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Human & Experimental Toxicology
Journal Prestige (SJR): 0.559
Citation Impact (citeScore): 2
Number of Followers: 6  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-3271 - ISSN (Online) 1477-0903
Published by Sage Publications Homepage  [1176 journals]
  • Tanshinone I induces ferroptosis in gastric cancer cells via the KDM4D/p53
           pathway

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      Authors: Minming Xia, Yifeng Wu, Hui Zhu, Wenbiao Duan
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      IntroductionTanshinone I (Tan I) is one of the bioactive components of Salvia miltiorrhiza. Whether it inhibits gastric cancer through ferroptosis has not been reported. This study aimed to confirm the effect of Tan I on ferroptosis in gastric cancer cells.MethodsAGS and HGC27 cells were treated with Tan I. First, oxidative stress-related parameters and the expression of ferroptosis-related proteins were examined. Combined with a ferroptosis inhibitor, Tan I was found to inhibit gastric cancer cells via the ferroptosis pathway. Finally, with bioinformatics analysis, the target protein of Tan I was identified.ResultsTan I significantly inhibited the expression level of GPX4. This molecule also increased ROS, MDA, and Fe2+ contents and decreased GSH enzyme activity. Therefore, we hypothesized that Tan I may inhibit gastric cancer cells by inducing ferroptosis. Western blotting results showed that Tan I inhibited the expression levels of the ferroptosis resistance-related proteins GPX4, SLC7A11, and FTH1, while the pro-ferroptosis-related proteins TFR1 and ACSL4 were significantly upregulated. A ferroptosis inhibitor effectively reversed these regulatory effects of Tan I in gastric cancer. With these data combined with the bioinformatics analysis, KDM4D was identified as a key regulatory target of Tan I. Mechanistically, Tan I induced positive regulation of ferroptosis resistance-related indicators by inhibiting KDM4D to upregulate p53 protein expression. Overexpression of KDM4D significantly reversed the effect of Tan I-induced ferroptosis resistance in gastric cancer cells.ConclusionsTan I induced ferroptosis inhibition in gastric cancer by regulating the KDM4D/p53 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-22T12:38:58Z
      DOI: 10.1177/09603271231216963
      Issue No: Vol. 42 (2023)
       
  • Effects of polycyclic aromatic hydrocarbon exposure on mitochondrial DNA
           copy number

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      Authors: Sun-Haeng Choi, Bolormaa Ochirpurev, Hwa Yeong Jo, Jong-Uk Won, Akira Toriba, Heon Kim
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Airborne polycyclic aromatic hydrocarbon (PAH) exposure can adversely affect human health by generating reactive oxygen species (ROS) and increasing oxidative stress, which causes changes in mitochondrial DNA copy number (mtDNAcn), a key indicator of mitochondrial damage and dysfunction. This study aimed to determine the effects of atmospheric benzo[a]pyrene (BaP) and 1-nitropyrene (1-NP) exposure on mtDNAcn in humans. One hundred and eight adults living in Cheongju, South Korea, were included in this study. Atmospheric BaP and 1-NP concentrations and urinary 6-hydroxy-1-nitropyrene (6-OHNP), N-acetyl-1-aminopyrene (1-NAAP), and 1-hydroxypyrene concentrations were measured. Blood samples were also collected to assess mtDNAcn. The mean mtDNAcn was 9.74 (SD 4.46). mtDNAcn decreased significantly with age but was not significantly associated with sex, sampling season, or smoking habit. While there was a borderline significant increase in mtDNAcn with increasing ambient total PAH levels, ambient PAH or urinary 1-hydroxypyrene concentrations showed no significant association with mtDNAcn. However, urinary 6-OHNP or 1-NAAP concentrations, 1-NP metabolites, were significantly associated with mtDNAcn. These results suggest that the metabolism of absorbed NPs generates excess ROS, which damages mitochondrial DNA, resulting in increased mtDNAcn.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-22T12:17:29Z
      DOI: 10.1177/09603271231216968
      Issue No: Vol. 42 (2023)
       
  • Impact of combined chronic exposure to low-dose bisphenol A and fructose
           on serum adipocytokines and the energy target metabolome in white adipose
           tissue

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      Authors: Xiaocheng Liu, Guojuan Li, Jing Zhong, Ouyan Rang, Guifang Ou, Xinru Qin, Yonghong Tang, Mu Wang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Background: Adipose tissue is a dynamic endocrine organ that plays a key role in regulating metabolic homeostasis. Previous studies confirmed that bisphenol A (BPA) or fructose can interfere with the function of adipose tissue. Nonetheless, knowledge on how exposure to BPA and fructose impacts energy metabolism in adipose tissue remains limited.Purpose: To determine impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue.Method: 57 energy metabolic intermediates in adipose tissue and 7 adipocytokines in serum from Sprague Dawley rats were examined after combined exposure to two levels of BPA (lower dose: 0.25, and higher dose: 25 μg/kg every other day) and 5% fructose for 6 months.Results: combined exposure to lower-dose BPA and fructose significantly increased omentin-1, pyruvic acid, adenosine triphosphate (ATP), adenosine monophosphate (AMP), inosine monophosphate (IMP), inosine, and l-lactate; however, these parameters were not significantly affected by higher-dose BPA combined with fructose. Interestingly, the level of succinate (an intermediate of the citric acid cycle) increased dose-dependently in adipose tissue, and the level of apelin 13 (a versatile adipocytokine) decreased dose-dependently in serum after combined exposure to BPA and fructose. Phosphoenolpyruvic acid, phenyl-lactate, and ornithine were significantly correlated with asprosin, omentin-1, apelin, apelin 13, and adiponectin, while l-tyrosine was significantly correlated with irisin and a-FABP under combined exposure to BPA and fructose.Conclusions: these findings indicated that lower-dose BPA combined with fructose could amplify the impact on glycolysis, energy storage, and purine nucleotide biosynthesis in adipose tissue, and adipocytokines, such as omentin-1 and apelin 13, may be related to metabolic interference induced by BPA and fructose exposure.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-22T06:48:32Z
      DOI: 10.1177/09603271231217992
      Issue No: Vol. 42 (2023)
       
  • Retraction notice: “Long noncoding RNA SNHG14 regulates ox-LDL-induced
           atherosclerosis cell proliferation and apoptosis by targeting
           miR-186-5p/WIPF2 axis”

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-21T10:46:52Z
      DOI: 10.1177/09603271231215964
      Issue No: Vol. 42 (2023)
       
  • The effects of esketamine on the intestinal microenvironment and
           intestinal microbiota in mice

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      Authors: Ying Zhang, Wenhao Ma, Hao Lin, Xuefeng Gu, Hong Xie
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveThis study aimed to investigate the impact of esketamine on the intestinal flora and microenvironment in mice using mRNA transcriptome sequencing and 16S rRNA sequencing.MethodsTen female mice were randomly assigned to two groups. One group received daily intramuscular injections of sterile water, while the other group received esketamine. After 24 days, the mice were sacrificed, and their intestinal tissues and contents were collected for 16S rRNA sequencing and mRNA transcriptome sequencing. The intergroup differences in the mouse intestinal flora were analyzed. Differentially expressed genes were utilized to construct ceRNA networks and transcription factor regulatory networks to assess the effects of esketamine on the intestinal flora and intestinal tissue genes.ResultsEsketamine significantly altered the abundance of intestinal microbiota, including Adlercreutzia equolifaciens and Akkermansia muciniphila. Differential expression analysis revealed 301 significantly upregulated genes and 106 significantly downregulated genes. The ceRNA regulatory network consisted of 6 lncRNAs, 44 miRNAs, and 113 mRNAs, while the regulatory factor network included 13 transcription factors and 53 target genes. Gene Ontology enrichment analysis indicated that the differentially expressed genes were primarily associated with immunity, including B-cell activation and humoral immune response mediation. The biological processes in the ceRNA regulatory network primarily involved transport, such as organic anion transport and monocarboxylic acid transport. The functional annotation of target genes in the TF network was mainly related to epithelial cells, including epithelial cell proliferation and regulation.ConclusionEsketamine induces changes in gut microbiota and the intestinal microenvironment, impacting the immune environment and transport modes.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-21T07:49:27Z
      DOI: 10.1177/09603271231211894
      Issue No: Vol. 42 (2023)
       
  • The antioxidant properties of resveratrol on sperm parameters, testicular
           tissue, antioxidant capacity, and lipid peroxidation in isoflurane-induced
           toxicity in mice

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      Authors: Zahra Mohammadi, Sanaz Alaee, Mohammad Reza Namavar, Zahra Khodabandeh, Nahid Ahmadi, Niloofar Rashidipour, Somayyeh Karami-Mohajeri
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      This study explores whether resveratrol effectively protects the reproductive system against isoflurane-induced toxicity in testicular tissue. In this experiment, we randomly divided 60 adult male C57BL/6 mice into six groups (n = 10). Five consecutive days per week, mice were exposed to 1.5% isoflurane for 1 h/day and were given 50 and 100 mg/kg resveratrol. After 35 days (the completion of the mouse spermatogenesis period), the left testis was removed for histomorphometric evaluations, while the right testis was used to determine the Capacity of total antioxidants and lipid peroxidation. To analyze the Parameters of sperm, chromatin maturation, and DNA fragmentation, the left caudal epididymis was used. Based on a one-way analysis of variance (ANOVA), we considered a difference in means of 0.05 to be significant (P0.05). Compared to the control group, the isoflurane group showed a significant decrease in testicular weight, volume, sperm parameters, and tissue histomorphometry. Comparatively, to the control group, malondialdehyde levels increased, and the total antioxidant capacity decreased significantly. Resveratrol improved all of the above parameters in the simultaneous treatment groups compared to the isoflurane group. It did not, however, reach the level of the control group in all cases. It has been demonstrated that resveratrol, with its powerful antioxidant properties, reduces the reproductive toxicity of isoflurane by inhibiting free radicals and increasing the testicular tissue's antioxidant capacity.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-21T01:19:36Z
      DOI: 10.1177/09603271231215036
      Issue No: Vol. 42 (2023)
       
  • Integrative analysis of renal microRNA and mRNA to identify hub genes and
           pivotal pathways associated with cyclosporine-induced acute kidney injury
           in mice

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      Authors: Qiaoling Yang, Xunjiang Wang, Hongjing Li, Xuedong Yin, Hongxia Liu, Wenjuan Hu, Ying Qing, Lili Ding, Li Yang, Zhiling Li, Huajun Sun
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Cyclosporine (CsA) is an immunosuppressive agent that often causes acute kidney injury (AKI) in children. The specific mechanisms underlying CsA-induced AKI are currently unknown. This study used an integrated network analysis of microRNA (miRNA) and mRNA expression profiles, biochemical and pathological analyses to further investigate these potential mechanisms of CsA-induced AKI. Small RNA sequence analysis identified 25 differentially expressed miRNAs, RNA sequencing analysis identified 4,109 differentially expressed mRNAs. We obtained a total of 4,367 target genes from the 25 differentially expressed miRNAs based on three algorithms, including the Mirdb, Mirtarbase, and TargetScan. 971 target genes overlapped between the 4,367 target genes and 4,109 differentially expressed mRNAs were identified for further bioinformatics analysis. Finally, 30 hub genes and two main modules were recognized. Functional enrichment analysis of 30 hub genes indicated that inflammation and epithelial-mesenchymal transition (EMT) related genes were mainly concentrated together. Pathway analysis revealed that the PI3K-Akt signaling pathway plays an integral role in CsA-induced AKI. Network analysis identified 3 important miRNAs, mmu‐miR-17b‐5p, mmu-miR-19b-3p, and mmu-mir-423-5p that may further promote the development of inflammatory responses and EMT by mediating a complex network of factors. Our research provides a clearer understanding the molecular mechanism of this specific drug-induced AKI by CsA use, which is useful for discovering potential targets for gene therapies, and drug development in CsA-induced AKI.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-11T02:36:59Z
      DOI: 10.1177/09603271231215499
      Issue No: Vol. 42 (2023)
       
  • Punicalagin is cytotoxic to human colon cancer cells by modulating cell
           proliferation, apoptosis, and invasion

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      Authors: Ding-Ping Sun, Hsuan-Yi Huang, Chia-Lin Chou, Li-Chin Cheng, Wen-Ching Wang, Yu-Feng Tian, Chia-Lang Fang, Kai-Yuan Lin
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Purpose: The purpose of this study was to explore the anticancer effect of punicalagin, an abundant bioactive tannin compound isolated from Punica granatum L., on three colon cancer cell lines, namely, HCT 116, HT-29, and LoVo.Research Design: Normal and colon cancer cells were treated with different concentrations of punicalagin for different periods. Data Collection and Analysis: Cell viability was measured with a CCK-8 assay. Programmed cell death and invasion were analyzed using an annexin V and cell death kit and a cell invasion analysis kit. The expression of active caspase-3, MMP-2, MMP-9, Snail, and Slug were measured by Western blot.Results: The results of the cell viability analysis showed that punicalagin was cytotoxic to colon cancer cells, but it was not to normal cells in a dose- and time-dependent manner. Additionally, punicalagin induced apoptosis in colon cancer cells (shown by the cumulative percentage of colorectal cancer cells in early and late apoptosis). It was found that caspase-3 activity increased following punicalagin treatment. Western blot results also showed that punicalagin increased the expression of activated caspase-3. In contrast, punicalagin inhibited the invasion of colon cancer cells. Further, treatment of colon cancer cells with punicalagin suppressed the expression of MMP-2, MMP-9, Snail, and Slug. Conclusions: These results showed that the activation of caspase-3 and the inhibition of MMP-2, MMP-9, Snail and Slug were involved in the effects of punicalagin on colon cancer cells.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-07T08:31:25Z
      DOI: 10.1177/09603271231213979
      Issue No: Vol. 42 (2023)
       
  • Retraction Notice: “Sulforaphane triggers iron overload-mediated
           ferroptosis in gastric carcinoma cells by activating the PI3K/IRP2/DMT1
           pathway”

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-11-06T04:25:01Z
      DOI: 10.1177/09603271231212067
      Issue No: Vol. 42 (2023)
       
  • Effects of methylphenidate on femoral bone growth in male rats

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      Authors: Gökçe Nur Say, Mehmet Emin Önger, Ferhat Say, Onur Yontar, Oktay Yapıcı
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      The use of Methylphenidate (MP) can have adverse effects on bone growth and mineralization. This study aimed to investigate the underlying pathophysiology of MP-induced skeletal deficits in growing rats using stereological and immunohistochemical methods. Male rats, aged 4 weeks, were orally treated with MP through an 8-h/day water drinking protocol. The rats (n=30) were randomly divided into three groups: MP-High Dose (30/60 mg/kg/day MP), MP-Low Dose (4/10 mg/kg/day MP), and control (water only). After 13 weeks, the femoral bones were assessed using calliper measurements, dual-energy X-ray absorptiometry, and biomechanical evaluation. The total femur volume, cartilage volume, growth zone volume, and volume fractions were determined using the Cavalieri method. Immunohistochemical analyses were conducted using alkaline phosphatase and anti-calpain antibody staining. Rats exposed to MP exhibited significant reductions in weight gain, femoral growth, bone mineralization, and biomechanical integrity compared to the control group. The total femoral volume of MP-treated rats was significantly lower than that of the control group. The MP-High Dose group showed significantly higher ratios of total cartilage volume/total femoral volume and total growth zone volume/total femoral volume than the other groups. Immunohistochemical evaluation of the growth plate revealed reduced osteoblastic activity and decreased intracellular calcium deposition with chronic MP exposure. The possible mechanism of MP-induced skeletal growth retardation may involve the inhibition of intracellular calcium deposition in chondrocytes of the hypertrophic zone in the growth plate. In this way, MP may hinder the differentiation of cartilage tissue from bone tissue, resulting in reduced bone growth and mineralization.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-10-30T10:34:47Z
      DOI: 10.1177/09603271231210970
      Issue No: Vol. 42 (2023)
       
  • Problems with the effectiveness of L-carnitine and paraffin oil in acute
           aluminum phosphide poisoning

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      Authors: Maryam Zaare Nahandi, Ali Banagozar Mohammadi
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-10-25T04:29:26Z
      DOI: 10.1177/09603271231210974
      Issue No: Vol. 42 (2023)
       
  • Toxic mechanisms of cadmium and exposure as a risk factor for oral and
           gastrointestinal carcinomas

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      Authors: Ali Tavakoli Pirzaman, Pouyan Ebrahimi, Shokat Niknezhad, Turan vahidi, Dariush Hosseinzadeh, Sousan Akrami, Arash M Ashrafi, Mohammad Moeen Velayatimehr, Rezvan Hosseinzadeh, Sohrab Kazemi
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Incidence and mortality rates of gastrointestinal (GI) and oral cancers are among the highest in the world, compared to other cancers. GI cancers include esophageal, gastric, colon, rectal, liver, and pancreatic cancers, with colorectal cancer being the most common. Oral cancer, which is included in the head and neck cancers category, is one of the most important causes of death in India. Cadmium (Cd) is a toxic element affecting humans and the environment, which has both natural and anthropogenic sources. Generally, water, soil, air, and food supplies are reported as some sources of Cd. It accumulates in organs, particularly in the kidneys and liver. Exposure to cadmium is associated with different types of health risks such as kidney dysfunction, cardiovascular disease, reproductive dysfunction, diabetes, cerebral infarction, and neurotoxic effects (Parkinson’s disease (PD) and Alzheimer’s disease (AD)). Exposure to Cd is also associated with various cancers, including lung, kidney, liver, stomach, hematopoietic system, gynecologic and breast cancer. In the present study, we have provided and summarized the association of Cd exposure with oral and GI cancers.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-10-23T03:23:08Z
      DOI: 10.1177/09603271231210262
      Issue No: Vol. 42 (2023)
       
  • Rhamnazin ameliorates 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin-evoked
           testicular toxicity by restoring biochemical, spermatogenic and
           histological profile in male albino rats

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      Authors: Muhammad Umar Ijaz, Shama Mustafa, Qurat Ul Ain, Ali Hamza, Shafaqat Ali
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a potential environmental toxin that has the ability to affect male reproductive tract. Rhamnazin is a naturally present flavone that displays multiple medicinal properties. Therefore, the current study was designed to determine the mitigative role of rhamnazin against TCDD induced reproductive damage. 48 adult male albino rats were randomly separated into four groups: control, TCDD (10 µgkg−1), TCDD + rhamnazin (10 µgkg−1 + 5 mgkg−1 respectively) and rhamnazin (5 mgkg−1). The trial was conducted for 56 days. TCDD intoxication notably affected superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GSR) and catalase (CAT) activities, besides reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations were augmented. TCDD administration also lowered sperm motility, viability, sperm number, while it augmented the sperm morphological (tail, neck/midpiece and head) anomalies. Moreover, it decreased the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma testosterone. Moreover, TCDD reduced steroidogenic enzymes i.e., 17-beta hydroxysteroid dehydrogenase (17β-HSD), steroidogenic acute regulatory protein (StAR) and 3-beta hydroxysteroid dehydrogenase (3β-HSD) as well as B-cell lymphoma 2 (Bcl-2) expressions, but increased the expressions of Bcl-2-associated X protein (Bax) and cysteine–aspartic acid protease (Caspase-3). Furthermore, TCDD exposure also induced histopathological anomalies in testicular tissues. However, the supplementation of rhamnazin recovered all the mentioned damages in the testicles. The outcomes revealed that rhamnazin can ameliorate TCDD induced reproductive toxicity due to its anti-oxidant, anti-apoptotic and androgenic nature.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-10-09T08:03:28Z
      DOI: 10.1177/09603271231205859
      Issue No: Vol. 42 (2023)
       
  • Biological function of C-X-C Motif Chemokine Ligand 1 gene (CXCL1) in
           ovarian malignant tumors

