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Showing 1 - 98 of 98 Journals sorted alphabetically
AAPS PharmSciTech     Hybrid Journal   (Followers: 9)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7)
Adipocyte     Open Access   (Followers: 1)
African Journal of Laboratory Medicine     Open Access   (Followers: 2)
American Journal of Experimental and Clinical Research     Open Access   (Followers: 4)
American Journal of Medical and Biological Research     Open Access   (Followers: 11)
Animal Models and Experimental Medicine     Open Access  
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
Applied In Vitro Toxicology     Hybrid Journal   (Followers: 2)
Archives of Clinical and Experimental Medicine     Open Access  
Archives of Medical Research     Hybrid Journal   (Followers: 3)
Archives of Pathology & Laboratory Medicine     Full-text available via subscription   (Followers: 32)
Archives of Preventive Medicine     Open Access   (Followers: 3)
Biomedical Engineering     Hybrid Journal   (Followers: 3)
Bulletin of Experimental Biology and Medicine     Hybrid Journal  
Clinica Chimica Acta     Hybrid Journal   (Followers: 30)
Clinical & Experimental Metastasis     Hybrid Journal  
Clinical and Experimental Medical Journal     Full-text available via subscription   (Followers: 1)
Clinical and Experimental Medicine     Hybrid Journal   (Followers: 4)
Clinical Trials     Hybrid Journal   (Followers: 21)
Clinical Trials in Degenerative Diseases     Open Access  
Clinical Trials in Orthopedic Disorders     Open Access   (Followers: 1)
Current Medicine Research and Practice     Full-text available via subscription  
Current Research in Drug Discovery     Open Access   (Followers: 1)
Drug Design, Development and Therapy     Open Access   (Followers: 4)
Ecography     Hybrid Journal   (Followers: 27)
European Journal of Hospital Pharmacy : Science and Practice (EJHP)     Hybrid Journal   (Followers: 9)
European Journal of Medical Research     Open Access   (Followers: 1)
European Journal of Nanomedicine     Hybrid Journal   (Followers: 1)
Experimental & Molecular Medicine     Open Access   (Followers: 1)
Experimental Aging Research: An International Journal Devoted to the Scientific Study of the Aging Process     Hybrid Journal   (Followers: 3)
Experimental and Therapeutic Medicine     Full-text available via subscription   (Followers: 1)
Experimental Biology and Medicine     Hybrid Journal   (Followers: 3)
Expert Opinion on Drug Delivery     Hybrid Journal   (Followers: 20)
Frontiers in Laboratory Medicine     Open Access  
Frontiers in Medical Technology     Open Access   (Followers: 1)
IN VIVO     Full-text available via subscription   (Followers: 5)
International Archives of Biomedical and Clinical Research     Open Access  
International Journal of Experimental Pathology     Hybrid Journal   (Followers: 1)
International Journal of Health Research and Innovation     Open Access   (Followers: 2)
International Journal of Research in Medical Sciences     Open Access   (Followers: 7)
International Journal of Statistics in Medical Research     Hybrid Journal   (Followers: 5)
Journal of Cell Science & Therapy     Open Access   (Followers: 1)
Journal of Applied Biomaterials & Functional Materials     Hybrid Journal   (Followers: 1)
Journal of Biomedical and Clinical Research     Open Access  
Journal of Clinical Laboratory Analysis     Open Access   (Followers: 14)
Journal of Clinical Medicine and Research     Open Access  
Journal of Clinical Medicine Research     Open Access   (Followers: 4)
Journal of Clinical Trials     Open Access   (Followers: 6)
Journal of Current and Advance Medical Research     Open Access   (Followers: 2)
Journal of Current Medical Research and Practice     Open Access  
Journal of Current Research in Scientific Medicine     Open Access  
Journal of Drug Delivery and Therapeutics JDDT     Open Access   (Followers: 1)
Journal of Enzyme Inhibition and Medicinal Chemistry     Open Access   (Followers: 4)
Journal of Experimental & Clinical Medicine     Full-text available via subscription   (Followers: 1)
Journal of Experimental & Clinical Cancer Research     Open Access   (Followers: 2)
Journal of Experimental and Clinical Medicine     Open Access  
Journal of Experimental Medicine     Full-text available via subscription   (Followers: 46)
Journal of Experimental Pharmacology     Open Access   (Followers: 2)
Journal of Histotechnology     Hybrid Journal   (Followers: 2)
Journal of International Medical Research     Open Access   (Followers: 3)
Journal of Investigative Medicine High Impact Case Reports     Open Access  
Journal of Medicine and Biomedical Research     Open Access   (Followers: 1)
Journal of Muhammadiyah Medical Laboratory Technologist     Open Access  
Journal of Operating Department Practitioners     Full-text available via subscription   (Followers: 2)
Journal of the American Society of Cytopathology     Hybrid Journal   (Followers: 5)
Journal of Trace Elements in Medicine and Biology     Hybrid Journal   (Followers: 1)
Lab on a Chip     Full-text available via subscription   (Followers: 43)
Laboratory Investigation     Hybrid Journal   (Followers: 3)
Medical Devices & Sensors     Hybrid Journal  
Medical Image Analysis     Hybrid Journal   (Followers: 15)
Medical Instrumentation     Open Access  
Medical Laboratory Observer     Full-text available via subscription  
Medical Laboratory Technology Journal     Open Access  
Medicinal Chemistry Research     Hybrid Journal   (Followers: 12)
Medtech Insight     Full-text available via subscription   (Followers: 4)
Nanomedicine: Nanotechnology, Biology and Medicine     Hybrid Journal   (Followers: 7)
New Zealand Journal of Medical Laboratory Science     Full-text available via subscription   (Followers: 1)
Oriental Pharmacy and Experimental Medicine     Partially Free   (Followers: 3)
Pathology and Laboratory Medicine International     Open Access   (Followers: 7)
Physical Biology     Hybrid Journal   (Followers: 4)
Practical Laboratory Medicine     Open Access   (Followers: 2)
Proceedings of the Institution of Mechanical Engineers Part H: Journal of Engineering in Medicine     Hybrid Journal   (Followers: 3)
Prosthetics and Orthotics International     Hybrid Journal   (Followers: 10)
Pulse     Full-text available via subscription  
Qualitative Research in Medicine & Healthcare     Open Access  
Recent Advances in Biology and Medicine     Open Access  
Regulatory Toxicology and Pharmacology     Hybrid Journal   (Followers: 43)
Reproduction     Full-text available via subscription   (Followers: 7)
Revista Peruana de Medicina Experimental y Salud Pública     Open Access  
Revista Romana de Medicina de Laborator     Open Access  
RSC Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
SA Pharmacist's Assistant     Open Access  
Savannah Journal of Medical Research and Practice     Full-text available via subscription  
SLAS Technology     Hybrid Journal   (Followers: 2)
Statistics in Medicine     Hybrid Journal   (Followers: 191)
Trends in Molecular Medicine     Full-text available via subscription   (Followers: 14)
Turkish Journal of Clinics and Laboratory     Open Access   (Followers: 1)
Similar Journals
Journal Cover
Experimental Biology and Medicine
Journal Prestige (SJR): 0.928
Citation Impact (citeScore): 3
Number of Followers: 3  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1535-3702 - ISSN (Online) 1535-3699
Published by Sage Publications Homepage  [1099 journals]
  • A Tribute to Peter Stambrook: A Friend and Leader of SEBM, EBM and an
           Iconic Figure in Cancer Research
    • Authors: Steven R. Goodman
      Pages: 1 - 4
      Abstract: Experimental Biology and Medicine, Volume 246, Issue 1, Page 1-4, January 2021.

      Citation: Experimental Biology and Medicine
      PubDate: 2021-01-07T09:42:01Z
      DOI: 10.1177/1535370220974253
      Issue No: Vol. 246, No. 1 (2021)
  • The effect of ultrasound cavitation on endothelial cells
    • Authors: Madhumithra Subramanian Karthikesh, Xinmai Yang
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Acoustic cavitation has been widely explored for both diagnostic and therapeutic purposes. Ultrasound-induced cavitation, including inertial cavitation and non-inertial cavitation, can cause microstreaming, microjet, and free radical formation. The acoustic cavitation effects on endothelial cells have been studied for drug delivery, gene therapy, and cancer therapy. Studies have demonstrated that the ultrasound-induced cavitation effect can treat cancer, ischaemia, diabetes, and cardiovascular diseases. In this minireview, we will review the impact of ultrasound-induced cavitation on the endothelial cells such as cell permeability, cell proliferation, gene expression regulation, cell viability, hemostasis interaction, oxygenation, and variation in the level of calcium ions, ceramide, nitric oxide (NO) and nitric oxide synthase (NOS) activity. The applications of these effects and the cavitation mechanism involved will be summarized, demonstrating the important role of acoustic cavitation in non-invasive ultrasound treatment of various physiological conditions.
      Citation: Experimental Biology and Medicine
      PubDate: 2021-01-19T06:08:48Z
      DOI: 10.1177/1535370220982301
  • Minireview: Insights into anti-interferon-γ autoantibodies
    • Authors: Kriangkrai Chawansuntati, Kritsadee Rattanathammethee, Jiraprapa Wipasa
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The association between the presence of anti-interferon-γ autoantibodies and the onset of immunodeficiency with intracellular infections has been clearly established. No standard regimen to control the production of these pathogenic autoantibodies, apart from antimicrobial therapy to eliminate infections, contributes to the medical burden of this syndrome, which sometimes has a fatal outcome. In this review, we summarize the findings on anti-interferon-γ autoantibodies to facilitate further research and to provide guidance for treatment strategies.
      Citation: Experimental Biology and Medicine
      PubDate: 2021-01-12T06:15:44Z
      DOI: 10.1177/1535370220981579
  • SIRT3 deficiency increases mitochondrial oxidative stress and promotes
           migration of retinal pigment epithelial cells
    • Authors: Jing-Xian Wang, Yuan Yang, Wen-Ying Li
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Retinal pigment epithelial cells are closely associated with the pathogenesis of diabetic retinopathy. The mechanism by which diabetes impacts retinal pigment epithelial cell function is of significant interest. Sirtuins are an important class of proteins that primarily possess nicotinamide adenine dinucleotide-dependent deacetylases activity and involved in various cellular physiological and pathological processes. Here, we aimed to examine the role of sirtuins in the induction of diabetes-associated retinal pigment epithelial cell dysfunction. High glucose and platelet-derived growth factor (PDGF) treatment induced epithelial–mesenchymal transition and the migration of retinal pigment epithelial cells, and decreased sirtuin-3 expression. Sirtuin-3 knockdown using siRNA increased epithelial–mesenchymal transition and migration of retinal pigment epithelial cells. In contrast, sirtuin-3 overexpression attenuated the effects caused by high glucose and PDGF on epithelial–mesenchymal transition and migration of retinal pigment epithelial cells, suggesting that sirtuin-3 deficiency contributed to retinal pigment epithelial cell dysfunction induced by high glucose and PDGF. Mechanistically, sirtuin-3 deficiency induced retinal pigment epithelial cell dysfunction by the overproduction of mitochondrial reactive oxygen species. These results suggest that sirtuin-3 deficiency mediates the migration of retinal pigment epithelial cells, at least partially by increasing mitochondrial oxidative stress, and shed light on the importance of sirtuin-3 and mitochondrial reactive oxygen species as potential targets in diabetic retinopathy therapy.
      Citation: Experimental Biology and Medicine
      PubDate: 2021-01-11T04:56:14Z
      DOI: 10.1177/1535370220976073
  • White matter abnormalities in fetal alcohol spectrum disorders: Focus on
           axon growth and guidance
    • Authors: Erin Mathews, Kevyn Dewees, Deborah Diaz, Carlita Favero
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Fetal Alcohol Spectrum Disorders (FASDs) describe a range of deficits, affecting physical, mental, cognitive, and behavioral function, arising from prenatal alcohol exposure. FASD causes widespread white matter abnormalities, with significant alterations of tracts in the cerebral cortex, cerebellum, and hippocampus. These brain regions present with white-matter volume reductions, particularly at the midline. Neural pathways herein are guided primarily by three guidance cue families: Semaphorin/Neuropilin, Netrin/DCC, and Slit/Robo. These guidance cue/receptor pairs attract and repulse axons and ensure that they reach the proper target to make functional connections. In several cases, these signals cooperate with each other and/or additional molecular partners. Effects of alcohol on guidance cue mechanisms and their associated effectors include inhibition of growth cone response to repellant cues as well as changes in gene expression. Relevant to the corpus callosum, specifically, developmental alcohol exposure alters GABAergic and glutamatergic cell populations and glial cells that serve as guidepost cells for callosal axons. In many cases, deficits seen in FASD mirror aberrancies in guidance cue/receptor signaling. We present evidence for the need for further study on how prenatal alcohol exposure affects the formation of neural connections which may underlie disrupted functional connectivity in FASD.
      Citation: Experimental Biology and Medicine
      PubDate: 2021-01-11T04:56:13Z
      DOI: 10.1177/1535370220980398
  • Post-treatment with glycyrrhizin can attenuate hepatic mitochondrial
           damage induced by acetaminophen in mice
    • Authors: Xue-Liang Dang, Long-Fei Yang, Lei Shi, Long-Fei Li, Ping He, Jie Chen, Bei-Jie Zheng, Peng Yang, Ai-Dong Wen
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Overdose of acetaminophen (APAP) is responsible for the most cases of acute liver failure worldwide. Hepatic mitochondrial damage mediated by neuronal nitric oxide synthase- (nNOS) induced liver protein tyrosine nitration plays a critical role in the pathophysiology of APAP hepatotoxicity. It has been reported that pre-treatment or co-treatment with glycyrrhizin can protect against hepatotoxicity through prevention of hepatocellular apoptosis. However, the majority of APAP-induced acute liver failure cases are people intentionally taking the drug to commit suicide. Any preventive treatment is of little value in practice. In addition, the hepatocellular damage induced by APAP is considered to be oncotic necrosis rather than apoptosis. In the present study, our aim is to investigate if glycyrrhizin can be used therapeutically and the underlying mechanisms of APAP hepatotoxicity protection. Hepatic damage was induced by 300 mg/kg APAP in balb/c mice, followed with administration of 40, 80, or 160 mg/kg glycyrrhizin 90 min later. Mice were euthanized and harvested at 6 h post-APAP. Compared with model controls, glycyrrhizin post-treatment attenuated hepatic mitochondrial and hepatocellular damages, as indicated by decreased serum glutamate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase activities as well as ameliorated mitochondrial swollen, distortion, and hepatocellular necrosis. Notably, 80 mg/kg glycyrrhizin inhibited hepatic nNOS activity and its mRNA and protein expression levels by 16.9, 14.9, and 28.3%, respectively. These results were consistent with the decreased liver nitric oxide content and liver protein tyrosine nitration indicated by 3-nitrotyrosine staining. Moreover, glycyrrhizin did not affect the APAP metabolic activation, and the survival rate of ALF mice was increased by glycyrrhizin. The present study indicates that post-treatment with glycyrrhizin can dose-dependently attenuate hepatic mitochondrial damage and inhibit the up-regulation of hepatic nNOS induced by APAP. Glycyrrhizin shows promise as drug for the treatment of APAP hepatotoxicity.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-21T05:38:51Z
      DOI: 10.1177/1535370220977823
  • COVID-19 global pandemic planning: Dry heat incubation and ambient
    • Authors: Douglas J Perkins, Robert A Nofchissey, Chunyan Ye, Nathan Donart, Alison Kell, Ivy Foo-Hurwitz, Timothy Muller, Steven B Bradfute
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The ongoing pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has placed a substantial strain on the supply of personal protective equipment, particularly the availability of N95 respirators for frontline healthcare personnel. These shortages have led to the creation of protocols to disinfect and reuse potentially contaminated personal protective equipment. A simple and inexpensive decontamination procedure that does not rely on the use of consumable supplies is dry heat incubation. Although reprocessing with this method has been shown to maintain the integrity of N95 respirators after multiple decontamination procedures, information on the ability of dry heat incubation to inactivate SARS-CoV-2 is largely unreported. Here, we show that dry heat incubation does not consistently inactivate SARS-CoV-2-contaminated N95 respirators, and that variation in experimental conditions can dramatically affect viability of the virus. Furthermore, we show that SARS-CoV-2 can survive on N95 respirators that remain at room temperature for at least five days. Collectively, our findings demonstrate that dry heat incubation procedures and ambient temperature for five days are not viable methods for inactivating SARS-CoV-2 on N95 respirators for potential reuse. We recommend that decontamination procedures being considered for the reuse of N95 respirators be validated at each individual site and that validation of the process must be thoroughly conducted using a defined protocol.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-21T05:38:50Z
      DOI: 10.1177/1535370220977819
  • Conformation and protein interactions of intramolecular DNA and
           phosphorothioate four-way junctions
    • Authors: Maria Troisi, Mitchell Klein, Andrew C Smith, Gaston Moorhead, Yonatan Kebede, Raymond Huang, Elliott Parker, Hector Herrada, Elizabeth Wade, Samara Smith, Payson Broome, Jonah Halsell, Louis Estevez, Anthony J Bell
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The objectives of this study are to evaluate the structure and protein recognition features of branched DNA four-way junctions in an effort to explore the therapeutic potential of these molecules. The classic immobile DNA 4WJ, J1, is used as a matrix to design novel intramolecular junctions including natural and phosphorothioate bonds. Here we have inserted H2-type mini-hairpins into the helical termini of the arms of J1 to generate four novel intramolecular four-way junctions. Hairpins are inserted to reduce end fraying and effectively eliminate potential nuclease binding sites. We compare the structure and protein recognition features of J1 with four intramolecular four-way junctions: i-J1, i-J1(PS1), i-J1(PS2) and i-J1(PS3). Circular dichroism studies suggest that the secondary structure of each intramolecular 4WJ is composed predominantly of B-form helices. Thermal unfolding studies indicate that intramolecular four-way junctions are significantly more stable than J1. The Tm values of the hairpin four-way junctions are 25.2° to 32.2°C higher than the control, J1. With respect to protein recognition, gel shift assays reveal that the DNA-binding proteins HMGBb1 and HMGB1 bind the hairpin four-way junctions with affinity levels similar to control, J1. To evaluate nuclease resistance, four-way junctions are incubated with DNase I, exonuclease III (Exo III) and T5 exonuclease (T5 Exo). The enzymes probe nucleic acid cleavage that occurs non-specifically (DNase I) and in a 5ʹ→3ʹ (T5 Exo) and 3ʹ→5ʹ direction (Exo III). The nuclease digestion assays clearly show that the intramolecular four-way junctions possess significantly higher nuclease resistance than the control, J1.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-20T05:49:12Z
      DOI: 10.1177/1535370220973970
  • Roles of kisspeptin in IVF/ICSI-treated infertile women and in human
           granulosa cells
    • Authors: Lixian Qin, Chantacha Sitticharoon, Somsin Petyim, Issarawan Keadkraichaiwat, Rungnapa Sririwichitchai, Pailin Maikeaw, Malika Churintaraphan, Chanakarn Sripong
