fasting/feeding mouse model, PMS (50 mg/kg) promoted metformin (200 mg/kg) induced proliferation arrest and apoptosis in vivo. Meanwhile, PMS reduced the level of pAkt(ser473) and GSK3β(ser9) in HepG2 and HuH-7 cells. Restoration of Akt/GSK3β signaling by a constitutively activated myr-Akt1 abrogated the effects of PMS on metformin-treated liver cancer cells. Our results demonstrated that PMS promoted the anticancer effects of metformin on liver cancer in vitro and in vivo.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-30T05:17:20Z
      DOI: 10.1177/09603271221078868
      Issue No: Vol. 41 (2022)
       
  • Inflammatory mediators of cytokines and chemokines in sepsis: From bench
           to bedside

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      Authors: Zuleyha Doganyigit, Ece Eroglu, Enes Akyuz
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background: Sepsis is a serious clinical condition characterized by damage to the immune system as a result of an uncontrolled response to infection. Septic patients show complications such as fever, cardiovascular shock, and/or systemic organ failure. Acute organ failure formed in sepsis mostly affects the respiratory and cardiovascular systems. In sepsis, responses including pro-inflammatory and anti-inflammatory processes in addition to the Toll-Like Receptor 4 (TLR4) signals leading to the release of inflammatory mediators have been suggested to be fundamental pathways in the pathophysiology of sepsis. Purpose: In this context, unregulated levels of sepsis-associated inflammatory mediators may increase the risk of mortality. In sepsis, infection-induced pathogens lead to a systemic inflammatory response. These systemic responses may contribute to septic shock and organ dysfunction. In the unfavorable clinical course of sepsis, an uncontrolled inflammatory response is observed. Accordingly, the mechanism of inflammatory mediators such as cytokines and chemokines in sepsis might increase. Neurotransmitters and gene regulators affect inflammatory mediators and control the inflammatory response. In this review, we aimed to show the new therapeutic targets in sepsis treatment with current studies. New clinical implications targeting inflammatory mediators in high mortality affected by the uncontrolled inflammatory response in sepsis can contribute to the understanding of the symptoms.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-26T03:40:37Z
      DOI: 10.1177/09603271221078871
      Issue No: Vol. 41 (2022)
       
  • Curculigoside mitigates hepatic ischemia/reperfusion-induced oxidative
           stress, inflammation, and apoptosis via activation of the Nrf-2/HO-1
           pathway

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      Authors: Peng Du, Xingjian Zhang, Kaifeng Luo, Yong Li, Chengchao Fu, Jiansheng Xiao, Qi Xiao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Curculigoside has been shown to decrease oxidative stress and inflammatory reactions in many disorders, but its effects during hepatic ischemia–reperfusion injury (IRI) remain unknown. This research aims to determine the protective role and the potential mechanism of action of curculigoside in hepatic IRI. Here, a well-established rat model of partial warm IRI was constructed; serum ALT/AST and H&E staining were employed to assay the extent of liver injury; the superoxide dismutase, malondialdehyde, IL-6, and TNF-α contents were determined using the corresponding kits; the apoptosis index was evaluated by TUNEL staining; and the expression of Nrf-2, HO-1, and apoptosis-associated proteins was detected by qRT–PCR and Western blotting. The results showed that curculigoside pretreatment effectively mitigated hepatic IRI, as demonstrated by decreases in the levels of serum aminotransferases, hepatocellular necrosis and apoptosis, oxidative stress markers, infiltration of inflammatory cells, and secretion of proinflammatory cytokines. Mechanistically, the expression of Nrf-2 and HO-1 was greatly suppressed by hepatic IRI and reactivated by curculigoside. Furthermore, cotreatment with ML-385, an inhibitor of Nrf-2, counteracted the protective effect of curculigoside against hepatic IRI. The results of our study show that curculigoside plays a protective role in hepatic IRI by inhibiting oxidative stress, inflammation, and apoptosis and that its effects may be associated with activation of the Nrf-2/HO-1 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-25T05:44:58Z
      DOI: 10.1177/09603271221087146
      Issue No: Vol. 41 (2022)
       
  • Regulatory mechanisms of Beta-carotene and BCMO1 in adipose tissues: A
           gene enrichment-based bioinformatics analysis

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      Authors: Yutao Wang, Jinshen Wang, Yuhua Zhao, Pingxiang Liu, Da Cai, Xiao Zhang, Lei Gao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Beta-carotene (β-carotene, BC) is one of the carotenoids most commonly consumed by humans. BCMO1 is expressed in various human tissues and is considered to be a key enzyme that converts BC into vitamin A. Studies indicated that BC-derived carotenoid signaling molecules affected the physiological functions of fat cells. In order to investigate the role and possible molecular mechanism of BC in mouse adipocytes, we conducted 4-group and 2-group difference analysis based on the data of GSE27271 chip in the Gene Expression Omnibus database. Genes differentially expressed in the inguinal white adipose tissue of mice were screened out and combined with the STRING database to construct protein-protein interaction (PPI) networks. Among them, Alb (albumin), Mug1 (murinoglobulin-1) and Uox (urate oxidase) genes were at relatively key positions and may affect the action of BC. Besides, Ppara (peroxisome proliferator-activated receptor alpha), Acly (ATP-citrate lyase) and Fabp5 (fatty acid-binding protein 5) genes constituted functional partners with many genes in the PPI network, and these genes may be Bcmo1 targeting molecules. Gene Ontology (GO) function and signaling pathways enrichment analysis were performed on the genes with protein interaction relationship in the PPI network. Fatty acid binding, cholesterol metabolic process, and regulation of fatty acid metabolic process were significantly enriched, and PPAR signaling pathway showed the most significant, indicating that BC and Bcmo1 might synergistically affect body metabolic functions such as fat metabolism. In general, BC and Bcmo1 may play a role in fat metabolism in mice, thereby affecting other functions or diseases.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-19T12:19:04Z
      DOI: 10.1177/09603271211072871
      Issue No: Vol. 41 (2022)
       
  • MicroRNA-122-5p prevents proliferation and promotes apoptosis of hepatic
           stellate cells by suppressing the cellular-Abelsongene/histone
           deacetylases 2 pathway

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      Authors: ZongYang Wu, JinBo Wang, JiYe Feng, LiPing Ying
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Liver fibrosis is a wound-healing response and the activation of the hepatic stellate cell (HSC) is the core of hepatic fibrosis. MicroRNAs (miRNAs) participate in the development of fibrosis. It is reported that histone deacetylases (HDAC2) tyrosine phosphorylation by cellular-Abelsongene (c-Abl) induces malignant growth of cells. Here, we investigated the effect of miR-122-5p on the proliferation and apoptosis of HSCs. Normal human HSC line LX-2 and LX-2 cells stimulated by transforming growth factor (TGF)-β1 for 24 h were cultured and assigned into the blank group and the TGF-β1 group. The miR-122-5p inhibitor and its negative control were transfected into LX-2 cells and miR-122-5p mimic and its negative control were transfected into LX-2 cells stimulated by TGF-β1. The result showed that miR-122-5p expression was decreased in TGF-β1-stimulated LX-2 cells. miR-122-5p overexpression reduced the mRNA and protein levels of collagen I and α-smooth muscle actin, inhibited cell proliferation, and accelerated cell apoptosis. miR-122-5p targeted c-Abl. Meanwhile, miR-122-5p overexpression inhibited HSC activation by suppressing the c-Abl/HDAC2 pathway. In summary, miR-122-5p overexpression exerted anti-fibrosis effect and inhibited HSC activation by suppressing the c-Abl/HDAC2 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-18T10:42:11Z
      DOI: 10.1177/09603271221084672
      Issue No: Vol. 41 (2022)
       
  • Oxymatrine attenuates TNBS-induced colinutis in rats through
           TLR9/Myd88/NF-κB signal pathway

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      Authors: Shengwei Li, Guangqing Feng, Min Zhang, Xing Zhang, Jihong Lu, Chenyahui Feng, Fangshi Zhu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Objective: Due to its well-known anti-inflammatory property, oxymatrine (OMT) has received more attention on the aspect of treating ulcerative colitis. Although efforts have been undertaken to understand the therapeutic mechanism of OMT on ulcerative colitis (UC), the remedial principle is still ambiguous. Numerous studies have shown that TLR9/Myd88/NF-κB signal pathway played a key role in the pathogenesis of UC. Moreover, TLR9/Myd88/NF-κB signal pathway is a part of the most important pathways for regulating the immune response.Methods: We explored the influence of OMT with different dosages on UC by establishing a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Moreover, the participation of TLR9/Myd88/NF-κB signal pathway and whether OMT protects against UC though targeting this pathway are further studied.Results: Our data revealed that OMT could significantly relieve the symptom of TNBS-induced colitis in rats by reactivating the tight junction protein and, more important, by inhibiting the activation of TLR9/Myd88/NF-κB pathway and protein expression levels of its downstream inflammatory factors.Conclusion: OMT could relieve colitis in rat models by impacting tight junction proteins’ TLR9/Myd88/NF-κB signal pathways and activity.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-15T04:51:06Z
      DOI: 10.1177/09603271221078866
      Issue No: Vol. 41 (2022)
       
  • Fluorometholone inhibits high glucose-induced cellular senescence in human
           retinal endothelial cells