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      Authors: Zhuang Li, Ning Huang, Wei Zhang, Li Li
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveTo determine the function of the chemokine (C-X-C motif) ligand 1 (CXCL1) gene in ovarian cancer cells and to investigate the relationship between CXCL1 gene mRNA expression and ovarian tumor clinical pathology.MethodsUsing bioinformatics methods to identify common differentially expressed genes associated with ovarian cancer in the GEO database. Growth curves of A2780 cells with or without CXCL1 expression were plotted by MTT assay. Cell cycles were measured by flow cytometry. Cell colony formation was enumerated in Transwell chambers. Migration and invasion in vitro were investigated using Cell Counting Kit-8 (CCK8), wound healing and Transwell, respectively. The relationship between CXCL1 gene mRNA expression and ovarian tumor clinical pathology was analyzed.ResultsCXCL1 was found to be one of the co-upregulated differentially expressed genes in the GEO database. The migration of A2780 cells expressing CXCL1 was significantly higher than that of A2780 cells without CXCL1 expression. CXCL1 mRNA expression in ovarian malignancy was significantly higher than those in benign lesions and the normal control (p < .01). In advanced ovarian cancer (Stages III-IV), CXCL1 mRNA expression was also significantly higher than that in patients with early-stage ovarian cancer (Stages I-II) (p = .005). Kaplan-Meier survival curve showed no correlation between CXCL1 mRNA expression and ovarian cancer prognosis. A Cox proportional hazard model also showed that CXCL1 expression was not an independent prognostic factor for ovarian cancer patients.ConclusionsCXCL1 gene could promotes ovarian cancer A2780 cell proliferation and invasion in vitro, and contributed theoretical knowledge for the target selection in molecular targeted therapy. CXCL1 mRNA over-expression may be correlated with the occurrence and development of ovarian malignancy. Level of plasma CXCL1 might serve as a biomarker for prognosis in ovarian carcinoma patients.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-10-03T09:44:28Z
      DOI: 10.1177/09603271231203392
      Issue No: Vol. 42 (2023)
       
  • Environmental contaminants, endocrine disruption, and transgender: Can
           “born that way” in some cases be toxicologically real'

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      Authors: Steven David Holladay
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Gender is viewed by many as strictly binary based on a collection of body traits typical of a female or male phenotype, presence of a genotype that includes at least one copy of a Y chromosome, or ability to produce either egg or sperm cells. A growing non-binary view is that these descriptors, while compelling, may nonetheless fail to accurately capture an individual’s true gender. The position of the American Psychological Association (APA) agrees with this view and is that transgender people are a defendable and real part of the human population. The considerable diversity of transgender expression then argues against any unitary or simple explanations, however, prenatal hormone levels, genetic influences, and early and later life experiences have been suggested as playing roles in development of transgender identities. The present review considers existing and emerging toxicologic data that may also support an environmental chemical contribution to some transgender identities, and suggest the possibility of a growing nonbinary brain gender continuum in the human population.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-26T10:15:02Z
      DOI: 10.1177/09603271231203382
      Issue No: Vol. 42 (2023)
       
  • Ginkgolide A downregulates transient receptor potential (melastatin) 2 to
           protect cisplatin-induced acute kidney injury in rats through the
           TWEAK/Fn14 pathway: Ginkgolide A improve acute renal injury

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      Authors: Haiyan He, Jun Ge, Shaona Yi, Yuhong Wang, Ye Liu, Ying Liu, Xiaoming Liu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      PurposeIn order to seek effective drugs for treating cisplatin-induced acute renal injury and explore the corresponding potential mechanism.MethodsMouse kidney injury model was established by intraperitoneal injection of 20 mg/kg cisplatin. The temporal expression of TRPM2 and the regulation of Ginkgolide A on its expression were analyzed by western blot. In order to perform the mechanical analysis, we used TRPM2-KO knockout mice. In this study, we evaluated the repair effect of GA on acute kidney injury through renal function factors, inflammatory factors and calcium and potassium content. Pathological injury and cell apoptosis were detected by H&E and TUNEL, respectively.ResultGinkgolide A inhibited inflammatory reaction and excessive oxidative stress, reduced renal function parameters, and improved pathological injury. Meanwhile, we also found that the repair effect of Ginkgolide A on renal injury is related to TRPM2, and Ginkgolide A downregulated TRPM2 expression and inactivated TWEAK/Fn14 pathway in cisplatin-induced renal injury model. We also found that inhibition of TWEAK/Fn14 pathway was more effective in TRPM2-KO mice than TRPM2-WT mice.ConclusionGinkgolide A was the effective therapeutic drug for cisplatin-induced renal injury through acting on TRPM2, and TWEAK/Fn14 pathway was the downstream pathway of Ginkgolide A in acute renal injury, and Ginkgolide A inhibited TWEAK/Fn14 pathway in cisplatin-induced renal injury model.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-16T03:51:54Z
      DOI: 10.1177/09603271231200868
      Issue No: Vol. 42 (2023)
       
  • Retraction Notice

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-13T09:27:55Z
      DOI: 10.1177/09603271231199146
      Issue No: Vol. 42 (2023)
       
  • TLR4/ MyD88/NF-κB signaling pathway involved in the protective effect of
           diacerein against lung fibrosis in rats

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      Authors: Asmaa Mohamed Abdel-Aziz, Eman Mahmoud Fathy, Heba M. Hafez, Amira F. Ahmed, Mervat Z. Mohamed
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      PurposePulmonary fibrosis (PF) is an inescapable problem. Diacerein, a chondro-protective drug, has antioxidant and anti-inflammatory effects. Its effect on PF injury has not yet been fully clarified. Therefore, the current study aimed to detect its protective effect on lung tissue with the explanation of possible underlying mechanisms.MethodsAdult male albino rats were assigned to four groups: control group, diacerein control group, PF non-treated group, and PF diacerein pretreated group. Lung tissue oxidative stress parameters, inflammatory biomarkers mainly Toll-like receptors-4 (TLR4), and myeloid differentiation factor 88 (MyD88) levels were determined. Histopathological examination of lung tissue and immunohistochemical studies of nuclear factor-kappa B (NF-κB), and transforming growth factor- β (TGF-β) were also done.ResultsDiacerein pretreatment has the ability to restore the PF damaging effect, proved by the reduction of the oxidative stress and lung tissue inflammation via downregulation of TLR4/NF-κB signaling pathway together with the restoration of TGF-β level and improvement of the histopathological and immunohistochemical study findings in the lung tissue.ConclusionThese results suggested the protective effect of diacerein on PF relies on its antioxidant and anti-inflammatory effects reducing TLR4/NF-κB signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-04T09:34:07Z
      DOI: 10.1177/09603271231200213
      Issue No: Vol. 42 (2023)
       
  • Retraction Notice

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:37:06Z
      DOI: 10.1177/09603271231192807
      Issue No: Vol. 42 (2023)
       
  • Retraction Notice

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:36:46Z
      DOI: 10.1177/09603271231192806
      Issue No: Vol. 42 (2023)
       
  • Retraction Notice

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:36:26Z
      DOI: 10.1177/09603271231192804
      Issue No: Vol. 42 (2023)
       
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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:36:06Z
      DOI: 10.1177/09603271231192802
      Issue No: Vol. 42 (2023)
       
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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:35:45Z
      DOI: 10.1177/09603271231192805
      Issue No: Vol. 42 (2023)
       
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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:35:26Z
      DOI: 10.1177/09603271231192803
      Issue No: Vol. 42 (2023)
       
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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:35:06Z
      DOI: 10.1177/09603271231192801
      Issue No: Vol. 42 (2023)
       
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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:34:46Z
      DOI: 10.1177/09603271231192800
      Issue No: Vol. 42 (2023)
       
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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-02T04:34:26Z
      DOI: 10.1177/09603271231192799
      Issue No: Vol. 42 (2023)
       
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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-09-01T09:48:27Z
      DOI: 10.1177/09603271231192798
      Issue No: Vol. 42 (2023)
       
  • The protective effects of topiramate and spirulina against
           doxorubicin-induced cardiotoxicity in rats

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      Authors: Radwa M Elmorsi, Ahmed M Kabel, Amira A El Saadany, Samia H Abou El-Seoud
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Doxorubicin (DOX) is a widely used chemotherapy drug that can cause significant cardiotoxicity, limiting its clinical application. This study aimed to investigate the potential protective effects of topiramate (TPM) and spirulina (SP), either alone or in combination, in preventing DOX-induced cardiotoxicity. Adult Sprague Dawley rats were divided into five groups, including a normal control group and groups receiving DOX alone, DOX with TPM, DOX with SP, or DOX with a combination of TPM and SP. Cardiotoxicity was induced by administering DOX intraperitoneally at a cumulative dose of 16 mg/kg over 4 weeks. TPM and/or SP administration started 1 week before DOX treatment and continued for 35 days. Body weight, serum markers of cardiac damage, oxidative stress and inflammatory parameters were assessed. Histopathological and immunohistochemical examinations were performed on cardiac tissues. Results showed that TPM and SP monotherapy led to significant improvements in serum levels of cardiac markers, decreased oxidative stress, reduced fibrosis-related growth factor levels, increased antioxidant levels, and improved histopathological features. SP demonstrated more prominent effects in comparison to TPM, and the combination of TPM and SP exhibited even more pronounced effects. In conclusion, TPM and SP, either alone or in combination, hold promise as therapeutic interventions for mitigating DOX-induced cardiotoxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-30T04:29:32Z
      DOI: 10.1177/09603271231198624
      Issue No: Vol. 42 (2023)
       
  • Avian riboflavin deficiency causes reliably reproducible peripheral nerve
           demyelination and, with vitamin supplementation, rapid remyelination

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      Authors: Zhao Cai, John Finnie, Jim Manavis, Peter Blumbergs
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Riboflavin deficiency produces severe peripheral neve demyelination in young, rapidly growing chickens. While this naturally-occurring vitamin B2 deficiency can cause a debilitating peripheral neuropathy, and mortality, in poultry flocks, it can also be a useful experimental animal model to study the pathogenesis of reliably reproducible peripheral nerve demyelination. Moreover, restitution of normal riboflavin levels in deficient birds results in brisk remyelination. It is the only acquired, primary, demyelinating tomaculous neuropathy described to date in animals. The only other substance that causes peripheral nerve demyelination similar to avian riboflavin deficiency is tellurium and the pathologic features of the peripheral neuropathy produced by this developmental neurotoxin in weanling rats are also described.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-09T03:45:34Z
      DOI: 10.1177/09603271231188970
      Issue No: Vol. 42 (2023)
       
  • Association between serum complement 1q and the associated factors of
           acute ischemic stroke in patients with type 2 diabetes

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      Authors: Zhen-ping Hu, Fang Wu, Yuan-hong Du, Mao Ye
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveThe aim of this study was to examine the association between serum complement 1q (C1q) and the associated factors of acute ischemic stroke in patients with type 2 diabetes (T2DM).MethodsThe baseline clinical variables of the participants were collected, and the levels of blood lipids, blood sugar, inflammatory cytokines, and C1q in the three groups were then compared. The variables which affected the associated factors of acute ischemic stroke in T2DM cases were determined.ResultsThe levels of C1q in the DAIS group were increased significantly compared with those in the T2DM group. Receiver operating characteristic curve analyses showed that the AUC for C1q and the combined diagnosis of acute ischemic stroke were 0.830 (95%CI 0.747–0.914), with a sensitivity of 0.854 and specificity of 0.780. The results of Pearson’s correlation analyses demonstrated that C1q was associated positively with low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (PBG), 2-h postprandial blood glucose (2h PG), and high-sensitive C reaction protein (hs-CRP) (all p < .05). Stratified analysis showed that there was a positive relationship between C1q and the associated factors of acute ischemic stroke for partial LDL-C, and hs-CRP strata. Logistic model analysis suggested that C1q was an independent risk factor for acute ischemic stroke in patients with T2DM. After adjusting for potential confounders, a one-standard deviation (SD) increase in C1q level was strongly related to an approximately 1.5-fold increased risk of acute ischemic stroke in cases with a hs-CRP ≥1.78 mg/L.ConclusionIn DAIS patients, the levels of C1q were increased significantly and were an independent associated factor which affected the occurrence of acute ischemic stroke.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-08T03:52:39Z
      DOI: 10.1177/09603271231188291
      Issue No: Vol. 42 (2023)
       
  • Acrylamide-induced meiotic arrest of spermatocytes in adolescent mice by
           triggering excessive DNA strand breaks: Potential therapeutic effects of
           resveratrol

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      Authors: Y Gao, D Zhang, P Wang, X Qu, J Xu, Y Yu, X Zhou
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Background: Baked carbohydrate-rich foods are the main source of acrylamide (AA) in the general population and are widely consumed by teenagers. Considering the crucial development of the reproductive system during puberty, the health risks posed by AA in adolescent males have raised public concern.Methods: In this study, we exposed 3-week-old male pubertal mice to AA for 4 weeks to evaluate its effect on spermatogenesis using computer-assisted sperm analysis (CASA) and historical analysis. Flow cytometric analysis and meiocyte spreading assay were conducted to assess meiosis in mice. The expression of meiosis-related proteins and double-strand break (DSB) proteins were evaluated by immunoblot analyses. Additionally, isolated spermatocytes were used to explore the role of resveratrol in AA-induced damages of meiosis.Results: Our results showed that AA decreased the testicular and epididymal indexes, reduced sperm count and motility, and induced morphological disruption of the testes in pubertal mice. Subsequent meiotic analysis revealed that AA increased the proportion of 4C spermatocytes and decreased the proportion of 1C spermatids. The expression levels of meiosis-related proteins (SYCP3, Cyclin A1 and CDK2) were downregulated, and signaling proteins (γH2AX, p-CHK2 and p-ATM) expression levels were upregulated in AA-treated mice testes. Similar expression patterns were observed in primary spermatocytes treated with AA and these effects were reversed significantly by resveratrol.Conclusions: Our results indicate that AA induces meiotic arrest via persistent activation of DSBs, which may contribute to AA-compromised spermatogenesis. Resveratrol could serve as a potential therapeutic agent against AA-induced meiotic toxicity. These data highlight the importance of natural product supplementation for treating AA-related reproductive toxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-08T03:18:49Z
      DOI: 10.1177/09603271231188293
      Issue No: Vol. 42 (2023)
       
  • Neurodevelopmental toxicity induced by PM2.5 Exposure and its possible
           role in Neurodegenerative and mental disorders

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      Authors: Xin-qi Liu, Jia Huang, Chao Song, Tian-liang Zhang, Yong-ping Liu, Li Yu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Recent extensive evidence suggests that ambient fine particulate matter (PM2.5, with an aerodynamic diameter ≤2.5 μm) may be neurotoxic to the brain and cause central nervous system damage, contributing to neurodevelopmental disorders, such as autism spectrum disorders, neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and mental disorders, such as schizophrenia, depression, and bipolar disorder. PM2.5 can enter the brain via various pathways, including the blood–brain barrier, olfactory system, and gut-brain axis, leading to adverse effects on the CNS. Studies in humans and animals have revealed that PM2.5-mediated mechanisms, including neuroinflammation, oxidative stress, systemic inflammation, and gut flora dysbiosis, play a crucial role in CNS damage. Additionally, PM2.5 exposure can induce epigenetic alterations, such as hypomethylation of DNA, which may contribute to the pathogenesis of some CNS damage. Through literature analysis, we suggest that promising therapeutic targets for alleviating PM2.5-induced neurological damage include inhibiting microglia overactivation, regulating gut microbiota with antibiotics, and targeting signaling pathways, such as PKA/CREB/BDNF and WNT/β-catenin. Additionally, several studies have observed an association between PM2.5 exposure and epigenetic changes in neuropsychiatric disorders. This review summarizes and discusses the association between PM2.5 exposure and CNS damage, including the possible mechanisms by which PM2.5 causes neurotoxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-04T05:46:47Z
      DOI: 10.1177/09603271231191436
      Issue No: Vol. 42 (2023)
       
  • Circular RNA 0000157 depletion protects human bronchial epithelioid cells
           from cigarette smoke extract-induced human bronchial epithelioid cell
           injury through the microRNA-149-5p/bromodomain containing 4 pathway

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      Authors: B Song, S Wu, L Ye, Z Jing, J Cao
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundCircular RNA (circRNA) has been reported to regulate respiratory diseases. In the study, we aimed to elucidate the role of circ_0000157 in smoke-related chronic obstructive pulmonary disease (COPD) and the inner mechanism.MethodsCOPD-like cell injury was induced by treating human bronchial epithelioid cells (16HBE) with cigarette smoke extract (CSE). The expression of circ_0000157, miR-149-5p, bromodomain containing 4 (BRD4), BCL2-associated x protein (Bax) and B-cell lymphoma-2 (Bcl-2) was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blotting. Enzyme-linked immunosorbent assay was performed to detect interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels. Malondialdehyde (MDA) production was detected by a lipid peroxidation MDA assay kit. Superoxide dismutase (SOD) activity was analyzed by a SOD activity assay kit.ResultsCirc_0000157 and BRD4 expression were upregulated, while miR-149-5p expression was downregulated in the blood of smokers with COPD and CSE-induced 16HBE cells compared with control groups. CSE treatment inhibited 16HBE cell proliferation and induced cell apoptosis, inflammation, and oxidative stress; however, these effects were remitted when circ_0000157 expression was decreased. In addition, circ_0000157 acted as a miR-149-5p sponge and regulated CSE-caused 16HBE cell damage by targeting miR-149-5p. The overexpression of BRD4, a target gene of miR-149-5p, attenuated the inhibitory effects of miR-149-5p introduction on CSE-induced cell damage. Further, circ_0000157 modulated BRD4 expression by associating with miR-149-5p in CSE-treated 16HBE cells.ConclusionCirc_0000157 knockdown ameliorated CSE-caused 16HBE cell damage by targeting the miR-149-5p/BRD4 pathway, providing a potential therapeutic strategy for clinic intervention in COPD.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-03T04:03:27Z
      DOI: 10.1177/09603271231167581
      Issue No: Vol. 42 (2023)
       
  • Role of hypoxia inducible factor/vascular endothelial growth
           factor/endothelial nitric oxide synthase signaling pathway in mediating
           the cardioprotective effect of dapagliflozin in cyclophosphamide-induced
           cardiotoxicity

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      Authors: Marwa Monier Mahmoud Refaie, Asmaa MA Bayoumi, Sahar Ahmed Mokhemer, Sayed Shehata, Nahla Mohammed Abd El-Hameed
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundCyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive alkylating agent. However, cardiac adverse effects of CP interfere with its clinical benefit. Cardio-oncology research is currently an important issue and finding effective cardiopreserving agents is a critical need. For the first time, we aimed to detect if dapagliflozin (DAP) could ameliorate CP-induced cardiac injury and investigated the role of hypoxia inducible factor α (HIF1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway.MethodsForty male Wistar albino rats were included in the current model. Studied groups are: control group; CP-induced cardiotoxicity group; CP group treated with DAP; CP group treated with DAP and administered a nitric oxide synthase inhibitor; nitro-ω-L-arginine (L-NNA) before DAP to explore the role of eNOS.ResultsOur data revealed that CP could induce cardiac damage as manifested by significant increases in cardiac enzymes, blood pressure, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), HIF1α, sodium glucose co-transporter 2 (SGLT2) and cleaved caspase-3 levels with toxic histopathological changes. However, there are significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, and eNOS. On the opposite side, co-administration of DAP showed marked improvement of CP-induced cardiac damage that may be due to its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties. Results showed decreasing the cardioprotective effect of DAP on administration of L-NNA, reflecting the critical effect of eNOS in mediating such protection.ConclusionDAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-01T11:31:05Z
      DOI: 10.1177/09603271231193392
      Issue No: Vol. 42 (2023)
       
  • Iron; Benefits or threatens (with emphasis on mechanism and treatment of
           its poisoning)

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      Authors: Mehrdad Rafati Rahimzadeh, Mehravar Rafati Rahimzadeh, Sohrab Kazemi, Ahmad Reza Moghadamnia, Maryam Ghaemi Amiri, Ali Akbar Moghadamnia
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a wide range of oxidation - reduction activities. Whenever iron exceeds the cellular metabolic needs, its excess causes changes in the products of cellular respiration, such as superoxide, hydrogen peroxide and hydroxyl. The formation of these compounds causes cellular toxicity. Lack of control over reactive oxygen species causes damages to DNA, proteins, and lipids. Conversely, superoxide, hydrogen peroxide and hydroxyl are reactive oxygen species, using antioxidants, restoring DNA function, and controlling iron stores lead to natural conditions. Iron poisoning causes clinical manifestations in the gastrointestinal tract, liver, heart, kidneys, and hematopoietic system. When serum iron is elevated, serum iron concentrations, total iron-binding capacity (TIBC) and ferritin will also increase. Supportive care is provided by whole bowel irrigation (WBI), esophagogastroduodenoscopy is required to evaluate mucosal injury and remove undissolved iron tablets. The use of chelator agents such as deferoxamine mesylate, deferasirox, deferiprone, deferitrin are very effective in removing excess iron. Of course, the combined treatment of these chelators plays an important role in increasing iron excretion, and reducing side effects.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-08-01T10:50:25Z
      DOI: 10.1177/09603271231192361
      Issue No: Vol. 42 (2023)
       