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Kisspeptin, a crucial central regulator of reproduction, has been used as a trigger in in vitro fertilization (IVF) treatment. This study aimed to investigate the roles of kisspeptin in IVF treatment in infertile females (n = 30); and in steroidogenesis in human granulosa-like tumor cell line (KGN). In the human study, blood was collected at three time points including (1) the beginning of gonadotropin stimulation (Phase I), (2) around eight days after gonadotropin stimulation (Phase II), and (3) on the day of ovum pick-up (Phase III). Follicular fluid (FF) was collected at Phase III. Serum human chorionic gonadotropin (hCG) was measured 15 days after embryo transfer and fetal heart beats were determined around 42 days of menstrual cycle to classify the subjects into successful and unsuccessful groups. FF kisspeptin levels were higher in successful compared with unsuccessful subjects (P 
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-17T05:03:50Z
      DOI: 10.1177/1535370220981006
  • Immunomodulatory effects of mesenchymal stem cells for the treatment of
           cardiac allograft rejection
    • Authors: Zhichao Wu, Jialiang Liang, Wei Huang, Lin Jiang, Christian Paul, Xiang Gao, Perwez Alam, Onur Kanisicak, Meifeng Xu, Yigang Wang
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Heart transplantation continues to be the gold standard clinical intervention to treat patients with end-stage heart failure. However, there are major complications associated with this surgical procedure that reduce the survival prognosis of heart transplant patients, including allograft rejection, malignancies, infections, and other complications that arise from the use of broad-spectrum immunosuppression drugs. Recent studies have demonstrated the use of mesenchymal stem cells (MSCs) against allotransplantation rejection in both in vitro and in vivo settings due to their immunomodulatory properties. Therefore, utilization of MSCs provides new and exciting strategies to improve heart transplantation and potentially reduce the use of broad-spectrum immunosuppression drugs while alleviating allograft rejection. In this review, we will discuss the current research on the mechanisms of cardiac allograft rejection, the physiological and immunological characteristics of MSCs, the effects of MSCs on the immune system, and immunomodulation of heart transplantation by MSCs.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-17T05:03:48Z
      DOI: 10.1177/1535370220978650
  • Identification of histone acetylation in a murine model of allergic asthma
           by proteomic analysis
    • Authors: Yuan Ren, Menglu Li, Shiyao Bai, Lingfei Kong, Xinming Su
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The pathogenesis of asthma is closely related to histone acetylation modification, but the specific acetylation sites related to this process remain indistinct. Herein, our study sought to identify differentially modified acetylation sites and their expression distribution in cells involved in asthma in lung tissues. The airway hyper-responsiveness, inflammation, and remodeling were assessed by non-invasive whole-body plethysmography, ELISA, and hematoxylin-eosin staining to confirm the successful establishment of the allergic asthma model. Afterward, the differentially modified acetylation sites in asthmatic lung tissues were identified and validated by using proteomics and western blotting, respectively. The immunohistochemistry analysis was applied to reveal the distribution of identified acetylation sites in asthmatic lung tissues. A total of 15 differentially modified acetylation sites, including 13 upregulated (H3K9ac, H3K14ac, H3K18ac, H3K23ac,H3K27ac, H3K36ac, H2B1KK120ac, H2B2BK20ac, H2BK16ac, H2BK20ac, H2BK108ac, H2BK116ac, and H2BK120ac) and 2 downregulated (H2BK5ac and H2BK11ac) sites were identified and validated. Furthermore, immunohistochemical staining of lung tissues showed that nine of the identified histone acetylation sites (H2BK5, H2BK11, H3K18, H2BK116, H2BK20, H2BK120, H3K9, H3K36, and H3K27) were differentially expressed in airway epithelial cells, and the acetylation of identified H3 histones were observed in both eosinophil and perivascular inflammatory cells. Additionally, differential expression of histone acetylation sites was also observed in nucleus of airway epithelial cells, vascular smooth muscle cells, perivascular inflammatory cells, and airway smooth muscle cells. In conclusion, we identified potential acetylation sites associated with asthma pathogenesis. These findings may contribute greatly in the search for therapeutic approaches for allergic asthma.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-17T05:03:48Z
      DOI: 10.1177/1535370220980345
  • Analyses of short-chain fatty acids and exhaled breath volatiles in
           dietary intervention trials for metabolic diseases
    • Authors: Jisun HJ Lee, Jiangjiang Zhu
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      As an alternative to pharmacological treatment to diseases, lifestyle interventions, such as dietary changes and physical activities, can help maintain healthy metabolic conditions. Recently, the emerging analyses of volatile organic compounds (VOCs) from breath and short-chain fatty acids (SCFAs) from plasma/feces have been considered as useful tools for the diagnosis and mechanistic understanding of metabolic diseases. Furthermore, diet-induced changes of SCFAs in individuals with diagnosed metabolic abnormalities have been correlated with the composition changes of the gut microbiome. More interestingly, the analysis of exhaled breath (breathomics) has gained attention as a useful technique to measure the human VOC profile altered as a result of dietary interventions. In this mini-review, we examined recent clinical trials that performed promising dietary interventions, SCFAs analysis in plasma/feces, and VOC profile analysis in exhaling breath to understand the relationship between dietary intervention and metabolic health.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-17T05:03:47Z
      DOI: 10.1177/1535370220979952
  • Genomic analysis of SARS-CoV-2 reveals local viral evolution in Ghana
    • Authors: Joyce M Ngoi, Peter K Quashie, Collins M Morang'a, Joseph HK Bonney, Dominic SY Amuzu, Selassie Kumordjie, Ivy A Asante, Evelyn Y Bonney, Miriam Eshun, Linda Boatemaa, Vanessa Magnusen, Erasmus N Kotey, Nicaise T Ndam, Frederick Tei-Maya, Augustina K Arjarquah, Evangeline Obodai, Isaac D Otchere, Yaw Bediako, Joe K Mutungi, Lucas N Amenga-Etego, John K Odoom, Abraham K Anang, George B Kyei, Bright Adu, William K Ampofo, Gordon A Awandare
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The confirmed case fatality rate for the coronavirus disease 2019 (COVID-19) in Ghana has dropped from a peak of 2% in March to be consistently below 1% since May 2020. Globally, case fatality rates have been linked to the strains/clades of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within a specific country. Here we present 46 whole genomes of SARS-CoV-2 circulating in Ghana, from two separate sequencing batches: 15 isolates from the early epidemic (March 12–April 1 2020) and 31 from later time-points ( 25–27 May 2020). Sequencing was carried out on an Illumina MiSeq system following an amplicon-based enrichment for SARS-CoV-2 cDNA. After genome assembly and quality control processes, phylogenetic analysis showed that the first batch of 15 genomes clustered into five clades: 19A, 19B, 20A, 20B, and 20C, whereas the second batch of 31 genomes clustered to only three clades 19B, 20A, and 20B. The imported cases (6/46) mapped to circulating viruses in their countries of origin, namely, India, Hungary, Norway, the United Kingdom, and the United States of America. All genomes mapped to the original Wuhan strain with high similarity (99.5–99.8%). All imported strains mapped to the European superclade A, whereas 5/9 locally infected individuals harbored the B4 clade, from the East Asian superclade B. Ghana appears to have 19B and 20B as the two largest circulating clades based on our sequence analyses. In line with global reports, the D614G linked viruses seem to be predominating. Comparison of Ghanaian SARS-CoV-2 genomes with global genomes indicates that Ghanaian strains have not diverged significantly from circulating strains commonly imported into Africa. The low level of diversity in our genomes may indicate lower levels of transmission, even for D614G viruses, which is consistent with the relatively low levels of infection reported in Ghana.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-16T04:09:13Z
      DOI: 10.1177/1535370220975351
  • COVID-19 global pandemic planning: Performance and electret charge of N95
           respirators after recommended decontamination methods
    • Authors: Anne M Grillet, Martin B Nemer, Steven Storch, Andres L Sanchez, Edward S Piekos, Jonathan Leonard, Ivy Hurwitz, Douglas J Perkins
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Shortages of N95 respirators for use by medical personnel have driven consideration of novel conservation strategies, including decontamination for reuse and extended use. Decontamination methods listed as promising by the Centers for Disease Control and Prevention (CDC) (vaporous hydrogen peroxide (VHP), wet heat, ultraviolet irradiation (UVI)) and several methods considered for low resource environments (bleach, isopropyl alcohol and detergent/soap) were studied for two commonly used surgical N95 respirators (3M™ 1860 and 1870+ Aura™). Although N95 filtration performance depends on the electrostatically charged electret filtration layer, the impact of decontamination on this layer is largely unexplored. As such, respirator performance following decontamination was assessed based on the fit, filtration efficiency, and pressure drop, along with the relationship between (1) surface charge of the electret layer, and (2) elastic properties of the straps. Decontamination with VHP, wet heat, UVI, and bleach did not degrade fit and filtration performance or electret charge. Isopropyl alcohol and soap significantly degraded fit, filtration performance, and electret charge. Pressure drop across the respirators was unchanged. Modest degradation of N95 strap elasticity was observed in mechanical fatigue testing, a model for repeated donnings and doffings. CDC recommended decontamination methods including VHP, wet heat, and UV light did not degrade N95 respirator fit or filtration performance in these tests. Extended use of N95 respirators may degrade strap elasticity, but a loss of face seal integrity should be apparent during user seal checks. NIOSH recommends performing user seal checks after every donning to detect loss of appropriate fit. Decontamination methods which degrade electret charge such as alcohols or detergents should not be used on N95 respirators. The loss of N95 performance due to electret degradation would not be apparent to a respirator user or evident during a negative pressure user seal check.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-16T04:09:12Z
      DOI: 10.1177/1535370220976386
  • High-throughput genotyping assays for identification of glycophorin B
           deletion variants in population studies
    • Authors: Dominic SY Amuzu, Kirk A Rockett, Ellen M Leffler, Felix Ansah, Nicholas Amoako, Collins M Morang’a, Christina Hubbart, Kate Rowlands, Anna E Jeffreys, Lucas N Amenga-Etego, Dominic P Kwiatkowski, Gordon A Awandare
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Glycophorins are the most abundant sialoglycoproteins on the surface of human erythrocyte membranes. Genetic variation in glycophorin region of human chromosome 4 (containing GYPA, GYPB, and GYPE genes) is of interest because the gene products serve as receptors for pathogens of major public health interest, including Plasmodium sp., Babesia sp., Influenza virus, Vibrio cholerae El Tor Hemolysin, and Escherichia coli. A large structural rearrangement and hybrid glycophorin variant, known as Dantu, which was identified in East African populations, has been linked with a 40% reduction in risk for severe malaria. Apart from Dantu, other large structural variants exist, with the most common being deletion of the whole GYPB gene and its surrounding region, resulting in multiple different deletion forms. In West Africa particularly, these deletions are estimated to account for between 5 and 15% of the variation in different populations, mostly attributed to the forms known as DEL1 and DEL2. Due to the lack of specific variant assays, little is known of the distribution of these variants. Here, we report a modification of a previous GYPB DEL1 assay and the development of a novel GYPB DEL2 assay as high-throughput PCR-RFLP assays, as well as the identification of the crossover/breakpoint for GYPB DEL2. Using 393 samples from three study sites in Ghana as well as samples from HapMap and 1000 G projects for validation, we show that our assays are sensitive and reliable for genotyping GYPB DEL1 and DEL2. To the best of our knowledge, this is the first report of such high-throughput genotyping assays by PCR-RFLP for identifying specific GYPB deletion types in populations. These assays will enable better identification of GYPB deletions for large genetic association studies and functional experiments to understand the role of this gene cluster region in susceptibility to malaria and other diseases.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-16T04:09:11Z
      DOI: 10.1177/1535370220968545
  • Rapid and ultrasensitive detection of circulating human papillomavirus E7
           cell-free DNA as a cervical cancer biomarker
    • Authors: Phetploy Rungkamoltip, Sasithon Temisak, Kitiya Piboonprai, Deanpen Japrung, Pattanapong Thangsunan, Saranya Chanpanitkitchot, Woraphot Chaowawanit, Nutthaporn Chandeying, Siriwan Tangjitgamol, Tawin Iempridee
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Circulating cell-free DNA (cfDNA) has attracted attention as a non-invasive biomarker for diagnosing and monitoring various cancers. Given that human papillomavirus (HPV) DNA integration and overexpression of E6/E7 oncogenes are pivotal events for carcinogenesis, we sought to determine if HPV E7 cfDNA could serve as a specific biomarker for cervical cancer detection. We applied droplet digital PCR (ddPCR) to quantify HPV16/18 E7 cfDNA from the serum of patients with cervical cancer, cervical intraepithelial neoplasia, and controls. HPV16/18 E7 cfDNA was highly specific for cervical cancer, displaying 30.77% sensitivity, 100% specificity, and an area under the curve of 0.65. Furthermore, we developed a sensitive isothermal detection of HPV16/18 E7 and the PIK3CA WT reference gene based on recombinase polymerase amplification combined with a lateral flow strip (RPA-LF). The assay took less than 30 min and the detection limit was 5–10 copies. RPA-LF exhibited 100% sensitivity and 88.24% specificity towards HPV16/18 E7 cfDNA in clinical samples. The agreement between RPA-LF and ddPCR was 83.33% (κ = 0.67) for HPV16 E7 and 100% (κ = 1.0) for HPV18 E7, indicating a good correlation between both tests. Therefore, we conclude that HPV E7 cfDNA represents a potential tumor marker with excellent specificity and moderate sensitivity for minimally invasive cervical cancer monitoring. Moreover, the RPA-LF assay provides an affordable, rapid, and ultrasensitive tool for detecting HPV cfDNA in resource-limited settings.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-14T06:22:30Z
      DOI: 10.1177/1535370220978899
  • Functional intrinsic optical signal imaging for objective optoretinography
           of human photoreceptors
    • Authors: Taeyoon Son, Tae-Hoon Kim, Guangying Ma, Hoonsup Kim, Xincheng Yao
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Functional mapping of photoreceptor physiology is important for better disease diagnosis and treatment assessment. Fast intrinsic optical signal (IOS), which arises before light-evoked pupillary response, promises a unique biomarker of photoreceptor physiology for objective optoretinography with high resolution. This study is to test the feasibility of non-mydriatic IOS mapping of retinal photoreceptors in awake human. Depth-resolved optical coherence tomography verified outer segment (OS) as the anatomic origin of fast photoreceptor-IOS. Dynamic IOS changes are primarily confined at OS boundaries connected with inner segment and retinal pigment epithelium, supporting transient OS shrinkage due to phototransduction process as the mechanism of the fast photoreceptor-IOS response.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-14T06:22:29Z
      DOI: 10.1177/1535370220978898
  • YAP activation in melanoma contributes to anoikis resistance and
    • Authors: Bei Zhao, Jun Xie, Xiyuan Zhou, Lixia Zhang, Xiankui Cheng, Chenglin Liang
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Melanoma is inherently heterogeneous, providing resistance to apoptosis. Anoikis resistance is a hallmark feature of metastatic melanoma to escape apoptosis when cells lose contact with adjacent cells or extracellular matrix. The yes-associated protein transcription co-activator is the effector of Hippo pathway. Herein, we investigated the function of yes-associated protein in anoikis resistance of melanoma cells. When melanoma cells were grown under anchorage-independent condition, anoikis-resistant cells displayed higher levels of yes-associated protein activation than the cells that were attached to the basement membrane, as evidenced by downregulated phosphorylated yes-associated protein at Ser127 and higher expression of downstream genes BCL2 and MCL-1. Yes-associated protein overexpression directly enhanced the anoikis resistance and metastatic potential of melanoma cells. Conversely, yes-associated protein inhibitor CA3 exhibited Dose-dependent induction of anoikis in resistant melanoma cells and exerted great inhibition on cell migration. Knockdown of yes-associated protein expression by shRNA also rendered melanoma cells susceptible to anoikis and interrupted cell invasiveness. Yes-associated protein inhibition in anoikis-resistant cells also reduced the number of metastatic nodules in the lung sections of SCID mice. Clinically, higher yes-associated protein level in the lung metastasis tissues correlated with higher BCL2 and MCL1 expressions compared with the non-metastasis tissues. Overall, our finding suggests that the aberrant activation of yes-associated protein exerts important role on anoikis resistance and metastatic capability of melanoma cells.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-14T06:22:28Z
      DOI: 10.1177/1535370220977101
  • The neurovascular extracellular matrix in health and disease
    • Authors: Aric F Logsdon, Elizabeth M Rhea, May Reed, William A Banks, Michelle A Erickson
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The blood–brain barrier (BBB) is a vital interface that supports normal brain functions. Endothelial cells (ECs) are the main component of the BBB and are highly specialized to govern the transfer of substances into brain. The EC lumen is enmeshed with an extracellular matrix (ECM), known as the endothelial glycocalyx layer (EGL). The lumen-facing EGL is primarily comprised of proteoglycans (PGs) and glycosaminoglycans (GAGs), which function as the first line of defense for blood-to-brain transfer of substances. Circulating factors must first penetrate the EGL before interacting with the EC. The abundance and composition of the PG and GAGs can dictate EGL function, and determine which circulating substances communicate with the ECs. The EGL can interact with circulating factors through physio-chemical interactions with the EC. Some disease states reveal a “thinning” of the EGL that may increase EC interactions with components of the systemic circulation and alter BBB function. EGL changes may also contribute to the cognitive complications of systemic diseases, such as sepsis and diabetes. For decades, researchers have measured how genetic and environmental factors influence the peripheral EGL constituents; however, much less is known about the neurovascular EGL. In this mini-review, we introduce components of the EGL and innovative ways to measure their abundance and composition that may contribute to BBB dysfunction.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-11T05:14:22Z
      DOI: 10.1177/1535370220977195
  • Nomograms-based prediction of overall and cancer-specific survivals for
           patients with chromophobe renal cell carcinoma
    • Authors: Chunyang Chen, Xinyu Geng, Rui Liang, Dongze Zhang, Meiyun Sun, Guangbo Zhang, Jianquan Hou