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      Authors: Xuemei Zhou, Lifeng Wang, Zhongwei Zhang, Jing Liu, Qun Qu, Yuanyuan Zu, Dejing Shi
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Diabetic retinopathy (DR) is a common diabetic complication that severely impacts the life quality of diabetic patients. Recently, cellular senescence in human retinal endothelial cells (HRECs) induced by high glucose has been linked to the pathogenesis of DR. Fluorometholone (FML) is a glucocorticoid drug applied in the treatment of inflammatory and allergic disorders of the eye. The objective of the present study is to investigate the protective function of FML on high glucose-induced cellular senescence in HRECs. The in vitro injury model was established by stimulating HRECs with 30 mm glucose. After evaluating the cytotoxicity of FML in HRECs, 0.05% and 0.1% FML were used as the optimal concentration in the entire experiment. It was found that the excessive released inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) in HRECs induced by high glucose were significantly suppressed by FML, accompanied by the inhibitory effects on the expression levels of vascular endothelial growth factor (VEGF) and tissue factor (TF). Declined telomerase activity and enhanced senescence-associated β-galactosidase (SA-β-gal) activity were found in high glucose-challenged HRECs, which were dramatically alleviated by FML, accompanied by the inactivation of the p53/p21 and retinoblastoma (Rb) signaling. Interestingly, FML ameliorated high glucose-induced dephosphorylation of Akt. Lastly, the protective effects of FML against high glucose-induced cellular senescence in HRECs were abolished by the co-treatment of the PI3K/Akt signaling inhibitor LY294002, suggesting the involvement of this pathway. Taken together, these data revealed that FML-inhibited high glucose-induced cellular senescence mediated by Akt in HERCs, suggesting a novel molecular mechanism of FML.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-10T02:01:10Z
      DOI: 10.1177/09603271221076107
      Issue No: Vol. 41 (2022)
       
  • Hypoxic preconditioning neural stem cell transplantation promotes spinal
           cord injury in rats by affecting transmembrane immunoglobulin
           domain-containing

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      Authors: Xiaoguang Fan, Hongchun Wei, Juan Du, Xiuguo Lu, Leisheng Wang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveTo explore the effects of hypoxic preconditioning neural stem cell (P-NSC) transplantation on rats with spinal cord injury (SCI).MethodsAfter identification, the NSCs were treated with hypoxic preconditioning. The NSCs migration was detected by Transwell method. RT-qPCR was used to detect the mRNA levels of HIF-1α, CXCR4 in NSC. The secretion of representative neurotrophic factors (VEGF, HGF, and BDNF) was checked by Western blot. Forty-six SCI rats were randomly divided into three experimental groups: SCI group (PBS injection, n = 10); N-NSC group (NSC atmospheric normoxic pretreatment injection, n = 18); and P-NSC group (NSC ’s hypoxic preconditioning injection, n = 18). The sham operation group was also included (rats underwent laminectomy but not SCI, n = 10). The recovery of hindlimb motor function was evaluated by BBB score. The level of spinal cord inflammation (IL-1β, TNF-α, and IL-6) was determined by ELISA. Western blot was used to detect the content of TMIGD1 and TMIGD3 in spinal cord.ResultsCompared with the N-NSC group, the number of NSC-passing membranes in the P-NSC group increased with the increase of the culture time (p < 0.05). Compared with N-NSC, P-NSC had higher levels of VEGF, HGF, and BDNF after 1 week of culture (p < 0.05). The BBB score of the P-NSC group was significantly higher than that of the N-NSC group at 7 and 28 days (p < 0.05). Compared with the SCI group, the levels of TNF-α, IL-1β, and IL-6 were significantly reduced after NSC treatment, and the P-NSC group was lower than the N-NSC group (p < 0.05). Compared with the SCI group, the levels of TMIGD1 and TMIGD3 increased. Compared with the N-NSC group, and the levels of TMIGD1 and TMIGD3 increased in the P-NSC group (p < 0.05).ConclusionP-NSC administration could improve SCI injury, and the levels of TMIGD1 and TMIGD3.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-04T10:25:03Z
      DOI: 10.1177/09603271211066587
      Issue No: Vol. 41 (2022)
       
  • Propofol suppresses proliferation, migration, invasion, and tumor growth
           of liver cancer cells via suppressing cancer susceptibility candidate
           9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic
           target of rapamycin kinase axis

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      Authors: Qing Chang, Jun Wu, Yang An, Haiyan Liu, Yang Sun
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Propofol is a commonly used drug for sedation and general anesthesia during cancer surgery. Previous studies indicate that propofol exerts anti-tumor effect in various cancers. The aim of this study was to investigate the underlying molecular mechanism of propofol in liver cancer. The effects of propofol on liver cancer cells were evaluated by cell viability assay, colony formation assay, and tumor xenograft model. Dysregulated lncRNAs of propofol-treated liver cancer cells were evaluated by transcriptome RNA sequencing. The underlying molecular mechanisms of lncRNA cancer susceptibility candidate 9 (CASC9) in propofol-induced anti-tumor effects were evaluated by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), wound scratch healing assay, transwell cell migration and invasion assay, TUNEL staining, fluorescence in situ hybridization, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP). We found that propofol suppressed proliferation, migration, invasion, and tumor xenograft growth of liver cancer cells in a dose-dependent manner. Exosomes transfer from propofol-treated cells inhibited proliferation, migration, and invasion and promoted apoptosis of liver cancer cells. Transcriptional profiling of propofol-treated liver cancer cells identified CASC9 as significantly downregulated lncRNA in cells and exosomes. Enforced CASC9 expression partially rescued the inhibitory effects of propofol on liver cancer cells. Furthermore, CASC9 was found to interact directly with EZH2 and epigenetically regulated PTEN expression. Restoration of CASC9 partially abrogated the inhibition of propofol on Akt/mTOR signaling. Our results indicated that propofol exerted anti-tumor effects by downregulating CASC9, and subsequently suppressed Akt/mTOR signaling. Our findings provided a novel insight into propofol-induced anti-tumor effects in liver cancer.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-03T12:53:49Z
      DOI: 10.1177/09603271211065972
      Issue No: Vol. 41 (2022)
       
  • Effects of lysophosphatidic acid receptor 5 on NLRC4 inflammasome in brain
           tissues of transient cerebral ischemia/reperfusion rat

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      Authors: Xuling Zhang, Tao Huang, Lubo Lang, Ling Yu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      AimTo explore whether LPA5 was involved in the inflammatory responses in CI/R injury by regulation of NLRC4.MethodThe cerebral I/R model in rats was constructed with ischemia of 2h and different time points of reperfusion. After that, western blot was used to determine protein expression (LPA5, NLRC4, AIM2, caspase-1, cleaved-caspase-1, mature IL-1β, and precursor IL-1β). And LPA5 and NLRC4 expression were also detected by using immunofluorescence experiment. Afterward, two sequence of LPA5-siRNA were injected into rats via intracerebroventricular administration. TTC staining and HE staining were performed.ResultAs the reperfusion time was prolonged, LPA5 content was continuously increased, and the highest expression of NLRC4 was found at 4h of reperfusion. And protein expression of AIM2, cleaved-caspase-1, and mature IL-1β was also at highest level at 4h. And after reperfusion of 4h, LPA5 siRNA1# or 2# was injected into lateral ventricles. LPA5 silence markedly reduced the infract volume and improved the histological change of ischemic zone. And LPA5 silence significantly downregulated NLRC4, AIM2, and the ratio of cleaved-caspase-1/caspase-1 and mature IL-1β/precursor IL-1β. And compared with LPA5-siRNA2#, LPA5-siRNA1# exerted a more significant effect.ConclusionLow expression of LPA5 can protect against the inflammatory responses in CI/R model of rats through inhibiting NLRC4 inflammasomes.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-03-01T02:53:13Z
      DOI: 10.1177/09603271221078870
      Issue No: Vol. 41 (2022)
       
  • T-2 toxin induces articular cartilage damage by increasing the expression
           of MMP-13 via the TGF-β receptor pathway

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      Authors: Ying Zhang, Zhengzheng Li, Ying He, Yinan Liu, Ge Mi, Jinghong Chen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      T-2 toxin pre-disposes individuals to osteoarthritis, Kashin–Beck disease (KBD). The major pathological change associated with KBD is the degradation of the articular cartilage matrix. Herein, we investigated the key molecules that regulate T-2 toxin-mediated cartilage degradation. Potential KBD treatments were also investigated. Sprague Dawley rats were divided into the T-2 toxin group and the control group. The T-2 toxin group received 100 ng/g BW/day, whereas the control group received a similar dose of PBS. The expression of matrix metalloproteinase-13 (MMP-13) and TGF-β receptor I/II (TGF-βRI/II) was analyzed using immunohistochemical staining. C28/I2 chondrocytes were exposed to TGF-βRI/II binding inhibitor (GW788388) for 24 h before incubation in different T-2 toxin concentrations (0, 6, 12, and 24 ng/mL for 72 h). The expression of mRNA for TGF-βRI/II, MMP-13 and proteins for MMP-13, and Smad-2 in chondrocytes were analyzed using RT-PCR and western blot, respectively. Safranin O staining revealed that T-2 toxin treatment modulated the expression of articular cartilage matrix. On the other hand, T-2 toxin treatment sharply increased the expression of MMP-13, TGF-βRI, and TGF-βRII in the rat cartilages. Interestingly, blocking the TGF-βRs-smad 2 signaling pathway using GW788388 abrogated the effect of T-2 toxin on upregulating MMP-13 expression. The expression of MMP-13 in chondrocytes induced with T-2 toxin is regulated via the TGF-βRs signaling pathway. As such, inhibiting the expression of TGF-βRs is a potential KBD treatment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-25T10:06:56Z
      DOI: 10.1177/09603271221075555
      Issue No: Vol. 41 (2022)
       