  • An artificial intelligence algorithm for analyzing globus pallidus
           necrosis after carbon monoxide intoxication

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      Authors: Ming-Jen Chan, Ching-Chih Hu, Wen-Hung Huang, Ching-Wei Hsu, Tzung-Hai Yen, Cheng-Hao Weng
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Globus pallidus necrosis (GPN) is one of typical neurological imaging features in patients with carbon monoxide (CO) poisoning. Current clinical guideline recommends neurological imaging examination for CO-intoxicated patients with conscious disturbance rather than routine screening, which may lead to undiagnosed GPN. We aimed to develop an artificial intelligence algorithm for predicting GPN in CO intoxication patients. We included CO intoxication patients with neurological images between 2000 and 2019 in Chang Gung Memorial Hospital. We collected 41 clinical and laboratory parameters on the first day of admission for algorithm development. We used fivefold cross validation and applied several machine learning algorithms. Random forest classifier (RFC) provided the best predictive performance in our cohort. Among the 261 patients with CO intoxication, 52 patients presented with GPN. The artificial intelligence algorithm using the RFC-based AI model achieved an accuracy = 79.2 ± 2.6%, sensitivity = 77.7%, precision score = 81.9 ± 3.4%, and F1 score = 73.2 ± 1.8%. The area under receiver operating characteristic was approximately 0.64. Top five weighted variables were Platelet count, carboxyhemoglobin, Glasgow Coma scale, creatinine, and hemoglobin. Our RFC-based algorithm is the first to predict GPN in patients with CO intoxication and provides fair predictive ability. Further studies are needed to validate our findings.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-07-26T05:35:16Z
      DOI: 10.1177/09603271231190906
      Issue No: Vol. 42 (2023)
       
  • Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease
           in hepatic lymphocytes infiltration

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      Authors: Khalid Alhazzani, Salah Q Alrewily, Khaldoon Aljerian, Khaled Alhosaini, Mohammad M. Algahtani, Mohammed Fhad Almutery, Abdullah S Alhamed, Ahmed Nadeem, Moureq R. Alotaibi, Ahmed Z. Alanazi
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Dasatinib is an effective treatment for chronic myeloid leukemia. However, cases of idiosyncratic hepatotoxicity were reported. This study was conducted to investigate the chemopreventive effects of hydroxychloroquine against dasatinib-induced hepatotoxicity. Balb/c mice were randomly assigned into four groups; vehicle control (5% DMSO, i.p., n = 6), dasatinib (50 mg/kg; i.p., n = 6), hydroxychloroquine (10 mg/kg, i.p., n = 6), and hydroxychloroquine + dasatinib (10 mg/kg + 50 mg/kg; i.p., n = 6). Treatments were given once every 2 days for 14 days. Serum and histopathological assessments of liver architecture and fibrosis were performed using H&E, Masson’s trichrome, and reticulin staining. The infiltration of lymphocytes was assessed using immunohistochemistry. The gene expression of antioxidant enzymes (CAT, SOD-2, GPX-1) was assessed using real-time quantitative PCR. Dasatinib showed a significant increase in liver injury biomarkers (AST and ALT) with higher lymphocytes infiltration (as indicated by CD3+, CD4+, CD8+, and CD20+ immunohistochemistry). Hepatic tissue of Dasatinib group exhibited significant downregulation in the gene expression of antioxidant enzymes (CAT, SOD-2, and GPX-1) compared to the control group. However, the combination of hydroxychloroquine with dasatinib showed a slight increase in AST and ALT. Also, hydroxychloroquine + dasatinib treated mice showed a significant reduction in lymphocytes infiltration as compared to dasatinib. The results showed that dasatinib induces an immune response leading to an increase in lymphocytes infiltration which promotes hepatocyte destruction and persistent liver injury. The results also suggest that hydroxychloroquine ameliorates dasatinib-induced hepatotoxicity via reduction in hepatic infiltration of T and B immune cells.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-07-11T12:58:35Z
      DOI: 10.1177/09603271231188492
      Issue No: Vol. 42 (2023)
       
  • Water-soluble Yb3+, Er3+ codoped NaYF4 nanoparticles induced SGC-7901 cell
           apoptosis through mitochondrial dysfunction and ROS-mediated ER stress

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      Authors: Chen Liu, Shaoqiang Sun, Jingwei Mao
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundNanoparticles are potential luminescent probes; among them, upconversion nanoparticles (UCNP) are currently being developed as fluorescent probes for biomedical applications. However, the molecular mechanisms of UCNP in human gastric cell lines remain poorly understood. Here, we aimed to examine UCNP cytotoxicity to SGC-7901 cells and explore its underlying mechanisms.MethodsThe effects of 50–400 μg/mL UCNP on human gastric adenocarcinoma (SGC-7901) cells were investigated. Flow cytometry was used to evaluate reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), intracellular Ca2+ levels, and apoptosis. Activated caspase-3 and nine activities were measured; meanwhile, cytochrome C (Cyt C) in the cytosol and B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), protein kinase B (Akt), phosphorylated-Akt (p-Akt), 78 kDa glucose-regulated protein (GRP78), 94 kDa glucose-regulated protein (GRP94), calpain-1, and calpain-2 protein levels were also detected.ResultsUCNP inhibited the viability of SGC-7901 cells in a concentration- and time-dependent manner and increased the proportion of cell apoptosis. Exposure to UCNP enhanced the ratio of Bax/Bcl-2, elevated the level of ROS, decreased ΔΨm, increased intracellular Ca2+ and Cyt C protein levels, decreased the levels of phosphorylated Akt, increased the activity of caspase-3 and caspase-9, and upregulated the protein expression of GRP-78, GRP-94, calpain-1 and calpain-2 in SGC-7901 cells.ConclusionUCNP induced SGC-7901 cell apoptosis by promoting mitochondrial dysfunction and ROS-mediated endoplasmic reticulum (ER) stress, initiating the caspase-9/caspase-3 cascade.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-07-08T12:35:47Z
      DOI: 10.1177/09603271231188493
      Issue No: Vol. 42 (2023)
       
  • Anlotinib induces apoptosis and second growth/mitosis phase block in
           cisplatin-resistant ovarian cancer cells via the aurora kinase A/p53
           pathway

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      Authors: Hongli Wang, Yu Wang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundCisplatin (DDP) resistance in ovarian cancer (OC) patients usually leads to treatment failure and increased mortality. Anlotinib has been shown to improve progression-free survival and overall survival in patients with platinum-resistant ovarian cancer, but the mechanism is unclear. This study aims to explore the mechanism by which anlotinib ameliorates platinum resistance in OC cells.MethodsCell viability was detected by the 3-4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide (MTT) method, and the apoptosis rate and changes in the cell cycle distribution were evaluated by flow cytometry. Bioinformatics analysis was used to predict the potential gene target of anlotinib in DDP-resistance SKOV3 cells, and its expression was verifies it by RT-qPCR, western blotting and immunofluorescence staining. Finally, ovarian cancer cells overexpressing AURKA were constructed, and the predicted results were verified by animal experiments.ResultsAnlotinib effectively induced apoptosis and G2/M arrest in OC cells and decreased the proportion of EdU-positive cells. AURKA was identified as a possible key target of anlotinib for inhibiting tumorigenic behaviors in SKOV3/DDP cells. Through combined immunofluorescence and western blot analyses, it was demonstrated that anlotinib could effectively inhibit the protein expression of AURKA and upregulate the expression of p53/p21, CDK1, and Bax protein. After overexpression of AURKA in OC cells, the induction of apoptosis and G2/M arrest by anlotinib were significantly inhibited. Anlotinib also effectively inhibited the growth of tumors in nude mice injected with OC cells.ConclusionsThis study demonstrated that anlotinib can induce apoptosis and G2/M arrest in cisplatin-resistant ovarian cancer cells through the AURKA/p53 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-07-01T01:26:02Z
      DOI: 10.1177/09603271231185774
      Issue No: Vol. 42 (2023)
       
  • Development and validation of a risk prediction nomogram for disposition
           of acute clozapine intoxicated patients to intensive care unit

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      Authors: AF Sharif, HA Aouissi, Z Kasemy, H Byeon, HI Lashin
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundClozapine is an atypical antipsychotic drug used for the treatment of refractory schizophrenia. It is reported as the most toxic in its class. Using serum clozapine level as a severity indicator is doubtful and unfeasible, particularly in low resourced countries.MethodsThis is an extended two-phase retrospective study that utilized medical records of patients diagnosed with acute clozapine intoxication and admitted to Tanta University Poison Control Center, Egypt during the past 6 years. Two hundred and eight medical records were used to establish and validate a nomogram for predicting the need for intensive care unit (ICU) admission in acute clozapine intoxicated patients.ResultsA reliable simple bedside nomogram was developed and proved its significant ability to predict the need for ICU admission, with an area under the curve (AUC) of 83.9% and 80.8% accuracy. It encompassed the age of admitted patients (AUC = 64.8%, p = .003), respiratory rate (AUC = 74.7%, p < .001), O2 saturation (AUC = 71.7%, p < .001), and random blood glucose level upon admission (AUC = 70.5%, p < .001). External validation of the proposed nomogram showed a high AUC (99.2%) with an overall accuracy of 96.2%.ConclusionThere is a need to develop a reliable objective tool predicting the severity and need for ICU admission in acute clozapine intoxication. The proposed nomogram is a substantially valuable tool to estimate ICU admission probabilities among patients with acute clozapine intoxication and will help clinical toxicologists make rapid decisions for ICU admission, especially in countries with low resources.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-28T07:51:29Z
      DOI: 10.1177/09603271231186154
      Issue No: Vol. 42 (2023)
       
  • Long noncoding RNA long intergenic non-protein-coding RNA 173 contributes
           to nasopharyngeal carcinoma progression by regulating microRNA-765/Gremlin
           1 pathway

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      Authors: Dan Wang, Heng Jiang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundLong intergenic non-protein-coding RNA 173 (LINC00173) executes vital functions in various cancers. Nevertheless, its role and expression in nasopharyngeal carcinoma (NPC) have yet to be investigated. Here, we investigated its effects on the malignancy characteristics of NPC and elucidated the potential molecular mechanism of LINC00173 in NPC progression.MethodsQuantitative real-time reverse transcription-PCR (qRT-PCR) and immunoblotting were conducted to estimate the LINC00173, microRNA-765 (miR-765), and Gremlin 1 (GREM1) expressions in NPC cells and tissues. Cell counting kit-8 (CCK8), colony formation, and wound healing experiments were done to evaluate the proliferation, growth, and migration of NPC cells, respectively. The tumorous growth of NPC cells in vivo was assessed through the xenograft tumor experiment. Furthermore, the interactions among miR-765, LINC00173, and GREM1 were investigated through bioinformatics analyses, luciferase reporter and RNA immunoprecipitation chip assays.ResultsAn upregulated LINC00173 expression was found in NPC cell lines and tissues. The functional experiments uncovered that its downregulation repressed NPC cell proliferation, growth, and migration. In addition, LINC00173 knockdown hampered the NPC cells’ tumorous growth in vivo. These effects could partially be reversed by downregulating miR-765. GREM1 is a downstream target of miR-765. GREM1 knockdown could repress the proliferation, growth, and migration of NPC cells. Nonetheless, these anti-tumor effects could be abolished by miR-765 downregulation. Mechanistically, LINC00173 increased the expression of GREM1 by binding with miR-765.ConclusionsLINC00173 functions as an oncogenic factor by binding with miR-765 to promote the progression of NPC via GREM1 upregulation. This study provides a novel insight into the molecular mechanisms involved in NPC progression.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-27T07:29:46Z
      DOI: 10.1177/09603271231172921
      Issue No: Vol. 42 (2023)
       
  • Protective effects of brain and muscle ARNT-like gene 1 on oxidized
           low-density lipoprotein-induced human brain microvascular endothelial cell
           injury by alleviating ferroptosis

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      Authors: Shui Yu, Yijun Zeng, Chenbin Ruan, Lei Bai, Zhang Liang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Ferroptosis plays an important role in atherosclerotic cerebrovascular diseases. The brain and muscle ARNT-like gene 1 (BMAL1) is an important mediator in the progression of cerebrovascular diseases. However, whether BMAL1 regulates ferroptosis in atherosclerotic cerebrovascular diseases remains obscure. Here, human brain microvascular endothelial cells (HBMECs) were exposed to oxidized low-density lipoprotein (ox-LDL) to imitate cerebrovascular atherosclerosis. It was found that ox-LDL treatment induced ferroptosis events and reduced BMAL1 expression in HBMECs, which could be reversed by ferroptosis inhibitor ferrostatin-1. Furthermore, BMAL1 overexpression markedly mitigated ox-LDL-induced ferroptosis events and cell damage. Moreover, BMAL1 overexpression significantly promoted nuclear factor erythroid 2-related factor 2 (Nrf2) expression in HBMECs under ox-LDL conditions. And, Nrf2 silencing attenuated the protective effects of BMAL1 on ox-LDL-stimulated HBMEC damage and ferroptosis. Altogether, our findings delineate the cerebrovascular protective role of BMAL1/Nrf2 by antagonizing ferroptosis in response to ox-LDL stimulation and provide novel perspectives for therapeutic strategies for atherosclerotic cerebrovascular diseases.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-21T05:25:38Z
      DOI: 10.1177/09603271231184630
      Issue No: Vol. 42 (2023)
       
  • Analysis of kidney proteomes to identify biological pathways associated
           with vancomycin-induced nephrotoxicity in mice by tandem mass tag-labeled
           quantitative and parallel reaction monitoring phosphoproteomics

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      Authors: Qiaoling Yang, Xuedong Yin, Hongjing Li, Lili Ding, Huajun Sun, Li Yang, Zhiling Li
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Vancomycin (VCM)-induced nephrotoxicity impedes its treatment applications. Thus, it is important to clarify the relevant mechanism. This study investigated phosphoprotein changes attributable to the VCM nephrotoxicity mechanisms. Biochemical, pathological and phosphoproteomic analyses based on C57BL/6 mice were performed to explore the mechanisms.VCM-treated mice showed increased levels of blood urea nitrogen and creatinine, and signs of acute tubular necrotic lesions. Phosphoproteomic profiling identified 3025 differentially phosphorylated phosphopeptides between the model and control group. Gene Ontology enrichment analysis demonstrated that Molecular Function “oxidoreductase activity” and Cellular Component “peroxisome” were markedly enriched. KEGG pathway analysis identified an enrichment in peroxisome pathway and PPAR (peroxisome proliferator-activated receptor) signaling pathways. Parallel reaction monitoring analysis revealed a significant downregulation of CAT, SOD-1, AGPS, DHRS4, and EHHADH at phosphorylation level by VCM. Notably, the phosphorylation of ACO, AMACR, and SCPX was downregulated by VCM, which are the fatty acid β-oxidation-related proteins involved in PPAR signaling pathways. The phosphorylated PEX5 involved in peroxisome biogenesis was upregulated by VCM. Collectively, these findings indicated that VCM-induced nephrotoxicity is closely associated with peroxisome pathway and PPAR signaling pathways. The current study provides important insight into the mechanisms of VCM nephrotoxicity and will aid in the development of preventive and therapeutic strategies against this nephropathy.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-21T04:51:01Z
      DOI: 10.1177/09603271231183885
      Issue No: Vol. 42 (2023)
       
  • Tanshinone IIA inhibits ischemia-reperfusion-induced inflammation,
           

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      Authors: Rui Zhang, Yunen Liu, Jihui You, Baiping Ge
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Ischemia-reperfusion (I/R) is a common clinical process, and the lung is one of the most sensitive organs of I/R injury, which often leads to acute lung injury (ALI). Tanshinone IIA (Tan IIA) has anti-inflammatory, antioxidant, and anti-apoptotic activities. However, the effects of Tan IIA on lung I/R injury remain uncertain. Twenty-five C57BL/6 mice were randomly divided into five groups: control (Ctrl), I/R, I/R + Tan IIA, I/R + LY294002 and I/R + Tan IIA + LY294002 group. Tan IIA (30 μg/kg) was injected intraperitoneally 1 h before injury in the I/R + Tan IIA and I/R + Tan IIA + LY294002 groups. These data showed that Tan IIA significantly improved I/R-induced histological changes and scores of lung injury, decreased lung W/D ratio, MPO and MDA contents, reduced infiltration of inflammatory cells, and decreased the expression of IL-1β, IL-6 and TNF-α. Meanwhile, Tan IIA significantly increased the expression of Gpx4 and SLC7A11, and decreased the expression of Ptgs2 and MDA. Moreover, Tan IIA significantly reversed the low expression of Bcl2, and the high expression of Bax, Bim, Bad and cleave-caspase 3. Furthermore, Tan IIA caused a significant increase in the phosphorylation levels of PI3K, Akt and mTOR in the lungs. However, these beneficial effects of Tan IIA on I/R-induced lung inflammation, ferroptosis and apoptosis were offset by LY294002. Our data suggest that Tan IIA significantly ameliorates I/R-induced ALI, which is mediated through activation of PI3K/Akt/mTOR pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-14T02:30:47Z
      DOI: 10.1177/09603271231180864
      Issue No: Vol. 42 (2023)
       
  • The possible cytotoxicity and genotoxicity assessment of indaziflam on
           HepG2 cells

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      Authors: Serpil Könen Adıgüzel
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      The use of pesticides in farmland has increased considerably to protect crops against pests, weeds, and diseases. However, pesticides and/or their residues in ecosystems may affect non-target organisms. Indaziflam is a widely used herbicide in agricultural areas in the southern region of Turkey. Therefore, this study aimed to investigate the possible genotoxic and cytotoxic effects of indaziflam on HepG2 cells using comet assay, micronucleus assay, and xCELLigence. The HepG2 cells were treated with various concentrations of indaziflam for different duration of time based on xCELLigence results. Accordingly, the cells were incubated with indaziflam at final concentrations of 1, 5, 10, 20, 40, and 80 μg/mL for 96 h for cytotoxicity assay. To assess genotoxicity, cells were treated with indaziflam at final concentrations of 10, 40, and 100 μg/mL for 4 and 24 h. Ethanol was used as a solvent for indaziflam. Hydrogen peroxide (40 μM) was used as a positive control. Studies have revealed that indaziflam did not show a statistically cytotoxic effect at the tested doses. Nevertheless, genotoxicity studies showed that indaziflam induced both DNA strand breaks and micronucleus numbers depending on the exposure time and dose.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-13T07:45:01Z
      DOI: 10.1177/09603271231183145
      Issue No: Vol. 42 (2023)
       
  • Identification and characterization of differentially expressed circRNA in
           2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cleft palate

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      Authors: Liyun Gao, Jingwen Tan, Chunhua Han, Junfei Fan, Jiayin He, Ting Luo, Shiqun Yu, Xiangxin Che, Lin Zhang, Xin Wang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Various circular RNAs (circRNAs) are novel class of non-coding RNAs, which are pervasively transcribed in the genome. CircRNAs play important roles in human, animals and plants. Up to now, there was no report regarding circRNAs of cleft palate by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) induce. The present study screened identification and characterization of differential expressed-circRNAs in TCDD-induced cleft palate. 6903 circRNAs candidates came from cleft palates. Among them, 3525 circRNAs are up-regulation, and 3378 circRNAs are down-regulation by TCDD induce. The cluster and GO analysis found that circRNAs involved in biological process, cellular component, and molecular function. Through the analysis of KEGG Pathway, circRNAs made functions via classical signaling pathway in cleft palate, such as TGF-beta signaling pathway, BMP signal pathway, MAPK signaling pathway. In addition, we found down-regulated circRNA224, circRNA3302 and up-regulated circRNA5021 targeted tgfbr3, but up-regulated circRNA4451 targeted tgfbr2. circRNA4451 may make functions through TGF-beta signaling pathway. These results suggested that many different circRNAs may make important role in TCDD-induced cleft palate, which provided a theoretical basis for further research.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-12T03:27:08Z
      DOI: 10.1177/09603271231183359
      Issue No: Vol. 42 (2023)
       
  • Renal glucose transporters play a role in removal of cadmium from kidney
           cells mediated by GMDTC – A novel metal chelator