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      This study built and tested two effective nomograms for the purpose of predicting cancer-specific survival and overall survival of chromophobe renal cell carcinoma (chRCC) patients. Multivariate Cox regression analysis was employed to filter independent prognostic factors predictive of cancer-specific survival and overall survival, and the nomograms were built based on a training set incorporating 2901 chRCC patients in a retrospective study (from 2004 to 2015) downloaded from the surveillance, epidemiology, and end results (SEER) database. The nomograms were verified on a validation cohort of 1934 patients, subsequently the performances of the nomograms were examined according to the receiver operating characteristic curve, calibration curves, the concordance (C-index), and decision curve analysis. The results showed that tumor grade, AJCC and N stages, race, marital status, age, histories of chemotherapy, radiotherapy and surgery were the individual prognostic factors for overall survival, and that AJCC, N and SEER stages, histories of surgery, radiotherapy and chemotherapy, age, tumor grade were individual prognostic factors for cancer-specific survival. According to C-indexes, receiver operating characteristic curves, and decision curve analysis outcomes, the nomograms showed a higher accuracy in predicting overall survival and OSS when compared with TNM stage and SEER stage. All the calibration curves were significantly consistent between predictive and validation sets. In this study, the nomograms, which were validated to be highly accurate and applicable, were built to facilitate individualized predictions of the cancer-specific survival and overall survival to patients diagnosed with chRCC between 2004 and 2015.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-11T05:14:21Z
      DOI: 10.1177/1535370220977107
  • Protease-activated receptor 1 as a potential therapeutic target for
    • Authors: Emanuel S. Rovai, Tomaz Alves, Marinella Holzhausen
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Acute respiratory disease caused by a novel coronavirus (SARS-CoV-2) has spread all over the world, since its discovery in 2019, Wuhan, China. This disease is called COVID-19 and already killed over 1 million people worldwide. The clinical symptoms include fever, dry cough, dyspnea, headache, dizziness, generalized weakness, vomiting, and diarrhea. Unfortunately, so far, there is no validated vaccine, and its management consists mainly of supportive care. Venous thrombosis and pulmonary embolism are highly prevalent in patients suffering from severe COVID-19. In fact, a prothrombotic state seems to be present in most fatal cases of the disease. SARS-CoV-2 leads to the production of proinflammatory cytokines, causing immune-mediated tissue damage, disruption of the endothelial barrier, and uncontrolled thrombogenesis. Thrombin is the key regulator of coagulation and fibrin formation. In severe COVID-19, a dysfunctional of physiological anticoagulant mechanisms leads to a progressive increase of thrombin activity, which is associated with acute respiratory distress syndrome development and a poor prognosis. Protease-activated receptor type 1 (PAR1) is the main thrombin receptor and may represent an essential link between coagulation and inflammation in the pathophysiology of COVID-19. In this review, we discuss the potential role of PAR1 inhibition and regulation in COVID-19 treatment.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-11T05:14:20Z
      DOI: 10.1177/1535370220978372
  • Characterizing disease progression of nonalcoholic steatohepatitis in
           Leptin-deficient rats by integrated transcriptome analysis
    • Authors: Ping Lu, Guang Yang, Lichun Jiang, Wen He, Wanwan Wu, Lingbin Qi, Shijun Shen, Junhua Rao, Peng Zhang, Zhigang Xue, Cizhong Jiang, Guoping Fan, Xianmin Zhu
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening human health, yet no medicine is developed to treat this disease. In this study, we first discovered that Leptin mutant rats (LepΔI14/ΔI14) exhibit characteristic NASH phenotypes including steatosis, lymphocyte infiltration, and ballooning after postnatal week 16. We then examined NASH progression by performing an integrated analysis of hepatic transcriptome in Leptin-deficient rats from postnatal 4 to 48 weeks. Initially, simple steatosis in LepΔI14/ΔI14 rats were observed with increased expression of the genes encoding for rate-limiting enzymes in lipid metabolism such as acetyl-CoA carboxylase and fatty acid synthase. When NASH phenotypes became well developed at postnatal week 16, we found gene expression changes in insulin resistance, inflammation, reactive oxygen species and endoplasmic reticulum stress. As NASH phenotypes further progressed with age, we observed elevated expression of cytokines and chemokines including C-C motif chemokine ligand 2, tumor necrosis factor ɑ, interleukin-6, and interleukin-1β together with activation of the c-Jun N-terminal kinase and nuclear factor-κB pathways. Histologically, livers in LepΔI14/ΔI14 rats exhibited increased cell infiltration of MPO+ neutrophils, CD8+ T cells, CD68+ hepatic macrophages, and CCR2+ inflammatory monocyte-derived macrophages associated with macrophage polarization from M2 to M1. Subsequent cross-species comparison of transcriptomes in human, rat, and mouse NASH models indicated that Leptin-deficient rats bear more similarities to human NASH patients than previously established mouse NASH models. Taken together, our study suggests that LepΔI14/ΔI14 rats are a valuable pre-clinical rodent model to evaluate NASH drug safety and efficacy.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-11T05:14:19Z
      DOI: 10.1177/1535370220976530
  • FOXM1 activates JAK1/STAT3 pathway in human osteoarthritis cartilage cell
           inflammatory reaction
    • Authors: Runming Zeng, Xiaohui Lu, Jing Lin, Zhijie Ron, Jiezhuang Fang, Zewa Liu, Wanting Zeng
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Osteoarthritis (OA), the most prevalent form of arthritis disease, is characterized by destruction of articular cartilage, osteophyte development, and sclerosis of subchondral bone. Transcription factors Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and Forkhead box M1 (FOXM1) are key mediators of this inflammatory reaction. In this study, we investigated the interaction between JAK1/STAT3 and FOXM1 in OA. Inflammation is related to the cartilage damage, and lipopolysaccharides (LPS) are a major pro-inflammatory inducer, so LPS was utilized to stimulate chondrocytes and establish a cell-based OA model. We found LPS treatment caused a generation of inflammatory cell factors (IL-1β, IL-6, and TNF-α), and upregulation of inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2) and other inflammatory mediators. Cell viability of chondrocytes was impaired with LPS stimulation, along with an upregulation of JAK1 expression, and phosphorylation and nuclear accumulation of STAT3. The administration of STAT3 inhibitor WP1066, which abated activation and nuclear location of STAT3, depleted the effect of LPS on inflammation and cell death. Co-immunoprecipitation showed that STAT3 was able to bind to FOXM1, and deactivation of STAT3 resulted in the downregulation of FOXM1. Moreover, FOXM1 silencing inhibited the generation of inflammatory cytokines induced by LPS, and the attenuation of cell survival. These findings indicated that the interaction between JAK1/STAT3 and FOXM1 may play a key role in OA pathogenic studies, and suggest the JAK1/STAT3 pathway may be a potential target for OA therapy.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-10T05:13:52Z
      DOI: 10.1177/1535370220974933
  • Integrating photoacoustic microscopy with other imaging technologies for
           multimodal imaging
    • Authors: Arash Dadkhah, Shuliang Jiao
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      As a hybrid optical microscopic imaging technology, photoacoustic microscopy images the optical absorption contrasts and takes advantage of low acoustic scattering of biological tissues to achieve high-resolution anatomical and functional imaging. When combined with other imaging modalities, photoacoustic microscopy-based multimodal technologies can provide complementary contrast mechanisms to reveal complementary information of biological tissues. To achieve intrinsically and precisely registered images in a multimodal photoacoustic microscopy imaging system, either the ultrasonic transducer or the light source can be shared among the different imaging modalities. These technologies are the major focus of this minireview. It also covered the progress of the recently developed penta-modal photoacoustic microscopy imaging system featuring a novel dynamic focusing technique enabled by OCT contour scan.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-10T05:13:51Z
      DOI: 10.1177/1535370220977176
  • Redox treatment ameliorates diabetes mellitus-induced skin flap necrosis
           via inhibiting apoptosis and promoting neoangiogenesis
    • Authors: Yeon S Kim, Hye-Young Lee, Jeon Y Jang, Hye R Lee, Yoo S Shin, Chul-Ho Kim
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Intractable wound healing is the habitual problem of diabetes mellitus. High blood glucose limits wound healing by interrupting inflammatory responses and inhibiting neoangiogenesis. Oxidative stress is commonly thought to be a major pathogenic cause of diabetic complications. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDV) is a free radical scavenger which suppress oxidative stress. This study investigates whether EDV can reduce oxidative stress in wound healing HaCaT/human dermal fibroblasts cells (HDFs) in vitro and in vivo animal model. Cell viability and wound healing assays, FACS flow cytometry, and Hoechst 33342 staining were performed to confirm apoptosis and cytotoxicity in H2O2 and EDV-treated HaCaT and HDFs. A streptozotocin-induced hyperglycemic animal model was made in adult C57BL6 mice. Full-thickness skin flap was made on dorsomedial back and re-sutured to evaluate the wound healing process. EDV was delivered slowly in the skin flap with degradable fibrin glue. The flap was monitored and analyzed on postoperative days 1, 3, and 5. CD31/DAPI staining was done to detect newly formed blood vessels. The expression levels of NF-κB, bcl-2, NOX3, and STAT3 proteins in C57BL6 mouse tissues were also examined. The wound healing process in hyper- and normoglycemic mice showed a difference in protein expression, especially in oxidative stress management and angiogenesis. Exogenous H2O2 reduced cell viability in a proportion to the concentration via apoptosis. EDV protected HaCaT cells and HDFs from H2O2 induced reactive oxygen species cell damage and apoptosis. In the mouse model, EDV with fibrin resulted in less necrotic areas and increased angiogenesis on postoperative day 5, compared to sham-treated mice. Our results indicate that EDV could protect H2O2-induced cellular injury via inhibiting early apoptosis and inflammation and also increasing angiogenesis. EDV might be valuable in the treatment of diabetic wounds that oxidative stress has been implicated.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-07T04:15:09Z
      DOI: 10.1177/1535370220974269
  • Importance of extracellular vesicles in hypertension
    • Authors: Zhi Z Liu, Pedro A Jose, Jian Yang, Chunyu Zeng
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Hypertension affects approximately 1.13 billion adults worldwide and is the leading global risk factor for cardiovascular, cerebrovascular, and kidney diseases. There is emerging evidence that extracellular vesicles participate in the development and progression of hypertension. Extracellular vesicles are membrane-enclosed structures released from nearly all types of eukaryotic cells. During their formation, extracellular vesicles incorporate various parent cell components, including proteins, lipids, and nucleic acids that can be transferred to recipient cells. Extracellular vesicles mediate cell-to-cell communication in a variety of physiological and pathophysiological processes. Therefore, studying the role of circulating and urinary extracellular vesicles in hypertension has the potential to identify novel noninvasive biomarkers and therapeutic targets of different hypertension phenotypes. This review discusses the classification and biogenesis of three EV subcategories (exosomes, microvesicles, and apoptotic bodies) and provides a summary of recent discoveries in the potential impact of extracellular vesicles on hypertension with a specific focus on their role in the blood pressure regulation by organs—artery and kidney, as well as renin-angiotensin-system.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-07T04:15:09Z
      DOI: 10.1177/1535370220974600
  • Nitric oxide and sickle cell disease—Is there a painful
    • Authors: Lillian Hallmark, Luis EF Almeida, Sayuri Kamimura, Meghann Smith, Zenaide MN Quezado
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Sickle cell disease is the most common hemoglobinopathy and affects millions worldwide. The disease is associated with severe organ dysfunction, acute and chronic pain, and significantly decreased life expectancy. The large body of work demonstrating that hemolysis results in rapid consumption of the endogenous vasodilator nitric oxide, decreased nitric oxide production, and promotion of vaso-occlusion provides the basis for the hypothesis that nitric oxide bioavailability is reduced in sickle cell disease and that this deficit plays a role in sickle cell disease pain. Despite initial promising results, large clinical trials using strategies to increase nitric oxide bioavailability in sickle cell disease patients yielded no significant change in duration or frequency of acute pain crises. Further, recent investigations showed that sickle cell disease patients and mouse models have elevated baseline levels of blood nitrite, a reservoir for nitric oxide formation and a product of nitric oxide metabolism, regardless of pain phenotype. These conflicting results challenge the hypotheses that nitric oxide bioavailability is decreased and that it plays a significant role in the pathogenesis in sickle cell disease acute pain crises. Conversely, a large body of work demonstrates that nitric oxide, as a neurotransmitter, has a complex role in pain neurobiology, contributes to the development of central sensitization, and can mediate hyperalgesia in inflammatory and neuropathic pain. These results support an alternative hypothesis: one proposing that altered nitric oxide signaling may contribute to the development of neuropathic and/or inflammatory pain in sickle cell disease through its role as a neurotransmitter.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-07T04:15:07Z
      DOI: 10.1177/1535370220976397
  • COMMD1 upregulation is involved in copper efflux from ischemic hearts
    • Authors: Chen Li, Tao Wang, Ying Xiao, Kui Li, Xia Meng, Y James Kang
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Copper depletion is associated with myocardial ischemic infarction, in which copper metabolism MURR domain 1 (COMMD1) is increased. The present study was undertaken to test the hypothesis that the elevated COMMD1 is responsible for copper loss from the ischemic myocardium, thus worsening myocardial ischemic injury. Mice (C57BL/6J) were subjected to left anterior descending coronary artery permanent ligation to induce myocardial ischemic infarction. In the ischemic myocardium, copper reduction was associated with a significant increase in the protein level of COMMD1. A tamoxifen-inducible, cardiomyocyte -specific Commd1 knockout mouse (C57BL/6J) model (COMMD1CMC▲/▲) was generated using the Cre-LoxP recombination system. COMMD1CMC▲/▲ and wild-type littermates were subjected to the same permanent ligation of left anterior descending coronary artery. At the 7th day after ischemic insult, COMMD1 deficiency suppressed copper loss in the heart, along with preservation of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 expression and the integrity of the vascular system in the ischemic myocardium. Corresponding to this change, infarct size of ischemic heart was reduced and myocardial contractile function was well preserved in COMMD1CMC▲/▲ mice. These results thus demonstrate that upregulation of COMMD1 is at least partially responsible for copper efflux from the ischemic heart. Cardiomyocyte-specific deletion of COMMD1 helps preserve the availability of copper for angiogenesis, thus suppressing myocardial ischemic dysfunction.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-12-07T04:15:05Z
      DOI: 10.1177/1535370220969844
  • Store-operated calcium entry: Pivotal roles in renal physiology and
    • Authors: Sarika Chaudhari, Robert T Mallet, Parisa Y Shotorbani, Yu Tao, Rong Ma
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Research conducted over the last two decades has dramatically advanced the understanding of store-operated calcium channels (SOCC) and their impact on renal function. Kidneys contain many types of cells, including those specialized for glomerular filtration (fenestrated capillary endothelium, podocytes), water and solute transport (tubular epithelium), and regulation of glomerular filtration and renal blood flow (vascular smooth muscle cells, mesangial cells). The highly integrated function of these myriad cells effects renal control of blood pressure, extracellular fluid volume and osmolality, electrolyte balance, and acid–base homeostasis. Many of these cells are regulated by Ca2+ signaling. Recent evidence demonstrates that SOCCs are major Ca2+ entry portals in several renal cell types. SOCC is activated by depletion of Ca2+ stores in the sarco/endoplasmic reticulum, which communicates with plasma membrane SOCC via the Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Orai1 is recognized as the main pore-forming subunit of SOCC in the plasma membrane. Orai proteins alone can form highly Ca2+ selective SOCC channels. Also, members of the Transient Receptor Potential Canonical (TRPC) channel family are proposed to form heteromeric complexes with Orai1 subunits, forming SOCC with low Ca2+ selectivity. Recently, Ca2+ entry through SOCC, known as store-operated Ca2+ entry (SOCE), was identified in glomerular mesangial cells, tubular epithelium, and renovascular smooth muscle cells. The physiological and pathological relevance and the characterization of SOCC complexes in those cells are still unclear. In this review, we summarize the current knowledge of SOCC and their roles in renal glomerular, tubular and vascular cells, including studies from our laboratory, emphasizing SOCE regulation of fibrotic protein deposition. Understanding the diverse roles of SOCE in different renal cell types is essential, as SOCC and its signaling pathways are emerging targets for treatment of SOCE-related diseases.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-29T04:42:32Z
      DOI: 10.1177/1535370220975207
  • Altered gene expression in glycolysis–cholesterol synthesis axis
           correlates with outcome of triple-negative breast cancer
    • Authors: Peng-Cheng Zhong, Rong Shu, Hui-Wen Wu, Zhi-Wen Liu, Xiao-Ling Shen, Ying-Jie Hu
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Identification of molecular subtypes of clinically resectable triple-negative breast cancer (TNBC) is of great importance to achieve better clinical outcomes. Inter- and intratumor metabolic heterogeneity improves cancer survival, and the interaction of various metabolic pathways may affect treatment outcome of TNBC. We speculated that TNBC can be categorized into prognostic metabolic subtype according to the expression changes of glycolysis and cholesterol synthesis. The genome, transcriptome, and clinical data were downloaded from the Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium and subsequently analyzed by integrated bioinformatics methods. Four subtypes, namely, glycolytic, cholesterogenic, quiescent, and mixed, were classified according to the normalized median expressions of the genes involved in glycolysis and cholesterol synthesis. In the four subtypes, the cholesterogenic type was correlated with the shortest median survival (log rank P = 0.044), while patients with high-expressed glycolytic genes tended to have a longer survival. Tumors with PIK3CA amplification and dynein axonemal heavy chain 2 deletion exhibited higher expressions of cholesterogenic genes than other mutant oncogenes. The expressions of mitochondrial pyruvate carrier MPC1 and MPC2 were the lowest in quiescent tumor, and MPC2 expression was higher in cholesterogenic tumor compared with glycolytic or quiescent tumor (t-test P 
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-27T08:41:03Z
      DOI: 10.1177/1535370220975206
  • Super-resolution ophthalmoscopy: Virtually structured detection for
           resolution improvement in retinal imaging
    • Authors: Xincheng Yao, Rongwen Lu, Benquan Wang, Yiming Lu, Tae-Hoon Kim
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Quantitative retinal imaging is essential for advanced study and clinical management of eye diseases. However, spatial resolution of retinal imaging has been limited due to available numerical aperture and optical aberration of the ocular optics. Structured illumination microscopy has been established to break the diffraction-limit resolution in conventional light microscopy. However, practical implementation of structured illumination microscopy for in vivo ophthalmoscopy of the retina is challenging due to inevitable eye movements that can produce phase artifacts. Recently, we have demonstrated the feasibility of using virtually structured detection as one alternative to structured illumination microscopy for super-resolution imaging. By providing the flexibility of digital compensation of eye movements, the virtually structured detection provides a feasible, phase-artifact-free strategy to achieve super-resolution ophthalmoscopy. In this article, we summarize the technical rationale of virtually structured detection, and its implementations for super-resolution imaging of freshly isolated retinas, intact animals, and awake human subjects.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-27T08:41:01Z