  • Role of the AMPK signalling pathway in the aetiopathogenesis of ocular
           diseases

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      Authors: Dhaval K Shukal, Pooja B Malaviya, Tusha Sharma
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundAMP-activated protein kinase (AMPK) plays a precise role as a master regulator of cellular energy homeostasis. AMPK is activated in response to the signalling cues that exhaust cellular ATP levels such as hypoxia, ischaemia, glucose depletion and heat shock. As a central regulator of both lipid and glucose metabolism, AMPK is considered to be a potential therapeutic target for the treatment of various diseases, including eye disorders.ObjectiveTo review all the shreds of evidence concerning the role of the AMPK signalling pathway in the pathogenesis of ocular diseases.MethodScientific data search and review of available information evaluating the influence of AMPK signalling on ocular diseases.ResultsReview highlights the significance of AMPK signalling in the aetiopathogenesis of ocular diseases, including cataract, glaucoma, diabetic retinopathy, retinoblastoma, age-related macular degeneration, corneal diseases, etc. The review also provides the information on the AMPK-associated pathways with reference to ocular disease, which includes mitochondrial biogenesis, autophagy and regulation of inflammatory response.ConclusionThe study concludes the role of AMPK in ocular diseases. There is growing interest in the therapeutic utilization of the AMPK pathway for ocular disease treatment. Furthermore, inhibition of AMPK signalling might represent more pertinent strategy than AMPK activation for ocular disease treatment. Such information will guide the development of more effective AMPK modulators for ocular diseases.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-24T04:12:40Z
      DOI: 10.1177/09603271211063165
      Issue No: Vol. 41 (2022)
       
  • Gallic acid ameliorates di-(2-ethylhexyl) phthalate-induced testicular
           injury in adult mice

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      Authors: Azam Hosseinzadeh, Saeed Mehrzadi, Amir Siahpoosh, Zahra Basir, Nosrat Bahrami, Mehdi Goudarzi
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background: Di-(2-ethylhexyl) phthalate (DEHP) is a well-known endocrine-disrupting compound inducing degeneration of testes. Gallic acid (GA) is a polyphenol with various pharmacological properties, including antioxidant and anti-inflammatory effects.Purpose: This research evaluated effects of different doses of GA on DEHP-induced testicular injury in adult mice.Research Design: Male mice were randomly divided into five groups and treated with agents for two weeks; group (I) received normal saline and corn oil (5 mL/kg/day, p. o.), group (II) received DEHP (2 g/kg/day, dissolved in corn oil, p. o.), groups (III, IV, and V) received DEHP + GA (25, 50, and 100 mg/kg/day, p. o.). Body and testes weights, serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels were evaluated. The number of sperms and sperm motility and viability were analyzed in the cauda epididymis. Histological changes, oxidative/nitrosative stress markers, and inflammatory cytokines levels were examined in testes.Results: Body and testes weights, the number of spermatogonia, primary spermatocyte and early spermatid, and late spermatid and sperm vitality, and progressive motility were significantly reduced in mice exposed to DEHP. Serum testosterone level decreased and serum LH and FSH levels increased in DEHP-exposed mice. These alterations were associated with the increased oxidative stress level and inflammatory responses in testicular tissue. Treatment with GA (50 and 100 mg/kg/day) attenuated DEHP-induced alterations in oxidative stress markers and inflammatory cytokines and reversed abnormality in sperm characteristic and number, tissue structure, and serum hormones levels.Conclusions: Results indicated that GA might be a promising agent against male gonadal toxicity induced by endocrine disrupting chemicals including DEHP.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-23T06:26:10Z
      DOI: 10.1177/09603271221078867
      Issue No: Vol. 41 (2022)
       
  • Gallic acid protects against isoproterenol-induced cardiotoxicity in rats

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      Authors: Dareuosh Shackebaei, Mahvash Hesari, Soudabeh Ramezani-Aliakbari, Zohreh Hoseinkhani, Fatemeh Ramezani-Aliakbari
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundGallic acid (GA) is a polyphenolic agent with interesting pharmacological impacts on the cardiovascular system.ObjectiveThe present study purposed to study the protective effects of GA at 25 and 50 mg/kg against isoproterenol (ISO)-induced cardiac damage in ischemia/reperfusion (I/R) in rats.MethodsMale Wistar rats were randomly assigned into six groups: Control, Control treated with GA at 25 mg/kg (GA25), Control treated with GA at 50 mg/kg (GA50), Hypertrophic rats induced by ISO (ISO), Hypertrophic rats treated with GA at 25 mg/kg (ISO+GA25), and Hypertrophic rats treated with GA at 50 mg/kg (ISO+GA50). Heart isolation was performed to induce a cardiac I/R injury model. Cardiac hemodynamic parameters were recorded. Serum Lactate Dehydrogenase (LDH) and Creatine Kinase-MB (CK-MB) and cardiac Superoxide dismutases (SOD) levels were evaluated. The gene expression of Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) was assessed.ResultsWe found that GA at 50 mg/kg was significantly increased cardiac function at post I/R period in ISO-induced hypertrophic hearts. Moreover, it suppressed cardiac hypertrophy, the serum LDH and CK-MB levels in ISO injected rats. Administration of GA at 50 mg/kg was significantly increased SOD level and SERCA2a gene expression in the hypertrophic hearts.ConclusionGA at 50 mg/kg could improve cardiac performance possibly by increasing antioxidant defense enzymes, reducing cell damage, and enhancing SERCA2a gene expression in hypertrophic heart induced by ISO in I/R injury conditions.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-23T05:41:22Z
      DOI: 10.1177/09603271211064532
      Issue No: Vol. 41 (2022)
       
  • Shenfu Administration Improves Cardiac Fibrosis in Rats With Myocardial
           Ischemia-Reperfusion Through Adenosine A2a Receptor Activation

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      Authors: Fangming Guo, Xiaohuan Wang, Yuanying Guo, Weiping Wan, Yanfang Cui, Jie Wang, Wenbo Liu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveShenfu injection (SFI) is commonly used for cardiac dysfunction in China. Adenosine receptors have been reported to exert anti-fibrosis effects. The intent of this study was to evaluate that SFI attenuates cardiac fibrosis through activating of adenosine A2a receptor (A2aR) in rats with myocardial ischemia-reperfusion (MI/R).MethodsSprague Dawley male rats were randomly divided into five groups, nine rats in each group. Injections in all rat groups were carried out prior to reperfusion, and in the sham and MI/R groups, only vehicle was injected. Injections in the remaining group were as follows: 5 mL/kg in the SFI group; 15 mg/kg nicorandil in the A2R agonist group; and 5 mL/kg SFI plus 5 mg/kg MSX-3 in the SFI + A2aR antagonist group. Changes in cyclic adenosine monophosphate (cAMP) and the development of myocardial infarction and cardiac fibrosis were documented among the groups. Additionally, the levels of A2aR, collagen Ⅰ, collagen Ⅲ, fibronectin, and matrix metalloproteinase-9 (MMP-9) were measured.ResultsFollowing injection with SFI or nicorandil, the cAMP concentration, infarct area, and cardiac fibrosis induced by MI/R injury were significantly decreased (p < 0.05). Additionally, the levels of collagen Ⅰ, collagen Ⅲ, fibronectin, and MMP-9 were clearly suppressed by SFI or nicorandil when compared with the MI/R group (p
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-23T05:23:52Z
      DOI: 10.1177/09603271221077684
      Issue No: Vol. 41 (2022)
       
  • Arsenic trioxide-induced cardiotoxicity triggers ferroptosis in
           cardiomyoblast cells

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      Authors: Linya Wang, Shuguang Liu, Chao Gao, Hui Chen, Jing Li, Jiran Lu, Yuan Yuan, Xueling Zheng, Hongbo He, Xixi Zhang, Ruidong Zhang, Yuanyuan Zhang, Ying Wu, Wei Lin, Huyong Zheng
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Arsenic trioxide (ATO) has been found to be effective in acute promyelocytic leukemia. However, ATO-induced severe cardiotoxicity limits its clinical application. To date, the mechanisms of ATO-induced cardiotoxicity remain unclear. It is hypothesized that ferroptosis may trigger ATO-induced cardiotoxicity; however, this has not yet been investigated. To clarify this hypothesis, rat cardiomyocyte H9c2 cells were treated with ATO with or without ferrostain-1 (Fer-1). The results indicated that ATO exposure induced H9c2 cell death and apoptosis, and the ferroptosis inhibitor Fer-1, administered for 24 h before ATO exposure, suppressed ATO-induced cell death, and apoptosis, as determined by Annexin V-APC/7-AAD apoptosis assay. Furthermore, Fer-1 displayed a cardioprotective effect through inhibiting the ATO-induced production of intracellular reactive oxygen species, improving the ATO-induced loss of the mitochondrial membrane potential, alleviating hyperactive endoplasmic reticulum stress, and alleviating the ATO-induced impairment in autophagy in H9c2 cells. Overall, the cardioprotective effect of Fer-1 against ATO-induced cell injury implies that ATO may trigger ferroptosis to induce cardiotoxicity. These findings lay the foundation for exploring the potential value of ferroptosis inhibitors against ATO-induced cardiotoxicity in the future.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-23T04:35:37Z
      DOI: 10.1177/09603271211064537
      Issue No: Vol. 41 (2022)
       
  • Protective effects of alpha-lipoic acid on bleomycin-induced skin fibrosis
           through the repression of NADPH Oxidase 4 and TGF-β1/Smad3 signaling
           pathways