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      Authors: Xiaojiang Tang, Bo Xiao, Qile Zhao, Wei Hu, Amber McKenery, Zhiyong Zhong
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Cadmium (Cd) is a toxic heavy metal, exposure to which leads to adverse health effects including chronic kidney damage. Tremendous efforts have been explored in identifying safe chelating agents for removing accumulated Cd from kidney, but with limited success owing to their associated side effects and the ineffectiveness in eliminating Cd. A newly developed chelating agent, sodium (S)-2-(dithiocarboxylato((2S,3 R,4R,5 R)-2,3,4,5,6-pentahydroxyhexyl) amino)-4(methylthio)butanoate (GMDTC), has been shown to effectively mobilize Cd from kidney. However, the mechanism(s) of removal are unclear, while it has been hypothesized that renal glucose transporters potentially play key roles mainly because GMDTC contains an open chain glucose moiety. To test this hypothesis, we utilized the CRISPR/Cas9 technology and human kidney tubule HK-2 cells, and constructed sodium-dependent glucose transporter 2 (SGLT2) or glucose transporter 2 (GLUT2) gene knockout cell lines. Our data showed that GMDTC’s ability in removing Cd from HK-2 cells was significantly reduced both in GLUT2−/− or SGLT2−/− cells, with a removal ratio reduced from 28.28% in the parental HK-2 cells to 7.37% in GLUT2−/− cells and 14.6% in SGLT2−/− cells. Similarly, knocking out the GLUT2 or SGLT2 led to a compromised protective effect of GMDTC in reducing cytotoxicity of HK-2 cells. This observation was further observed in animal studies, in which the inhibition of GLUT2 transporter by phloretin treatment resulted in reduced efficiency of GMDTC in removing Cd from the kidney. Altogether, our results show that GMDTC is safe and highly efficient in removing Cd from the cells, and this effect is mediated by renal glucose transporters.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-09T10:42:34Z
      DOI: 10.1177/09603271231183056
      Issue No: Vol. 42 (2023)
       
  • LINC00641 impeded the malignant biological behaviors of papillary thyroid
           carcinoma cells via interacting with IGF2BP1 to reduce GLI1 mRNA stability
           

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      Authors: Dongdong Meng, Shuiying Zhao, Lina Wu, Xiaojun Ma, Di Zhao, Zhifu Li
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Dysregulation of long intergenic non-protein coding RNA 00,641 (LINC00641) is associated with the malignancy progression of multiple cancers, including thyroid carcinoma. The current study aimed to determine the role of LINC00641 in papillary thyroid carcinoma (PTC) and the underlying mechanism. We found that LINC00641 was downregulated in PTC tissues and cells(p < 0.05), and overexpression of LINC00641 inhibited PTC cell proliferation and invasion, and induced apoptosis(p < 0.05), while silencing LINC00641 promoted the proliferation and invasion in PTC cells, and inhibited cell apoptosis(p < 0.05). Furthermore, we found that Glioma-associated oncogene homolog 1 (GLI1) expression was negatively correlated with LINC00641 expression in PTC tissues (r2 = 0.7649, p < 0.0001), and silencing GLI1 inhibited PTC cell proliferation and invasion, and induced apoptosis(p < 0.05). Meanwhile, RNA immunoprecipitation (RIP) and RNA pull-down assays confirmed that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) bound to LINC00641 as an RNA binding protein, and overexpression of LINC00641 destabilized GLI1 mRNA by competitively binding to IGF2BP1. Rescue experiments revealed that overexpression of GLI1 restored the inhibitory effect of LINC00641 overexpression on activation of the AKT pathway, as well as PTC cell proliferation and invasion, and counteracted the induction of cell apoptosis by LINC00641 overexpression. Finally, in vivo experimental results showed that overexpression of LINC00641 markedly suppressed tumor growth and reduced expression of GLI1 and p-AKT in xenograft tumor mice(p < 0.05). In summary, this study highlighted that LINC00641 plays a critical role in the malignant biological progression of PTC by regulating the LINC00641/IGF2BP1/GLI1/AKT signaling pathway, which may serve as a potential therapeutic target for PTC.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-09T06:30:20Z
      DOI: 10.1177/09603271231180856
      Issue No: Vol. 42 (2023)
       
  • Withania somnifera Alter BCL2/Bax signaling and trigger apoptosis of MCF-7
           and MDA-MB231 breast cancer cells exposed to γ-radiation

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      Authors: Rokaya E Maarouf, Khaled Shaaban Azab, Neama M El Fatih, Hamed Helal, Laila Rashed
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Treatment strategies encompass synchronization of more than one therapy with specific dependence on zeroing side effects of natural products that might represent a niche in the continuous struggle against cancer. Thus, this study aimed at assessing the role of Withania somnifera; WS (Ashwagandha) in forcing MCF7 or MDA-MB 231 irradiated breast cancer cells to outweigh the route of programmed cell death. We check to what extent SIRT1-BCL2/Bax signaling pathway was interrelated to form apoptotic cancer cells. MDA or MCF7 cells are categorized into four groups: gp1, Control (C): MDA-MB-231 or MCF7 cells not treated with WS or exposed to γ-rays, gp2 (WS): cells challenged with WS for MDA-MB-231 or MCF7 cells respectively, gp3: irradiated (R) MDA-MB-231 or MCF7 cells exposed to γ-rays (4 Gy; one shot) and gp4 WS and irradiated (WS + R): cells challenged with WS as in gp2 and exposed to gamma rays as in gp3. The results revealed that, WS established IC50 equivalent to 4897.8 μg/ml in MDA-MB-231 cells or equivalent to 3801.9 μg/ml in MCF7 cells. The flowcytometric analysis (Annexin V and cell cycle) showed that WS induces apoptosis at pre-G phase and induces cell arrest at G2/M and preG1 phases for MDA-MB-231 and at the preG1 for MCF7 cells. Furthermore, the WS + R group of cells (MDA-MB-231 and MCF7) showed significant increases in the expression of SIRT1, and BCL2 and a decrease in BAX compared with WS or R group. It could be concluded that WS has an anti-proliferative action on MDA-MB-231 and MCF7 cells because of its capability to enhance apoptosis.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-06-09T03:43:53Z
      DOI: 10.1177/09603271231180849
      Issue No: Vol. 42 (2023)
       
  • LINC00294/miR-620/MKRN2 axis provides biomarkers and negatively regulates
           malignant progression in colorectal carcinoma

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      Authors: Puliang Qi, Zhihua Yexie, Chen Xue, Guoqiang Huang, Zhanxue Zhao, Xikun Zhang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundColorectal carcinoma (CRC) ranks the third most frequent malignancy worldwide. Makorin RING zinc finger-2 (MKRN2) has been identified as a tumor suppressor in CRC, and the bioinformatics prediction indicated that some non-coding RNAs (ncRNAs) that directly or indirectly regulate MKRN2 might play critical roles in CRC progression. This study aimed to analyze the regulatory effect of LINC00294 on CRC progression, and to explore the underlying mechanisms by assessing miR-620 and MKRN2. The potential prognostic value of the ncRNAs and MKRN2 was also investigated.MethodsThe expression of LINC00294, MKRN2, miR-620 was examined by qRT-PCR. Cell counting kit-8 assay was used to assess the proliferation of CRC cells. Transwell assay was used to evaluate the migration, invasion of CRC cells. Kaplan-Meier method and log-rank test were used to perform comparative analysis of overall survival in CRC patients.ResultsLower expression of LINC00294 was observed in both CRC tissues and cell lines. In CRC cells, LINC00294 overexpression inhibited cell proliferation, migration and invasion, but these effects were directly reversed by the overexpression of miR-620, which was demonstrated as a target of LINC00294. Additionally, MKRN2 was found to be a target gene of miR-620, and might mediate the regulatory function of LINC00294 in CRC progression. In CRC patients, low LINC00294, MKRN2 and high miR-620 expression was associated poor overall survival of CRC.ConclusionsLINC00294/miR-620/MKRN2 axis had the potential to provide prognostic biomarkers for CRC patients, and negatively regulated the malignant progression of CRC cells, including proliferation, migration and invasion.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-05-23T06:40:30Z
      DOI: 10.1177/09603271231167577
      Issue No: Vol. 42 (2023)
       
  • Anti-EMT properties of ergothioneine attenuate lipopolysaccharide-induced
           oxidative stress-mediated acute lung injury via modulating
           TGF-β/smad/snail signaling pathway

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      Authors: Shabnoor Iqbal, Farhat Jabeen, Noman Aslam, Maria Manan
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Acute lung injury (ALI) is a heterogeneous pulmonary illness that is fast developing and has a high fatality rate. The current investigation set out to interpret the convergence of oxidative stress, inflammatory cytokines, TNF-α, snail, vimentin, e-cadherin, and NF-kB activation in ALI pathology. The outcome of assays of oxidative stress, ELISA, and western blot showed the declined of CAT, SOD, GPx, IL-1β, TNF-α, and upregulation of TGF-β, smad2/3, smad4, NF-kB, snail, and vimentin, concurrently with downregulation of e-cadherin expression in lung tissues as well as BALF in LPS-injected rats. The photomicrographs of the lungs marked severe congestion, infiltration of cytokines, and thickening of the alveolar walls. Pretreatments of ergothioneine after LPS-induced ALI, inhibited EMT-induction by blocking TGF-β, smad2/3, smad4, snail, vimentin, NF-kB, and inflammatory cytokines, and increased the expression of E-cadherin and antioxidant levels in a dose-dependent manner. These events helped to restore lung histoarchitecture and reduce acute lung injury. The present findings suggest that ergothioneine at 100 mg/kg is as effective as febuxostat (reference drug). The study concluded that ergothioneine may be replaced with febuxostat as a treatment option for ALI owing to its side effects after clinical trials for pharmaceutical purposes.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-05-22T11:18:26Z
      DOI: 10.1177/09603271231178015
      Issue No: Vol. 42 (2023)
       
  • Sulforaphane triggers iron overload-mediated ferroptosis in gastric
           carcinoma cells by activating the PI3K/IRP2/DMT1 pathway

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      Authors: Jing Wen, Fan Yang, Cheng-xiang Fang, Hong-liu Chen, Li Yang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveIncreasing evidence indicates that prolonged exposure to sulforaphane (SFN) can improve malignancies. However, the role of iron in SFN-triggered death in gastric carcinoma cells and the underlying molecular mechanisms remain unclear. Thus, the current study explored the effects of SFN on iron overload-mediated ferroptosis and the PI3K/IRP2/DMT1 pathway in gastric carcinoma cells.MethodsWe utilized the MGC-803 cell line to assess whether SFN affected iron metabolism and whether this effect contributed to cell death. Pharmacological inhibition of iron metabolism also was performed to determine the molecular mechanism underlying SFN-triggered iron overload and the disturbance in iron metabolism.ResultsOur data revealed that SFN treatment altered iron homeostasis and led to iron overload in vitro. Interestingly, SFN-stimulated cell death resulted from ferroptosis, a recently identified iron-dependent form of regulated cell death. Furthermore, an iron chelator, deferiprone, ameliorated the SFN-triggered mitochondrial dysfunction and reduced the iron overload. In addition, we found that the SFN-triggered iron overload was regulated by the PI3K/IRP2/DMT1 signaling pathway.ConclusionWe discovered that disturbance in iron metabolism might be involved in the SFN-triggered cell death in gastric carcinoma cells. Blockade of the PI3K/IRP2/DMT1 axis could provide a feedback effect on SFN-induced ferroptosis to protect tumor cells from growth.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-05-18T09:30:56Z
      DOI: 10.1177/09603271231177295
      Issue No: Vol. 42 (2023)
       
  • Expression of concern: “Sesamol induces cytotoxicity via mitochondrial
           apoptosis in SCC-25 cells”

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-05-12T02:00:46Z
      DOI: 10.1177/09603271231176139
      Issue No: Vol. 42 (2023)
       
  • Microsomal glutathione S-transferase 1 targets the autophagy signaling
           pathway to suppress ferroptosis in gastric carcinoma cells

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      Authors: Z Peng, N Peng
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveFerroptosis is a newly discovered form of programmed cell death; however, the specific mechanisms that regulate ferroptosis have yet to be fully elucidated in gastric carcinoma. In this study, we aimed to investigate how microsomal glutathione S-transferase 1 (MGST1) regulates ferroptosis in gastric carcinoma cells.MethodsGastric adenocarcinoma (SGC7901) cells that overexpressed MGST1 or expressed only low levels of MGST1, were treated with specific compounds (erastin, sorafenib, RSL3, MK-2206 and SC79). Then, we detected the levels of malondialdehyde (MDA), glutathione (GSH), iron and reactive oxygen species (ROS). Protein expression levels of the non-classical autophagy and protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathways were determined by western blotting and cell viability was analyzed by Cell Counting Kit-8 (CCK-8) assays. The expressions of target genes were detected using qRT-PCR.ResultsWe evaluated a range of ferroptosis-inducing compounds and found that MGST1 expression was down-regulated during ferroptosis in SGC7901 cells. The ferroptosis inducer RSL3 played a role in classical ferroptotic events while the overexpression of MGST1 impaired these effects. Interestingly, the overexpression of MGST1 resulted in the inactivation of autophagy by repressing the expression of ATG16L1 and the conversion of LC3-I to LC3-II. The upregulation of ATG16L1 eliminated the inhibitory action of MGST1 on ferroptosis. Notably, the overexpression of MGST1 induced the activation of the Akt/GSK-3β pathway. An Akt inhibitor antagonized the inhibitory effects of MGST1 on autophagy and ferroptosis.ConclusionCollectively, our findings demonstrate a novel molecular mechanism and signaling pathway for ferroptosis. We also characterized that the overexpression of MGST1 induces gastric carcinoma cell proliferation by activating the Akt/GSK-3β signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-05-10T09:48:31Z
      DOI: 10.1177/09603271231172915
      Issue No: Vol. 42 (2023)
       
  • Cathepsin B mediates the lysosomal-mitochondrial apoptosis pathway in
           arsenic-induced microglial cell injury

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      Authors: Zheyu Zhang, Ruozheng Pi, Yuheng Jiang, Mashaal Ahmad, Heng Luo, Jieya Luo, Jie Yang, Baofei Sun
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Arsenic is a prevalent environmental pollutant that targets the nervous system of living beings. Recent studies indicated that microglial injury could contribute to neuroinflammation and is associated with neuronal damage. Nevertheless, the neurotoxic mechanism underlying the arsenic-induced microglial injury requires additional research. This study explores whether cathepsin B promotes microglia cell damage caused by NaAsO2. Through CCK-8 assay and Annexin V-FITC and PI staining, we discovered that NaAsO2 induced apoptosis in BV2 cells (a microglia cell line). NaAsO2 was verified to increase mitochondrial membrane permeabilization (MMP) and promote the generation of reactive oxygen species (ROS) through JC-1 staining and DCFDA assay, respectively. Mechanically, NaAsO2 was indicated to increase the expression of cathepsin B, which could stimulate pro-apoptotic molecule Bid into the activated form, tBid, and increase lysosomal membrane permeabilization by Immunofluorescence and Western blot assessment. Subsequently, apoptotic signaling downstream of increased mitochondrial membrane permeabilization was activated, promoting caspase activation and microglial apoptosis. Cathepsin B inhibitor CA074-Me could mitigate the damage of microglial. In general, we found that NaAsO2 induced microglia apoptosis and depended on the role of the cathepsin B-mediated lysosomal-mitochondrial apoptosis pathway. Our findings provided new insight into NaAsO2-induced neurological damage.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-05-08T12:33:11Z
      DOI: 10.1177/09603271231172724
      Issue No: Vol. 42 (2023)
       
  • Neurologic disease produced by Rathayibacter toxicus-derived corynetoxins

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      Authors: John Finnie
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Corynetoxins, members of the tunicamycin group of antibiotics, are produced by the bacterium, Rathayibacter toxicus. They cause a severe neurologic disorder in domestic livestock, are hepatotoxins, and can damage retinal photoreceptors. For these toxins to be ingested by livestock, the bacterium must first be transported onto host plants by adhering to nematode larvae. In the infected seed heads, bacterial galls (gumma) then form. While corynetoxicity occurs most commonly in Australia, it has occurred sporadically in other countries and, due to the widespread global distribution of the bacterium, nematode, and host plants, there is great potential for further spread, particularly as the range of host plant species and nematode vectors identified for R. toxicus is increasing. Since many animal species are susceptible to corynetoxins poisoning, it is likely that humans would also be vulnerable if exposed to these potent, lethal toxins.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-05-03T02:30:49Z
      DOI: 10.1177/09603271231165672
      Issue No: Vol. 42 (2023)
       
  • Establishment of an animal model of sciatic nerve injury induced by local
           anesthetics

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      Authors: Qi E, Yunlin Wu, Xiaoxia Liang, Meixin Chen, Jiayi Peng, Ziyin Zhou, Xianjie Wen
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Peripheral neurotoxicity injury caused by local anesthetics is a common complication of clinical anesthesia. The study of its mechanism is helpful to prevent and treat the neurotoxic injury of local anesthetics. Previous studies on peripheral neurotoxicity injury caused by local anesthetics have mainly focused on in vitro cell experiments. Due to the lack of an animal model of peripheral neurotoxicity damage caused by local anesthetics, there are few in vivo experimental studies regarding this topic. Herein, 1% ropivacaine hydrochloride was injected into the sciatic nerve by direct incision and exposure of the sciatic nerve to create a local anesthetic neurotoxic injury model. The results showed that 1% ropivacaine hydrochloride could reduce the lower limb motor score and mechanical paw withdrawal threshold in mice 48 hours after injection. Pathological sections showed that 48 hours after treatment with 1% ropivacaine hydrochloride, the sciatic nerve showed increased axonal edema and degeneration, edema between nerve fiber bundles, increased degeneration of axon and myelin sheath vacuoles, edema of nerve bundle membrane and local degeneration and necrosis, and a large number of inflammatory cells around the nerve adventitia were soaked. The above results show that under open vision, 1% ropivacaine hydrochloride can cause injury to the sciatic nerve after 48 h of treatment, which can simulate the neurotoxic damage of local anesthetics. This animal model provides a research tool for studying the mechanism of neurotoxic injury caused by local anesthetics.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-26T11:16:04Z
      DOI: 10.1177/09603271231173382
      Issue No: Vol. 42 (2023)
       
  • Rhamnetin alleviates polystyrene microplastics-induced testicular damage
           by restoring biochemical, steroidogenic, hormonal, apoptotic,
           inflammatory, spermatogenic and histological profile in male albino rats

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      Authors: Ali Hamza, Muhammad Umar Ijaz, Haseeb Anwar
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      The current research was performed to evaluate the ameliorative effects of Rhamnetin (RHM) on polystyrene microplastics (PS-MPs)-instigated testicular dysfunction in male albino rats. 48 albino rats were distributed in four groups, i.e., control, PS-MPs treated, PS-MPs + RHM co-treated and RHM only supplemented group. PS-MPs exposure considerably reduced anti-oxidant enzymes i.e., catalase (CAT), glutathione peroxidase (GSR), superoxide dismutase (SOD) and glutathione reductase (GPx) activities. Whereas, reactive oxygen species (ROS) level along with malondialdehyde (MDA) was considerably escalated in PS-MPs treated rats as well as a potential decline was observed in sperm progressive motility. Additionally, a substantial upsurge was noticed in the count of dead sperms, deformity in the tail, mid-piece and head of sperms in PS-MPs treated rats. PS-MPs exposure also decreased steroidogenic enzymes, 17β-hydroxysteroid dehydrogenase (17β-HSD), steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) expressions. Moreover, the levels of inflammatory indices i.e., Interleukin-6 (IL-6), Nuclear factor kappa-B (NF-κB), Interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) activity were also increased in PS-MPs administrated group. Besides it increased the expression of apoptotic markers (Bax and caspase-3) expression. Whereas, anti-apoptotic marker i.e., Bcl-2 expression was reduced. Moreover, luteinizing hormone (LH), follicle-stimulating hormone (FSH) as well as plasma testosterone levels were also decreased. PS-MPs exposure also led to a substantial histopathological damage in testicular tissues. However, RHM supplementation potentially reduced the damaging effects of PS-MPs in the reproductive tissues of male albino rats. Thus, the current study revealed, RHM possesses potential to prevent PS-MPs-induced testicular damage due to its anti-oxidant anti-apoptotic, anti-inflammatory as well as androgenic properties.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-26T03:28:41Z
      DOI: 10.1177/09603271231173378
      Issue No: Vol. 42 (2023)
       