      DOI: 10.1177/1535370220970533
  • Elevated RUNX1 is a prognostic biomarker for human head and neck squamous
           cell carcinoma
    • Authors: Xiaodong Feng, Zhiwei Zheng, Yi Wang, Guanghui Song, Lu Wang, Zhijun Zhang, Jinxia Zhao, Qing Wang, Limin Lun
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Runt-related transcription factors regulate many developmental processes such as proliferation and differentiation. In this study, the function of the runt-related transcription factor 1 (RUNX1) was investigated in head and neck squamous cell carcinoma (HNSCC). Our results show that RUNX1 expression was elevated in HNSCC patients, which was greatly correlated with the N stage, tumor size, and American Joint Committee on Cancer stage. Cox proportional hazard models showed that RUNX1 could be used as a prognostic indicator for the overall survival of HNSCC patients (hazard ratio, 5.572; 95% confidence interval, 1.860–9.963; P 
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-26T12:17:57Z
      DOI: 10.1177/1535370220969663
  • The clinical phenotype of bronchiectasis and its clinical guiding
    • Authors: Li Gao, Ke-Ru Qin, Ting Li, Hai-Long Wang, Min Pang
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Bronchiectasis is a chronic airway disease with abnormal and persistent bronchial dilatation caused by a variety of reasons. In recent years, numerous reports have shown that bronchiectasis is heterogeneous, the clinical characteristics of patients with different phenotypes are different, and the efficacy of a treatment regimen may vary greatly in patients with different bronchiectasis phenotypes. This paper summarizes the current clinical phenotypic classification of bronchiectasis from the perspective of etiology, microbiology, and the frequency of acute exacerbation, and cluster analysis was used to determine new clinical phenotypes and their statistical and clinical significance. Different tools for assessing disease severity yield different outcomes. This article summarizes the research progress in the above areas, hoping to provide a more comprehensive understanding of the disease.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-26T12:17:57Z
      DOI: 10.1177/1535370220972324
  • Regional heterogeneity in rat Peyer’s patches through whole
           transcriptome analysis
    • Authors: Charles L Phillips, Bradley A Welch, Michael R Garrett, Bernadette E Grayson
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Peyer’s patches are gut-associated lymphoid tissue located throughout the intestinal wall. Peyer’s patches consist of highly organized ovoid-shaped follicles, classified as non-encapsulated lymphatic tissues, populated with B cells, T cells, macrophages, and dendritic cells and function as an organism’s intestinal surveillance. Limited work compares the gene profiles of Peyer’s patches derived from different intestinal regions. In the current study, we first performed whole transcriptome analysis using RNAseq to compare duodenal and ileal Peyer’s patches obtained from the small intestine of Long Evans rats. Of the 12,300 genes that were highly expressed, 18.5% were significantly different between the duodenum and ileum. Using samples obtained from additional subjects (n = 10), we validated the novel gene expression patterns in Peyer’s patches obtained from the three regions of the small intestine. Rats had a significantly reduced number of Peyer’s patches in the duodenum in comparison to either the jejunum or ileum. Regional differences in structural, metabolic, and immune-related genes were validated. Genes such as alcohol dehydrogenase 1, gap junction protein beta 2, and serine peptidase inhibitor clade b, member 1a were significantly reduced in the ileum in comparison to other regions. On the other hand, genes such as complement C3d receptor type, lymphocyte cytosolic protein 1, and lysozyme C2 precursor were significantly lower in the duodenum. In summary, the gene expression pattern of Peyer’s patches is influenced by intestinal location and may contribute to its role in that segment.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-25T10:50:30Z
      DOI: 10.1177/1535370220973014
  • Increased alpha and beta cell mass during mouse pregnancy is not dependent
           on transdifferentiation
    • Authors: Sandra K Szlapinski, Jamie Bennett, Brenda J Strutt, David J Hill
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Maternal pancreatic beta-cell mass (BCM) increases during pregnancy to compensate for relative insulin resistance. If BCM expansion is suboptimal, gestational diabetes mellitus can develop. Alpha-cell mass (ACM) also changes during pregnancy, but there is a lack of information about α-cell plasticity in pregnancy and whether α- to β-cell transdifferentiation can occur. To investigate this, we used a mouse model of gestational glucose intolerance induced by feeding low-protein (LP) diet from conception until weaning and compared pregnant female offspring to control diet-fed animals. Control and LP pancreata were collected for immunohistochemical analysis and serum glucagon levels were measured. In order to lineage trace α- to β-cell conversion, we utilized transgenic mice expressing yellow fluorescent protein behind the proglucagon gene promoter (Gcg-Cre/YFP) and collected pancreata for histology at various gestational timepoints. Alpha-cell proliferation increased significantly at gestational day (GD) 9.5 in control pregnancies resulting in an increased ACM at GD18.5, and this was significantly reduced in LP animals. Despite these changes, serum glucagon was higher in LP mice at GD18.5. Pregnant Gcg-Cre/YFP mice showed no increase in the abundance of insulin+YFP+glucagon– cells (phenotypic β-cells). A second population of insulin+YFP+glucagon+ cells was identified which also did not alter during pregnancy. However, there was an altered anatomical distribution within islets with fewer insulin+YFP+glucagon– cells but more insulin+YFP+glucagon+ cells being present in the islet mantle at GD18.5. These findings demonstrate that dynamic changes in ACM occur during normal pregnancy and were altered in glucose-intolerant pregnancies.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-24T04:36:34Z
      DOI: 10.1177/1535370220972686
  • Identification and analysis of immune-related subtypes of hepatocellular
    • Authors: Qimeng Wang, Jin Huang, Huihua Zhang, Huan Liu, Min Yu
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Hepatocellular carcinoma is a malignance that remains difficult to cure. Immunotherapy has shown its potential application in a variety of refractory malignancies. Due to the complexity of immune microenvironment of hepatocellular carcinoma, the efficacy of immunotherapy for hepatocellular carcinoma is not as effective as expected. Expression data of hepatocellular carcinoma from the TCGA and ICGC databases were used for classification and verification of hepatocellular carcinoma subtypes. The immune-related functions and pathways were identified via gene set enrichment analysis, while the sections denoting the subsets of the immune cells were estimated using the CIBERSORT algorithm. Immunity low (Immunity_L), immunity medium (Immunity_M), and immunity high (Immunity_H) were specified as the three immune-related subtypes of hepatocellular carcinoma. The quantity of stromal and immune cells was the most substantial in Immunity_H, compared to the other subtypes. Interestingly, the proportion of M0 macrophages decreased from Immunity_L to Immunity_H, while the proportion of CD8 T cells increased. Furthermore, the HLA genes expression levels, as well as those of six immune checkpoint genes were substantially lower in Immunity_L than in Immunity_H. Functional analysis was performed for 1512 differentially expressed genes between Immunity_L and Immunity_H. Finally, the PPI network was constructed with 118 nodes. The highest connectivity degree nodes were B2M, HLA-DRA, and HLA-DRB1. The above results were verified in ICGC-JP and ICGC-FR databases with a consistent trend. In this study, we divided hepatocellular carcinoma into three subtypes and explored the immune-related characteristics of these subtypes. These results may provide new insights for immunotherapy of hepatocellular carcinoma.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-24T04:36:33Z
      DOI: 10.1177/1535370220970130
  • Resveratrol alleviates alveolar epithelial cell injury induced by
           hyperoxia by reducing apoptosis and mitochondrial dysfunction
    • Authors: Xiaodan Zhu, Fan Wang, Xiaoping Lei, Wenbin Dong
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Bronchopulmonary dysplasia is a severe and long-term pulmonary disease in premature infants. Hyperoxia-induced acute lung injury plays a critical role in bronchopulmonary dysplasia. Resveratrol is a polyphenolic phytoalexin and a natural agonist of Sirtuin 1. Many studies have shown that resveratrol has a protective effect on hyperoxia-induced lung damage, but its specific protective mechanism is still not clear. Further exploration of the possible protective mechanism of resveratrol was the main goal of this study. In this study, human alveolar epithelial cells were used to establish a hyperoxia-induced acute lung injury cell model, and resveratrol (Res or R), the Sirtuin 1 activator SRT1720 (S) and the Sirtuin 1 inhibitor EX-527 (E) were administered to alveolar epithelial cells, which were then exposed to hyperoxia to investigate the role of Res in mitochondrial function and apoptosis. We divided human alveolar epithelial cells into the following groups: (1) the control group, (2) hyperoxia group, (3) hyperoxia+Res20 group, (4) hyperoxia+Res20+E5 group, (5) hyperoxia+Res20+E10 group, (6) hyperoxia+S2 group, (7) hyperoxia+S2+E5 group, and (8) hyperoxia+S2+E10 group. Hyperoxia-induced cell apoptosis and mitochondrial dysfunction were alleviated by Res and SRT1720. Res and SRT1720 upregulated Sirtuin 1, PGC-1α, NRF1, and TFAM but decreased the expression of acetyl-p53 in human alveolar epithelial cells that were exposed to hyperoxia. These findings revealed that Res may alleviated hyperoxia-induced mitochondrial dysfunction and apoptosis in alveolar epithelial cells through the SIRT1/PGC-1a signaling pathway. Thus, Sirtuin 1 upregulation plays an important role in lung protection.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-20T12:04:20Z
      DOI: 10.1177/1535370220975106
  • Pre-diabetes and COVID-19, could we be missing the silent killer'
    • Authors: Aubrey Mbulelo Sosibo, Andile Khathi
      Abstract: Experimental Biology and Medicine, Ahead of Print.

      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-20T11:24:40Z
      DOI: 10.1177/1535370220973451
  • A mini-review on the effects of COVID-19 on younger individuals
    • Authors: Madhumitha Manivannan, Manasi P Jogalekar, Muthu Subash Kavitha, Balu Alagar Venmathi Maran, Prakash Gangadaran
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Coronavirus disease 2019 (COVID-19) pandemic has uprooted our lives like never before since its onset in the late December 2019. The world has seen mounting infections and deaths over the past few months despite the unprecedented measures countries are implementing, such as lockdowns, social distancing, mask-wearing, and banning gatherings in large groups. Interestingly, young individuals seem less likely to be impacted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19. While the rate of transmission, symptom presentation, and fatality is lower in children than people from other age groups, they have been disproportionately affected by strict lockdown measures needed to curb viral spread. In this review, we describe the association between patient age and COVID-19, epidemiology of SARS-CoV-2 infection in children, psychological effects associated with lockdowns and school closures, and possible mechanisms underlying lower transmission rate of COVID-19 in children.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-19T12:59:27Z
      DOI: 10.1177/1535370220975118
  • Fatty acid ethyl esters in meconium: A biomarker of fetal alcohol exposure
           and effect
    • Authors: Charlie T Cheng, Enrique M Ostrea Jr, Joseph NB Alviedo, Felix P Banadera, Ronald L Thomas
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      To determine if meconium fatty acid ethyl esters (FAEE) in rat pups is a good biomarker of prenatal exposure and effect to alcohol, three groups of pregnant rats were studied: one control (pair fed) and two treatment groups given 25% alcohol at 2.2 or 5.5 g−1 kg−1 d−1. The pups were delivered on day 20 and, for each dam, were separated into a male and female group. The body, brain, intestines, and placenta of the pups were obtained, weighed, and stored at −20°C. The pups’ intestines (as surrogate of meconium) from each group were pooled, and meconium was analyzed by gas chromatography/mass spectroscopy for FAEE. The meconium showed the following FAEE: ethyl palmitate, ethyl stearate, and ethyl linolenate and were only found in the alcohol-treated group and with high specificity but low sensitivity. Mean body weight of the pups was lower in the treatment groups compared to the control groups. Ethyl palmitate concentration correlated negatively to the pups’ mean body and brain weights. Therefore, ethyl palmitate, stearate, and linolenate, in meconium of rat pups prenatally exposed to alcohol, are useful biomarkers of prenatal alcohol exposure, with ethyl palmitate a good biomarker of adverse effect on the pups’ body and brain weight.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-19T12:59:26Z
      DOI: 10.1177/1535370220971562
  • Human-derived osteoblast-like cells and pericyte-like cells induce
           distinct metastatic phenotypes in primary breast cancer cells
    • Authors: Vera Mayo, Annie C Bowles, Laura E Wubker, Ismael Ortiz, Albert M Cordoves, Richard J Cote, Diego Correa, Ashutosh Agarwal
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Approximately 70% of advanced breast cancer patients will develop bone metastases, which accounts for ∼90% of cancer-related mortality. Breast cancer circulating tumor cells (CTCs) establish metastatic tumors in the bone after a close interaction with local bone marrow cells including pericytes and osteoblasts, both related to resident mesenchymal stem/stromal cells (BM-MSCs) progenitors. In vitro recapitulation of the critical cellular players of the bone microenvironment and infiltrating CTCs could provide new insights into their cross-talk during the metastatic cascade, helping in the development of novel therapeutic strategies. Human BM-MSCs were isolated and fractionated according to CD146 presence. CD146+ cells were utilized as pericyte-like cells (PLCs) given the high expression of the marker in perivascular cells, while CD146− cells were induced into an osteogenic phenotype generating osteoblast-like cells (OLCs). Transwell migration assays were performed to establish whether primary breast cancer cells (3384T) were attracted to OLC. Furthermore, proliferation of 3384T breast cancer cells was assessed in the presence of PLC- and OLC-derived conditioned media. Additionally, conditioned media cultures as well as transwell co-cultures of each OLCs and PLCs were performed with 3384T breast cancer cells for gene expression interrogation assessing their induced transcriptional changes with an emphasis on metastatic potential. PLC as well as their conditioned media increased motility and invasion potential of 3384T breast cancer cells, while OLC induced a dormant phenotype, downregulating invasiveness markers related with migration and proliferation. Altogether, these results indicate that PLC distinctively drive 3384T cancer cells to an invasive and migratory phenotype, while OLC induce a quiescence state, thus recapitulating the different phases of the in vivo bone metastatic process. These data show that phenotypic responses from metastasizing cancer cells are influenced by neighboring cells at the bone metastatic niche during the establishment of secondary metastatic tumors.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-19T12:59:26Z
      DOI: 10.1177/1535370220971599
  • Blockade of OGFr delays the onset and reduces the severity of diabetic
           ocular surface complications
    • Authors: Ian S Zagon, Joseph W Sassani, Indira Purushothaman, Patricia J McLaughlin
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The opioid growth factor (OGF)–OGF receptor (OGFr) pathway is present in the ocular surface and functions to maintain homeostasis of the epithelium. The OGF–OGFr pathway has been reported to be dysregulated in diabetic individuals and animal models, and is reflected in elevations of the inhibitory growth factor, OGF, chemically termed [Met5]-enkephalin. Recently, our laboratory reported elevated levels of OGF and OGFr in the serum and corneal epithelium of type 1 diabetic rats, suggesting that dysregulation of the OGF–OGFr axis may lead to dry eye, abnormal corneal surface sensitivity, and delayed re-epithelialization. Blockade of OGF–OGFr pathway using naltrexone, a potent opioid receptor antagonist, reverses dry eye symptoms and restores corneal surface sensitivity in diabetic rats when used as a therapy. Based on the evidence that both OGF and OGFr are elevated in type 1 diabetic rats, this study examined whether systemic or topical naltrexone treatment initiated at the time of induction of hyperglycemia could protect against the development of diabetic ocular surface complications. Diabetic male Sprague-Dawley rats treated systemically or topically with naltrexone had a delayed onset of dry eye and altered corneal surface sensitivity, and an improved healing rate for corneal wounds, that were comparable to non-diabetic rats. Serum levels of OGF were normal for rats receiving systemic naltrexone, and OGF tissue levels were normal for type 1 diabetic rats receiving twice daily naltrexone drops. OGFr levels remained elevated. These data support the role of the OGF–OGFr axis in regulation of ocular surface complications, and suggest that naltrexone therapy may be beneficial for pre-diabetic and early diabetic individuals.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-18T05:39:25Z
      DOI: 10.1177/1535370220972060
  • Boronate probe-based hydrogen peroxide detection with AlGaN/GaN HEMT
    • Authors: Isra Mahaboob, Roger J Reinertsen, Benjamin McEwen, Kasey Hogan, Emma Rocco, J Andres Melendez, Nathaniel C Cady, F Shahedipour-Sandvik
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The results from this study demonstrate the potential of an AlGaN/GaN high electron mobility transistor sensor for the detection of reactive and transient biological molecules such as hydrogen peroxide. A boronate-based fluorescent probe was used with this device to detect the presence of micromolar levels of hydrogen peroxide typically associated with intracellular processes. The real-time electrical response of the high electron mobility transistor sensor showed a gradual decrease in the two-dimensional electron gas current as the reaction proceeded over time. A corresponding increase in the emission intensity was measured from the fluorescent probe with the progression of the reaction. The fluorescence from the boronate probe was used as an indicator to confirm the detection of hydrogen peroxide. These results demonstrate the dynamic measurement capability of AlGaN/GaN high electron mobility transistor sensors in monitoring real-time reactions of reactive oxygen species such as hydrogen peroxide.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-18T05:39:04Z
      DOI: 10.1177/1535370220972030
  • Identification of two molecular subtypes of dysregulated immune lncRNAs in
           ovarian cancer
    • Authors: Xiaojun Liu, Jinghai Gao, Jing Wang, Jing Chu, Jiahao You, Zhijun Jin
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Long non-coding RNA (lncRNA) has increasingly been identified as a key regulator in pathologies such as cancer. Multiple platforms were used for comprehensive analysis of ovarian cancer to identify molecular subgroups. However, lncRNA and its role in mapping the ovarian cancer subpopulation are still largely unknown. RNA-sequencing and clinical characteristics of ovarian cancer were acquired from The Cancer Genome Atlas database (TCGA). A total of 52 lncRNAs were identified as aberrant immune lncRNAs specific to ovarian cancer. We redefined two different molecular subtypes, C1(188) and C2(184 samples), in “iClusterPlus” R package, among which C2 grouped ovarian cancer samples have higher survival probability and longer median survival time (P
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-18T05:38:45Z
      DOI: 10.1177/1535370220972024
  • Corrigendum
    • Abstract: Experimental Biology and Medicine, Ahead of Print.