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      Authors: Ayse Kocak, Cemre Ural, Duygu Harmanci, Mehmet Asi Oktan, Aysan Afagh, Sulen Sarioglu, Osman Yilmaz, Merih Birlik, Gul Guner Akdogan, Zahide Cavdar
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The aim of this study was to determine the protective effects of alpha-lipoic acid (ALA), which is known as a powerful antioxidant, and the possible related molecular mechanisms that mediate its favorable action on skin fibrosis in the bleomycin (BLM)-induced scleroderma (SSc) model in mice. The experimental design was established with four groups of eight mice: Control, ALA (100 mg/kg), BLM (5 μg/kg), and BLM + ALA group. BLM was administered via subcutaneous (sc) once a day while ALA was injected intraperitoneally (ip) twice a week for 21 days. Histopathological and biochemical analyses showed that ALA significantly reduced BLM-induced dermal thickness, inflammation score, and mRNA expression of tumor necrosis factor-alpha (TNF-α) in the skin. Besides, the mRNA expressions of the subunits of NADPH oxidase, which are Nox4 and p22phox, were found to be significantly induced in the BLM group. However, ALA significantly reduced their mRNA expression, which were in parallel to its decreasing effect on serum total oxidant status (TOS) level. Moreover, it was found that ALA downregulated the mRNA expressions of alpha-smooth muscle actin (α-SMA), collagen type I and fibronectin in the skin tissue of the BLM group. Additionally, it was shown that ALA reduced significantly the TGF-β1 and p-Smad3 protein expressions in the BLM + ALA group. On the other hand, ALA did not exhibit any significant effect on the p38 mitogen-activated kinase (MAPK) activation induced by BLM. All these findings point out that ALA may be a promising treatment for the attenuation of skin fibrosis in SSc patients.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-21T12:09:45Z
      DOI: 10.1177/09603271211065975
      Issue No: Vol. 41 (2022)
       
  • Inhibition of SET domain–containing (lysine methyltransferase) 7
           alleviates cognitive impairment through suppressing the activation of
           NOD-like receptor protein 3 inflammasome in isoflurane-induced aged mice

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      Authors: Chao Ma, Xianjun Yu, Dong Li, Youwen Fan, Yajun Tang, Qiang Tao, Lei Zheng
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundAs a common postoperative complication to elderly patients, postoperative cognitive dysfunction (POCD) is a central nervous system complication, often taking place after anesthesia and surgery. (Su(var)3-9, enhancer-of-zeste, and trithorax) domain–containing protein 7 (SETD7) plays important roles in metabolic-related diseases, viral infections, tumor formation, and some inflammatory reactions. However, the role and mechanism of SETD7 in POCD have not been previously studied.MethodsRT-PCR and Western blot were performed to evaluate the efficiency of knockdown of SETD7. The pathological changes of hippocampal neurons in isoflurane-anesthetized mice were detected by HE staining, and the Morris water maze experiment was performed to evaluate the learning and memory abilities of mice. The effect of SETD7 on the hippocampus in isoflurane-induced aged mice was examined by Western blot and TUNEL assay. Then ELISA assay was applied to determine the expression of some inflammatory cytokines, followed by the detection of expression of NOD-like receptor protein 3 (NLRP3) inflammasome through Western blot.ResultsThe data of this research revealed that SETD7 knockdown improved cognitive impairment in isoflurane-anesthetized mice, ameliorated cell pyroptosis, inhibited the release of inflammatory cytokines, and suppressed the activation of NLRP3 inflammasome in the hippocampus in isoflurane-induced aged mice.ConclusionCollectively, these results provided evidence that the inhibition of SETD7 could alleviate neuroinflammation, pyroptosis, and cognitive impairment by suppressing the activation of the NLRP3 inflammasome in isoflurane-induced aged mice.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-21T12:00:05Z
      DOI: 10.1177/09603271211061497
      Issue No: Vol. 41 (2022)
       
  • The effects of ellagic acid and other pomegranate (Punica granatum L.)
           derivatives on human gastric cancer AGS cells

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      Authors: Hamid Cheshomi, Ahmad Reza Bahrami, Houshang Rafatpanah, Maryam M Matin
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Although surgery with or without (neo)adjuvant chemo/radiotherapy, as the standard treatments, can be suitable therapeutic strategies for gastric cancer, side effects and drug resistance are two main treatment obstacles. It has been discovered that pomegranate and its natural derivatives, especially ellagic acid (EA), offer significant anti-cancer effects while causing trivial side effects. In this study, we aimed to explore the anti-cancer effects of EA on a human gastric adenocarcinoma cell line (AGS) as well as in immunocompromised mice bearing human gastric tumors, for the first time. HPLC was used for determining EA in samples. MTT assay, apoptosis and scratch assay, gelatin zymography, and quantitative RT-PCR were used to determine the anti-cancer properties of different concentrations of pomegranate fruit juice, pomegranate peel extract, and EA. Furthermore, the effects of these compounds were investigated on immunosuppressed C57BL/6 mice carrying human gastric cancer tumors. EA could inhibit the proliferation and migration of gastric cancer cells. It also had significant effects on reducing both expression and activity of MMP-2 and MMP-9. Further, it was demonstrated that with alterations in the expression of genes involved in apoptosis and inflammation including P53, BAX, APAF1, BCL2, iNOS, NF-κB, IL-8, and TNF-α, EA treatment led to increased cancer cell death and reduced inflammation. Furthermore, its use in mice bearing gastric tumors resulted in a significant reduction in tumor volume without any obvious side effects. Ellagic acid exhibited anti-cancer effects on gastric adenocarcinoma, and can be considered as a safe anti-cancer agent for further preclinical studies on this cancer.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-18T03:02:22Z
      DOI: 10.1177/09603271211064534
      Issue No: Vol. 41 (2022)
       
  • The influence of PM2.5 exposure on kidney diseases

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      Authors: Wenqi Xu, Shaopeng Wang, Liping Jiang, Xiance Sun, Ningning Wang, Xiaofang Liu, Xiaofeng Yao, Tianming Qiu, Cong Zhang, Jing Li, Haoyuan Deng, Guang Yang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The harm of air pollution to public health has become a research hotspot, especially atmospheric fine-particulate matter (PM2.5). In recent years, epidemiological investigations have confirmed that PM2.5 is closely related to chronic kidney disease and membranous nephropathy Basic research has demonstrated that PM2.5 has an impact on the normal function of the kidneys through accumulation in the kidney, endothelial dysfunction, abnormal renin-angiotensin system, and immune complex deposition. Moreover, the mechanism of PM2.5 damage to the kidney involves inflammation, oxidative stress, apoptosis, DNA damage, and autophagy. In this review, we summarized the latest developments in the effects of PM2.5 on kidney disease in human and animal studies, so as to provide new ideas for the prevention and treatment of kidney disease.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-17T12:30:55Z
      DOI: 10.1177/09603271211069982
      Issue No: Vol. 41 (2022)
       
  • Myricetin (3,3′,4′,5,5′,7-hexahydroxyflavone) prevents
           ethanol-induced biochemical and inflammatory damage in the liver of Wistar
           rats

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      Authors: Sheikh Bilal Ahmad, Shahzada Mudaisr Rashid, Adil Farooq Wali, Shafat Ali, Muneeb U Rehman, Mir Tahir Maqbool, Ahmed Nadeem, Sheikh Fayaz Ahmad, Nahid Siddiqui
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Purpose: The current investigation was carried out to evaluate the efficacy of myricetin in ethanol-induced liver toxicity in Wistar rats. Research Design: Twenty-four rats were randomly divided into four groups with six animals per group. Group-I animals were administered with vehicle (distilled water), Group II, III, and IV were treated orally with sequential (per week) increase in the dose of ethanol (5, 8, 10, and 12 g/kg b wt per week in each group) for 28 days. Myricetin was treated orally to Group-III and IV animals at the respective doses of 25 mg/kg b wt. and 50 mg/kg b wt. Results: Our results showed that myricetin prevented hepatotoxicity by modulating the production of free radicals, ethanol metabolizing enzymes, and inflammatory markers in vivo. Myricetin also helped maintain lipid membrane integrity, oxidant-antioxidant status, and histoarchitecture. Ethanol administration caused elevation in XO, ADH, and CYP2E1 in hepatic tissue, which significantly normalized with myricetin administration. After ethanol administration, there was a steep increase in the hepatotoxicity biomarkers, including ALT, MDA, and AST. The level of cytotoxicity marker LDH also increased after ethanol administration; myricetin administration decreased the level of all these markers. Moreover, myricetin treatment also reduced ethanol-induced inflammatory markers such as NF-κB and IL-6. Conclusion: Findings from the current study demonstrate that myricetin administration prevents alcohol-induced hepatic injury by influencing the metabolism of ethanol, inhibiting oxidative stress, maintaining lipid profile, and suppressing inflammatory markers.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-14T03:05:51Z
      DOI: 10.1177/09603271211066843
      Issue No: Vol. 41 (2022)
       
  • Antenatal dexamethasone retarded fetal long bones growth and development
           by down-regulating of insulin-like growth factor 1 signaling in fetal rats
           