  • Discovery of the mechanism of n-propylparaben-promoting the proliferation
           of human breast adenocarcinoma cells by activating human estrogen
           receptors via metabolomics analysis

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      Authors: Yunxia Chen, Chan Zhao, Jun Zheng, Ning Su, Hainan Ji
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundN-propylparaben (PP), a type of paraben, is commonly used as a preservative or antibacterial agent in daily chemicals, medicine, food, cosmetics, feed, and various industrial preservatives. Although PP promotes the growth of human breast adenocarcinoma (MCF-7) cells by activating the human estrogen receptor (ER), the mechanism responsible for this type of programmed cell proliferation is poorly understood.ObjectiveTo clarify the effect of PP on cell metabolic function and the potential molecular mechanism of PP induced MCF-7 cell proliferation from a new perspective.MethodsTo use high-resolution mass spectrometry-based metabolomics combined with bioinformatics analysis to analyze the molecular mechanism.ResultsThe results illustrated that differential endogenous compounds related to the effects of PP on cell metabolic functions were detected. PP was found to promote glycolysis in MCF-7 cells and enhance the tricarboxylic acid cycle (TCA cycle) in mitochondria, thus improving the energy supply to these tumor cells for metabolic function and promotion of rapid proliferation. Moreover, we found that PP promoted cell proliferation by affecting the mitogen-activated protein kinase (MAPK) signaling pathway of MCF-7 cells.ConclusionOur results revealed the molecular mechanism of low concentration PP promoting MCF-7 cell proliferation by activating ER.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-25T11:53:00Z
      DOI: 10.1177/09603271231171648
      Issue No: Vol. 42 (2023)
       
  • Preclinical Evaluation of interferon-gamma primed human Wharton’s
           jelly-derived mesenchymal stem cells

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      Authors: Sang-Jin Park, Dae Seong Kim, Myeongjin Choi, Kang-Hyun Han, Ji-Seok Han, Keon Hee Yoo, Kyoung-Sik Moon
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      The potential of human mesenchymal stem cells (MSCs) for cell therapy has been investigated in numerous immune-mediated conditions; MSCs are considered one of the most promising cellular therapeutics to treat intractable diseases. Recently, approaches to prime MSCs have been investigated, thereby generating cellular products with enhanced potential for a variety of clinical applications. Interferon-gamma (IFN-γ) priming is a current approach used to increase the therapeutic efficacy of MSCs. In this study, we determined the systemic toxicity, tumorigenicity and biodistribution of IFN-γ-primed Wharton’s jelly-derived (WJ)-MSCs in male and female BALB/c-nu/nu mice. There were no deaths or pathologic lesions in the mice treated with 5 × 106 cells/kg IFN-γ-primed MSCs in the repeated dose study. In the tumorigenicity study, one of the subcutaneously treated mice showed bronchioloalveolar adenoma in the lung but tested negative for human-specific anti-mitochondrial antibody, suggesting the spontaneous murine origin of the adenoma. A biodistribution study using real-time quantitative polymerase chain reaction demonstrated the systemic IFN-γ-primed MSC clearance by day 28. Based on the toxicity, biodistribution, and tumorigenicity studies, we concluded that IFN-γ-primed MSCs at 5 × 106 cells/kg do not induce tumor formation and adverse changes.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-24T10:43:34Z
      DOI: 10.1177/09603271231171650
      Issue No: Vol. 42 (2023)
       
  • Salidroside attenuates LPS-induced kidney injury through activation of
           SIRT1/Nrf2 pathway

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      Authors: Jiaying Pan, Jie Zhu, Liang Li, Tao Zhang, Zhenyu Xu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundSalidroside (SAL) is an anti-inflammatory, antioxidant, anticancer, neuroprotective, and renal protective active ingredient extracted from the Chinese herb. Rhodiola Rosea. However, the role of SAL in kidney injury has not yet been elucidated. The study investigates SAL’s protective effect and mechanism in lipopolysaccharide (LPS)-induced kidney injury.MethodsMale C57BL/6 wild-type mice (6–8 weeks old) were intraperitoneally injected with 10 mg/kg LPS for 24 h and SAL (50 mg/kg) 2 h before the LPS injection. Biochemical and TUNNEL staining assay analyses were carried out to assess kidney injury. The Elisa assay analyzed the mRNA expression of NGAL and KIM-1. RT-qPCR and Western blotting measured the mRNA and protein expression of HO-1, NQO1, Beclin1, P62, SIRT1, Nrf2, and PNCA, respectively.ResultsOur study found that mice co-treated with SAL had significantly reduced blood urea nitrogen (BUN), serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) levels in serum of LPS-induced mice. SAL cotreatment potentially decreased the apoptosis rate of kidney tissue and podocytes induced by LPS. SAL significantly reduced the content of malondialdehyde (MDA) and increased superoxide dismutase (SOD) in LPS-treated mice. Autophagy-related proteins Beclin-1 increased but decreased P62 protein expression by cotreatment of SAL in LPS-injected mice. SAL enhanced the Sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in LPS-induced kidney tissues.ConclusionOur results speculate that SAL protects against LPS-induced kidney injury through activation of the SIRT1/Nrf2 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-20T06:12:19Z
      DOI: 10.1177/09603271231169520
      Issue No: Vol. 42 (2023)
       
  • Tricin attenuates diabetic retinopathy by inhibiting oxidative stress and
           angiogenesis through regulating Sestrin2/Nrf2 signaling

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      Authors: Xueli Yang, Dalei Li
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      To explore the potential function of tricin in diabetic retinopathy (DR) and investigate whether Sestrin2 is closely involved in DR. A single intraperitoneal injection of streptozotocin-induced diabetes model in Sprague-Dawley rats and a high glucose-induced retinal epithelial cell model in ARPE-19 cells were established. The retinas were removed and examined by hematoxylin-eosin (HE) staining and dihydroethidium (DHE) staining. The proliferation ability and reactive oxygen species (ROS) level of ARPE-19 cells were detected by 5-ethynyl-2′-deoxyuridine (EdU) and flow cytometry. Then, the content of superoxide dismutase (SOD), malonaldehyde (MDA), and glutathione peroxidase (GSH-Px) in serum or cell supernatant was tested using enzyme linked immunosorbent assay (ELISA). In addition, the expression of Sestrin2, nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), platelet endothelial cell adhesion molecule-1 (CD31), and vascular endothelial growth factor receptor 2 (VEGFR2) in retina tissue or ARPE-19 cells were validated through western blot and immunofluorescence assays. With the increase of MDA and ROS concentration, Sestrin2 expression was downregulated significantly, and Nrf2 and HO-1 expression was also reduced in retina tissue or ARPE-19 cells of model group, whereas CD31 and VEGFR2 expression was upregulated. However, tricin ameliorated the oxidative stress and angiogenesis and rectified the abnormal expression of Sestrin2/Nrf2 in diabetic retinopathy. Further mechanistic studies showed that silence Sestrin2 reduced the protective effect of tricin on ARPE-19 cells, as well as abolished its regulating effect on the Nrf2 pathway. These results suggested that tricin inhibits oxidative stress and angiogenesis in retinal epithelial cells of DR rats via reinforcing Sestrin2/Nrf2 signaling.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-20T04:57:58Z
      DOI: 10.1177/09603271231171642
      Issue No: Vol. 42 (2023)
       
  • Anti-oxidative properties of nanocrocin in Zearalenone induced toxicity on
           Hek293 cell; The novel formulation and cellular assessment

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      Authors: Fatemeh Ghafari, Zohre Sadeghian, Akram Oftadeh Harsin, Sodabe Khodabandelo, Akram Ranjbar
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundZearalenone (ZEA) is a mycotoxin produced by fungi and induces cytotoxicity by the generation of reactive oxygen species. The aim of this study was to evaluate and compare the nephroprotective effects of crocin and nano-crocin against ZEA-induced toxicity in HEK293 cell line via modulation of oxidative stress and special formulation to make nano-crocin.MethodNano-crocin physicochemical properties, such as size, load, appearance, and drug release profile were determined. Also, the viability of intoxicated HEK293 cells was evaluated by MTT assay. Furthermore, lactate dehydrogenase lipid Peroxidation (LPO), and oxidative stress biomarkers were measured.ResultThe best nano-crocin formulation with superior entrapment effectiveness (54.66 ± 6.02), more significant drug loading (1.89 ± 0.01), better zeta potential (−23.4 ± 2.844), and smaller particle size (140.3 ± 18.0 nm) was chosen. This study showed that treatment with crocin and nano-crocin in ZEA-induced cells, significantly decreased LDH and LPO levels and increased superoxide dismutase (SOD), catalase (CAT) activities, and total antioxidant capacity (TAC) levels compared to the control group. Moreover, nano-crocin had a more curative effect against oxidative stress than crocin.ConclusionNiosomal structure of crocin, when administered with the special formulation, may be more beneficial in reducing ZEA-induced in vitro toxicity than conventional crocin.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-18T11:32:51Z
      DOI: 10.1177/09603271231169911
      Issue No: Vol. 42 (2023)
       
  • Relationship between clock gene expression and CYP2C19 and CYP3A4 with
           benzodiazepines

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      Authors: Naoto Tani, Tomoya Ikeda, Takaki Ishikawa
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      The present study aimed to clarify the expressions and roles of clock genes involved in drug metabolism in patients taking benzodiazepines (BZDs), as well as the drug metabolism regulators controlled by clock genes for each BZD type. The relationships between the expressions of the clock genes BMAL1, PER2, and DBP and the drug-metabolizing enzymes CYP3A4 and CYP2C19 were investigated using livers from BZD-detected autopsy cases. In addition, the effect of BZD exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. The expressions of DBP, CYP3A4, and CYP2C19 in the liver were lower in the diazepam-detected group than in the non-detected group. Furthermore, BMAL1 expression correlated with CYP2C19 expression. Cell culture experiments showed that the expressions of DBP and CYP3A4 decreased, whereas those of BMAL1 and CYP2C19 increased after diazepam and midazolam exposure. The results of the analyses of autopsy samples and cultured cells suggested that DBP regulates CYP3A4 when exposed to BZD. Understanding the relationship between these clock genes and CYPs may help achieve individualized drug therapy.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-18T11:00:40Z
      DOI: 10.1177/09603271231171643
      Issue No: Vol. 42 (2023)
       
  • Hyperoside exerts protective effects against anticardiolipin
           antibody-induced recurrent pregnancy loss in vivo and in vitro

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      Authors: Yanli Song, Dongjie He, Shaoqi Shi, Tianwei Cui, Hui Zhang, Xianmin Zhao, Tingting Ni, Huidongzi Xiao, Aiwu Wei
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundWomen with antiphospholipid syndrome (APS) or antiphospholipid antibodies (aPLs) are at high risk for obstetric complications, including recurrent pregnancy loss (RPL). However, effective treatments for RPL are lacking.ObjectiveThis study aimed to reveal the function and underlying mechanism of hyperoside (Hyp) in RPL associated with antiphospholipid antibodies (aCLs).MethodsThe pregnant rats (N = 24) were divided randomly into four groups: normal human-IgG (NH-IgG); aCL-pregnancy loss (aCL-PL); aCL-PL + Hyp (40 mg/kg/day); aCL-PL + low molecular weight heparin (LMWH, 525 μg/kg/day). HTR‐8 cells were treated with 80 μg/mL aCL to establish the cell models of miscarriage.ResultsIn pregnant rats, aCL-IgG injection raised the abortion rate of embryos, while Hyp treatment inhibited the effects. Additionally, Hyp inhibited the platelet activation and uteroplacental insufficiency caused by aCL. In vivo and in vitro experiments further suggested that Hyp suppressed aCL-induced inflammation and apoptosis by downregulating NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-related factors and decreasing apoptotic rates. After aCL administration, Hyp therapy downregulated the expression of purinergic ligand-gated ion channel 7 (P2X7), which is reported to induce cytokine release and apoptosis. Furthermore, we found that the treatment of 3′-O-(4-Benzoyl) benzoyl-ATP (BzATP, an agonist of the P2X7 receptor) reversed the inhibitory effects of Hyp on cell function.ConclusionsHyp exerts protective effects on aCL-induced pregnancy loss by preventing platelet activation-mediated P2X7/NLRP3 pathway. Therefore, Hyp may provide a feasible pharmaceutical strategy for the treatment of RPL.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-12T09:32:44Z
      DOI: 10.1177/09603271231163476
      Issue No: Vol. 42 (2023)
       
  • Beneficial effects of sennoside B on pentylenetetrazole-induced seizures
           in rats

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      Authors: Hüseyin Sahin, Oytun Erbaş
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundEpilepsy is a common disorder affecting approximately 50 million people worldwide. Oxidative stress is known to play an important role in the pathophysiology of diseases, including epilepsy. In this study, we investigated the effects of sennoside B on PTZ-induced seizures in rats.MethodThe rats were grouped into Group Electroencephalography and Group Behavioral. Both Groups were divided into eight subgroups, and these subgroups were compared in terms of the time of first myoclonic jerk, Racine’s Convulsion Scale, malondialdehyde levels, and brain superoxide dismutase activity. The experimental seizure model was performed with pentylenetetrazol.ResultsThe spike percentage was significantly lower in groups that received sennoside B, and this beneficial effect was shown to be associated with the dose of sennoside B received. The RCS score was lower and the FJM onset time was higher in the sennoside B-administered groups. Additionally, brain MDA and brain aquaporin-3 levels were lower and brain SOD activity was higher in the sennoside-administered groups.ConclusionsThe present study shows the beneficial effects of sennoside B on PTZ-induced convulsion in rats. It is considered that sennoside B which is a natural and safe product would be a good candidate for strengthening the management of epilepsy without serious side effects.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-04-06T06:47:09Z
      DOI: 10.1177/09603271231168764
      Issue No: Vol. 42 (2023)
       
  • Retraction Notice

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      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.

      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-31T12:41:48Z
      DOI: 10.1177/09603271231167718
      Issue No: Vol. 42 (2023)
       
  • Sitagliptin attenuates neuronal apoptosis via inhibiting the endoplasmic
           reticulum stress after acute spinal cord injury

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      Authors: Chengxuan Tang, Tianzhen Xu, Minghai Dai, Xiqiang Zhong, Guangjie Shen, Liangle Liu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Regulation of endoplasmic reticulum stress (ER) stress-induced apoptosis and nerve regeneration is a hopeful way for acute spinal cord injury (SCI). Sitagliptin (Sita) is one of dipeptidyl peptidase-4 (DPP-4) inhibitor, which is beneficial neurons damaged diseases. However, its protective mechanisms of avoiding nerve injury remain unclear. In this study, we further investigated the mechanism of the anti-apoptotic and neuroprotective effects of Sita in promoting locomotor recovery from SCI. In vivo results showed that Sita treatment reduced neural apoptosis caused by SCI. Moreover, Sita effectively attenuated the ER tress and associated apoptosis in rats with SCI. A striking feature was the occurrence of nerve fiber regeneration at the lesion site, which eventually led to significant locomotion recovery. In vitro results showed that the PC12 cell injury model induced by Thapsigargin (TG) also showed similar neuroprotective effects. Overall, sitagliptin showed potent neuroprotective effects by targeting the ER stress-induced apoptosis both in vivo and vitro, thus facilitating the regeneration of the injured spinal cord.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-28T11:37:27Z
      DOI: 10.1177/09603271231168761
      Issue No: Vol. 42 (2023)
       
  • Treatment with paraquat affects the expression of ferroptosis-related
           genes

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      Authors: Xiaogang Ge, Qiqi Cai, Sheng Zhang, Xianlong Wu, Pan Ying, Jingjing Ke, Zhihui Yang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveWe aimed to explore the mechanisms underlying paraquat (PQ)-induced damage using cell lines (NCTC1469, TC-1, TCMK-1) and bioinformatic analysis of the GSE153959 dataset. Assessment of changes in the expression of ferroptosis-related genes in cellular damage due to paraquat poisoning and the important value of these genes in the pathogenesis.MethodsData were retrieved from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) related to ferroptosis were identified by Venn plots and analyzed for enrichment. Proteins encoded by these DEGs were studied for interactions. qRT-PCR and western blotting analyses of cultured cells were used to determine the expression of ferroptosis-related DEGs and their corresponding protein levels.ResultsWe identified 25 DEGs primarily involved in epidermal growth factor receptor signaling, apoptotic signaling pathways, endoplasmic reticulum (ER) stress, and ferroptosis. From these, we uncovered eight ferroptosis-related DEGs, four of which were involved in ER response and regulators of ferroptosis—Chac1 (ChaC glutathione specific gamma-glutamylcyclotransferase 1), Atf3 (activating transcription factor 3), Tfrc (transferrin receptor), and Slc7a11 (solute carrier family 7 member 11). Significant changes in mRNA and protein levels of CHAC1, ATF3, TFRC, and SLC7A11 were confirmed in PQ-exposed cells.ConclusionER stress and ferroptosis are critical for PQ-induced cell damage. CHAC1, ATF3, TFRC, and SLC7A11 are essential molecules implicated in PQ-induced ferroptosis that may serve as therapeutic targets for the amelioration of PQ poisoning.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-24T10:14:39Z
      DOI: 10.1177/09603271231167585
      Issue No: Vol. 42 (2023)
       
  • Syringaresinol inhibits cardiorenal fibrosis through HSP90 in a
           cardiorenal syndrome type 2

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      Authors: Jianjie Wang, Jianqin Zou, Cheng Zhao, Han Yu, Jiajia Teng, Lei Dong
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundSyringaresinol processes anti-inflammatory and antioxidative activity. However, the effects of syringaresinol on cardiorenal fibrosis caused by cardiorenal syndrome type 2 (CRS2) are unclear.MethodsMolecular docking predicted binding activity of syringaresinol to heat shock protein 90 (HSP90). The toxicity of a 4-weeks treatment with 20 mg/kg of syringaresinol was observed by measuring serum pro-inflammatory cytokines levels and by cardiorenal pathology. A CRS2 rad model was established by myocardial infarction using ligation over an 8 week-period. Rats were divided into five groups, including sham, CRS2, pimitespib, syringaresinol, and HSP90 + syringaresinol. Rats were received a 4-weeks daily treatment with 10 mg/kg pimitespib (a HSP90 inhibitor) or 20 mg/kg syringaresinol. Recombinant adeno-associated virus (rAAV) carrying a periostin (PE) promoter driving the expression of wild-type HSP90 (rAAV9-PE-HSP90, 1 × 1011 μg) was treated intravenously once in CRS2 model rats. Cardiorenal function and pathology were assessed. Expressions of HSP90 and TGF-β1 in the myocardium and kidney were measured by immunohistochemistry and western blotting.ResultsSyringaresinol showed good binding activity with HSP90, and no signs of toxicity in rats following treatment. Pimitespib or syringaresinol significantly improved the cardiorenal function and fibrosis in rats with CRS2. Meanwhile, the rAAV9-PE-HSP90 injection obviously blocked the effects of syringaresinol.ConclusionsSyringaresinol targets HSP90 to suppress CRS2-induced cardiorenal fibrosis, providing a promising therapeutic drug for CRS2.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-24T08:36:53Z
      DOI: 10.1177/09603271231165678
      Issue No: Vol. 42 (2023)
       
  • Intraperitoneal pretreatment of ellagic acid and chrysin alleviate
           ifosfamide-induced neurotoxicity, but betanin induces death in male wistar
           rats

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      Authors: Ahmad Salimi, Mohammad Shabani, Hossein Mohammadi, Vahid Sudi
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundIfosfamide (IFO) is a widely used antineoplastic drug with broad-spectrum efficacy against various types of cancer. However, different toxicities associated with IFO has limited its use. This study was to establish the prophylactic effects of betanin, chrysin and ellagic acid against IFO-induced neurotoxicity in rats.MethodsAnimals were randomly divided into eight groups, control, IFO, IFO + betanin, IFO + chrysin, IFO + ellagic acid, betanin, chrysin and ellagic acid groups. Betanin (50 mg/kg, i.p.), chrysin (25 mg/kg, i.p.) and ellagic acid (25 mg/kg, i.p.) were administered to rats once daily for two consecutive days. IFO (500 mg/kg, i.p.) was administered on third day.ResultsResults demonstrated that only ellagic acid markedly decreased the activity of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) compared with IFO alone, while chrysin was only effective on BChE activity. Also, ellagic acid ameliorated IFO-induced lipid peroxidation and glutathione (GSH) depletion, while chrysin only decreased GSH depletion. Histopathological alteration in the IFO-induced brain tissues were decreased especially after administration of ellagic acid. Intraperitoneal pretreatment with betanin, followed by IFO resulted in death of all treated animals. In addition, all mitochondrial toxicity parameters induced by IFO in the rat brain tissue were ameliorated by ellagic acid, chrysin and even betanin.ConclusionTaken together, our results demonstrated that especially ellagic acid and to some extent chrysin show a typical neuroprotective effect on IFO-induced acute neurotoxicity through mitochondrial protection and antioxidant properties. Also, the results of our studies showed that pretreatment with betanin followed by IFO was lethal.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-23T04:04:15Z
      DOI: 10.1177/09603271221147883
      Issue No: Vol. 42 (2023)
       