      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-16T11:19:16Z
      DOI: 10.1177/1535370220976078
  • Crosstalk between adipocytes and M2 macrophages compensates for osteopenic
           phenotype in the Lrp5-deficient mice
    • Authors: Lisha Li, Xuemin Qiu, Na Zhang, Yan Sun, Yan Wang, Ling Wang
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      A loss-of-function mutation in the Lrp5 gene in mice leads to a low bone mass disorder due to the inhibition of the canonical Wnt signaling pathway; however, the role of bone marrow microenvironment in mice with this mutation remains unclear. In this study, we evaluated proliferation and osteogenic potential of mouse osteoblasts using the MTT assay and Alizarin red staining. The levels of alkaline phosphatase, tartrate-resistant acid phosphatase, and adiponectin in culture supernatants were measured using the enzyme-linked immunosorbent assay. Osteoclast bone resorbing activity was evaluated by toluidine staining and the number and area of bone resorption pits were determined. We observed increased osteogenesis in osteoblasts co-cultured with the BM-derived myeloid cells compared to the osteoblasts cultured alone. Mice with global Lrp5 deletion had a relatively higher bone density compared to the mice carrying osteoblast/osteocyte-specific Lrp5 deletion. An increased frequency of M2 macrophages and reduced expression of inflammatory cytokines were detected in the myeloid cells derived from the bone marrow of mice with global Lrp5 deletion. Higher adipogenic potential and elevated levels of adiponectin in the global Lrp5 deletion mice contributed to the preferential M2 macrophage polarization. Here, we identified a novel systemic regulatory mechanism of bone formation and degradation in mice with global Lrp5 deletion. This mechanism depends on a crosstalk between the adipocytes and M2 macrophages in the bone marrow and is responsible for partly rescuing osteopenia developed as a result of decreased Wnt signaling.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-16T11:16:27Z
      DOI: 10.1177/1535370220972320
  • Heparin-mediated dimerization of follistatin
    • Authors: Ryan G Walker, Chandramohan Kattamuri, Erich J Goebel, Fuming Zhang, Michal Hammel, John A Tainer, Robert J Linhardt, Thomas B Thompson
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins, including the transforming growth factor-β (TGFβ) family ligand antagonist, follistatin 288 (FS288). Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a nearly irreversible non-signaling complex by surrounding the ligand and preventing interaction with TGFβ receptors. The FS288-ligand complex has higher affinity than unbound FS288 for heparin/HS, which accelerates ligand internalization and lysosomal degradation; however, limited information is available for how FS288 interactions with heparin affect ligand binding. Using surface plasmon resonance (SPR) we show that preincubation of FS288 with heparin/HS significantly decreased the association kinetics for both myostatin and activin A with seemingly no effect on the dissociation rate. This observation is dependent on the heparin/HS chain length where small chain lengths less than degree of polymerization 10 (dp10) did not alter association rates but chain lengths>dp10 decreased association rates. In an attempt to understand the mechanism for this observation, we uncovered that heparin induced dimerization of follistatin. Consistent with our SPR results, we found that dimerization only occurs with heparin molecules>dp10. Small-angle X-ray scattering of the FS288 heparin complex supports that FS288 adopts a dimeric configuration that is similar to the FS288 dimer in the ligand-bound state. These results indicate that heparin mediates dimerization of FS288 in a chain-length-dependent manner that reduces the ligand association rate, but not the dissociation rate or antagonistic activity of FS288.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-16T11:15:47Z
      DOI: 10.1177/1535370220966296
  • Pulmonary gene delivery—Realities and possibilities
    • Authors: Uday K Baliga, David A Dean
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Delivery of genetic material to tissues in vivo is an important technique used in research settings and is the foundation upon which clinical gene therapy is built. The lung is a prime target for gene delivery due to a host of genetic, acquired, and infectious diseases that manifest themselves there, resulting in many pathologies. However, the in vivo delivery of genetic material to the lung remains a practical problem clinically and is considered the major obstacle needed to be overcome for gene therapy. Currently there are four main strategies for in vivo gene delivery to the lung: viral vectors, liposomes, nanoparticles, and electroporation. Viral delivery uses several different genetically modified viruses that enter the cell and express desired genes that have been inserted to the viral genome. Liposomes use combinations of charged and neutral lipids that can encapsulate genetic cargo and enter cells through endogenous mechanisms, thereby delivering their cargoes. Nanoparticles are defined by their size (typically less than 100 nm) and are made up of many different classes of building blocks, including biological and synthetic polymers, cell penetrant and other peptides, and dendrimers, that also enter cells through endogenous mechanisms. Electroporation uses mild to moderate electrical pulses to create pores in the cell membrane through which delivered genetic material can enter a cell. An emerging fifth category, exosomes and extracellular vesicles, may have advantages of both viral and non-viral approaches. These extracellular vesicles bud from cellular membranes containing receptors and ligands that may aid cell targeting and which can be loaded with genetic material for efficient transfer. Each of these vectors can be used for different gene delivery applications based on mechanisms of action, side-effects, and other factors, and their use in the lung and possible clinical considerations is the primary focus of this review.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-13T07:38:28Z
      DOI: 10.1177/1535370220965985
  • Treatment of osteoporosis with a modified zeolite shows beneficial effects
           in an osteoporotic rat model and a human clinical trial
    • Authors: Sandra Kraljević Pavelić, Vedran Micek, Dragica Bobinac, Edo Bazdulj, Alessandra Gianoncelli, Dalibor Krpan, Marta Žuvić, Sandra Eisenwagen, Peter J Stambrook, Krešimir Pavelić
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The severity of osteoporosis in humans manifests in its high incidence and by its complications that diminish quality of life. A societal consequence of osteoporosis is the substantial burden that it inflicts upon patients and their families. Several bone-modifying drugs have been prescribed to patients with osteoporosis. However, evidence for their anti-fracture efficacy remains inconclusive. To the contrary, long-term use of anti-osteoporotic drugs such as bisphosphonates and Denosumab, an RANKL inhibitor, have resulted in adverse events. We now present an alternative and adjuvant approach for treatment of osteoporosis. The data derive from in vivo studies in an ovariectomized rat model and from a randomized double blind, placebo-controlled human clinical study. Both studies involved treatment with Panaceo Micro Activation (PMA)-zeolite-clinoptilolite, a defined cation exchange clinoptilolite, which clearly improved all bone histomorphometric parameters examined from ovariectomized animals, indicative for increased bone formation. Moreover, intervention with PMA-zeolite-clinoptilolite for one year proved safe in humans. Furthermore, patients treated with PMA-zeolite-clinoptilolite showed an increase in bone mineral density, an elevated level of markers indicative of bone formation, a significant reduction in pain, and significantly improved quality of life compared with patients in the control (placebo) group. These encouraging positive effects of PMA-zeolite-clinoptilolite on bone integrity and on osteoporosis warrant further evaluation of treatment with PMA-zeolite-clinoptilolite as a new alternative adjuvant therapy for osteoporosis.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-13T07:38:28Z
      DOI: 10.1177/1535370220968752
  • The use of DNA methylation clock in aging research
    • Authors: Xi He, Jiaojiao Liu, Bo Liu, Jingshan Shi
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      One of the key characteristics of aging is a progressive loss of physiological integrity, which weakens bodily functions and increases the risk of death. A robust biomarker is important for the assessment of biological age, the rate of aging, and a person's health status. DNA methylation clocks, novel biomarkers of aging, are composed of a group of cytosine-phosphate-guanine dinucleotides, the DNA methylation status of which can be used to accurately measure subjective age. These clocks are considered accurate biomarkers of chronological age for humans and other vertebrates. Numerous studies have demonstrated these clocks to quantify the rate of biological aging and the effects of longevity and anti-aging interventions. In this review, we describe the purpose and use of DNA methylation clocks in aging research.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-11T05:15:10Z
      DOI: 10.1177/1535370220968802
  • Influence of Pseudomonas autoinducer N-3-oxododecanoyl homoserine lactone
           on human corneal epithelial cells
    • Authors: Renjian Hu, Kelan Yuan, Jie Zhou, Yue Zhang, Jiao Zheng, Yingying Zhao, Xiaodan Huang, Xiuming Jin
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The quorum-sensing (QS) signaling-dependent extracellular virulence factors of Pseudomonas aeruginosa can cause infections such as P. aeruginosa keratitis. P. aeruginosa communicates by secreting and sensing small chemical molecules called autoinducers in QS system. The key QS signal molecule, N-3-oxododecanoyl-homoserine lactone (3OC12HSL), can affect the behavior of host cells and initiate immune response. In this report we investigated the influence of 3OC12HSL on human corneal epithelial cells (HCECs) and the mechanisms of 3OC12HSL on activated toll-like receptor 2 (TLR2)-dependent interleukin-8 (IL-8) secretion in HCECs. Cells were cultured under different concentrations of 3OC12HSL. Cell viability was assessed using Crystal violet staining and the cell counting kit-8 assay. We demonstrated the administration of 3OC12HSL decreased HCEC viability and survival in a concentration- and time-dependent manner. At high concentrations, 3OC12HSL rapidly promoted a time-dependent increase in the expressions of TLR2 and TLR4. It was found that the nuclear translocation and expression of nuclear factor-κB (NF-κB) were also increased in response to 3OC12HSL treatment. The significantly elevated expressions of TLR2, TLR4, and NF-κB, encouraged us to further test their mechanisms that cause inflammatory response. Among the inflammatory factors examined (IL-6, IL-8, IL-10, and TNF-α), we found that IL-8 was significantly increased after treatment with 3OC12HSL and its expression was inhibited when TLR2 was specifically blocked or silenced. These results indicated that the QS signaling molecule 3OC12HSL could be recognized by the host innate immune system in HCECs. This recognition then triggered an immune inflammatory response involving the activation of TLR2 and an increase in expression of IL-8. This crosstalk between 3OC12HSL and host immunity in HCECs contributes to the development and progression of P. aeruginosa keratitis.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-11T05:15:10Z
      DOI: 10.1177/1535370220969838
  • Shortened derivatives from native antimicrobial peptide LyeTx I: In vitro
           and in vivo biological activity assessment
    • Authors: Leonardo Lima Fuscaldi, Joaquim Teixeira de Avelar Júnior, Daniel Moreira dos Santos, Daiane Boff, Vívian Louise Soares de Oliveira, Karla Aparecida Guimarães Gusmão Gomes, Rosana de Carvalho Cruz, Patrícia Luciana de Oliveira, Paula Prazeres Magalhães, Patricia Silva Cisalpino, Luiz de Macêdo Farias, Elaine Maria de Souza-Fagundes, Johannes Delp, Marcel Leist, Jarbas Magalhães Resende, Flávio Almeida Amaral, Adriano Monteiro de Castro Pimenta, Simone Odília Antunes Fernandes, Valbert Nascimento Cardoso, Maria Elena de Lima
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      In the continuing search for novel antibiotics, antimicrobial peptides are promising molecules, due to different mechanisms of action compared to classic antibiotics and to their selectivity for interaction with microorganism cells rather than with mammalian cells. Previously, our research group has isolated the antimicrobial peptide LyeTx I from the venom of the spider Lycosa erythrognatha. Here, we proposed to synthesize three novel shortened derivatives from LyeTx I (LyeTx I mn; LyeTx I mnΔK; LyeTx I mnΔKAc) and to evaluate their toxicity and biological activity as potential antimicrobial agents. Peptides were synthetized by Fmoc strategy and circular dichroism analysis was performed, showing that the three novel shortened derivatives may present membranolytic activity, like the original LyeTx I, once they folded as an alpha helix in 2.2.2-trifluorethanol and sodium dodecyl sulfate. In vitro assays revealed that the shortened derivative LyeTx I mnΔK presents the best score between antimicrobial (↓ MIC) and hemolytic (↑ EC50) activities among the synthetized shortened derivatives, and LUHMES cell-based NeuriTox test showed that it is less neurotoxic than the original LyeTx I (EC50 [LyeTx I mnΔK] ⋙ EC50 [LyeTx I]). In vivo data, obtained in a mouse model of septic arthritis induced by Staphylococcus aureus, showed that LyeTx I mnΔK is able to reduce infection, as demonstrated by bacterial recovery assay (∼10-fold reduction) and scintigraphic imaging (less technetium-99m labeled-Ceftizoxime uptake by infectious site). Infection reduction led to inflammatory process and pain decreases, as shown by immune cells recruitment reduction and threshold nociception increment, when compared to positive control group. Therefore, among the three shortened peptide derivatives, LyeTx I mnΔK is the best candidate as antimicrobial agent, due to its smaller amino acid sequence and toxicity, and its greater biological activity.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-11T05:15:09Z
      DOI: 10.1177/1535370220966963
  • Animal models of regenerative medicine for biological treatment approaches
           of degenerative disc diseases
    • Authors: Demissew Shenegelegn Mern, Tanja Walsen, Anja Beierfuß, Claudius Thomé
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Degenerative disc disease (DDD) is a painful, chronic and progressive disease, which is characterized by inflammation, structural and biological deterioration of the intervertebral disc (IVD) tissues. DDD is specified as cell-, age-, and genetic-dependent degenerative process that can be accelerated by environmental factors. It is one of the major causes of chronic back pain and disability affecting millions of people globally. Current treatment options, such as physical rehabilitation, pain management, and surgical intervention, can provide only temporary pain relief. Different animal models have been used to study the process of IVD degeneration and develop therapeutic options that may restore the structure and function of degenerative discs. Several research works have depicted considerable progress in understanding the biological basis of disc degeneration and the therapeutic potentials of cell transplantation, gene therapy, applications of supporting biomaterials and bioactive factors, or a combination thereof. Since animal models play increasingly significant roles in treatment approaches of DDD, we conducted an electronic database search on Medline through June 2020 to identify, compare, and discuss publications regarding biological therapeutic approaches of DDD that based on intradiscal treatment strategies. We provide an up-to-date overview of biological treatment strategies in animal models including mouse, rat, rabbit, porcine, bovine, ovine, caprine, canine, and primate models. Although no animal model could profoundly reproduce the clinical conditions in humans; animal models have played important roles in specifying our knowledge about the pathophysiology of DDD. They are crucial for developing new therapy approaches for clinical applications.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-11T05:15:08Z
      DOI: 10.1177/1535370220969123
  • Identification of potential lipid biomarkers for active pulmonary
           tuberculosis using ultra-high-performance liquid chromatography-tandem
           mass spectrometry
    • Authors: Yu-Shuai Han, Jia-Xi Chen, Zhi-Bin Li, Jing Chen, Wen-Jing Yi, Huai Huang, Li-Liang Wei, Ting-Ting Jiang, Ji-Cheng Li
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Early diagnosis of active pulmonary tuberculosis (TB) is the key to controlling the disease. Host lipids are nutrient sources for the metabolism of Mycobacterium tuberculosis. In this research work, we used ultra-high-performance liquid chromatography-tandem mass spectrometry to screen plasma lipids in TB patients, lung cancer patients, community-acquired pneumonia patients, and normal healthy controls. Principal component analysis, orthogonal partial least squares discriminant analysis, and K-means clustering algorithm analysis were used to identify lipids with differential abundance. A total of 22 differential lipids were filtered out among all subjects. The plasma phospholipid levels were decreased, while the cholesterol ester levels were increased in patients with TB. We speculate that the infection of M. tuberculosis may regulate the lipid metabolism of TB patients and may promote host-assisted bacterial degradation of phospholipids and accumulation of cholesterol esters. This may be related to the formation of lung cavities with caseous necrosis. The results of receiver operating characteristic curve analysis revealed four lipids such as phosphatidylcholine (PC, 12:0/22:2), PC (16:0/18:2), cholesteryl ester (20:3), and sphingomyelin (d18:0/18:1) as potential biomarkers for early diagnosis of TB. The diagnostic model was fitted by using logistic regression analysis and combining the above four lipids with a sensitivity of 92.9%, a specificity of 82.4%, and the area under the curve (AUC) value of 0.934 (95% CI 0.873 – 0.971). The machine learning method (10-fold cross-validation) demonstrated that the model had good accuracy (0.908 AUC, 85.3% sensitivity, and 85.9% specificity). The lipids identified in this study may serve as novel biomarkers in TB diagnosis. Our research may pave the foundation for understanding the pathogenesis of TB.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-11T05:14:52Z
      DOI: 10.1177/1535370220968058
  • Long non-coding RNA IGF2-AS represses breast cancer tumorigenesis by
           epigenetically regulating IGF2
    • Authors: Yanan Zhang, Hanbing Yan, Yan Jiang, Tao Chen, Zhijin Ma, Fei Li, Min Lin, Yanzhi Xu, Xuemei Zhang, Jianming Zhang, Hui He
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Long non-coding RNAs are a kind of endogenous ncRNAs with a length of more than 200 bp. Accumulating evidence suggests that long non-coding RNAs function as pivotal regulators in tumorigenesis and progression. However, their biological roles in breast cancer remain largely unknown. Here, we found that IGF2 antisense RNA (IGF2-AS) was significantly decreased in breast cancer tissues, cell lines, and plasma. Patients with low IGF2-AS were more likely to develop larger tumor size and later clinical stage. Overexpression of IGF2-AS evidently inhibited the proliferation and induced apoptosis of MCF-7 and T47D cells in vitro, as well as retarded tumor growth in vivo. Further investigation revealed that IGF2-AS inhibited the expression of its sense-cognate gene IGF2 in an epigenetic DNMT1-dependent manner, resulting in the inactivation of downstream oncogenic PI3K/AKT/mTOR signaling pathway. Enforced expression of IGF2 could significantly block the tumor inhibitory effect of IGF2-AS. Importantly, we found that IGF2-AS could be used as an effective biomarker for breast cancer diagnosis and prognosis. Taken together, our study indicates that IGF2-AS is a tumor suppressor in breast cancer, restoration of IGF2-AS may be a promising treatment for this fatal disease.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-11T05:14:51Z
      DOI: 10.1177/1535370220966253
  • Etiological classification and treatment strategies for secondary bile
           duct dilatation
    • Authors: Yunfu Lv, Ning Liu, Hongfei Wu, Zhuori Li
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Secondary intra- and extrahepatic bile duct dilatation is a very common condition that can be caused by several diseases. However, it has been rarely discussed in the specialized literature. Moreover, no distinct etiology can be determined in some cases, which hampers the diagnosis and treatment. Here, we discuss the etiological classification and treatment strategies of secondary intra- and extrahepatic bile duct dilatation based on an extensive literature review, as well as our experimental research and clinical experience. The etiology of secondary intra- and extrahepatic bile duct dilatation can be classified in different ways. From a clinicopathological perspective, it can be classified into obstruction-, lesion-, and compression-induced dilatation. Treatment varies depending on the cause. For example, endoscopic dilation or stenting is used for biliary strictures, laparoscopic choledochectomy for stone removal, and resection for cholangiocarcinoma.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-10T07:02:48Z
      DOI: 10.1177/1535370220966767
  • Detection of severe acute respiratory syndrome coronavirus 2 and influenza
           viruses based on CRISPR-Cas12a
    • Authors: Oraphan Mayuramart, Pattaraporn Nimsamer, Somruthai Rattanaburi, Naphat Chantaravisoot, Kritsada Khongnomnan, Jira Chansaenroj, Jiratchaya Puenpa, Nungruthai Suntronwong, Preeyaporn Vichaiwattana, Yong Poovorawan, Sunchai Payungporn
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Due to the common symptoms of COVID-19, patients are similar to influenza-like illness. Therefore, the detection method would be crucial to discriminate between SARS-CoV-2 and influenza virus-infected patients. In this study, CRISPR-Cas12a-based detection was applied for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus, and influenza B virus which would be a practical and attractive application for screening of patients with COVID-19 and influenza in areas with limited resources. The limit of detection for SARS-CoV-2, influenza A, and influenza B detection was 10, 103, and 103 copies/reaction, respectively. Moreover, the assays yielded no cross-reactivity against other respiratory viruses. The results revealed that the detection of influenza virus and SARS-CoV-2 by using RT-RPA and CRISPR-Cas12a technology reaches 96.23% sensitivity and 100% specificity for SARS-CoV-2 detection. The sensitivity for influenza virus A and B detections was 85.07% and 94.87%, respectively. In addition, the specificity for influenza virus A and B detections was approximately 96%. In conclusion, the RT-RPA with CRISPR-Cas12a assay was an effective method for the screening of influenza viruses and SARS-CoV-2 which could be applied to detect other infectious diseases in the future.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-06T06:18:55Z