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      Authors: Junlan Qiu, Xiaorong Fan, Hongmei Ding, Meng Zhao, Ting Xu, Jiahui Lei, Bingyu Ji, Zhixiang Zhuang, Qinqin Gao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveDexamethasone (DEX), a synthetic glucocorticoid, has been widely used as a medication for premature delivery. However, the side effects of antenatal DEX treatment on fetal bone development, as well as the underlying mechanisms still remain to be elucidated. Here, we aimed to explore the effects and the related mechanisms of antenatal DEX exposure during late pregnancy on fetal bone growth and development.MethodsPregnant Sprague–Dawley rats were randomly divided into DEX group and vehicle group from gestational day 14 (GD14). Pregnant rats in DEX group were intraperitoneally injected once with DEX (200 µg/kg body weight) on GD14, 16, 18, and 20. The vehicle group rats were administered the same amount of normal saline at the same time. Pregnant rats were anesthetized at GD21 to harvest fetal femurs for analysis.ResultsAntenatal DEX treatment delayed fetal skeletal growth via inhibiting extracellular matrix (ECM) synthesis and downregulating insulin-like growth factor 1 (IGF1) signaling. Several components of IGF1 signaling pathway, including IGF1 receptor, insulin receptor substrate, as well as serine–threonine protein kinase, were down-regulated in fetal growth plate chondrocytes following DEX treatment.ConclusionThis study indicated that antenatal DEX treatment-retarded fetal skeletal growth was associated with the down-regulation of IGF1 signaling in growth plate chondrocytes, providing important information about the impact of antenatal DEX application four courses on premature infant.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-12T02:53:00Z
      DOI: 10.1177/09603271211072870
      Issue No: Vol. 41 (2022)
       
  • Protective effects of necrostatin-1 on doxorubicin-induced cardiotoxicity
           in rat heart

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      Authors: Zeynep Erdogmus Ozgen, Meral Erdinc, İlker Kelle, Levent Erdinc, Yusuf Nergiz
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background: Doxorubicin (Dox) is one of the most effective antineoplastic drugs which has severe cardiotoxic effects, limiting its clinical usage. Though the exact mechanism of doxorubicin-induced cardiotoxicity is yet to be elucidated, it is shown that production of reactive oxygen species (ROS) increases oxidative stress and leads to cardiomyocyte apoptosis and necroptosis which is also defined as a programmed cell death.Purpose: In the present study, we investigate the effects of necrostatin-1 (Nec-1)—an inhibitor of receptor interaction proteins 1 (RIP1) and necroptosis—on doxorubicin-induced cardiotoxicity in rats.Research Design: Hearts were isolated and perfused by the Langendorff system in all four groups. Perfusion pressure (PP), left ventricular developed pressure (LVDP) and heart rate per minute (HR), LV (dP/dt) max, and LV (dP/dt) min which shows cardiac contractility and relaxation were recorded.Results: Results showed that PP significantly increased with Dox treatment and significantly decreased with Nec-1 treatment, while HR, LVDP, LV (dP/dt) max, and LV (dP/dt) min values significantly decreased with the Dox-treated group and significantly increased with Nec-1 treatment. Also with Nec-1 treatment, gene expression levels of anti-apoptotic Bcl-2 significantly increased and pro-apoptotic protein Bax, apoptotic marker caspase-3, and Nox-2 significantly decreased compared to the Dox-treated group. In heart tissues, MDA levels were significantly increased with Dox and decreased with Nec-1 treatment. These results were supported by the histological analysis indicated that Nec-1 reduced doxorubicin-induced cellular injury.Conclusions: In conclusion, our data indicate that Nec-1 ameliorates doxorubicin-induced cardiotoxicity by reducing oxidative stress injury and attenuating apoptosis and necroptosis.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-09T12:19:34Z
      DOI: 10.1177/09603271211066066
      Issue No: Vol. 41 (2022)
       
  • Lipid emulsions attenuate the inhibition of carnitine acylcarnitine
           translocase induced by toxic doses of local anesthetics in rat
           cardiomyoblasts

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      Authors: Seong-Ho Ok, Dawon Kang, Soo Hee Lee, Hyun-Jin Kim, Seung Hyun Ahn, Ju-Tae Sohn
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The aim of this study was to examine the effects of lipid emulsions on carnitine palmitoyltransferase I (CPT-I), carnitine acylcarnitine translocase (CACT), carnitine palmitoyltransferase II (CPT-II), and the mitochondrial dysfunctions induced by toxic doses of local anesthetics in H9c2 rat cardiomyoblasts. The effects of local anesthetics and lipid emulsions on the activities of CPT-I, CACT, and CPT-II, and concentrations of local anesthetics were examined. The effects of lipid emulsions, N-acetyl-L-cysteine (NAC), and mitotempo on the bupivacaine-induced changes in cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), and intracellular calcium levels were examined. CACT, without significantly altering CPT-I and CPT-II, was inhibited by toxic concentration of local anesthetics. The levobupivacaine- and bupivacaine-induced inhibition of CACT was attenuated by all concentrations of lipid emulsion, whereas the ropivacaine-induced inhibition of CACT was attenuated by medium and high concentrations of lipid emulsion. The concentration of levobupivacaine was slightly attenuated by lipid emulsion. The bupivacaine-induced increase of ROS and calcium and the bupivacaine-induced decrease of MMP were attenuated by ROS scavengers NAC and mitotempo, and the lipid emulsion. Collectively, these results suggested that the lipid emulsion attenuated the levobupivacaine-induced inhibition of CACT, probably through the lipid emulsion-mediated sequestration of levobupivacaine.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-09T07:59:55Z
      DOI: 10.1177/09603271211065978
      Issue No: Vol. 41 (2022)
       
  • Induced pathophysiological alterations by the venoms of the most dangerous
           Moroccan scorpions Androctonus mauretanicus and Buthus occitanus: A
           comparative pathophysiological and toxic-symptoms study

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      Authors: Bouchra Darkaoui, Ayoub Lafnoune, Fatima Chgoury, Khadija Daoudi, Salma Chakir, Khadija Mounaji, Mehdi Karkouri, Rachida Cadi, Oukkache Naoual
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Scorpion envenomation is a serious public health issue. Androctonus mauretanicus (Am) and Buthus occitanus (Bo) are the most dangerous scorpions in Morocco. Despite their medical relevance, no study has yet related their kinetics of symptom apparition and the consequent tissue disorders at the same interval post-injection. This work achieved the first comparative pathophysiological and toxic-symptoms study between the Am and Bo venoms from a biochemical, toxicological and physiopathological standpoint. The activity of venoms and their subletal dose were determined by administration of increasing concentrations of the venoms. 30, 60 and 120 min following the experimental envenomation in mice, the profile of clinical symptoms was underlined and the main organs: brain, heart, lungs, liver and kidneys were removed for histological examination. The Am venom is a rich source of proteins and three-times more toxic than the Bo. The most observed clinical symptoms are neurological and cardiopulmonary. The Am venom caused histopathological alterations at 30, 60, and 120 min which were more important than the Bo. This study highlighted that both venoms exhibited a strong toxicity with variable intensities. Moreover, we showed the presence of correlation between the level of histopathological disorders observed and the intensity of signs appeared at the same time following venom inoculation.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-08T07:40:59Z
      DOI: 10.1177/09603271211072872
      Issue No: Vol. 41 (2022)
       
  • The involvement of long noncoding RNA APOA1-AS in the pathogenesis of
           preeclampsia

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      Authors: Hai-Yan Yang, Ling Jiang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveLong noncoding RNAs (lncRNAs) are involved in preeclampsia (PE), and apolipoprotein A-1 antisense RNA (APOA1-AS) and has been found to be associated with a number of diseases. Our study aims to understand the involvement of APOA1-AS in PE.MethodsClinically, APOA1-AS expression in early-onset severe PE (EOSPE) patients and healthy controls was detected by real-time quantitative polymerase chain reaction. In vitro experiments were divided into control [coculturing trophoblasts with human uterine microvascular endothelial cells (UtMVECs)], TNF-α [coculturing trophoblasts with UtMVECs treated with tumor necrosis factor-α (TNF-α)], and TNF-α + control siRNA/APOA1-AS siRNA groups (UtMVECs transfected with control siRNA/APOA1-AS siRNA were cocultured with trophoblasts in the presence of TNF-α). The animals were divided into normal group, PE group (PE model was established by administrating nitro-L-arginine methyl ester (L-NAME) in rats), PE + control siRNA group (PE rats were treated with control siRNA), and PE + APOA1-AS siRNA group (PE rats were treated with APOA1-AS siRNA).ResultsIncreased APOA1-AS was found in the placental tissues of EOSPE patients. APOA1-AS siRNA abolished the decreased integration of trophoblasts into UtMVEC networks induced by TNF-α. Furthermore, APOA1-AS siRNA improved pregnancy outcomes in PE rats with increased expression of vascular endothelial growth factor, placental growth factor, and fms-like tyrosine kinase receptor (Flt-1) but decreased expression of E-cadherin, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).ConclusionDownregulation of APOA1-AS protected against TNF-α-induced inhibition of trophoblast integration into endothelial networks, thus exerting protective effects against PE rats.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-08T04:54:34Z
      DOI: 10.1177/09603271211066586
      Issue No: Vol. 41 (2022)
       
  • Effects of butein on human osteosarcoma cell proliferation, apoptosis, and
           autophagy through oxidative stress