  • Protective effects of butylated hydroxytoluene on the initiation of
           N-nitrosodiethylamine-induced hepatocellular carcinoma in albino rats

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      Authors: Sally A Fahim, Samar Ibrahim, Samer A Tadros, Osama A Badary
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Diethylnitrosamine (DEN), a hepatocarcinogen, is found in a variety of smoked and fried foods and was reported to be hepatotoxic in mice. Butylated hydroxytoluene (BHT) is a potent antioxidant used in cosmetic formulations and as a food additive and preservative. As a result, BHT was studied as a potential inhibitor in the early stages of diethylnitrosamine (DEN)-induced HCC. Male Wistar albino rats (n = 24) were equally subdivided. Group 1 was the negative control; Group 2 and 3 administered BHT and DEN, respectively; Group 4 received BHT followed by DEN. Blood samples and rat livers were taken for biochemical and histological investigation. Hepatotoxicity was assessed by increased liver enzymes and HCC indicators, along with reduced antioxidant and pro-apoptotic factors. AFP, AFPL3, GPC3, GSH, SOD, MDA, CASP3 and BAX expression increased significantly after DEN treatment. DEN also reduced GPx, CAT, and CYP2E1 activity, and BCl-2 expression. Moreover, in the hepatic parenchyma, the DEN caused histological alterations. Pretreatment with BHT enhanced antioxidant status while preventing histopathological and most biochemical alterations. BHT pretreatment suppresses DEN-initiated HCC by decreasing oxidative stress, triggering intrinsic mitotic apoptosis, and preventing histopathological changes in liver tissue.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-21T04:29:24Z
      DOI: 10.1177/09603271231165664
      Issue No: Vol. 42 (2023)
       
  • Genistein attenuates renal ischemia-reperfusion injury via ADORA2A pathway

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      Authors: HY He, HZ Shan, SQ Li, RG Diao
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundStudies have shown oxidative stress and apoptosis are the main pathogenic mechanisms of renal ischemia/reperfusion (IR) injury (IRI). Genistein, a polyphenolic non-steroidal compound, has been extensively explored in oxidative stress, inflammation and apoptosis. Our research aims to reveal the potential role of genistein on renal IRI and its potential molecular mechanism both in vivo and in vitro.MethodsIn vivo experiments, mice were pretreated with or without genistein. Renal pathological changes and function, cell proliferation, oxidative stress and apoptosis were measured. In vitro experiments, overexpression of ADORA2A and knockout of ADORA2A cells were constructed. Cells proliferation, oxidative stress and apoptosis were analyzed.ResultsOur results in vivo showed that the renal damage induced by IR was ameliorated by genistein pretreatment. Moreover, ADORA2A was activated by genistein, along with inhibition of oxidative stress and apoptosis. The results in vitro showed that genistein pretreatment and ADORA2A overexpression reversed the increase of apoptosis and oxidative stress in NRK-52E cells induced by H/R, while the knockdown of ADORA2A partially weakened this reversal from genistein treatment.ConclusionsOur results demonstrated that genistein have a protective effect against renal IRI by inhibiting oxidative stress and apoptosis via activating ADORA2A, presenting its potential use for the treatment of renal IRI.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-18T11:49:59Z
      DOI: 10.1177/09603271231164913
      Issue No: Vol. 42 (2023)
       
  • Azilsartan suppresses the antiapoptotic biomarker and pro-inflammatory
           cytokines in rat model of cisplatin-induced retinal and optic nerve
           toxicity

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      Authors: Noor Majid Raheem, Naza Mohammed Ali Mahmood
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundThe local renin-angiotensin system has been discovered in the eyes; thus, this study evaluates the Azilsartan effect in the retina and optic nerve toxicity induced by Cisplatin in vivo.MethodologyForty-eight male rats were randomly assigned into six groups of 8 animals. Group 1 was healthy control that received 0.5 mL/day of 0.5% carboxymethyl cellulose (CMC) orally (PO). Group 2 received a single dose of the 7.0 mg/kg CIS intraperitoneally with 0.5 mL/day of 0.5% CMC-PO. Groups 3 and 4 received 3.5 and 7.0 mg/kg/day of AZIL-PO, respectively. Groups 5 and 6 received 3.5 and 7.0 mg/kg/day of AZIL-PO, respectively together with a single dose of 7.0 mg/kg of CIS-IP. The ocular tissue and serum estimated the TNF-α, NF-kβ, and Casp-3. A complete blood count was also measured, and the eye was sent for histological examination.ResultsThe administration of the 3.5 mg/kg AZIL significantly (p < 0.05) reduced the ocular tissue and serum TNF-α, NF-kB, and Casp-3 levels, when given to CIS treated group, while the 7.0 mg/kg AZIL does not. Additionally, azilsartan shows no negative impact on the CBC in rats. Finally, the eye histological examination showed a significant (p < 0.05) drop in the signs of inflammation and cellular degeneration, particularly after administration of the 3.5 mg/kg AZIL to the CIS-treated group.ConclusionA low dose of AZIL exerts an anti-inflammation and an anti-apoptotic effect through significant suppression of the pro-inflammatory mediators and an apoptotic biomarker by blocking the local angiotensin II type
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-17T09:32:19Z
      DOI: 10.1177/09603271231155092
      Issue No: Vol. 42 (2023)
       
  • Glutathione S-transferase zeta 1 alters the HMGB1/GPX4 axis to drive
           ferroptosis in bladder cancer cells

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      Authors: Hongyan Zhu, Qitian Chen, Yang Zhang, Lingling Zhao
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveThe ability of glutathione S-transferase zeta 1 (GSTZ1) to modulate homeostasis of cellular redox and induce ferroptosis was explored in bladder cancer cells, and the involvement of the high mobility group protein 1/glutathione peroxidase 4 (HMGB1/GPX4) in these effects was studied.MethodsBIU-87 cells stably overexpressing GSTZ1 were transfected with appropriate plasmids to deplete HMGB1 or overexpress GPX4, then treated with deferoxamine and ferrostatin-1. Antiproliferative effects were assessed by quantifying levels of ferroptosis markers, such as iron, glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS), GPX4, transferrin, and ferritin.ResultsGSTZ1 was significantly downregulated in bladder cancer cells. GSTZ1 overexpression downregulated GPX4 and GSH, while greatly increasing levels of iron, MDA, ROS, and transferrin. GSTZ1 overexpression also decreased proliferation of BIU-87 cells and activated HMGB1/GPX4 signaling. The effects of GSTZ1 on ferroptosis and proliferation were antagonized by HMGB1 knockdown or GPX4 overexpression.ConclusionGSTZ1 induces ferroptotic cell death and alters cellular redox homeostasis in bladder cancer cells, and these effects involve activation of the HMGB1/GPX4 axis.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-11T10:58:01Z
      DOI: 10.1177/09603271231161606
      Issue No: Vol. 42 (2023)
       
  • Prenatal cyanuric acid exposure induced spatial learning impairments
           associated with alteration of acetylcholine-mediated neural information
           flow at the hippocampal CA3-CA1 synapses of male rats

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      Authors: Wei Sun, Xuanyin Zhao, Yiwen Wan, Yang Yang, Xiaoliang Li, Xiao Chen, Yazi Mei, Lei An
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Cyanuric acid (CA) is reported to induce nephrotoxicity but its toxic effect is not fully known. Prenatal CA exposure causes neurodevelopmental deficits and abnormal behavior in spatial learning ability. Dysfunction of the acetyl-cholinergic system in neural information processing is correlated with spatial learning impairment and was found in the previous reports of CA structural analogue melamine. To further investigate the neurotoxic effects and the potential mechanism, the acetylcholine (ACh) level was detected in the rats which were exposed to CA during the whole of gestation. Local field potentials (LFPs) were recorded when rats infused with ACh or cholinergic receptor agonist into hippocampal CA3 or CA1 region were trained in the Y-maze task. We found the expression of ACh in the hippocampus was significantly reduced in dose-dependent manners. Intra-hippocampal infusion of ACh into the CA1 but not the CA3 region could effectively mitigate learning deficits induced by CA exposure. However, activation of cholinergic receptors did not rescue the learning impairments. In the LFP recording, we found that the hippocampal ACh infusions could enhance the values of phase synchronization between CA3 and CA1 regions in theta and alpha oscillations. Meanwhile, the reduction in the coupling directional index and the strength of CA3 driving CA1 in the CA-treated groups was also reversed by the ACh infusions. Our findings are consistent with the hypothesis and provide the first evidence that prenatal CA exposure induced spatial learning defect is attributed to the weakened ACh-mediated neuronal coupling and NIF in the CA3-CA1 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-09T06:32:35Z
      DOI: 10.1177/09603271231163477
      Issue No: Vol. 42 (2023)
       
  • A review of challenges and prospects of 3D cell-based culture models used
           for studying drug induced liver injury during early phases of drug
           development

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      Authors: John K Chipangura, Yonela Ntamo, Bert Mohr, Nireshni Chellan
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Drug-induced liver injury (DILI) is the leading cause of compound attrition during drug development. Over the years, a battery of in-vitro cell culture toxicity tests is being conducted to evaluate the toxicity of compounds prior to testing in laboratory animals. Two-dimensional (2D) in-vitro cell culture models are commonly used and have provided a great deal of knowledge; however, these models often fall short in mimicking natural structures of tissues in-vivo. Testing in humans is the most logical method, but unfortunately there are ethical limitations associated with human tests. To overcome these limitations better human-relevant, predictive models are required. The past decade has witnessed significant efforts towards the development of three-dimensional (3D) in-vitro cell culture models better mimicking in-vivo physiology. 3D cell culture has advantages in being representative of the interactions of cells in-vivo and when validated can act as an interphase between 2D cell culture models and in-vivo animal models. The current review seeks to provide an overview of the challenges that make biomarkers used for detection of DILI not to be sensitive enough during drug development and explore how 3D cell culture models can be used to address the gap with the current models.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-07T06:19:29Z
      DOI: 10.1177/09603271221147884
      Issue No: Vol. 42 (2023)
       
  • Genotoxicity of oxidative hair dye precursors: A systematic review

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      Authors: Željka Babić, Sarah Hallmann, Martin S Havmose, Jeanne D Johansen, Swen M John, Cara Symanzik, Wolfgang Uter, Patricia Weinert, Henk F van der Molen, Sanja Kezic, Jelena Macan, Rajka Turk
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      This systematic review, conducted according to the PRISMA guidelines, focuses on genotoxicity of oxidative hair dye precursors. The search for original papers published from 2000 to 2021 was performed in Medline, Web of Science, Cochrane registry, Scientific Committee on Consumer Safety of the European Commission and German MAK Commission opinions. Nine publications on genotoxicity of p-phenylenediamine (PPD) and toluene-2,5-diamine (p-toluylenediamine; PTD) were included, reporting results of 17 assays covering main genotoxicity endpoints. PPD and PTD were positive in bacterial mutation in vitro assay, and PPD tested positive also for somatic cell mutations in the Rodent Pig-a assay in vivo. Clastogenicity of PPD and PTD was revealed by in vitro chromosomal aberration assay. The alkaline comet assay in vitro showed DNA damage after PPD exposure, which was not confirmed in vivo, where PTD exhibited positive results. PPD induced micronucleus formation in vitro, and increased micronucleus frequencies in mice erythrocytes following high dose oral exposure in vivo. Based on the results of a limited number of data from the classical genotoxicity assay battery, this systematic review indicates genotoxic potential of hair dye precursors PPD and PTD, which may present an important health concern for consumers and in particular for professional hairdressers.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-03-07T06:14:02Z
      DOI: 10.1177/09603271231159803
      Issue No: Vol. 42 (2023)
       
  • Sevoflurane Postconditioning Attenuates Cerebral Ischemia-Reperfusion
           Injury by Inhibiting SP1/ACSL4-Mediated Ferroptosis

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      Authors: Ning Lyu, Xiaoyun Li
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Sevoflurane is the most commonly used anesthetic in clinical practice and exerts a protective effect on cerebral ischemia-reperfusion (I/R) injury. This study aims to elucidate the molecular mechanism by which sevoflurane postconditioning protects against cerebral I/R injury. Oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro and the middle cerebral artery occlusion (MCAO) model in vivo were established to simulate cerebral I/R injury. Sevoflurane postconditioning reduced neurological deficits, cerebral infarction, and ferroptosis after I/R injury. Interestingly, sevoflurane significantly inhibited specificity protein 1 (SP1) expression in MACO rats and HT22 cells exposed to OGD/R. SP1 overexpression attenuated the neuroprotective effects of sevoflurane on OGD/R-treated HT22 cells, evidenced by reduced cell viability, increased apoptosis, and cleaved caspase-3 expression. Furthermore, chromatin immunoprecipitation and luciferase experiments verified that SP1 bound directly to the ACSL4 promoter region to increase its expression. In addition, sevoflurane inhibited ferroptosis via SP1/ACSL4 axis. Generally, our study describes an anti-ferroptosis effect of sevoflurane against cerebral I/R injury via downregulating the SP1/ASCL4 axis. These findings suggest a novel sight for cerebral protection against cerebral I/R injury and indicate a potential therapeutic approach for a variety of cerebral diseases.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-27T02:02:51Z
      DOI: 10.1177/09603271231160477
      Issue No: Vol. 42 (2023)
       
  • MAPK-interacting kinases inhibition by eFT508 overcomes chemoresistance in
           preclinical model of osteosarcoma

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      Authors: Bin Huang, Peicheng Jin, Kaijun Yi, Junhu Duan
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for many cancers with little known in osteosarcoma. This study evaluated the efficacy of eFT508, a highly selective inhibitor of MNK1/2, as single drug alone and in combination with paclitaxel in preclinical models of osteosarcoma. EFT508 is active against multiple osteosarcoma cell lines via inhibiting growth, survival and migration. It also demonstrates anti-osteosarcoma selectivity with much less toxicity on normal osteoblastic than osteosarcoma cells. Consistent with in vitro findings, eFT508 at non-toxic dose significantly arrested tumor growth in mice throughout the whole duration of treatment. Mechanistically, eEFT508 is highly effective in blocking eIF4E phosphorylation and eIF4E-mediated protein translation. Combination index shows that eFT508 and paclitaxel is synergistic in osteosarcoma cells. Our findings highlight the therapeutic value of MNK1/2 inhibition and suggest eFT508 as a promising candidate for the treatment of osteosarcoma.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-25T09:59:30Z
      DOI: 10.1177/09603271231158047
      Issue No: Vol. 42 (2023)
       
  • Signature of miR-21 and MEG-2 and their correlation with TGF-β
           signaling in breast cancer

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      Authors: EM Desouky, AK Khaliefa, WG Hozayen, SM Shaaban, NA Hasona
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Breast cancer is highly prevalent and considered the main challenge to public health among females in Egypt as in other countries. MicroRNA-21 (miR-21) and MEG-2 are noncoding RNA attributed to their aberrant expression in several diseases, including breast cancer. This study aimed to assess the reliability of serum expression levels of miR-21 and MEG-2 in discriminating stages of breast cancer and scrutinize their correlations with the targeted transforming growth factor-beta (TGF-β) expression. One hundred and 30 participants whose ages ranged from 28 to 62 years were included in this study, divided into one hundred breast cancer patients and 30 healthy participants. miR-21 and TGF-β expression levels showed upregulation in patients with BC and elevated miR-21/TGF-β levels consistent with the BC stage. In addition, LncRNA (MEG-2) showed down-regulation in patients with BC. MEG-2 expression levels revealed a gradual decrease consistent with the BC stage. In addition, a negative relationship between the MEG-2 and the miR-21 and TGF-β differential expression was also noticed. This study suggested that miR-21 and MEG-2 can be used as prospective diagnostic biomarkers and emphasized the crucible role of TGF-β as therapeutic targets for BC.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-24T10:24:39Z
      DOI: 10.1177/09603271231159799
      Issue No: Vol. 42 (2023)
       
  • Kaempferol inhibits airway inflammation induced by allergic asthma through
           NOX4-Mediated autophagy

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      Authors: Jianfeng Xu, Zhenyu Yu, Wei Li
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundKaempferol has important medicinal value in the treatment of asthma. However, its mechanism of action has not been fully understood and needs to be explored and studied.MethodsA binding activity of kaempferol with nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was analyzed by molecular docking. Human bronchial epithelial cells (BEAS-2B) were treated with different concentrations (0, 1, 5, 10, 20, 40 μg/mL) of kaempferol to select its suitable concentration. In the transforming growth factor (TGF)-β1-induced BEAS-2B, cells were treated with 20 μg/mL kaempferol or 20 μM GLX35132 (a NOX4 inhibitor) to analyze its effects on NOX4-mediated autophagy. In the ovalbumin (OVA)-induced mice, 20 mg/kg kaempferol or 3.8 mg/kg GLX351322 administration was performed to analyze the therapeutic effects of kaempferol on NOX4-mediated autophagy. An autophagy activator, rapamycin, was used to confirm the mechanism of kaempferol in treatment of allergic asthma.ResultsA good binding of kaempferol to NOX4 (score = −9.2 kcal/mol) was found. In the TGF-β1-induced BEAS-2B, the NOX4 expression was decreased with kaempferol dose increase. The secretions of IL-25 and IL-33, and the NOX4-mediated autophagy were significantly decreased by kaempferol treatment in the TGF-β1-induced BEAS-2B. In the OVA-challenged mice, kaempferol treatment improved airway inflammation and remodeling through suppressing NOX4-mediated autophagy. The rapamycin treatment clearly hampered the therapeutic effects of kaempferol in the TGF-β1-induced cells and OVA-induced mice.ConclusionsThis study identifies kaempferol binds NOX4 to perform its functions in the treatment of allergic asthma, providing an effective therapeutic strategy in the further treatment of asthma.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-21T07:07:16Z
      DOI: 10.1177/09603271231154227
      Issue No: Vol. 42 (2023)
       
  • Silencing lncRNA HCG18 regulates GPX4-inhibited ferroptosis by adsorbing
           miR-450b-5p to avert sorafenib resistance in hepatocellular carcinoma

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      Authors: Xiaoming Li, Yunhui Li, Peilong Lian, Qigang lv, Fangfeng Liu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Ferroptosis is potential to relieve drug resistance in hepatocellular carcinoma (HCC). Glutathione peroxidase 4 (GPX4) is a critical modulator of ferroptosis. This study discussed the mechanism of GPX4-inhibited ferroptosis in sorafenib resistance in HCC. HCG18 in HCC cells was detected. Sorafenib resistant (SR) cell line Huh7-SR cells were treated with sorafenib (0, 2.5, 5, 7.5, 10 μM). After silencing HCG18 in Huh7-SR cells, cell activity, proliferation and apoptosis were detected. The levels of iron, the concentration of MDA, GSH and lipid reactive oxygen species (ROS) were measured to evaluate the ferroptosis. The downstream mechanism of HCG18 was predicted and verified. Huh7-SR cells were infected with lentivirus sh-HCG18 to establish xenograft tumor model. HCG18 was elevated in HCC cells and associated with sorafenib resistance. Silencing HCG18 inhibited cell proliferation, promoted apoptosis, and impaired sorafenib resistance. Ferroptosis was inhibited in Huh7-SR cells, while silencing HCG18 inhibited sorafenib resistance by promoting ferroptosis. GPX4 overexpression averted the promotion of sh-HCG18 on ferroptosis, thereby reducing sorafenib resistance. HCG18 sponged miR-450b-5p to regulate GPX4. Collectively, Silencing HCG18 inhibits GPX4 by binding to miR-450b-5p, promotes GPX4-inhibited ferroptosis, and averts sorafenib resistance in HCC.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-14T11:48:44Z
      DOI: 10.1177/09603271221142818
      Issue No: Vol. 42 (2023)
       