      DOI: 10.1177/1535370220963793
  • Transcriptomic profiles in Parkinson’s disease
    • Authors: Lille Kurvits, Freddy Lättekivi, Ene Reimann, Liis Kadastik-Eerme, Kristjan M Kasterpalu, Sulev Kõks, Pille Taba, Anu Planken
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Transcriptomics in Parkinson’s disease offers insights into the pathogenesis of Parkinson’s disease but obtaining brain tissue has limitations. In order to bypass this issue, we profile and compare differentially expressed genes and enriched pathways (KEGG) in two peripheral tissues (blood and skin) of 12 Parkinson’s disease patients and 12 healthy controls using RNA-sequencing technique and validation with RT-qPCR. Furthermore, we compare our results to previous Parkinson’s disease post mortem brain tissue and blood results using the robust rank aggregation method. The results show no overlapping differentially expressed genes or enriched pathways in blood vs. skin in our sample sets (25 vs. 1068 differentially expressed genes with an FDR ≤ 0.05; 1 vs. 9 pathways in blood and skin, respectively). A meta-analysis from previous transcriptomic sample sets using either microarrays or RNA-Seq yields a robust rank aggregation list of cortical gene expression changes with 43 differentially expressed genes; a list of substantia nigra changes with 2 differentially expressed genes and a list of blood changes with 1 differentially expressed gene being statistically significant at FDR ≤ 0.05. In cortex 1, KEGG pathway was enriched, four in substantia nigra and two in blood. None of the differentially expressed genes or pathways overlap between these tissues. When comparing our previously published skin transcription analysis, two differentially expressed genes between the cortex robust rank aggregation and skin overlap. In this study, for the first time a meta-analysis is applied on transcriptomic sample sets in Parkinson’s disease. Simultaneously, it explores the notion that Parkinson’s disease is not just a neuronal tissue disease by exploring peripheral tissues. The comparison of different Parkinson’s disease tissues yields surprisingly few significant differentially expressed genes and pathways, suggesting that divergent gene expression profiles in distinct cell lineages, metabolic and possibly iatrogenic effects create too much transcriptomic noise for detecting significant signal. On the other hand, there are signs that point towards Parkinson’s disease-specific changes in non-neuronal peripheral tissues in Parkinson’s disease, indicating that Parkinson’s disease might be a multisystem disorder.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-05T06:24:21Z
      DOI: 10.1177/1535370220967325
  • Prenatal indole-3-carbinol administration activates aryl hydrocarbon
           receptor-responsive genes and attenuates lung injury in a bronchopulmonary
           dysplasia model 
    • Authors: Gabriela Guzmán-Navarro, Mario Bermúdez de León, Irene Martín-Estal, Raquel Cuevas-Díaz Durán, Laura Villarreal-Alvarado, Anakaren Vaquera-Vázquez, Tania Cuevas-Cerda, Karina Garza-García, Luis Eduardo Cuervo-Pérez, Álvaro Barbosa-Quintana, José Eduardo Pérez-Saucedo, Víctor J Lara-Díaz, Fabiola Castorena-Torres
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Hyperoxia−hypoxia exposure is a proposed cause of alveolar developmental arrest in bronchopulmonary dysplasia in preterm infants, where mitochondrial reactive oxygen species and oxidative stress vulnerability are increased. The aryl hydrocarbon receptor (AhR) is one of the main activators of the antioxidant enzyme system that protects tissues and systems from damage. The present study aimed to determine if the activation of the AhR signaling pathway by prenatal administration of indole-3-carbinol (I3C) protects rat pups from hyperoxia–hypoxia-induced lung injury. To assess the activation of protein-encoding genes related to the AhR signaling pathway (Cyp1a1, Cyp1b1, Ugt1a6, Nqo1, and Gsta1), pup lungs were excised at 0, 24, and 72 h after birth, and mRNA expression levels were quantified by reverse transcription-quantitative polymerase chain reaction assays (RT-qPCR). An adapted Ratner's method was used in rats to evaluate radial alveolar counts (RACs) and the degree of fibrosis. The results reveal that the relative expression of AhR-related genes in rat pups of prenatally I3C-treated dams was significantly different from that of untreated dams. The RAC was significantly lower in the hyperoxia–hypoxia group (4.0 ± 1.0) than that in the unexposed control group (8.0 ± 2.0; P 
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-05T05:17:33Z
      DOI: 10.1177/1535370220963789
  • Silencing p53 inhibits interleukin 10-induced activated hepatic stellate
           cell senescence and fibrotic degradation in vivo
    • Authors: Qilan Guo, Minghua Chen, Qingduo Chen, Guitao Xiao, Zhixin Chen, Xiaozhong Wang, Yuehong Huang
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Activated hepatic stellate cells are reported to play a significant role in liver fibrogenesis. Beside the phenotype reversion and apoptosis of activated hepatic stellate cells, the senescence of activated hepatic stellate cells limits liver fibrosis. Our previous researches have demonstrated that interleukin-10 could promote hepatic stellate cells senescence via p53 signaling pathway in vitro. However, the relationship between expression of p53 and senescence of activated hepatic stellate cells induced by interleukin-10 in fibrotic liver is unclear. The purpose of present study was to explore whether p53 plays a crucial role in the senescence of activated hepatic stellate cells and degradation of collagen mediated by interleukin-10. Hepatic fibrosis animal model was induced by carbon tetrachloride through intraperitoneal injection and transfection of interleukin-10 gene to liver was performed by hydrodynamic-based transfer system. Depletions of p53 in vivo and in vitro were carried out by adenovirus-based short hairpin RNA against p53. Regression of fibrosis was assessed by liver biopsy and collagen staining. Cellular senescence in the liver was observed by senescence-associated beta-galactosidase (SA-β-Gal) staining. Immunohistochemistry, immunofluorescence double staining, and Western blot analysis were used to evaluate the senescent cell and senescence-related protein expression. Our data showed that interleukin-10 gene treatment could lighten hepatic fibrosis induced by carbon tetrachloride and induce the aging of activated hepatic stellate cells accompanied by up-regulating the expression of aging-related proteins. We further demonstrated that depletion of p53 could abrogate up-regulation of interleukin-10 on the expression of senescence-related protein in vivo and vitro. Moreover, p53 knockout in fibrotic mice could block not only the senescence of activated hepatic stellate cells, but also the degradation of fibrosis induced by interleukin-10 gene intervention. Taken together, our results suggested that interleukin-10 gene treatment could attenuate carbon tetrachloride-induced hepatic fibrosis by inducing senescence of activated hepatic stellate cells in vivo, and this induction was closely related to p53 signaling pathway.Impact statementThis work further expanded the knowledge of the molecular mechanisms underlying IL-10 anti-fibrogenic effect by exploring the function of p53 in IL-10-induced activated HSCs senescence and fibrotic degradation in vivo. Our data showed that IL-10 gene intervention could lighten hepatic fibrosis induced by CCL4 and induce the senescence of activated HSCs accompanied by up-regulating the expression of senescence-related proteins. In addition, depletion of p53 could abrogate up-regulation of IL-10 on the expression of aging-related proteins in vivo and vitro. Moreover, p53 knockout in fibrotic mice could block the senescence of activated HSCs and the degradation of fibrosis induced by IL-10 gene treatment. In summary, our results suggested that IL-10 gene intervention could attenuate CCL4-induced hepatic fibrosis by inducing senescence of activated HSCs in vivo, and this induction was closely related to p53 signaling pathway. Our study sheds important light into the anti-fibrogenic therapy of IL-10.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-08T05:55:36Z
      DOI: 10.1177/1535370220960391
  • Attenuation of acute and chronic inflammation using compounds derived from
    • Authors: Stephen C Bondy, Meixia Wu, Kedar N Prasad
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The appearance of excessive inflammatory activity is associated with onset of many disease states. Such non-productive responses are often the basis of the mortality consequent to incurring numerous disorders. The current outbreak of coronavirus disease 2019 caused by the virus “severe acute respiratory syndrome coronavirus 2” is a striking reflection of the inadequacy of current medical science to adequately address this issue. The usefulness of a range of materials of botanical origin in the attenuation of both chronic and acute inflammatory responses to various disease stressors is described. The properties of preparations of plant-based origin often parallel those of synthesized pharmacologics, but differ from them in some key respects. These differences can lead to more traditional preparations having distinct therapeutic advantages but also a number of specific shortcomings. The strengths and weaknesses of these materials are objectively contrasted with that of a more orthodox pharmacological approach. Each of these emphases in style has specific advantages and they should not be considered as competitors, but rather as accomplices in combating adverse states involving derangement of immune function.Impact statementA large component of many disease states is the improper regulation of immune function. This commonly leads to the appearance of redundant inflammation which does not effectively address any underlying issue but actually impedes a successful response to disease-induced metabolic derangement. There is currently no means of successfully addressing this problem which is especially relevant in the ongoing viral pandemic of SARS-CoV-2. In view of this failure, new courses of action need to be contemplated. This review proposes reconsideration of the potential utility of natural compounds originating from plants in order to address this deficit. Such a new direction, in concert with more conventional strategies could help to alleviate this wide-ranging crisis.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-07T06:32:57Z
      DOI: 10.1177/1535370220960690
  • Modeling the pathophysiology of Parkinson’s disease in
           patient-specific neurons
    • Authors: Jian Feng
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The 30 trillion cells that self-assemble into a human being originate from the pluripotent stem cells in the inner cell mass of a human blastocyst. The discovery of induced pluripotent stem cells (iPSCs) makes it possible to approximate various aspects of this natural developmental process artificially by generating materials that can be used in invasive mechanistic studies of virtually all human conditions. In Parkinson’s disease, instructions computed by the basal ganglia to control voluntary motor functions break down, leading to widespread rhythmic bursting activities in the basal ganglia and beyond. It is thought that these oscillatory neuronal activities, which disrupt aperiodic neurotransmission in a normal brain, may reduce information content in the instructions for motor control. Using midbrain neuronal cultures differentiated from iPSCs of Parkinson’s disease patients with parkin mutations, we find that parkin mutations cause oscillatory neuronal activities when dopamine D1-class receptors are activated. This system makes it possible to study the molecular basis of rhythmic bursting activities in Parkinson’s disease. Further development of stem cell models of Parkinson’s disease will enable better approximation of the situation in the brain of Parkinson’s disease patients. In this review, I will discuss what has been found in the past about the pathophysiology of motor dysfunction in Parkinson’s disease, especially oscillatory neuronal activities and how stem cell technologies may transform our abilities to understand the pathophysiology of Parkinson’s disease.Impact statementResearch on the pathophysiology of Parkinson’s disease (PD) has generated effective therapies such as deep brain stimulation. A better understanding of PD pathophysiology calls for patient-specific materials amenable for invasive mechanistic studies. In this minireview, I discuss our recent work on oscillatory neuronal activities in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations. These patient-specific neurons enable a variety of studies previously not feasible in the human system. Further development in stem cell technologies may generate more realistic models for us to decipher PD pathophysiology. These new developments will transform research and development in Parkinson’s disease.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-25T06:35:05Z
      DOI: 10.1177/1535370220961788
  • Contrast effects of autophagy in the treatment of bladder cancer
    • Authors: Ece Konac, Yener Kurman, Sümer Baltaci
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Bladder cancer is a disease that negatively affects patients’ quality of life, but treatment options have remained unchanged for a long time. Although promising results have been achieved with current bladder cancer treatments, cancer recurrence, progression, and therapy resistance are the most severe problems preventing the efficiency of bladder cancer treatments. Autophagy refers to an evolutionarily conserved catabolic process in which proteins, damaged organelles, and cytoplasmic components are degraded by lysosomal enzymes. Autophagy regulates the therapeutic response to the chemotherapy drugs, thus determining the effect of therapy on cancer cells. Autophagy is a stress-induced cell survival mechanism and its excessive stimulation can cause resistance of tumor cells to therapeutic agents. Depending on the conditions, an increase in autophagy may cause treatment resistance or autophagic cell death, and it is related to important anti-cancer mechanisms, such as apoptosis. Therefore, understanding the roles of autophagy under different conditions is important for designing effective anti-cancer agents. The dual role of autophagy in cancer has attracted considerable attention in respect of bladder cancer treatment. In this review, we summarize the basic characteristics of autophagy, including its mechanisms, regulation, and functions, and we present examples from current studies concerning the dual role of autophagy in bladder cancer progression and therapy.Impact statementAutophagy acts as an intracellular recycling system. Infection and mitochondrial damage, maintaining cellular homeostasis, orchestrating nutrient stress, hypoxia, and oxidative stress are some of the physiological roles associated with autophagy. Autophagy has also context-dependent roles in cancer. Autophagy has a significant impact on tumor initiation and promotion, with both tumor-suppressive and tumor-promoting roles. Unfortunately, conventional systemic chemotherapy for cancer therapy has been reported to have primary limitations such as chemo-resistance of targeted cells. The cytoprotective role of autophagy has been postulated as one of the causes of this resistance. Hence, combination therapy using autophagy inhibitors has recently started to emerge as a noteworthy strategy in the treatment of cancer. Therefore, targeting the autophagy pathways may be a potential therapeutic strategy for addressing cancer progression or therapy resistance in the near future. This review will provide a novel insight to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-21T06:03:43Z
      DOI: 10.1177/1535370220959336
  • Microengineered systems with iPSC-derived cardiac and hepatic cells to
           evaluate drug adverse effects
    • Authors: Keri Dame, Alexandre JS Ribeiro
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects.Impact statementCardiac and hepatic adverse drug effects are among the leading causes of attrition in preclinical and clinical drug development programs as well as marketing withdrawals. The insufficiency of animal testing models has led to considerable interest in the employment of cardiac and hepatic models using human-induced pluripotent stem cells (iPSCs) for drug toxicity testing. However, current batches of iPSC-derived cardiomyocytes and hepatocytes are variable and not matured as adult primary tissues, which limit their prediction of drug effects. This article discusses how the use of microfluidics can create microenvironments to better control differentiation protocols and increase the physiological relevance of iPSC-derived cardiomyocytes and hepatocytes. Development and standardization of technologies will enable evaluation of the potential value of cellular microsystems to improve the in vitro models used in drug development programs. Future steps in this field include controlled connections of organ systems to better recreate clinical metabolism and pharmacokinetics.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-17T08:36:41Z
      DOI: 10.1177/1535370220959598
  • Liquiritigenin decreases tumorigenesis by inhibiting DNMT activity and
           increasing BRCA1 transcriptional activity in triple-negative breast cancer
    • Authors: Fang Liang, Hao Zhang, Hui Gao, Duo Cheng, Nan Zhang, Jie Du, Junmin Yue, Peng Du, Beibei Zhao, Lu Yin
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      As a selective estrogen receptor β agonist, the natural flavonoid liquiritigenin reportedly inhibits invasiveness of breast cancer cells, but its specific role and mechanism remain largely unclear. In this study, cells from the triple negative breast cancer lines MDA-MB-231 and BT549 were incubated with different concentrations of liquiritigenin. The results indicated that low concentrations had no significant cytotoxic effect, whereas high concentrations decreased viability of both MDA-MB-231 and BT549 cells. Liquiritigenin treatment also resulted in increased apoptosis and enhanced Caspase3 activity. After liquiritigenin treatment, we observed decreased invasive and migratory capacities of cells, as well as upregulated E-cadherin and downregulated N-cadherin, vimentin, and MMP9. Interestingly, liquiritigenin increased the mRNA and protein expression of breast cancer 1 (BRCA1). It also increased p21 and growth arrest and DNA-damage-inducible 45 alpha (GADD45A) levels, accompanied by decreased cellular DNA methyltransferase (DNMT) activity and downregulation of DNMT1, DNMT3a, and DNMT3b. These findings suggest that liquiritigenin can inhibit malignant behavior of triple negative breast cancer cells by inhibiting DNMT activity and increasing BRCA1 expression and its transcriptional activity. Liquiritigenin thus may be a promising candidate for the treatment of breast cancer.Impact statementTriple negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis and higher metastatic rates and relapse frequencies than other breast cancers. Natural flavonoid liquiritigenin reportedly inhibits invasiveness of TNBC MDA-MB-231 cells, but its specific role and mechanism remain unclear. This study administered different doses of liquiritigenin into TNBC cell lines MDA-MB-231 and BT549, and found that it hindered cell proliferation, increased apoptosis, and repressed cell invasion and migration. BRCA1 exerts multiple functions and is closely related to the occurrence and development of breast cancer. Interestingly, the mRNA and protein expression of BRCA1 increased after liquiritigenin administration. Liquiritigenin also upregulated two downstream genes of BRCA1 (p21 and DNA-damage-inducible 45 alpha), decreased cellular DNA methyltransferase (DNMT) activity, and reduced BRCA1 promoter methylation. Thus, liquiritigenin may be a promising candidate for the treatment of TNBC due to its inhibition of DNMT activity and upregulation of BRCA1.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-17T08:36:40Z
      DOI: 10.1177/1535370220957255
  • At the dawn of the transcriptomic medicine
    • Authors: Gea Koks, Abigail L Pfaff, Vivien J Bubb, John P Quinn, Sulev Koks
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Impact statementThis review describes the impact of transcriptomics on experimental biology and its integration into medical practice. Transcriptomics is an essential part of modern biomedical research based on highly sophisticated and reliable technology. Transcriptomics can aid clinical practice and improve the precision of clinical diagnoses and decision-making by complementing existing clinical best practice. The power of which will be increased when combined with genomic variation from genome wide association studies and next generation sequencing. We are witnessing the implementation of RNA-based technologies in clinical practice that will eventually lead to the establishment of transcriptional medicine as a routine tool in diagnosis.Progress in genomic analytical technologies has improved our possibilities to obtain information regarding DNA, RNA, and their dynamic changes that occur over time or in response to specific challenges. This information describes the blueprint for cells, tissues, and organisms and has fundamental importance for all living organisms. This review focuses on the technological challenges to analyze the transcriptome and what is the impact of transcriptomics on precision medicine. The transcriptome is a term that covers all RNA present in cells and a substantial part of it will never be translated into protein but is nevertheless functional in determining cell phenotype. Recent developments in transcriptomics have challenged the fundamentals of the central dogma of biology by providing evidence of pervasive transcription of the genome. Such massive transcriptional activity is challenging the definition of a gene and especially the term “pseudogene” that has now been demonstrated in many examples to be both transcribed and translated. We also review the common sources of biomaterials for transcriptomics and justify the suitability of whole blood RNA as the current optimal analyte for clinical transcriptomics. At the end of the review, a brief overview of the clinical implications of transcriptomics in clinical trial design and clinical diagnosis is given. Finally, we introduce the transcriptome as a target for modern drug development as a tool for extending our capacity for precision medicine in multiple diseases.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-11T05:01:31Z