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      Authors: Pei Zhang, Jiale Zhang, Huahong Quan, Pengtao Chen, Jingcheng Wang, Yuan Liang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      PurposeOsteosarcoma (OS) is a primary malignant bone tumor, and the cure rate has stagnated in the past three decades. Butein, a plant polyphenol extracted from many herbs, has been proved to possess anti-tumor activity. However, the effect of butein on human OS and the underlying mechanisms remain to be elucidated.Materials and MethodsThe OS cell line 143B was used. The effects of butein were evaluated through the cell proliferation assay, flow cytometry, florescence and transmission electron microscopy, and western blotting. All statistical analyses were performed using GraphPad Prism 7.0.ResultsButein was found to inhibit cell proliferation by causing G2/ M phase arrest in the 143B cells. In addition, butein suppressed the invasion of 143B cells upon IL‐6 treatment. Additionally, we found that butein inhibited the invasion of 143B cells stimulated with IL-6 via the p-STAT3-MMP9 signaling pathway. Remarkably, butein triggered extrinsic and intrinsic apoptosis and autophagy of 143B cells. The process of autophagy may have tumor-supporting effects. Furthermore, butein induced oxidative stress as evidenced by ROS generation, increase in malondialdehyde (MDA) level, and decrease in GSH/GSSH ratio and GPX4 expression. N-acetylcysteine can reverse the change of ROS. Further experiments indicated apoptosis and autophagy could be attenuated by the N-acetyl-L-cysteine and c-Jun N-terminal kinase (JNK) inhibitor SP600125. Additionally, butein inhibited the Akt/mammalian target of rapamycin (mTOR) signaling pathway, and suppressed the Akt kinase activity increased apoptosis and autophagy.ConclusionOur results revealed butein induced apoptosis and autophagy by regulating oxidative stress, activating the JNK signaling pathway and blocking the Akt/mTOR signaling pathway in OS cells. Additionally, butein inhibited the invasion of 143B cells stimulated with IL-6 through the pSTAT3- MMP9 signaling pathway. In view of these results, butein may be a potential anti-tumor drug targeting osteosarcoma.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-08T04:18:29Z
      DOI: 10.1177/09603271221074346
      Issue No: Vol. 41 (2022)
       
  • A comprehensive gene expression profile of allergic rhinitis-derived nasal
           fibroblasts and the potential mechanism for its phenotype

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      Authors: Zhengwen Li, Wentao Zou, Jingwen Sun, Shuang Zhou, Yue Zhou, Xiaojing Cai, Jiaxiong Zhang
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundAllergic rhinitis (AR) is a common immunoglobulin E-mediated immune response involved various cell types, while the role of nasal fibroblasts (NFs) in the pathogenesis of AR is less understood.PurposeThe study aimed to uncover the gene expression profile of AR-derived NFs and the potential mechanism for the changed phenotype of AR-NFs.Research DesignThe primary NFs were isolated from 3 AR patients (AR-NFs) and 3 controls (Ctrl-NFs), and the proliferation, migration and interleukins production abilities of NFs were detected respectively. RNA-sequence was used to identify differentially expressed genes (DEGs) in AR-NFs. Transcription factor (TF) regulatory network and bioinformatic analyses were both conducted to clarify the biological roles of DEGs including the TFs. The DEG with the highest validated fold change (FC) value, detected by qPCR, was selected for further confirmation.ResultsAR-NFs showed a higher proliferation and migration abilities as well as released higher levels of IL-33 and IL-6, compared to Ctrl-NFs. A total of 729 DEGs were screened out in AR-NFs. TF regulatory network indicated that BARX homeobox 1 (BARX1) and forkhead box L1 were the major node TFs. Bioinformatic analyses showed that a large number of DEGs including several target genes of BARX1 were both enriched cytokine-related GO terms, and immune- or inflammation-related pathways. BARX1 had the highest FC value, and silencing BARX1 in AR-NFs resulted in the significant downregulation of proliferation and migration abilities, and the production of interleukins.ConclusionsOur study for the first time provided the gene expression profile of AR-derived NFs, and BARX1 could be developed as a potent target to alleviate the pathogenesis of AR.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-08T03:30:41Z
      DOI: 10.1177/09603271211069038
      Issue No: Vol. 41 (2022)
       
  • Protective effect of rosuvastatin pretreatment against acute myocardial
           injury by regulating Nrf2, Bcl-2/Bax, iNOS, and TNF-α expressions
           affecting oxidative/nitrosative stress and inflammation

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      Authors: Faheem Sultan, Rajdeep Kaur, Najeeb U Tarfain, Arshad H Mir, Vinod K Dumka, Suresh K Sharma, Simrat P Singh Saini
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Cardiovascular disorders are the leading cause of death globally. Rosuvastatin is a member of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) with many pleiotropic properties. This study investigated cardioprotective effects of rosuvastatin in isoprenaline-induced myocardial injury. Male rats were given rosuvastatin (1, 5, or 10 mg/kg, oral) daily for 1 week and on seventh and eighth day isoprenaline (150 mg/kg, subcutaneous) was given to induce cardiac injury. On ninth day, rats were euthanized and different samples were harvested for analysis. Isoprenaline administration resulted in increased cardiac mass, increased cardiac injury marker levels (cTnI, CK-MB, ALT, and AST), increased lipid/protein oxidation, and increased cardiac nitrite levels. It also decreased superoxide dismutase, CAT, GST, and glutathione reductase activities, and total antioxidant activity. Isoprenaline also increased TNF-α and IL-6 levels. Decreased mRNA expression of Nrf2 and Bcl-2 along with increased mRNA expression of Bax, eNOS and iNOS genes was observed in isoprenaline treated animals. Histopathological evaluations of rosuvastatin pre-treated groups showed reduction of myocardial necrosis. Pretreatment with rosuvastatin (5 and 10 mg/kg) reduced many of these pathological changes. The current study showed that rosuvastatin significantly reduces myocardial injury induced by isoprenaline.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-08T01:50:09Z
      DOI: 10.1177/09603271211066065
      Issue No: Vol. 41 (2022)
       
  • Silymarin protects the rats against paraquat-induced acute kidney injury
           via Nrf2

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      Authors: C Jia, Z Zhang, J Wang, Z Nie
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundParaquat (PQ) poisoning induces severe acute kidney injury and causes extremely high rate of death. In this study, we aimed to investigate the protective effects of silymarin on PQ-induced acute kidney injury and explore the underlying mechanisms.MethodsA rat model was established through intraperitoneal injection of PQ. Rats were administrated with saline or silymarin for 3 days. Then, survival rate, physiological parameters, and renal injury score were evaluated. The apoptosis and oxidative stress in kidney tissues were determined through hematoxylin and eosin staining, quantitative reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assays.ResultsSilymarin administration could significantly increase the survival rate of PQ-poisoned rats. It was found that silymarin treatment improved renal function, decreased injury score in kidney tissues, and inhibited the apoptosis and oxidative stress in PQ-induced acute kidney injury through the activating the signaling pathway of Nrf2 and promoting its nuclear translocation.ConclusionSilymarin exhibited a protective effect against PQ-induced kidney injury, suggesting that treatment with this flavonoid could be a potential therapeutic agent for the treatment of acute kidney injury.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-07T12:53:12Z
      DOI: 10.1177/09603271221074334
      Issue No: Vol. 41 (2022)
       
  • Taraxasterol attenuates melanoma progression via inactivation of reactive
           oxygen species-mediated PI3K/Akt signaling pathway

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      Authors: Wenfang Liu, Qianying Yu, Fei Wang, Yunxia Li, Guohua Zhang, Sirui Tao
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background: Taraxasterol (TX), a pentacyclic triterpene, is one of the main active constituents isolated from Taraxacum officinale. A growing number of studies have reported that TX exhibits a wide range of biological activities such as anti-oxidative, anti-inflammatory, and neuro-protective effects. Recently, TX has been demonstrated to be a potential drug candidate for treatment of some types of cancers. However, the specific role of TX in melanoma remains unclear.Purpose: In this study, we aimed at exploration of the effect of TX on melanoma cell viability, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) as well as the underlying mechanisms.Research design: A375 and SK-MEL-28 cells were treated with various concentrations of TX for different times. Cell viability was measured using CCK-8 assay. Cell apoptosis was determined by flow cytometry. Transwell assays were performed to measure cell migration and invasion. The expression of E-cadherin, α-catenin, N-cadherin, vimentin, p-PI3K, PI3K, p-Akt and Akt was detected using western blot.Results: The study showed that TX induced A375 and SK-MEL-28 cell apoptosis. Furthermore, exposure to TX inhibited A375 and SK-MEL-28 cell migration and invasion. Besides, the EMT process was reversed in A375 and SK-MEL-28 cells after TX treatment. We also observed that TX reduced the protein expression of p-PI3K and p-Akt; thus, inhibiting activity of the PI3K/Akt pathway in A375 and SK-MEL-28 cells. In addition, TX treatment increased the levels of reactive oxygen species (ROS) in A375 and SK-MEL-28 cells, and treatment with the ROS scavenger NAC significantly rescued TX-induced down-regulation of p-PI3K and p-Akt in A375 and SK-MEL-28 cells.Conclusions: In conclusion, our study demonstrated that TX induced ROS accumulation followed by inactivation of the PI3K/Akt pathway and subsequently attenuated melanoma progression, suggesting that TX may be a potential candidate for treatment of melanoma.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-07T11:05:59Z
      DOI: 10.1177/09603271211069034
      Issue No: Vol. 41 (2022)
       
  • Piperlongumine inhibits diethylnitrosamine induced hepatocellular
           carcinoma in rats