  • Serum and glucocorticoid inducible kinase 1 modulates mitochondrial
           dysfunction and oxidative stress in doxorubicin-induced cardiomyocytes by
           regulating Hippo pathway via Neural precursor cell-expressed
           developmentally down-regulated 4 type 2

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      Authors: Zongyi Zou, Tingting Zhao, Zhu Zeng, Yuan An
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Doxorubicin (Dox) was reported to cause mitochondrial dysfunction and oxidative stress in cardiomyocytes, leading to cardiomyocyte apoptosis and ultimately heart failure. Serum and glucocorticoid inducible kinase 1 (SGK1) participates in the progression of various cardiovascular diseases. Thus, we aimed to explore the role and regulatory mechanism of SGK1 in Dox-induced cardiomyocyte injury. The expression of SGK1 was evaluated in blood samples of heart failure children, and in myocardial tissues and blood samples of Dox-induced rats. Subsequently, we treated cardiomyocytes with Dox in vitro. A gain-of-function assay was performed to assess the effects of SGK1 on mitochondrial dysfunction and oxidative stress in Dox-induced cardiomyocytes. Furthermore, the modulation of SGK1 on Neural precursor cell-expressed developmentally down-regulated 4 type 2 (NEDD4-2) expression and the subsequent Hippo pathway was validated. In our study, we found that SGK1 was downregulated in blood samples of heart failure children, as well as myocardial tissues and blood samples of Dox-induced rats. SGK1 overexpression alleviated the decreases of mitochondrial complex activity, mitochondrial membrane potential, adenosine triphosphate (ATP) content and ATP synthetase activity stimulated by Dox. Besides, SGK1 overexpression reversed the promoting effects of Dox on oxidative stress and apoptosis. Mechanistically, SGK1 overexpression inhibited the expression of NEDD4-2 and blocked the subsequent activation of Hippo pathway. NEDD4-2 overexpression or activation of Hippo reversed the protective effects of SGK1 overexpression on Dox-induced cardiomyocyte injury. In conclusion, our results revealed that SGK1 modulated mitochondrial dysfunction and oxidative stress in Dox-induced cardiomyocytes by regulating Hippo pathway via NEDD4-2.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-14T02:39:03Z
      DOI: 10.1177/09603271231158039
      Issue No: Vol. 42 (2023)
       
  • Albiflorin ameliorates mesangial proliferative glomerulonephritis by
           PI3K/AKT/NF-κB pathway

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      Authors: Haiyan Yu, Yu Wang, Zida He, Ruixue Chen, Yingni Dai, Yingqian Tang, Ye Chen
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Background: The most common type of glomerulonephritis in China is mesangial proliferative glomerulonephritis (MPGN) featured with mesangial cell overproliferation and inflammation, as well as fibrosis. Albiflorin (AF) is an effective composition extracted from Paeonia Alba Radix and has been administrated for various diseases. Nevertheless, there is no research reporting the effect of AF on MPGN.Purpose: Our work aims to probe into the role and possible mechanism of AF on MPGN.Research Design: We investigated the effects of AF on mesangial cell overproliferation, inflammation, and fibrosis in vitro and in vivo and identified the related signaling pathways.Study Sample: human mesangial cells (HMCs) and male Sprague Dawley (SD) rats.Data Analysis: SPSS 18.0 was used to analyze the data.Results: AF attenuated the proliferation and inflammation both in vitro and in vivo. In detail, AF decreased the ki67 expression in lipopolysaccharides (LPS)-treated HMCs and MPGN rats, and the mRNA expression or contents of inflammatory cytokines were reduced after AF treatment. The fibrosis of LPS-treated HMCs and MPGN rats was also reduced by AF. Moreover, AF effectively restrained 24 h urinary protein, improved kidney function, and mitigated dyslipidemia and pathological injury of MPGN rats. Additionally, we found that the protective effects of AF were accompanied by the blocking of PI3K/AKT/NF-κB pathway, and the inhibitory effects of AF on MPGN were reversed by insulin-like growth factor (IGF-1), the PI3K agonist.Conclusions: AF alleviates MPGN via restraining mesangial cell overproliferation, inflammation, and fibrosis via PI3K/AKT/NF-κB signaling.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-13T06:07:51Z
      DOI: 10.1177/09603271221145386
      Issue No: Vol. 42 (2023)
       
  • Irigenin attenuates lipopolysaccharide-induced acute lung injury by
           inactivating the mitogen-activated protein kinase (MAPK) signaling pathway
           

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      Authors: Dan Liu, Qing Wang, Wen Yuan, Qiang Wang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Acute lung injury (ALI) is a serious pulmonary inflammation disease with high mortality. Irigenin, an isoflavone from rhizomes of the Belamcanda chinensis, has been reported to exert anti-inflammatory, anti-oxidative, and anti-apoptotic activities in several diseases. However, it is still unclear whether irigenin can exert a beneficial effect in ALI. A network pharmacology method was utilized to predict the hub targets and potential therapeutic mechanisms of irigenin against ALI. Lipopolysaccharide (LPS) was used to establish the mice model of ALI for evaluating the effects of irigenin. According to the protein-protein interaction (PPI) network, we identified EGFR, HRAS, AKT1, SRC, and HSP90AA1 as the top five significant genes. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment assays showed that irigenin might affect inflammatory response, cytokine production, and cell death by the mitogen-activated protein kinase (MAPK) signaling pathway. In vivo experiment results manifested that irigenin decreased pathological changes, lung Wet/Dry weight ratio, and total protein content in bronchoalveolar lavage fluid (BALF). Irigenin also reduced the production of inflammatory cytokines, including tumor necrosis factor-a (TNF-a), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-18 (IL-18), and neutrophil infiltration. Additionally, irigenin inhibited pulmonary apoptosis in LPS-treated ALI mice. Moreover, LPS-induced phosphorylation of p38, JNK, and ERK was significantly abated due to the treatment of irigenin. In summary, irigenin ameliorates LPS-induced ALI by suppressing pulmonary inflammation and apoptosis via inactivation of the MAPK signaling pathway. These findings indicated the therapeutic potential of irigenin in ALI.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-04T11:59:02Z
      DOI: 10.1177/09603271231155098
      Issue No: Vol. 42 (2023)
       
  • Circ_0000285 regulates nasopharyngeal carcinoma progression through
           miR-1278/FNDC3B axis

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      Authors: Qingjiao Zeng, Xiaolin Ji, Xueshen Li, Yanxun Tian
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundNasopharyngeal carcinoma (NPC) is cancer with high mortality and poor prognosis. Circular RNAs (circRNAs) have been identified in a wide variety of cancers. But the functional mechanism of circ_000285 in NPC remains unclear.PurposeTo decipher the biological function and molecular mechanism of circ_000285 in NPC.MethodsQuantitative PCR (RT-qPCR) was applied for detecting the expression of circ_0000285, miR-1278, and FNDC3B. Western blot was used to measure the protein levels of Fibronectin type III domain containing 3B (FNDC3B), Bcl2 associated X (Bax), and B cell leukemia/lymphoma 2 (Bcl2). Cell proliferation, migration, and invasion were analyzed by colony formation, 5-ethynyl-2′-deoxyuridine (EdU), and transwell assays. Cell apoptosis was detected by flow cytometry assays. ELISA assay was used to analyze Caspase-3 activity. Bioinformatics was used to predict, and the target relationship between miR-1278 and circ_0000285 or FNDC3B was verified by luciferase reporter assay. Tumor xenograft models were established to examine how circ_0000285 functions during the mediation of NPC tumor growth in vivo.ResultsIncreased circ_0000285 and FNDC3B expressions, and a decreased miR-1278 expression were observed in NPC tissues and cell lines. Knockdown of circ_0000285 inhibited NPC cell proliferation, migration, invasion, and while promoting NPC cell apoptosis in vitro. Circ_0000285 knockdown-mediated anti-tumor effects in NPC cells could be largely reversed by silencing of miR-1278 or overexpression of FNDC3B. Circ_0000285 could up-regulate FNDC3B expression by sponging miR-1278 in NPC cells. Knockdown of circ_0000285 could inhibit tumor growth in vivo.ConclusionCirc_0000285 upregulates FNDC3B expression by adsorbing miR-1278 to promote NPC development.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-04T09:22:18Z
      DOI: 10.1177/09603271221141689
      Issue No: Vol. 42 (2023)
       
  • CircKRT14 upregulates E2F3 by interacting with miR-1256 to act as an
           oncogenic factor in esophageal cancer

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      Authors: Xingzhuo Guan, Tingzhu Lan, Yuanshi Wang, Yan Cui, Jinyu Duan, Hongjun Xu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundA growing number of studies have focused on the regulatory role of circular RNAs (circRNAs) in a variety of cancers. The purpose of this study was to investigate the effect of circRNA Keratin 14 (circKRT14) on the progression of esophageal cancer (EC).MethodsThe levels of circKRT14, miR-1256 and E2F transcription factor 3 (E2F3) were analyzed by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot. The circular structure of circKRT14 was confirmed by RNase R digestion assay. Cell apoptosis, migration and invasion were detected by flow cytometry and transwell assay. The protein levels of related factors were determined by western blot. The relationship between miR-1256 and circKRT14 or E2F3 was verified by dual-luciferase reporter assay. The in vivo function of circKRT14 was studied by xenograft tumor assay.ResultsCircKRT14 was significantly increased in EC tissues and cells. CircKRT14 silencing inhibited EC cell proliferation, migration, and invasion, but promoted EC cell apoptosis in vitro. CircKRT1 acted as a sponge for miR-1256 in EC, and in-miR-1256 abolished the inhibitory effect of circKRT14 suppression on EC cell progression. E2F3 was a target of miR-1256 and functioned as an oncogene in EC cells. MiR-1256 curbed EC progression by downregulating E2F3. CircKRT14 could affect E2F3 expression by targeting miR-1256. CircKRT14 regulated EC progression in vivo through miR-1256/E2F3 axis.ConclusionsThese results uncovered that circKRT14 up-regulated the expression of E2F3 and promoted the malignant development of EC through sponging miR-1256.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-02-04T01:04:56Z
      DOI: 10.1177/09603271231155093
      Issue No: Vol. 42 (2023)
       
  • MiR-155-5p-SOCS1/JAK1/STAT1 participates in hepatic lymphangiogenesis in
           liver fibrosis and cirrhosis by regulating M1 macrophage polarization

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      Authors: Jian Bi, Jia Liu, Xiuli Chen, Na Shi, Hao Wu, Haiying Tang, Jingwei Mao
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundThe role and underlying mechanism of liver macrophages and their derived miR-155-5p in hepatic lymphangiogenesis in liver fibrosis remain unclear. Here, we investigated the mechanism by which macrophages and miR-155-5p were involved in lymphangiogenesis during liver fibrosis and cirrhosis.MethodsIn vivo, hepatic lymphatic vessel expansion was evaluated; the liver macrophage subsets, proportion of peripherally-derived macrophages and expressions of CCL25, MCP-1, VAP-1 and MAdCAM-1 were documented; and miR-155-5p in the peripheral blood and liver was detected. In vitro, macrophages with miR-155-5p overexpression and inhibition were used to clarify the effect of miR-155-5p on regulation of macrophage polarization and the possible signalling pathway.ResultsHepatic lymphangiogenesis was observed in mice with liver fibrosis and cirrhosis challenged with carbon tetrachloride (CCl4). In the liver, the number of M1 macrophages was associated with lymphangiogenesis and the degree of fibrosis. The liver recruitment of peripherally-derived macrophages occurred during liver fibrosis. The levels of miR-155-5p in the liver and peripheral blood gradually increased with aggravation of liver fibrosis. In vitro, SOCS1, a target of miR-155-5p, regulated macrophage polarization into the M1 phenotype through the JAK1/STAT1 pathway.ConclusionMiR-155-5p-SOCS1/JAK1/STAT1 pathway participates in hepatic lymphangiogenesis in mice with liver fibrosis and cirrhosis induced by CCl4 by regulating the polarization of macrophages into the M1 phenotype.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-18T03:44:40Z
      DOI: 10.1177/09603271221141695
      Issue No: Vol. 42 (2023)
       
  • Cysteine-rich 61(CYR61) alleviates cyclophosphamide-induced proliferation
           inhibition in ovarian granulosa cells via suppressing
           NLRP3/caspase1-mediated pyroptosis

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      Authors: Hongxia Xu, Xiumin Bao, Junya Yang, Hanxin Kong, Yan Li, Zhiwei Sun
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundWe investigated the level of Cysteine-rich 61 (CYR61) in premature ovarian failure as well as its regulatory molecular mechanism in this study.Methods and ResultsCyclophosphamide (CTX) was used to induce OGCs (rat ovarian granulosa cells) and rats to establish in vivo and in vitro premature ovarian failure models. H&E staining was used to detect the pathological changes of ovarian histopathology. Si-NLRP3 (NOD-like receptor thermal protein domain associated protein 3, NLRP3) and si-CYR61 were transfected into OGCs using lipofectamine 3000. RT-qPCR and western blot were used to detect the expressions of CYR61 in ovarian tissue and OGCs. It showed that the expression of CYR61 was significantly down-regulated in premature ovarian failure model. Cell viability was detected using a Cell Counting Kit-8 (CCK-8) kit. TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling) staining was used to detect the apoptosis. 5-Ethynyl-2′-deoxyuridine (EdU) and SA-β-gal (senescence-associated β-galactosidase) staining were used to assess the proliferation and senescence. The expression of CYR61 in OGCs and ovarian tissues were detected by immunofluorescence and immunohistochemical staining. Overexpression of CYR61 significantly promoted OGCs proliferation and inhibited pyroptosis and apoptosis. Western blot was used to detect the protein expressions of p53 and p21 in OGCs. Flow cytometry was used to detect the pyroptosis. CYR61 overexpression inhibited the expression of NLRP3 and caspase-1 in CTX-induced OGCs according to western blot results. Moreover, we found that CYR61 overexpression down-regulated the protein expressions of p53 and p21 in CTX-induced OGCs.Conclusion:CYR61 inhibited CTX-induced OGCs senescence, and the mechanism may be related to the regulation of caspase-1/NLRP3-induced pyroptosis.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-18T02:26:07Z
      DOI: 10.1177/09603271231152831
      Issue No: Vol. 42 (2023)
       
  • The IL-6/HO-1/STAT3 signaling pathway is implicated in the amelioration of
           acetaminophen-induced hepatic toxicity: A neonatal rat model

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      Authors: Remon Roshdy Rofaeil, Nermeen N Welson, Michael A Fawzy, Amira F Ahmed, Medhat Atta, Mohamed Ahmed Bahaa El-deen, Walaa Yehia Abdelzaher
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      The widespread use of acetaminophen (APAP) in children as an over-the-counter treatment can cause acute liver failure through accidental overdose or ingestion. Therefore, the current research sought to investigate the function of hemin in mitigating the acute hepatotoxic effect of APAP in rat offspring. Thirty-two rats were assigned into four groups: control, hemin, APAP, and hemin/APAP groups. Liver enzymes were measured in serum along with oxidative stress indicators, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), total nitrites (NOx), and caspase 3 in liver. Immunoblotting of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), Janus kinase 2 (Jak2), and signal transducer and activator of transcription 3 (STAT3) was carried out. The Bax/Bcl2 mRNA expression ratio was determined. A histological study and an immunohistochemical study of phosphorylated STAT3 were also done. Hemin reduced liver enzymes, MDA, TNF-α, NOx, caspase 3, IL-1β, p-STAT3 expression, p-Jak2 expression, IL-6 expression, and Bax/Bcl2 mRNA expression ratio. In contrast, hemin increased GSH, TAC, and the expression of HO-1, improving the histopathological picture of liver tissue. Thus, hemin could ameliorate APAP-induced hepatic toxicity in rat offspring through anti-oxidant, anti-apoptotic, and anti-inflammatory actions with a possible role for the IL-6/HO-1/Jak2/STAT3 pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-10T11:09:30Z
      DOI: 10.1177/09603271231151376
      Issue No: Vol. 42 (2023)
       
  • Mitochondrial ROS induced by ML385, an Nrf2 inhibitor aggravates the
           ferroptosis induced by RSL3 in human lung epithelial BEAS-2B cells

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      Authors: Indra Putra Taufani, Jiro Hasegawa Situmorang, Rifki Febriansah, Sri Tasminatun, Sunarno Sunarno, Liang-Yo Yang, Yi-Ting Chiang, Chih-Yang Huang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Ferroptosis is a new type of cell death marked by iron and lipid ROS accumulation. GPX4 is one of the glutathione peroxidases known to regulate ferroptosis tightly. On the other hand, Nrf2 also plays a vital role in ferroptosis as it targets genes related to oxidant defense. Herein, we employed beas-2 human epithelial cells treated with a low concentration of RSL3 to induce ferroptosis. To study the protective role of Nrf2, we used ML385 as its specific inhibitor. A combination of ML385 and a low concentration of RSL3 synergistically induced more toxicity to RSL3. Furthermore, we found that mitochondrial ROS is elevated in ML385 and RSL3 combination group. In addition, Mito TEMPOL application successfully prevents the upregulation of mitochondrial ROS, lipid ROS, reduces the toxicity of RSL3, restores the antioxidant capacity of the cells, and mitochondrial functions reflected by mitochondrial membrane potential and mitochondrial oxidative phosphorylation system (OXPHOS) expression. Altogether, our study demonstrated that Nrf2 inhibition by ML385 induces more toxicity when combined with RSL3 through the elevation of mitochondrial ROS and disruption of mitochondrial function.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-10T08:46:10Z
      DOI: 10.1177/09603271221149663
      Issue No: Vol. 42 (2023)
       
  • Wasp-stung rat model translationally expresses the coagulopathy
           manifestations of human wasp patients

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      Authors: Dong Lai, Yan Tian, Chang-Fu Ji, Yuan Zang, Yaw-Syan Fu, Ching-Feng Weng
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Two over 80 wasp stings male victims appeared severe abnormal coagulation were consecutively examined by thromboelastography (TEG) guided with heparinase during hospitalization. However, the cause of coagulopathy remains unsolved. Rats were applied to establish a wasp-stung animal model highly resembled the manifestations of wasp-stung patients. According body surface area conversion, Sprague-Dawley rats were stung based on wasp sting numbers (0, 4, 8, 12 stings; n = 6 each) with various exposure times (0, 1, 3, 6 h) to determine the simulation of coagulopathy. The blood R, K values, and angle degree of wasp-stung rats were measured by TEG. The TEG profiles of stung rats were found to be concomitant with that of wasp-stung patients. Data showed that the endogenous heparinization of rats was time-dependent. Compared to the TEG profile of eight stings given rat, the coagulation time of 2 mm clot formation at 3 h (R value) was longer than that at 0 h. The coagulation time was prolonged with increasing sting numbers when compared to the various stings at 1, 3, and 6 h exposed. Interestingly, there was observed the peak coagulation at 3 h of eight stings. The Ck-standard and Ck-heparinase at 3 h after 8 stings given were R: 9.6–4.4 min; K: 3.8–1.8 min; angle degree: 49.8–68.0, respectively. The original data of R, K values and angle degree in two wasp-stung victims were 11.7–13.6 min, 4.3–5.5 min, and 41.2-32.8° in CK-standard, respectively; whereas those of the CK-heparinase groups were 5.6–6.7 min, 2.4–2.5 min, and 59.5–58.8°, correspondingly. Conclusively, this massive wasp-stung animal model can be applied to the investigations of pathogenesis and provides a clinical strategy or guideline for clinical intervention.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-09T10:00:06Z
      DOI: 10.1177/09603271221149013
      Issue No: Vol. 42 (2023)
       
  • Follow-up of patients with a 5-year survival after paraquat poisoning
           using computed tomography images and spirometry