      DOI: 10.1177/1535370220954788
  • Secondary hemophagocytic lymphohistiocytosis versus cytokine release
           syndrome in severe COVID-19 patients
    • Authors: Nausheen N Hakim, Jeffrey Chi, Coral Olazagasti, Johnson M Liu
      First page: 5
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      COVID-19 or SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome/pneumonia with features of cytokine storm reminiscent of secondary hemophagocytic lymphohistiocytosis (HLH), which can be diagnosed by the calculated HScore. Recent reports have suggested favorable responses to the interleukin-1 receptor antagonist, anakinra in patients with COVID-19 associated secondary HLH. In our single institution study, we compared 14 COVID-19 cytokine storm patients with 10 secondary HLH patients seen immediately prior to the pandemic (non-COVID-19), to determine whether diagnostic features of secondary HLH were typically seen in COVID-19 patients presenting with cytokine storm. Although most of our COVID-19 patients did not fulfill diagnostic criteria for HLH, we hypothesize that identification of HLH may relate to the severity or timing of cytokine release. Based on our observations, we would suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria.Impact statementSevere COVID-19 associated pneumonia and acute respiratory distress syndrome has recently been described with life-threatening features of cytokine storm and loosely referred to as hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). Although a recent report indicated favorable responses to the interleukin-1 receptor antagonist, anakinra in eight patients with COVID-19 secondary HLH diagnosed using the HScore calculation, others have suggested that the diagnosis of secondary HLH is uncommon and that the use of the HScore has limited value in guiding immunomodulatory therapy for COVID-19. Here, we provide additional perspective on this important controversy based upon comparisons between 14 COVID-19 cytokine storm patients and 10 secondary HLH patients seen immediately prior to the pandemic. We hypothesize that identification of HLH may relate to the severity or timing of cytokine release and suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-25T06:10:09Z
      DOI: 10.1177/1535370220962043
  • Localization and function of a Plasmodium falciparum protein
           (PF3D7_1459400) during erythrocyte invasion
    • Authors: Emmanuel Amlabu, Prince B Nyarko, Grace Opoku, Damata Ibrahim-Dey, Philip Ilani, Henrietta Mensah-Brown, Grace A Akporh, Ojo-Ajogu Akuh, Evelyn A Ayugane, David Amoh-Boateng, Kwadwo A Kusi, Gordon A Awandare
      First page: 10
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Nearly 60% of Plasmodium falciparum proteins are still uncharacterized and their functions are unknown. In this report, we carried out the functional characterization of a 45 kDa protein (PF3D7_1459400) and showed its potential as a target for blood stage malaria vaccine development. Analysis of protein subcellular localization, native protein expression profile, and erythrocyte invasion inhibition of both clinical and laboratory parasite strains by peptide antibodies suggest a functional role of PF3D7_1459400 protein during erythrocyte invasion. Also, immunoreactivity screens using synthetic peptides of the protein showed that adults resident in malaria endemic regions in Ghana have naturally acquired plasma antibodies against PF3D7_1459400 protein. Altogether, this study presents PF3D7_1459400 protein as a potential target for the development of peptide-based vaccine for blood-stage malaria.Impact statementPlasmodium falciparum malaria is a global health problem. Erythrocyte invasion by P. falciparum merozoites appears to be a promising target to curb malaria. We have identified and characterized a novel protein that is involved in erythrocyte invasion. Our data on protein subcellular localization, stage-specific protein expression pattern, and merozoite invasion inhibition by α-peptide antibodies suggest a role for PF3D7_1459400 protein during P. falciparum erythrocyte invasion. Even more, the human immunoepidemiology data present PF3D7_1459400 protein as an immunogenic antigen which could be further exploited for the development of new anti-infective therapy against malaria.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-06T05:10:51Z
      DOI: 10.1177/1535370220961764
  • SNHG1 represses the anti-cancer roles of baicalein in cervical cancer
           through regulating miR-3127-5p/FZD4/Wnt/β-catenin signaling
    • Authors: Xiaolan Yu, Jiyi Xia, Yong Cao, Li Tang, Xiaoping Tang, Zhengyu Li
      First page: 20
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      As a flavonoid, baicalein exhibits remarkable anti-cancer roles in several cancers. However, the factors regulating the antitumorigenic roles of baicalein in cervical cancer remain undefined. Here, we revealed that long noncoding RNA SNHG1 is implicated in the tumor-suppressive roles of baicalein. Functional assays demonstrated that ectopic expression of SNHG1 attenuates the roles of baicalein in repressing cervical cancer cell viability, inducing apoptosis, and repressing migration. SNHG1 silencing promotes the tumor-suppressive roles of baicalein in cervical cancer cell viability, apoptosis, and migration. Xenograft assays showed that SNHG1 reverses the tumor-suppressive roles of baicalein in repressing cervical cancer growth in vivo. Mechanistic investigations revealed that SNHG1 directly binds miR-3127-5p and up-regulates FZD4, a target of miR-3127-5p. Via regulating miR-3127-5p/FZD4, SNHG1 activates Wnt/β-catenin signaling. Moreover, SNHG1 reverses the repressive role of baicalein on Wnt/β-catenin signaling. The effect of SNHG1 on the antitumorigenic process of baicalein was abolished by Wnt/β-catenin signaling inhibitor ICG-001. Together, our observations demonstrated that SNHG1 represses the tumor-suppressive roles of baicalein in cervical cancer through regulating miR-3127-5p/FZD4/Wnt/β-catenin axis, and suggested that targeting SNHG1 represents a potential strategy to enhance the tumor-suppressive roles of baicalein in cervical cancer.Impact statementBaicalein exhibits anti-cancer roles in several cancers. However, the factors influencing the antitumorigenic efficiencies of baicalein in CC remain largely unclear. Here, we provide convincing evidences that lncRNA SNHG1 attenuates the tumor-suppressive roles of baicalein in CC cell viability, apoptosis, migration, and CC tumor growth. This study further demonstrates that the influences of SNHG1 in the antitumorigenic process of baicalein are achieved through modulating the miR-3127-5p/FZD4Wnt/β-catenin axis. SNHG1 attenuates the repressive role of baicalein on Wnt/β-catenin. Therefore, SNHG1 is a novel modulator of the tumor-suppressive roles of baicalein and SNHG1 represents a therapeutic intervention target to reinforce the tumor-suppressive roles of baicalein in CC.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-04T04:36:22Z
      DOI: 10.1177/1535370220955139
  • Prevalence of class I–III BRAF mutations among 114,662 cancer patients
           in a large genomic database
    • Authors: Jeff Owsley, Matt Stein, Jason Porter, Gino K In, Mohamed Salem, Steven O’Day, Andrew Elliott, Kelsey Poorman, Geoffrey Gibney, Ari VanderWalde
      First page: 31
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      BRAF mutations are relatively common in many cancers, particularly melanoma, colorectal cancer, and thyroid cancer and to a lesser extent in lung cancer. These mutations can be targeted by BRAF and MEK inhibitors, which exhibit good clinical activity. There are conflicting reports of the various relative rates of BRAF Class I mutations (V600 locus), defined as those that exhibit extremely strong kinase activity by stimulating monomeric activation of BRAF, Class II, define as non-V600 mutations that activate BRAF to signal as a RAS-independent dimer, and Class III mutations, defined as “kinase-dead” with low kinase activity as compared to wild type BRAF. Prospective studies have largely focused on patients with tumors harboring Class I BRAF mutations (limited to the V600 locus) where response rates up to 70% with BRAF plus MEK inhibition have been demonstrated. We report on the relative prevalence of various types of BRAF mutations across human cancers in a cohort of 114,662 patients that received comprehensive genomic profiling using next-generation sequencing. Of these patients, 4517 (3.9%) a pathogenic or presumed pathogenic BRAF mutation (3.9%). Of these, 1271 were seen in melanoma, representing 39.7% of all melanomas sequenced, representing the highest rate in all tumors. Class I (V600) mutations were seen overall in 2841 patients (62.1% of BRAF mutations, 2.4% of total cancers). Class II mutations were seen in 746 tumors (16.5% of BRAF mutant, 0.7% of total), and Class III mutations were seen in 801 tumors (17.7% of BRAF, 0.7% of total). Knowledge of the relative prevalence of these types of mutations can aid in the development of agents that might better address non-V600 mutations in cancer.Impact statementThese data represent the largest aggregation of BRAF mutations within a single clinical database to our knowledge. The relative proportions of both BRAF V600 mutations and non-V600 mutations are informative in all cancers and by malignancy, and can serve as a definitive gold-standard for BRAF mutation cancer incidence by malignancy. The rate of BRAF mutation in human cancer in a real-world large database is lower than previously reported likely representing testing more broadly across tumor types. The relative percentages of Class II and Class III BRAF mutations are higher than previously reported, representing almost 35% of BRAF mutations in cancer. These findings provide support for the development of effective treatments for non-V600 BRAF mutations in cancer.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-06T05:10:52Z
      DOI: 10.1177/1535370220959657
  • Role of GATA3 exon 6 germline mutations in breast cancer progression in
           Egyptian female patients
    • Authors: Iman H Ibrahim, Heba G Abdel-Aziz, Fatema EM Hassan, Hesham SA El-Sameea
      First page: 40
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Several mutations act as driver mutations in breast cancer, including GATA3 mutations. Reports of the relation between GATA3 mutations and breast cancer prognosis remain conflicting. Also, the role of GATA3 germline mutations is not well studied. We hypothesize that different mutation types could have different effects. Also, this study aims to assess effect of GATA3 mutations on GATA3 protein function as a transcription factor, and target pathways affected. DNA from de novo breast cancer female patients was sequenced to detect exon 6 GATA3 mutation. Sequence analysis was performed along with clinical and prognostic parameters and disease-free survival. Public datasets were analyzed for differentially expressed genes and pathways with mutant GATA3 patients. Mutations in GATA3 exon 6 were detected in 56.1% of patients (including 2 novel, Lys368fs, Pro354Lys). Intronic mutations were significantly higher in long disease-free survival group, while frameshift mutations were significantly higher in short DFS group. Patients with tumor size ≥20 had significantly higher protein coding and lower intronic mutations compared to patients with tumor size
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-17T08:36:40Z
      DOI: 10.1177/1535370220958610
  • Prevalence and correlation of human papillomavirus genotypes with clinical
           factors in cervical samples from Mexican women
    • Authors: Fabiola Hernández-Rosas, Erika Orozco-Hernández, Liliana Maza-Sánchez, Pamela Citlalli Salgado-García, Enrique Navarro-Vidal, Mercedes Piedad de León-Bautista
      First page: 48
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      In the last decade, the inclusion of HPV DNA testing in cervical cancer screening has provided one of the best strategies for the prevention and timely detection of HPV. We conducted a high-throughput HPV genotyping study based on MALDI-TOF mass spectrometry to determine the prevalence of 24 HPV genotypes, including oncogenic genotypes, in Mexican women and correlated the results with cytological findings and clinical variables. We likewise identified the risk factors in patients with the HPV infection. Our study included 1000 women from Sonora, Mexico, who participated in cervical cancer screening campaigns and who underwent a Pap smear and HPV DNA test. The results showed that the overall prevalence of HPV was 27.2%, 18.5% with single, and 8.7% multiple infections. The low-risk HPV genotype 6 (8.5%) and oncogenic genotypes 31 (8.1%) and 53 (4.4%) were the most prevalent in the study population. The number of lifetime sexual partners, previous STIs, and age at first intercourse was significantly associated with HPV infection (P ≤ 0.05). Smoking (OR = 1.5609; 95% IC 1.062–2.292) and more than three lifetime sexual partners (OR = 1.609; 95% IC = 1.124–2.303) represented risk factors for HPV infection. Cytological abnormalities were found in 3.4% of the HPV-positive samples. CIN 1–3 occurred in 0.6% of high-risk HPV cases. In general, the prevalence of the HPV genotypes is high in Mexican women with normal cytological findings. This issue highlights the importance of HPV research in seemingly healthy women and could help guide screening strategies for cervical cancer prevention in Mexico.Impact statementWe are submitting data regarding the prevalence and type distribution of the HPV infection and the risk factors associated with it, which may provide a valuable reference to reinforce screening strategies, and to maintain HPV genotype surveillance in Mexico. We discuss the overall prevalence of HPV infection as detected in normal cytological samples stratified by age, different types of infection, and oncogenic capacity. One of the most important findings was that common HPV genotypes detected in healthy women were the genotype numbers: 6, 31, 16, and 56, likewise, smoking and having a history of more than three sexual partners over their lifetime, represented the main risk factors in this study. Furthermore, we found a low frequency of cytological abnormalities and CIN 1–3 in women with HR-HPV.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-23T04:09:30Z
      DOI: 10.1177/1535370220959747
  • IL-17A is involved in diabetic inflammatory pathogenesis by its receptor
    • Authors: Ao-Wang Qiu, Xin Cao, Wei-Wei Zhang, Qing-Huai Liu
      First page: 57
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Interleukin (IL)-17A, a proinflammatory cytokine produced by T-helper (Th)17 cells, has been associated with autoimmune diseases. Type 1 diabetes (T1D) is caused either due to mutation of insulin gene or developed as an autoimmune disease. Studies have shown that IL-17A expression is upregulated in the pancreas in T1D patients and animal models. However, role or importance of IL-17A in T1D pathogenesis needs elucidation. Particularly, evidence for a direct injury of IL-17A to pancreatic β cells through activating IL-17 receptor A (IL-17RA) is lacking. Ins2Akita (Akita) mouse, a T1D model with spontaneous mutation in insulin 2 gene leading to β-cell apoptosis, was crossed with IL-17A-knockout mouse and male IL-17A-deficient Akita mice were used. Streptozotocin, a pancreatic β-cell-specific cytotoxin, was employed to induce a diabetic model in MIN6 cells, a mouse insulinoma cell line. IL-17A expression in the pancreas was upregulated in both Akita and streptozotocin-induced diabetic mice. IL-17A-knockout Akita mice manifested reduced blood glucose concentration and raised serum insulin level. IL-17A deficiency also decreased production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, IL-1β, and interferon (IFN)-γ in Akita mice. IL-17RA expression in MIN6 cells was upregulated by IL-17A. IL-17A enhanced expression of TNF-α, IL-1β, IFN-γ, and inducible nitric oxide synthase (iNOS) and further increased streptozotocin-induced expression of the inflammatory factors in MIN6 cells. IL-17A exacerbated streptozotocin-induced MIN6 cell apoptosis and insulin secretion impairment. Blocking IL-17RA with anti-IL-17RA-neutralizing antibody reduced all these deleterious effects of IL-17A on MIN6 cells. Collectively, IL-17A deficiency alleviated hyperglycemia, hypoinsulinemia, and inflammatory response in Akita mice that are characteristic for T1D. IL-17A exerted an alone and synergistic destruction with streptozotocin to pancreatic β cells through IL-17RA pathway. Thus, the data suggest that targeting IL-17A and/or IL-17RA is likely to preserve remaining β-cell function and treat T1D.Impact statementThe participation of interleukin (IL)-17A in diabetic pathogenesis is suggested in animal models of autoimmune diabetes and in patients with type 1 diabetes (T1D), but with some contradictory results. Particularly, evidence for a direct injury of IL-17A to pancreatic β cells is lacking. We showed that IL-17A deficiency alleviated diabetic signs including hyperglycemia, hypoinsulinemia, and inflammatory response in Ins2Akita (Akita) mice, a T1D model with spontaneous mutation in insulin 2 gene leading to β-cell apoptosis. IL-17A enhanced inflammatory reaction, oxidative stress, and cell apoptosis but attenuated insulin level in mouse insulin-producing MIN6 cells. IL-17A had also a synergistic destruction to MIN6 cells with streptozotocin (STZ), a pancreatic β-cell-specific cytotoxin. Blocking IL-17 receptor A (IL-17RA) reduced all these deleterious effects of IL-17A on MIN6 cells. The results demonstrate the role and the importance of IL-17A in T1D pathogenesis and suggest a potential therapeutic strategy for T1D targeting IL-17A and/or IL-17RA.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-09T06:37:23Z
      DOI: 10.1177/1535370220956943
  • Overexpression of p53 accelerates puberty in high-fat diet–fed mice
           through Lin28/let-7 system
    • Authors: Ting Chen, Cailong Chen, Haiying Wu, Xiuli Chen, Rongrong Xie, Fengyun Wang, Hui Sun, Linqi Chen
      First page: 66
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      High fat intake is one of the most important reasons of the surging prevalence of childhood obesity all over the world. Obesity and high fat intake have been revealed to cause premature activation of hypothalamo-pituitary-gonadal axis and central precocious puberty. The onset of puberty is controlled by neuroendocrine mechanisms containing overlapping and interacting gene networks. The latter contains five major transcriptional level hubs, among which the transcriptional factor p53, a well-established tumor suppressor protein, also plays a crucial role in obesity and metabolic disorders. In the current study, we repeated prior observations that high-fat diet advances vaginal opening in rodents and extended these findings by demonstrating that high-fat diet mice had higher expression of p53 in hypothalami than mice fed with normal chow. More importantly, in high-fat diet mice, hypothalamus-specific overexpression of p53 can make vaginal opening much earlier, while inhibition of p53 expression relatively delayed vaginal opening. The c-Myc and Lin28b levels increased, while let-7a mRNA levels decreased in the high-fat diet mice. Overexpression of p53 reduced c-Myc and Lin28b mRNA and protein levels, whereas elevated let-7a mRNA levels in high-fat diet mice. Inhibition of p53 expression by pifithrin-α elevated c-Myc and Lin28b but reduced let-7a levels in high-fat diet mice. In conclusion, high fat intake can accelerate the onset of puberty by up-regulation of p53 expression in hypothalamus. Overexpressed p53 may accelerate hypothalamo-pituitary-gonadal axis activation partially through the c-Myc/Lin28/let-7 system.Impact statement High-fat intake and subsequent obesity are associated with premature onset of puberty, but the exact neuroendocrine mechanisms are still unclear. The transcriptional factor p53 has been predicted to be a central hub of the gene networks controlling the pubertal onset. Besides, p53 also plays crucial roles in metabolism. Here, we explored p53 in the hypothalami of mice fed a high-fat diet (HFD), which showed an up-regulated expression. Besides, we also revealed that overexpressed p53 may accelerate hypothalamo-pituitary-gonadal (HPG) axis activation partially through the c-Myc/Lin28/let-7 system. These results can deepen our understanding of the interaction between metabolic regulation and puberty onset control, and may shed light on the neuroendocrine mechanisms of obesity-related central precocious puberty.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-30T10:28:35Z
      DOI: 10.1177/1535370220961320
  • A novel microRNA-based signature predicts prognosis among nasopharyngeal
           cancer patients
    • Authors: Tianyu Wang, Jian Wu, Yun Wu, Yin Cheng, Yue Deng, Jianchun Liao, Huanhai Liu, Hu Peng
      First page: 72
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Nasopharyngeal cancer is one of the most common malignant tumors in the head and neck. Identification of promising miRNA biomarkers might benefit a lot to the detection of nasopharyngeal carcinoma. miRNA expression profile and clinical information were obtained from two microarray profiling data sets from the Gene Expression Omnibus (GEO) database. miRNA signature model was constructed via univariate Cox survival analysis, multivariate Cox survival analysis, and least absolute shrinkage and selection operator Cox regression analysis. Kaplan–Meier curve, area under the curve (AUC), decision curve analysis, Box plot, and nomogram were used to evaluate the prognosis of the model to patients. 67 up-regulated and 93 down-regulated miRNAs were identified from GEO microarray data sets (P 
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-17T05:30:58Z
      DOI: 10.1177/1535370220958680
  • Hypoxia–CXCL6 axis affects arteriolar niche remodeling in acute
           myeloid leukemia
    • Authors: Lijun Li, Jiancheng Man, Li Zhao
      First page: 84