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      Authors: Ashish Kumar, Manisha Naithani, Nitesh Kumar, Neha Singh, Shruti Agrawal, Ambika Sharma, Surabhi Thapliyal, Jagjit Singh, Shailendra Handu
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Piperlongumine (PL) has been claimed to have cytotoxic and HCC inhibitory effects in various cancer cell lines and xenograft models, but the chemopreventive potential of PL has not been studied in experimentally induced HCC yet.Research Design:Twenty-four Wistar male rats were divided into four groups of six each, Group A: untreated control; Group B: Diethylnitrosamine (DEN) control (200 mg/kg), Group C: DEN + PL 10 mg/kg; and Group D: DEN + PL 20 mg/kg. Rats from all groups were assessed for liver cancer progression or inhibition by evaluating biochemical, cytokines, tumor markers, lipid peroxidation, and histological profiles. Results:The liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) levels, and lipid peroxidation were significantly decreased in Group C and Group D compared to Group B. Upregulation in the level of pro-inflammatory cytokines IL-1B, TNF-α, inflammatory mediator (NF-κB) and tumour marker alpha-fetoprotein (AFP) in Group B were brought down upon treatment with piperlongumine in a dose-dependent manner. Antitumor cytokine (IL-12) was upregulated in PL-treated rats compared to DEN control rats. DEN treated group (Group B) showed histological features of HCC, and in rats treated with PL (Groups C, D) partial to complete reversal to normal liver histoarchitecture was observed.Conclusions:The potential chemopreventive actions of piperlongumine may be due to its free radical scavenging and antiproliferative effect. Therefore, piperlongumine may serve as a novel therapeutic agent for the treatment of hepatocellular carcinoma.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-03T05:57:26Z
      DOI: 10.1177/09603271211073593
      Issue No: Vol. 41 (2022)
       
  • Preliminary safety assessment of CIGB-210, an investigational peptide for
           HIV infection

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      Authors: Anna C Ramírez-Suárez, Taimi Paneque-Guerrero, Dionne Casillas-Casanova, Karelia Cosme, Dania Bacardí, Carlos A Duarte, Julio Ancízar, Emma Brown, Jorge Castro, José Suárez-Alba, Hilda Garay, Karla Pereira, Celia Fernández-Ortega
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Current human immunodeficiency virus treatments need to be periodically administered lifelong. In this study we assess the effect of repeated doses of an anti-HIV peptide drug candidate in C57BL6 strain. Two schemes of up to 15 administrations and one of 30, daily dosing for 5 days per week, all by the subcutaneous route were evaluated. Different dose concentrations of the peptide were assayed. CIGB-210 treated animals showed no symptoms or abnormal behavior as compared with placebo. All the animals gained weight during the study. Macroscopic evaluation showed no alterations in any of the organs studied. Microscopic analysis of the tissues did not show morphological changes in thymus, stomach, small and large intestines, kidney, brain, or cerebellum. The proliferative response of splenocytes and their capacity to secrete gamma interferon were not compromised by the repeated administration of CIGB-210. There were not statistically significant differences for any of the parameters evaluated during the study among treated and non-treated groups. We can conclude that CIGB-210 is well tolerated in C57BL6 mice in the dose concentration range explored and merits subsequent toxicological studies.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-03T03:38:05Z
      DOI: 10.1177/09603271211073708
      Issue No: Vol. 41 (2022)
       
  • AgNPs reduce reproductive capability of female mouse for their toxic
           effects on mouse early embryo development

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      Authors: Di Zhang, Fangfang Yu, Huanhuan Li, Qiuyue Wang, Meiya Wang, Hongli Qian, Xiaoqing Wu, Fengrui Wu, Yong Liu, Shuanglin Jiang, Pu Li, Rong Wang, Wenyong Li
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Silver nanoparticles (AgNPs) are widely applied in the field of personal protection for their powerful toxic effects on cells, and recently, a new type of vaginal gel with AgNPs is used to protect the female reproductive tract from microbes and viruses. However, a high risk of AgNPs to the fetus and the underlying mechanism of AgNPs to interfere in embryo development still remain unclear. Thus, this study investigated the impact of two drugs of vaginal gel with AgNPs on reproductive capability of the female mouse by animal experiment. Then, kinetics of AgNPs affecting embryo development was investigated by in vitro embryos culturing, and cell membrane potential (CMP) of zygotes was analyzed by DiBAC4(3) staining. Results indicated that one of the drugs of vaginal gel certainly injured embryo development in spite of no apparent histological change found in ovaries and uteruses of drug-treated mice. In vitro embryo culturing discovered that the toxic effect of AgNPs on embryo development presented particle sizes and dose dependent, and AgNP treatment could rapidly trigger depolarization of the cell membrane of zygotes. Moreover, AgNPs changed the gene expression pattern of Oct-4 and Cdx2 in blastocysts. All these findings suggest that AgNPs can interfere with normal cellular status including cell membrane potential, which has not been noticed in previous studies on the impact of AgNPs on mammalian embryos. Thus, findings of this study alarm us the risk of applying vaginal gel with AgNPs in individual caring and protection of the female reproductive system.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-02-01T10:47:24Z
      DOI: 10.1177/09603271221080235
      Issue No: Vol. 41 (2022)
       
  • Effects of real-ambient PM2.5 exposure plus lipopolysaccharide on multiple
           organ damage in mice

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      Authors: Wenqi Chen, Shanshan Chen, Lifang Zhao, Mei Zhang, Hong Geng, Chuan Dong, Ruijin Li
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Background: The toxicological effects of fine particulate matter (PM2.5) on the cardiopulmonary and nervous systems have been studied widely, whereas the study of PM2.5 on systemic toxicity is not in-depth enough. Lipopolysaccharide (LPS) can cause multiple organ damage. The combined effects of co-exposure of PM2.5 plus LPS on the stomach, spleen, intestine, and kidney are still unclear. Purpose: This study was aimed to explore the toxicological effects of co-exposure of PM2.5 and LPS on the different organs of mice. Research Design and Study Sample Using a real-ambient PM2.5 exposure system and an intraperitoneal LPS injection mouse model, we investigated multiple organ damage effects on male BALB/c mice after co-exposure of PM2.5 plus LPS for 23 weeks in Linfen, a city with a high PM2.5 concentration in China. Data Collection: Eosin-hematoxylin staining, ELISA and the biochemical assay analysed the toxicological effects. Results: The pathological tissue injury on the four organs above appeared in mice co-exposed to PM2.5 plus LPS, accompanied by the body weight and stomach organ coefficient abnormality, and significant elevation of pro-inflammatory cytokines levels, oxidative stress in the spleen and kidney, and levels of kidney injury molecule (KIM-1) increase in the kidney. There were tissue differences in the pathological damage and toxicological effects on mice after co-exposure, in which the spleen and kidney were more sensitive to pollutants. In the PM2.5 + LPS group, the superoxide dismutase inhibition and catalase (CAT) activity promotion in the kidney or spleen of mice were significant relative to the PM2.5 group; the CAT and interleukin-6 (IL-6) levels in the spleen were raised considerably compared with the LPS group. Conclusions: These findings suggested the severity and sensitivity of multiple organ injuries in mice in response to PM2.5 plus LPS.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-31T10:30:39Z
      DOI: 10.1177/09603271211061505
      Issue No: Vol. 41 (2022)
       
  • Cytochrome P450 3A5 polymorphism affects the metabolism of sorafenib and
           its toxicity for hepatocellular carcinoma cells in vitro

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      Authors: Hong-yan Song, Jing-sheng Xia, Yong-gang Chen, Ling Chen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      ObjectiveCytochrome P450 3A5 (CYP3A5) is a highly polymorphic gene and the encoded protein variants differ in catalytic activity, leading to inter-individual variation in metabolic ability. The aim of the current study was to investigate the effects of seven allelic variants on the ability of CYP3A5 to metabolize sorafenib in vitro and further explore the impacts of CYP3A5 polymorphism on the proliferation and apoptosis of hepatocellular carcinoma cell line (HepG2) induced by sorafenib.MethodsWild-type and variant CYP3A5 enzymes were expressed in Spodoptera frugiperda insect cells using a baculovirus dual-expression system, and protein expression was checked by western blot. The enzymes were incubated with sorafenib at 37°C for 30 min, and formation of the major metabolite sorafenib N-oxide was assayed using ultra-performance liquid chromatography and tandem mass spectrometry. Intrinsic clearance values (Vmax/Km) were calculated for each enzyme. Additionally, recombinant HepG2 cells transfecting with CYP3A5 variants were used to investigate the effects of sorafenib on the proliferation of HepG2 cells.ResultsIntrinsic clearance of the six variants CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 was 26.41–71.04% of the wild-type (CYP3A5*1) value. In contrast, the clearance value of the variant CYP3A5*6 was significantly higher (174.74%). Additionally, the decreased ATP levels and cell viability and the increased cell apoptosis in HepG2 cells transfected with CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 were observed, whereas, the increased ATP levels and cell viability and the reduced cell apoptosis in HepG2 cells transfected with CYP3A5*6 were also investigated when compared to CYP3A5*1.ConclusionOur results suggest that CYP3A5 polymorphism influences sorafenib metabolism and pharmacotherapeutic effect in hepatic carcinomas. These data may help explain differential response to drug therapy for hepatocellular carcinoma, and they support the need for individualized treatment.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-31T04:44:27Z
      DOI: 10.1177/09603271221080236
      Issue No: Vol. 41 (2022)
       
  • Effect of nano zinc oxide on proliferation and toxicity of human gingival
           cells