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      Authors: Lu Fan, Xuejie Wang, Tianyi Lv, Fei Xue, Benhe Wu, Aiwen Ma, Mingfeng Lu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectivesThe study aimed to examine long-term survival of patients with acute paraquat poisoning using computed tomography (CT) images and spirometry.MethodsA total of 36 patients with long-term survival after paraquat poisoning were followed-up and divided into mild (11 patients), moderate (17 patients), and severe (8 patients) paraquat poisoning groups. Differences among the groups were compared using clinical indicators, such as peripheral capillary oxygen saturation, arterial partial pressure of oxygen and 6-min walk test (6-MWT), chest CT, spirometry, and serum immunoglobulin E (IgE).ResultsThe 6-MWT distance was significantly shorter in the severe paraquat poisoning group than that in the mild and moderate paraquat poisoning groups. In the mild paraquat poisoning group, CT revealed no obvious lung injury, and spirometry showed normal lung function in most patients. In moderate or severe paraquat poisoning group, CT images showed fibrotic lesions as cord-like high-density shadows, reticulations, and honeycombs. In addition, other pulmonary changes, including bronchiectasis, increased lung transparency, and pulmonary bullae, were discovered. In moderate or severe paraquat poisoning group, obvious obstructive ventilation dysfunction with slight restrictive and diffuse impairment were observed in some patients, with positive bronchial relaxation test and high serum IgE level.ConclusionIn the long-term follow-up, patients with severe paraquat poisoning showed the lowest exercise endurance. In moderate or severe paraquat poisoning group, CT images revealed diversified changes, not only dynamic evolution of pulmonary fibrosis process, but also signs of bronchiectasis, and chronic obstructive pulmonary disease. Some patients with moderate or severe paraquat poisoning developed obstructive ventilatory dysfunction with airway hyperresponsiveness.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-09T04:25:24Z
      DOI: 10.1177/09603271221150243
      Issue No: Vol. 42 (2023)
       
  • Hyperglycemia-induced endothelial exosomes trigger trophoblast
           dysregulation and abnormal placentation through PUM2-mediated repression
           of SOX2

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      Authors: Aibing Zhu, Suwan Qi, Wenjuan Li, Dashu Chen, Xiaomin Zheng, Jianjuan Xu, Yaling Feng
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundHyperglycemia is closely related to adverse pregnancy outcomes including pre-eclampsia (PE), a life-threatening complication with a substantial morbidity and mortality. However, the pathogenesis of abnormal placentation in gestational diabetes mellitus (GDM)-associated PE remains elusive.MethodHere we isolated exosomes from the human umbilical vein endothelial cells (HUVECs) treated with normal level of glucose (NG) and high levels of glucose (HG). The exosomes were added to HTR-8a/SVneo cells, a trophoblast cell line. High-throughput RNA-sequencing was performed to analyzed the changed RNAs in the exosomes and exosome-treated HTR-8a/SVneo cells. HTR-8a/SVneo cell phenotypes were evaluated from the aspects of cell proliferation, cell invasion and DNA damage.ResultsAfter treatment with HG, the changed RNAs in exosomes was enriched in RNA stabilization and oxidative stress. The altered RNAs in the HTR-8a/SVneo cells treated with exosomes from HG-induced HUVECs were enriched in pathways related to cell adhesion, migration, DNA damage response and angiogenesis. The HG-induced exosomes impaired the proliferation and invasion of HTR-8a cells and caused the DNA damage. HG up-regulated PUM2 in the exosomes and exosome-treated HTR-8a/SVneo cells. PUM2 interacted with SOX2 mRNA, resulting in the mRNA degradation. Overexpression of SOX2 prevented the damage to HTR-8a/SVneo cells caused by the exosomes from HG-induced HUVECs.ConclusionsWe demonstrate that high glucose-induced endothelial exosomes mediate abnormal phenotypes of trophoblasts through PUM2-mediated repression of SOX2. Our results reveal a novel regulatory mechanism of hyperglycemia in development of abnormal placentation and provide potential targets for preventing adverse pregnancy outcomes.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-06T03:28:44Z
      DOI: 10.1177/09603271221149656
      Issue No: Vol. 42 (2023)
       
  • Kaempferol ameliorates palmitate-induced lipid accumulation in HepG2 cells
           through activation of the Nrf2 signaling pathway

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      Authors: Li Zhao, Liping Yang, Khalidamir Ahmad
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectivesKaempferol (KMF), has beneficial effects against hepatic lipid accumulation. In this study, we aimed to investigate molecular mechanism underlying the protective effect of KMF on lipid accumulation. MethodsHepG2 cells were treated with different concentrations of KMF and 0.5 mM palmitate (PA) for 24  h. The mRNA and protein levels of genes involved in lipid metabolism were evaluated using real-time PCR and western blot. The expression of Nrf2 was silenced using siRNA. ResultsData indicated that KMF (20 μM) reversed PA-induced increased triglyceride (TG) levels and total lipid content. These effects were accompanied by down-regulation of the mRNA and protein levels of lipogenic genes (FAS, ACC and SREBP1), and up-regulation of genes related to fatty acid oxidation (CPT-1, HADHα and PPARα). Kaempferol significantly decreased the levels of the oxidative stress markers (ROS and MDA) and enhanced the activities of antioxidant enzymes SOD and GPx in PA-challenged cells. Luciferase analysis showed that KMF increased the transactivation of Nrf2 in hepatocytes. The results also revealed that KMF-mediated activation of Nrf2 target genes was suppressed by Nrf2 siRNA. Furthermore, Nrf2 siRNA abolished the KMF-induced reduction in ROS and MDA levels in PA treated cells. In addition, the inhibitory effect of KMF on TG levels and the mRNA and protein levels of FAS, ACC and SREPB-1 were significantly abolished by Nrf2 inhibition. Nrf2 inhibition also suppressed the KMF-induced activation of genes involved in β oxidation (CPT-1 and PPAR-α).ConclusionThe results suggest that KMF protects HepG2 cells from PA-induced lipid accumulation via activation of the Nrf2 signaling pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-06T02:49:07Z
      DOI: 10.1177/09603271221146780
      Issue No: Vol. 42 (2023)
       
  • MiR-3612 targeting THBS1 suppresses nasopharyngeal carcinoma progression
           by PI3K/AKT signaling pathway

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      Authors: Wei Zhang, Qiu Zhang, Qianbo Cui, Yu Xu
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      BackgroundMicroRNA-3612 (miR-3612) is considered a tumor suppressor in different cancers. Nonetheless, its function in nasopharyngeal carcinoma (NPC) has yet to be uncovered.MethodsNPC cells and tissues were tested by means of reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting to quantify the expressions of miR-3612 and Thrombospondin 1 (THBS1). Cell Counting Kit-8 (CCK-8) and scratch experiments were carried out to evaluate the migration and proliferation of NPC cells. NPC cell adhesion was also assessed. The predicted interaction of miR-3612 with THBS1 was verified by means of a luciferase reporter assay. In vivo experiments were also conducted to examine how miR-3612 overexpression affects in vivo tumorigenicity. Lastly, phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway status was assessed via western blotting.ResultsMiR-3612 was downregulated in NPC cells and tissues, whereas THBS1 expression showed an opposite trend. The MiR-3612 mimic inhibited the NPC cell proliferation, adhesion, and migration and also inactivated the PI3K/AKT signaling pathway. Furthermore, miR-3612 mimic also hampered NPC tumorigenesis in vivo. MiR-3612 targeted THBS1 and downregulated THBS1 expression. THBS1 offset the miR-3612-overexpression-induced repression of the migration, adhesion, and proliferation of NPC cells via the activation of the PI3K/AKT pathway.ConclusionMiR-3612 retarded NPC cell migration, adhesion, and proliferation by targeting THBS1 and inactivating the PI3K/AKT signaling pathway. This provides a novel therapeutic approach for NPC intervention.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-06T02:22:27Z
      DOI: 10.1177/09603271221150248
      Issue No: Vol. 42 (2023)
       
  • Thymol co-administration abrogates hexachlorobenzene-induced reproductive
           toxicities in male rats

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      Authors: Abiola S Tijani, Ebenezer O Farombi, David O Olori
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      This present study was designed to investigate ameliorating potential of thymol (THY) on hexachlorobenzene (HBC)-induced epididymal and testicular toxicities in adult male rats. Forty adult male rats were orally treated by gavage daily for 28 consecutive days and divided into four groups; control group administered with corn oil, HBC-treated group (16 mg/kg b. wt), thymol-treated group (30 mg/kg b. wt), and HBC + THY-treated group. The results revealed that HBC exposure caused a significant decrease in the body weight change, organ weights, sperm functional parameters, serum testosterone level with widespread histological abnormalities. Furthermore, HBC-treated rats showed increased in the serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), epididymal and testicular myeloperoxidase activity, tumor necrosis-α, interleukin-1β level and caspase-3 activity, induced oxidative damage as evidenced by elevated malondialdehyde (MDA), reactive oxygen species (RONS) levels and significant reduction in antioxidant enzyme activities and reduced glutathione (GSH). However, co-treatment of THY with HBC alleviated the HBC-induced epididymal and testicular toxicities. Our findings revealed that HBC acts as a reproductive toxicant in rats and thymol could be a potential remedial agent for HBC-induced reproductive toxicity.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-06T01:41:47Z
      DOI: 10.1177/09603271221149201
      Issue No: Vol. 42 (2023)
       
  • Emodin protects against apoptosis and inflammation by regulating reactive
           oxygen species-mediated NF-κB signaling in interleukin‐1β-stimulated
           human nucleus pulposus cells

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      Authors: Xiaojuan Zhu, Shuqin Guo, Mingyuan Zhang, Xiaoliang Bai
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Intervertebral disc degeneration (IDD) is a complex degradative disorder associated with inflammation. Emodin, an anthraquinone derivative, possesses strong anti-inflammatory activity. This study focused on the in vitro therapeutic action of emodin in a cellular model of IDD. Human nucleus pulposus cells (NPCs) were stimulated with interleukin‐1β (IL-1β) to induce inflammation. Cell Counting Kit-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining assays were performed to evaluate the viability and apoptosis of NPCs, respectively. Caspase-3 activity was measured to indirectly assess cell apoptosis. Western blot analysis was performed to detect protein expression levels. Reverse transcription‐polymerase chain reaction was performed for the detection of relative mRNA levels of tumor necrosis factor-α (TNF-α) and IL-6. Enzyme-linked immunosorbent assay was performed to analyze TNF-α and IL-6 secretion. Our results showed that emodin treatment mitigated IL-1β-induced reduction of cell viability in NPCs. Moreover, the increase in reactive oxygen species (ROS) production, apoptotic rate, and caspase-3 activity in IL-1β-stimulated NPCs was reduced by emodin treatment. Treatment with emodin also abolished IL-1β-induced inflammation in NPCs, as indicated by reduced secretion of IL-6 and TNF-α. Besides, the increase in expression levels of phosphorylated p65 and nuclear p65 in IL-1β-stimulated NPCs was suppressed by emodin treatment. Furthermore, inhibition of nuclear factor kappa B (NF-κB) activation with pyrrolidine dithiocarbamate aggravated the protective effects of emodin. These results suggested that emodin protected NPCs against IL-1β-induced apoptosis and inflammation via inhibiting ROS-mediated activation of NF-κB.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-04T04:35:23Z
      DOI: 10.1177/09603271221138552
      Issue No: Vol. 42 (2023)
       
  • A mechanistic investigation about hepatoxic effects of borneol using
           zebrafish

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      Authors: L Liu, Y Yang, F Yang, Y Lin, K Liu, X Wang, Y Zhang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Except for clinical value, borneol is routinely used in food and cosmetics with seldom safety evaluation. To investigate its hepatoxicity, we exposed 3 dpf (days post fertilization) larval zebrafish to borneol at a gradient of concentrations (200–500 μM) for 3 days. Herein, our results revealed that high doses of borneol (300–500 μM) caused liver size decrease or lateral lobe absence. Borneol also seriously disturbed the hepatic protein metabolism presented with the increased activity of alanine aminotransferase (ALT) and lipid metabolism shown with the increased level of triglycerides (TG) and total cholesterol (TC). The lipid accumulation (oil red staining) was detected as well. Additionally, significant upregulation of genes was detected that related to oxidative stress, lipid anabolism, endoplasmic reticulum stress (ERS), and autophagy. Conversely, the lipid metabolism-related genes were markedly downregulated. Moreover, the changes in the superoxide dismutase activity and the level of glutathione and malondialdehyde raised the likelihood of lipid peroxidation. The outcomes indicated the involvement of oxidative stress, ERS, lipid metabolism, and autophagy in borneol-induced lipid metabolic disorder and hepatic injury. This study will provide a more comprehensive understanding of borneol hepatoxicity and the theoretical basis for the safe use of this compound.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-03T07:26:20Z
      DOI: 10.1177/09603271221149011
      Issue No: Vol. 42 (2023)
       
  • Alpha-lipoic acid inhibits sodium arsenite-mediated autophagic death of
           rat insulinoma cells

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      Authors: Yong Cheng, Xiuli Yang, Wenjuan Tang, Qiong Fu, Hong Li, Bing Liang
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      AimTo investigate the protective effect of α-lipoic acid on sodium arsenite (NaAsO2) induced INS-1 cells injury and its mechanism.MethodsThe cell viability was measured by CCK-8 assay. The autophagosomes was observed under transmission electron microscopy. The autophagosomes in cells transfected with green fluorescent protein microtubule-associated protein light chain 3 (GFP-LC3) plasmids were observed under a laser scanning con-focal microscope. The expression of LC3-II, P62, PI3K, and mTOR proteins in INS-1 cells treated with a combination of chloroquine (CQ, autophagy inhibitor) and NaAsO2 were detected by Western blot assay. The expression of LC3-II, P62, PI3K, and mTOR proteins were detected in INS-1 cells treated with a combination of rapamycin (autophagy inducer, mTOR inhibitor) and α-LA.ResultsThe cytotoxicity induced by NaAsO2 was reversed by α-LA, and the viability of NaAsO2-treated INS-1 cells increased. α-LA pretreatment decreased the autophagosome accumulation induced by NaAsO2. α-LA also reduced the fluorescence spot aggregation of GFP-LC3 in INS-1 cells exposed to NaAsO2 as observed under a laser scanning con-focal microscope. α-LA inhibited NaAsO2 induced autophagy by up-regulating PI3K and mTOR and down-regulating LC3-II and P62. CQ inhibited NaAsO2 induced autophagy by up-regulating PI3K, mTOR, P62 and down-regulating LC3-II. α-LA inhibited rapamycin-induced autophagy by up-regulating PI3K, mTOR and P62 and down-regulating LC3-II. The results showed that NaAsO2 could induce autophagy activation in INS-1 cells. The α-LA may inhibit autophagy activation by regulating the PI3K/mTOR pathway.ConclusionThe data indicated that α-LA might inhibit the NaAsO2-induced autophagic death of INS-1 cells by regulating the PI3K/mTOR pathway.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-03T04:36:31Z
      DOI: 10.1177/09603271221149196
      Issue No: Vol. 42 (2023)
       
  • The transcript NR 134251.1 of lncRNA APTR with an opposite function to all
           transcripts inhibits proliferation and induces apoptosis by regulating
           proliferation and apoptosis-related genes

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      Authors: Jinyi Yu, Shuting Li, Simin Shen, Qian Zhou, Jinyao Yin, Ruihuan Zhao, Jingwen Tan, Chenglan Jiang, Yuefeng He
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Arsenic (As) exposure has been a global public health concern for hundreds of millions worldwide. LncRNA APTR (Alu-mediated p21 transcriptional regulator) plays an essential role in tumor growth and development. However, its function in arsenic-induced toxicological responses is still unknown. In this study, we found that the expressions of all transcripts and the transcript NR 134251.1 of APTR were increased in a dose-dependent manner in 16HBE cells treated with sodium arsenite (NaAsO2). Silencing the transcript NR 134251.1 of APTR inhibited cell proliferation and induced apoptosis. However, silencing all transcripts of APTR had the opposite function to the transcript NR 134251.1. Then we examined the protein level of the proliferation and apoptosis-related genes after silencing the transcript NR 134251.1 of APTR. The results showed that silencing the transcript NR 134251.1 of APTR up-regulated the expression of transcription factor E2F1 and regulated its downstream genes involved in proliferation and apoptosis, including p53, phospho-p53-S392, phospho-p53-T55, p21, Cyclin D1, PUMA, Fas, Bim, BIK, Caspase-3, Caspase-7, and Cyt-c. In conclusion, arsenic induced APTR expression and the transcript NR 134251.1 of APTR have an opposite function to all transcripts, providing a theoretical basis for the prevention and treatment of arsenic exposure.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-03T04:29:51Z
      DOI: 10.1177/09603271221150247
      Issue No: Vol. 42 (2023)
       
  • Comparing the effectiveness of L-carnitine and paraffin oil in acute
           aluminum phosphide poisoning using predictive biomarkers and scores: A
           randomized controlled clinical trial

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      Authors: Walaa G Abdelhamid, Mahmoud L Sakr, Olfat E Mostafa, Dalia Zaafar, Hanan M Abdelwahab
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      Aluminum phosphide (AlP) poisoning is a serious medical emergency with a high mortality rate. The absence of an exact antidote for AlP poisoning necessitates the quest for alternative treatment options. The study sought to assess the efficacy of adding L-carnitine or medicated paraffin oil to the conventional approach of treatment employed in cases of acute AlP poisoning. We conducted a 1 year, randomized, controlled, parallel-group, single-blind clinical study. 96 individuals with acute AlP poisoning were randomly assigned to one of three groups. The standard AlP therapy was administered to all groups according to the Poison Control Center guidelines at the Ain-Shams University hospitals. All patients underwent a medical history review, clinical examination, and laboratory tests. The outcomes were assessed. The participants in the study groups had mean ages ranging from 25.6 to 26.3 years. The cases analyzed were evenly distributed between genders, with the majority originating from rural areas. The average delay time varied from 2.9 to 4.2 h. All patients in the study reported ingesting AlP during suicide attempts. 12 hours after admission, many clinical and biochemical data improved in both intervention groups including cytochrome c oxidase, caspase-3, caspase-9, catalase, and superoxide dismutase. The intervention groups required significantly less mechanical ventilation and had a lower mortality rate than the control group. Decontamination with paraffin oil could be advantageous for reducing the severity of AlP poisoning, improving prognosis, and lowering the mortality rate.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-02T03:21:28Z
      DOI: 10.1177/09603271221149650
      Issue No: Vol. 42 (2023)
       
  • Hepatoprotective potential of diosmin against hepatotoxic effect of
           isoniazid and rifampin in wistar rats

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      Authors: Tarique Anwer, Mohammed N. Alruwaili, Saeed Alshahrani, Saad S. Alqahtani, Abdulmajeed Jali, Rayan A. Ahmed, Mohammad Firoz Alam, Sivakumar S. Moni
      Abstract: Human & Experimental Toxicology, Volume 42, Issue , January-December 2023.
      ObjectiveThe treatment of tuberculosis with isoniazid and rifampin is associated with hepatocellular damage. Therefore, the study was designed to evaluate the hepatoprotective potential of diosmin against hepatotoxic effect of isoniazid and rifampin in Wistar rats.MethodsHepatotoxicity was induced by administering isoniazid and rifampin (100 mg/kg), whereas diosmin was given as treatment control. Markers of liver function (ALT, AST, ALP and bilirubin), inflammatory cytokines (TNFα, IL-6 and IL-1β), apoptosis (caspase-3), oxidative stress parameters (LPO, GSH, CAT and SOD) and histological changes in liver were assessed in normal, hepatotoxic control and treatment groups.ResultsThe administration of isoniazid and rifampin significantly increased markers of liver dysfunction (ALT, AST, ALP and bilirubin), cytokines (TNFα, IL-6 and IL-1β) and apoptosis (caspase-3). However, daily dosing of diosmin significantly reduced these markers of liver dysfunction, inflammatory cytokines and apoptosis to near normal levels. Additionally, markers of hepatocellular oxidative stress parameters were significantly altered as evident from increased LPO level and decreased endogenous antioxidants such as GSH, SOD and CAT in isoniazid-and rifampin-treated hepatotoxic group. It was observed that diosmin treatment reduced high levels of LPO and demonstrated significant improvement in antioxidant levels. Histological studies of liver also supported our biochemical findings, which are also manifested as diosmin treatment exhibited protection against hepatocellular degeneration and inflammation.ConclusionResults of the present study demonstrate hepatoprotective potential of diosmin against isoniazid-and rifampin-treated hepatotoxicity. Thus, we conclude that diosmin may be used along with anti-tubercular drugs (isoniazid and rifampin) in tuberculosis patients to overcome their hepatotoxic adverse effect.
      Citation: Human & Experimental Toxicology
      PubDate: 2023-01-02T02:38:27Z
      DOI: 10.1177/09603271221149199
      Issue No: Vol. 42 (2023)
       
 
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