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      Authors: Fang-Chuan Chen, Cong-Ming Huang, Xiao-Wan Yu, Ya-Yu Chen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundPeriodontal dressing is used to cover the gum surface and protect the wound after periodontal surgery. Nanomaterials have been widely applied in dentistry in recent years. Zinc oxide (ZnO) is one of the main components of periodontal dressing.AimThis study aims to explore the toxicity ZnO nanoparticles (ZnO NPs) causes to human gingival fibroblast cells (HGF-1) and its effect on cell proliferation.MethodsFirst, we identified and analyzed HGF-1, including cell morphology, growth curve, and immunohistochemistry staining. Then, we treated HGF-1 with ZnO NP. Cell viability, the integrity of the cell membrane, oxidative damage, and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release assay, fluorescent probe, and flow cytometry. Furthermore, the expression of murine double minute 2 (MDM2) and p53 was determined by quantitative real-time polymerase chain reaction (qPCR) and Western blotting. We finally overexpressed MDM2 in HGF-1 to verify the relationship between MDM2 and cell proliferation.ResultsOur research indicated ZnO NPs did not affect cell proliferation at low concentrations. However, high-concentration ZnO NP inhibited cell proliferation, destroyed the integrity of cell membranes, and induced oxidative stress and apoptosis. In addition, high concentration of ZnO NPs inhibited the proliferation of HGF-1 by regulating the expression of MDM2 and p53.ConclusionHigh concentration of ZnO NP caused toxicity to HGF-1 cells and inhibited cell proliferation by regulating MDM2 and p53 expression.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-31T04:35:45Z
      DOI: 10.1177/09603271221080237
      Issue No: Vol. 41 (2022)
       
  • Methylation patterns of the CDKN2B and CDKN2A genes in an indigenous
           population exposed to pesticides

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      Authors: Diana M Paredes-Céspedes, Yael Yvette Bernal-Hernández, José Francisco Herrera-Moreno, Aurora Elizabeth Rojas-García, Irma Martha Medina-Díaz, Cyndia A González-Arias, Briscia Socorro Barrón-Vivanco
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      The INK4-ARF locus includes the CDKN2B and CDKN2A genes and is functionally relevant in the regulation of both cell proliferation and senescence. Studies have reported modifications of DNA methylation in this locus by exposure to environmental contaminants including pesticides; however, until now, specific methylation profiles have not been reported in genetically conserved populations exposed to occupational pesticides. The aim of this study was to determine the methylation profiles of the CDKN2B and CDKN2A genes in a genetically conserved population exposed to pesticides. A cross-sectional and analytical study was carried out in 190 Huichol indigenous persons. Information related to pesticide exposure, diet and other variables were obtained through the use of a structured questionnaire. Blood and urine samples were collected for methylation test and dialkylphosphates (DAP) determination, respectively. DNA methylation was measured by the pyrosequencing of bisulfite-treated DNA and DAP concentrations by gas chromatography-tandem mass spectrometry (GC/MS). The most frequent metabolite in the population was dimethylthiophosphate. The farmer group presented a higher methylation percentage of CDKN2B than the non-farmer group, but no differences in CDKN2A were observed between groups. A positive correlation between methylation of CpG site 3 of CDKN2B and time working in the field was observed in the farmer group. An association between methylation percentage of CDKN2B and age was also observed in the non-farmer group. These results suggest that pesticide exposure and exposure time in Huichol indigenous individuals could modify the methylation pattern of the CDKN2B gene.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-24T05:49:29Z
      DOI: 10.1177/09603271211063161
      Issue No: Vol. 41 (2022)
       
  • Assessment of antidiabetic effect of 4-HIL in type 2 diabetic and healthy
           Sprague Dawley rats

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      Authors: Pragati Singh, Sharmeen Ishteyaque, Ramanand Prajapati, Karan Singh Yadav, Rupali Singh, Akhilesh Kumar, Sharad Sharma, Tadigoppula Narender, Madhav Nilakanth Mugale
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and insulin resistance. 4-hydroxyisoleucine (4-HIL) is a non-proteinogenic amino acid isolated from the fenugreek seeds and has enormous pharmacological activities. The present study was undertaken to investigate the antihyperglycemic effect of 4-HIL in streptozotocin (STZ)-induced diabetic rats. Moreover, its toxicity was evaluated in vitro and in vivo employing human embryonic kidney cells (HEK-293) and healthy rats, respectively. In experiment 1, STZ-induced diabetic male rats were subjected to an oral treatment of 4-HIL (100 mg/kg), while experiment 2 deals with the effects of 4-HIL on healthy male and female rats following oral administration. The treatment (experiment 1) declined the elevated blood glucose level, feed intake, and increased body weight(s). Additionally, blood glucose impairment was improved as observed by OGTT and IPGT tests. Pancreatic histopathology revealed mild changes in the 4-HIL group. Moreover, experiment 2 showed increased body weight, normal blood glucose levels (male—106.06 ± 7.49 mg/dl and female—100.06 ± 14.69 mg/dL), hematological parameters, and histopathological profiles in the treatment group. 4-HIL did not affect the viability of HEK-293 cells, and no signs of toxicity were observed in healthy rats. Therefore, the study concludes that 4-HIL has potential antihyperglycemic activity without any toxic effects.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-24T03:37:15Z
      DOI: 10.1177/09603271211061873
      Issue No: Vol. 41 (2022)
       
  • Circ_0006220 promotes non-small cell lung cancer progression via sponging
           miR-203-3p and regulating RGS17 expression

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      Authors: Shaochun Wang, Chengcheng Zhang, Ruilin Chen
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundLung cancer is the most common malignancy, and its mortality ranks first among malignancies. Non-small cell lung carcinoma (NSCLC) is the most common pathological subtype of lung cancer. It is reported that circular RNAs (circRNAs) feature prominently in the occurrence and metastasis of NSCLC.PurposeThis study aims to decipher the biological functions of circ_0006220 in NSCLC and the underlying mechanism.MethodsThe microarray data (GSE101586) were downloaded from the Gene Expression Omnibus database, and differentially expressed circRNAs in NSCLC tissues were screened using the GEO2R tool. Quantitative real-time polymerase chain reaction was used for detecting the expression of circ_0006220, miR-203-3p, and regulator of G-protein signaling 17 (RGS17) mRNA in NSCLC tissues and cells. The connection between circ_0006220 expression and clinicopathological indicators was analyzed through the chi-square test. EdU and cell counting kit-8 assays were carried out to detect cell growth. Cell migration and invasion were detected by transwell assays. Bioinformatics was used to predict, and RNA immunoprecipitation assay and dual-luciferase reporter gene assay were conducted for verifying, the targeted relationship among circ_0006220, miR-203-3p, and RGS17.ResultsThe expression of circ_0006220 was elevated in NSCLC cells and tissues, and high circ_0006220 expression was significantly associated with unfavorable clinicopathological indicators. In addition, it was revealed that circ_0006220 overexpression facilitated NSCLC cell growth, migration, and invasion, whereas knocking down circ_0006220 had contrary effects. Furthermore, miR-203-3p was identified as a downstream target of circ_0006220, and circ_0006220 could sponge miR-203-3p; RGS17 was identified as a downstream target of miR-203-3p and was positively modulated by circ_0006220.ConclusionsCirc_0006220 up-regulates RGS17 expression by adsorbing miR-203-3p to promote NSCLC development.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-18T07:56:05Z
      DOI: 10.1177/09603271211062854
      Issue No: Vol. 41 (2022)
       
  • Oxidative stress and biochemical indicators in blood of patients addicted
           to alcohol treated for acute ethylene glycol poisoning

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      Authors: Karina Sommerfeld-Klatta, Magdalena Łukasik-Głębocka, Barbara Zielińska-Psuja
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      Ethylene glycol (EG), in addition to its neurotoxic and nephrotoxic effects, evokes oxidative stress. The aim of this study was to assess the influence of the ethylene glycol on the biochemical indicators and oxidoreductive balance of patients treated for acute poisoning. The total study group consisted of 56 persons including 26 alcoholics who took EG as a substitute for ethyl alcohol in the course of alcohol dependence syndrome and 30 controls. Severity of poisoning, results of acid-base parameters, biochemical, and toxicological tests as well as biomarkers of the oxidative stress in blood were analyzed during the patients’ hospitalization. The key issue was to assess the oxidative stress and biochemical disturbances caused by EG and the type of treatment applied in the course of poisoning. Significant changes in some parameters were found both at time of diagnosis and after treatment initiation (ethanol as an antidote and hemodialysis). The most important differences included the activity of hepatic parameters (aspartate aminotransferase, AST) and oxidative stress markers like catalase (CAT); correlation of the lipid peroxidation products level (TBARS) with urea concentration has been shown. On the last day of the hospitalization, in some cases, the mutual correlation between the evaluated markers were observed, for example, between alanine transaminase (ALT) and glutathione reductase (GR), and urea concentration and glutathione level (GSH/GSSG). The concentration of ions (H+) had a major impact on the oxidoreductive balance, correlating with the elevated GR and GSH/GSSG levels.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-13T01:37:47Z
      DOI: 10.1177/09603271211061502
      Issue No: Vol. 41 (2022)
       
  • Toxicity assessment of gelsenicine and the search for effective antidotes

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      Authors: Yu-Juan Li, Kun Yang, Xue-Ming Long, Gang Xiao, Si-Juan Huang, Zi-Yue Zeng, Zhao-Ying Liu, Zhi-Liang Sun
      Abstract: Human & Experimental Toxicology, Volume 41, Issue , January-December 2022.
      BackgroundGelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth (G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available.ObjectiveThis study aimed to analyse the toxicity characteristics of gelsenicine.MethodsBoth acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened.ResultsIn the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood–brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice.ConclusionsGelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine-related poisoning and its toxicity mechanisms.
      Citation: Human & Experimental Toxicology
      PubDate: 2022-01-12T11:19:30Z
      DOI: 10.1177/09603271211062857
      Issue No: Vol. 41 (2022)
       
 
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