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Acute myeloid leukemia (AML) is a malignant clonal disease derived from hematopoietic stem/progenitor cell. Leukemia blasts cause extensive hypoxia of bone marrow (BM), which lead to disorder and remodeling of BM niche, thereby becoming “leukemic niche” to support the development and drug-resistance of AML as well as the maintenance of normal hematopoietic stem cells. In this study, the biological characteristics (such as self-renewal, apoptosis, migration, autocrine) and function (vascularization) of mesenchymal stem cells (MSCs) and human umbilical artery endothelial cells (HUAECs) that make up BM arteriolar niche in simulated hypoxia AML context were investigated. It was found that moderate hypoxia enhanced the viability of the arteriolar niche cells, but severe hypoxia of AML BM resulted in the damage of arteriolar niche cells and the disorder of vascular cytokines C-X-C motif chemokine ligand 6 (CXCL6). The dynamic changes of CXCL6 in the system as well as its anti-apoptotic and promoting angiogenic effects suggested that CXCL6 played an important role in the remodeling of BM arteriolar niche in AML. Taking advantage of CXCL6 can save the damaged MSCs and HUAECs, which is the hope of rescuing arteriolar niche. It is suggested that CXCL6 may be an assistant strategy for microenvironment targeted therapy of AML.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-10T07:02:47Z
      DOI: 10.1177/1535370220960675
  • Mitophagy promotes the stemness of bone marrow-derived mesenchymal stem
    • Authors: Xiaorong Feng, Wen Yin, Jialing Wang, Li Feng, Y James Kang
      First page: 97
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Previous studies demonstrated that mitochondrial fission arguments the stemness of bone marrow-derived mesenchymal stem cells (BMSCs). Because mitophagy is critical in removing damaged or surplus mitochondrial fragments and maintaining mitochondrial integrity, the present study was undertaken to test the hypothesis that mitophagy is involved in mitochondrial fission-enhanced stemness of BMSCs. Primary cultures of rat BMSCs were treated with tyrphostin A9 (TA9, a potent inducer of mitochondrial fission) to increase mitochondrial fission, which was accompanied by enhanced mitophagy as defined by increased co-staining of MitoTracker Green for mitochondria and LysoTracker Deep Red for lysosomes, as well as the increased co-localization of autophagy markers (LC3B, P62) and mitochondrial marker (Tom20). A mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) was used to promote mitophagy, which was confirmed by an increased co-localization of mitochondrial and lysosome biomarkers. The argumentation of mitophagy was associated with enhanced stemness of BMSCs as defined by increased expression of stemness markers Oct4 and Sox2, and enhanced induction of BMSCs to adipocytes or osteocytes. Conversely, transfection of BMSCs with siRNA targeting mitophagy-essential genes Pink1/Prkn led to diminished stemness of the stem cells, as defined by depressed stemness markers. Importantly, concomitant promotion of mitochondrial fission and inhibition of mitophagy suppressed the stemness of BMSCs. These results thus demonstrate that mitophagy is critically involved in mitochondrial fission promotion of the stemness of BMSCs.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-11T04:57:21Z
      DOI: 10.1177/1535370220964394
  • Role of age and neuroinflammation in the mechanism of cognitive deficits
           in sickle cell disease
    • Authors: Raven A Hardy, Noor Abi Rached, Jayre A Jones, David R Archer, Hyacinth I Hyacinth
      First page: 106
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      This study aims to determine whether sickle cell mice could recapitulate features of cognitive and neurobehavioral impairment observed in sickle cell patients and whether neuroinflammation could be a potential therapeutic target as in other non-sickle cell disease-related cognitive dysfunction. Cognitive (learning and memory) and behavioral (anxiety) deficits in 13- and later 6-month-old male Townes humanized sickle cell (SS) and matched control (AA) mice were evaluated using novel object recognition (NOR) and fear conditioning tests. Immunohistochemistry was performed to quantify peripheral immune cell (CD45+) and activated microglia (Iba1+) as markers of neuroinflammation in the dentate and peri-dentate gyrus areas. We evaluated cell fate by measuring 5'-bromodeoxyuridine and doublecortin fluorescence and phenotyped proliferating cells using either glial fibrillary acid protein (GFAP+), neuronal nuclei (NeuN+), CD45+, and Iba1+. In addition, Golgi-Cox staining was used to assess markers of neuroplasticity (dendritic spine density and morphology and density of dendrite arbors) on cortical and hippocampal pyramidal neurons. Compared to matched AA controls, 13-month-old SS mice showed significant evidence of cognitive and behavioral deficit on NOR and fear conditioning tests. Also, SS mice had significantly higher density of CD45+ and activated microglia cells (i.e. more evidence of neuroinflammation) in the dentate and peri-dentate gyrus area. Additionally, SS mice had significantly lower dendritic spine density, but a higher proportion of immature dendritic spines. Treatment of 13-month-old SS mice with minocycline resulted in improvement of cognitive and behavioral deficit compared to matched vehicle-treated SS mice. Also, treated SS mice had significantly fewer CD45+ and activated microglia cells (i.e. less evidence of neuroinflammation) in the dentate and peri-dentate gyrus, as well as a significant improvement in markers of neuroplasticity.Impact statementThis study provides crucial information that could be helpful in the development of new or repurposing of existing therapies for the treatment of cognitive deficit in individuals with sickle cell disease (SCD). Its impact is in demonstrating for the first time that neuroinflammation and along with abnormal neuroplasticity are among the underlying mechanism of cognitive and behavioral deficits in SCD and that drugs such as minocycline which targets these pathophysiological mechanisms could be repurposed for the treatment of this life altering complication of SCD.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-23T04:09:30Z
      DOI: 10.1177/1535370220958011
  • CD248+CD8+ T lymphocytes suppress pathological vascular remodeling in
           human thoracic aortic aneurysms
    • Authors: Xiaojuan Hu, Ting Wu, Chenxi Wang, Jun Li, Chunmei Ying
      First page: 121
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Aortic aneurysms are characterized by vascular inflammation, neovascularization, and extracellular matrix destruction of the aortic wall. Although experimental studies indicate a potential role of CD248 in microvessel remodeling, the functions of CD248 in human vascular pathologies remain unexplored. Here we aimed to study how CD248 interferes with pathological vascular remodeling of human aortic aneurysms. Immunofluorescent staining showed that CD248 expression was mainly localized in the CD8+ T cells infiltrating in the adventitia and media of aortic walls of patients with ascending thoracic aortic aneurysms. qPCR and immunofluorescent staining analyses revealed increased aortic CD248 expression and infiltrating CD248+CD8+ T cells in aortic aneurysms than in nonaneurysmal aortas. Flow cytometry analysis of human peripheral blood further identified a fraction of circulating CD248+ cells which was confined in the CD8+ T-cell compartment. The increased infiltrating of CD248+CD8+ T cells was coincident with reduced circulating CD248+CD8+ T cells in patients with ascending TAA when compared with patients with coronary artery diseases and healthy donors. The CD248+CD8+ T cells were characterized by upregulated IL-10 and downregulated IL-1β/INF-γ expression when compared with CD248-CD8+ T cells. Moreover, when co-cultured with human aortic endothelial cells, the CD248+CD8+ T cells not only downregulated endothelial expression of ICAM1/VCAM1 and MMP2/3 but also suppressed endothelial migration. This study shows that CD248 reduces pathological vascular remodeling via anti-inflammatory CD248+CD8+ T cells, revealing a CD248-mediated cellular mechanism against human aortic aneurysms.Impact statementIn spite of recent evidence indicating that CD248 is linked to microvasculature remodeling, immune response, and MMP activity, the functions of CD248 in human TAA remain unexplored. In this work, by analyzing cellular components of in situ as well as of blood circulation of human TAA, we have identified a novel T cell subset, the CD248+CD8+ T cells, which exhibits anti-inflammatory properties, and that we have also provided the first evidence that these cells not only suppress endothelial expression of ICAM1/VCAM1 and MMP2/3, but also inhibit endothelial migration, thus uncovering a CD248-mediated cellular mechanism against pathological vascular remodeling in human aortic aneurysms.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-01T05:47:19Z
      DOI: 10.1177/1535370220953386
  • Serum-derived exosomes from neurofibromatosis type 1 congenital tibial
           pseudarthrosis impaired bone by promoting osteoclastogenesis and
           inhibiting osteogenesis
    • Authors: Ge Yang, Hui Yu, Yaoxi Liu, Weihua Ye, Guanghui Zhu, An Yan, Qian Tan, Haibo Mei
      First page: 130
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Treatment of congenital pseudarthrosis of the tibia (CPT) still is full of challenges in pediatric orthopedist. Serum-derived exosomes (SDEs) have been proven to be participated in bone remodeling. However, the molecular changes in SDEs of CPT children and their pathologies have not been elucidated. In this study, SDEs were isolated and purified from CPT patients (CPT-SDEs) associated with neurofibromatosis type 1 (NF1) and normal children (Norm-SDEs). Then we obtained the proteomics profile of SDEs by combining liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tandem mass tag label-based quantitation. In vitro, the efficacy of SDEs on osteoblastic differentiation of MC3T3-E1 cells and osteoclastogenesis ability of RAW264.7 cells were evaluated by quantitative real-time PCR (qRT-PCR) and cytochemical staining. In vivo, we used micro-CT to assess cortical bone mass and trabecular microstructures to reflect the influence of SDEs on bone remodeling after injection into the tail vein of rats. Based on proteomics analysis, 410 differentially expressed proteins, including 289 downregulated proteins and 121 upregulated proteins, were identified in the CPT-SDEs. These proteins have multiple biological functions associated with cellular metabolic processes, catalytic activity, and protein binding, which are important for cell differentiation and proliferation. In vitro, CPT-SDEs decreased the osteogenic differentiation of MC3T3-E1 cells and promoted the osteoclastogenesis of RAW264.7 cells. Injection of CPT-SDEs into the tail vein for two months resulted in bone loss in rats, as indicated by the decrease in trabecular and cortical bone mass. Our findings demonstrated the differences in proteins in SDEs between normal and CPT children with NF1. These differentially expressed proteins in CPT-SDEs contributed to deteriorating trabecular bone microstructures by inhibiting bone formation and stimulating bone resorption.Impact statementCongenital pseudarthrosis of the tibia (CPT) is an uncommon and puzzling disease associated with a high rate of disability. To date, the biological mechanisms related to this disease have largely not been elucidated. In this study, we determined the biological functions of serum-derived exosomes (SDEs) from children with neurofibromatosis type 1 (NF1) associated with CPT (CPT-SDEs) and compared their proteomic profiles with those of SDEs from normal children. Based on proteomics analysis, 410 differentially expressed proteins, including 289 downregulated proteins and 121 upregulated proteins, were identified in the CPT-SDEs. In addition, CPT-SDEs decreased the osteogenic differentiation of MC3T3-E1 cells and promoted the osteoclastogenesis ability of RAW264.7 cells. Moreover, injecting CPT-SDEs into the tail veins led to bone loss in rats, as detected by the reduction in trabecular and cortical bone mass. These findings indicate that CPT-SDEs impair bone quality, which may provide a reasonable explanation for the low bone quality and tibial nonunion in children with NF1 associated with congenital tibial pseudarthrosis.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-07T06:32:57Z
      DOI: 10.1177/1535370220962737
  • Long non-coding RNA CCAT1 promotes non-small cell lung cancer progression
           by regulating the miR-216a-5p/RAP2B axis
    • Authors: Lingling Pang, Qianqian Zhang, Yanmin Wu, Qingru Yang, Jinghao Zhang, Yuanyuan Liu, Ruoran Li
      First page: 142
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      The long non-coding RNA colon cancer-associated transcript 1 (CCAT1) has been investigated to involve in the progression of non-small cell lung cancer (NSCLC). Thus, this study aims to explore the detailed molecular mechanisms of CCAT1 in NSCLC. The expression of CCAT1, miR-216a-5p, RAP2B, Bax, Bcl-2, and cleaved caspase 3 was detected by qRT-PCR or Western blot. Cell proliferation, apoptosis, migration, and invasion were analyzed using cell counting kit-8, flow cytometry or Transwell assays, respectively. The interaction between miR-216a-5p and CCAT1 or RAP2B was analyzed by luciferase reporter, RNA immunoprecipitation, and pull-down assays. The expression of CCAT1 was elevated in NSCLC, and CCAT1 deletion could inhibit NSCLC cell proliferation, migration, and invasion but induce apoptosis in vitro as well as imped tumor growth in vivo. MiR-216a-5p was confirmed to be a target of CCAT1, and silencing miR-216a-5p could reverse CCAT1 depletion-mediated inhibitory effects on cell tumorigenesis in NSCLC. Besides that, miR-216a-5p was decreased in NSCLC, and miR-216a-5p restoration inhibited cell tumorigenesis by regulating RAP2B, which was verified to be a target of miR-216a-5p. Additionally, co-expression analysis suggested that CCAT1 indirectly regulated RAP2B level by targeting miR-216a-5p in NSCLC cells. Taken together, CCAT1 deletion could inhibit cell progression in NSCLC through miR-216a-5p/RAP2B axis, indicating a novel pathway underlying NSCLC cell progression and providing new potential targets for NSCLC treatment.Impact statementWe investigated that CCAT1 expression was elevated in NSCLC and CCAT1 deletion was identified to inhibit cell carcinogenic phenotypes in NSCLC cells via miR-216a-5p/RAP2B axis, which reveals a novel pathway underlying progression in NSCLC cells and providing potential targets for NSCLC treatment.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-07T06:32:58Z
      DOI: 10.1177/1535370220961013
  • ADMA (asymmetric dimethylarginine) and angiogenic potential in patients
           with type 2 diabetes and prediabetes
    • Authors: Radosław Wieczór, Anna M Wieczór, Arleta Kulwas, Danuta Rość
      First page: 153
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Asymmetric dimethylarginine is an endogenous competitive inhibitor of nitric oxide synthase and marker of endothelial dysfunction, but the question remains as to whether asymmetric dimethylarginine is a marker of cardiovascular episodes or their independent risk factor. ADMA/DDAH (dimethylaminohydrolase) pathway regulates vascular endothelial growth factor (VEGF)-mediated angiogenesis due to its impact on the NO formation. The aim of the study was to assess the concentrations of asymmetric dimethylarginine and the angiogenic potential in the blood of subjects with type 2 diabetes (T2DM, n = 33) and patients with prediabetes (n = 32)—impaired fasting glycemia and/or impaired glucose tolerance (WHO criteria). The study found that both the prediabetes group and subjects with T2DM had significantly elevated concentrations of asymmetric dimethylarginine, significantly high levels of VEGF-A, low ratio of sVEGF-R1/VEGF-A, and sVEGF-R2/VEGF-A. This may suggest endothelial damage at early stages of carbohydrate metabolism dysfunction—before T2DM is diagnosed. Higher proangiogenic potential in prediabetes and T2DM patients than in healthy subjects, is not only the effect of an increase in VEGF-A levels, but also reduced inhibition of circulating receptors.Impact statementOur research provided new insight into the mechanisms governing vascular complications in prediabetes and type 2 diabetes. Unfortunately, most studies focus on angiogenesis markers (VEGF-A, sVEGF-R1, sVEGF-R2) and endothelial dysfunction marker (ADMA) separately. Our findings reported for the first time that endothelial damage and angiogenic potential at early stage of carbohydrate dysfunction appear in prediabetes before type 2 diabetes is diagnosed.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-22T07:03:06Z
      DOI: 10.1177/1535370220959738
  • Epigallocatechin gallate decreases plasma triglyceride, blood pressure,
           and serum kisspeptin in obese human subjects
    • Authors: Saimai Chatree, Chantacha Sitticharoon, Pailin Maikaew, Kitchaya Pongwattanapakin, Issarawan Keadkraichaiwat, Malika Churintaraphan, Chanakarn Sripong, Rungnapa Sririwichitchai, Sompol Tapechum
      First page: 163
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Obesity is one of major risk factors increasing chronic diseases including type II diabetes, cardiovascular diseases, and hypertension. The effects of epigallocatechin gallate (EGCG), the major active compound in green tea, on reduced obesity and improved metabolic profiles are still controversial. Furthermore, the effects of EGCG on human adipocyte lipolysis and browning of white adipocytes have not been elucidated. This study aimed to investigate the effects of EGCG on obesity, lipolysis, and browning of human white adipocytes. The results showed that, when compared to the baseline values, EGCG significantly decreased fasting plasma triglyceride levels (P
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-13T04:23:57Z
      DOI: 10.1177/1535370220962708
  • Lnc-ATG9B-4 aggravates progress of hepatocellular carcinoma through cell
           proliferation and migration by upregulating CDK5
    • Authors: Ming Li, Le Wei, Pin-Yue Liu, Xue-Mei Zhang, Fang Liu, Fen Yang, Xiang-Shang Hu, Zhong-Cheng Mo
      First page: 177
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Long noncoding RNAs play an important role in the occurrence, invasion, as well as metastasis of various human cancers, including hepatocellular carcinoma. Long noncoding RNAs can affect the biological functions of hepatocellular carcinoma cells by regulating various genes; however, only a small fraction of molecular mechanisms of long noncoding RNAs have been elucidated. In the present study, lnc AC010973.1 (lnc-ATG9B-4) was first identified by microarray analysis from 8 patients with hepatocellular carcinoma and confirmed by quantitative PCR in 176 patients with hepatocellular carcinoma. We demonstrated that lnc-ATG9B-4 was tightly relative to the tumorous size, TNM stages, portal vein tumor thrombus (PVTT), the tumor capsule, metastasis, degree of differentiation, and poor prognosis of hepatocellular carcinoma according to long-term follow-up data. In hepatocellular carcinoma cells, overexpression of lnc-ATG9B-4 promoted proliferation, invasion, as well as migration, while inhibiting lnc-ATG9B-4 by siRNA significantly attenuated the proliferation, invasion, as well as migration. Interestingly, lnc-ATG9B-4 increased the expression of cyclin-dependent kinase 5 (CDK5), which was closely related to the development and chemotherapy sensitivity of hepatocellular carcinoma. In summary, our results revealed that lnc-ATG9B-4 suggests an unfavorable prognosis of hepatocellular carcinoma and facilitates the proliferation, invasion, as well as migration of hepatocellular carcinoma cells by upregulating CDK5. This research suggests that lnc-ATG9B-4 may be a new biomarker for predicting the prognosis of hepatocellular carcinoma; meanwhile, targeting lnc-ATG9B-4 might serve as a potential strategy for the treatment hepatocellular carcinoma.Impact statementIn this study, we explored the expression profile of lncRNA in HCC tumor tissues and paracancerous tissues using microarray assays. Furthermore, a new lncRNA (lnc-ATG9B-4) was identified, which was about 3.5 times more expressed in tumor tissues than in paracancerous tissues. Through clinicopathological analysis, lnc-ATG9B-4 was determined to be related to the tumorous size, TNM stages, portal vein tumor thrombus (PVTT), the tumor capsule, metastasis, and the degree of differentiation. Lnc-ATG9B-4 promoted the proliferation, invasion, as well as migration of the HCC cells by upregulating the expression of CDK5. Here, we further exploited the molecular mechanisms of lnc-ATG9B-4 to screen new drug intervention targets for recurrence and metastasis of HCC.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-07T06:32:58Z
      DOI: 10.1177/1535370220963197
  • Identification of a three-long non-coding RNA signature for predicting
           survival of temozolomide-treated isocitrate dehydrogenase mutant low-grade
    • Authors: Ruichun Li, Wei Chen, Ping Mao, Jia Wang, Jiangpeng Jing, Qinli Sun, Maode Wang, Xiao Yu
      First page: 187
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Temozolomide (TMZ) is the major chemotherapy agent in glioma, and isocitrate dehydrogenase (IDH) is a well-known prognostic marker in glioma. O6-methylguanine-DNA methyltransferase promoter methylation (MGMTmethyl) is a predictive biomarker in overall gliomas rather than in IDH mutant gliomas. To discover effective biomarkers that could predict TMZ efficacy in IDH mutant low-grade gliomas (LGGs), we retrieved data of IDH mutant LGGs from TMZ arm of the EORTC22033-26033 trial as the training-set (n = 83), analyzed correlations between long non-coding RNAs (lncRNAs) and progression-free survival (PFS) using Lasso-Cox regression, and created a risk score (RS) to stratify patients. We identified a three-lncRNA signature in TMZ-treated IDH mutant LGGs. All of the three lncRNAs, as well as the RS derived, were significantly correlated with PFS. Patients were classified into high-risk and low-risk groups according to RS. PFS of the high-risk group was significantly worse than that of the low-risk group (P 
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-08T05:55:36Z
      DOI: 10.1177/1535370220962715
  • Whole exome sequencing identifies rare coding variants in novel
           human-mouse ortholog genes in African individuals diagnosed with
           non-syndromic hearing impairment
    • Authors: Oluwafemi G Oluwole, Kevin K Esoh, Edmond Wonkam-Tingang, Noluthando Manyisa, Jean Jacques Noubiap, Emile R Chimusa, Ambroise Wonkam
      First page: 197
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Physiologically, the human and murine hearing systems are very similar, justifying the extensive use of mice in experimental models for hearing impairment (HI). About 340 murine HI genes have been reported; however, whether variants in all human-mouse ortholog genes contribute to HI has been rarely investigated. In humans, nearly 120 HI genes have been identified to date, with GJB2 and GJB6 variants accounting for half of congenital HI cases, of genetic origin, in populations of European and Asian ancestries, but not in most African populations. The contribution of variants in other known genes of HI among the populations of African ancestry is poorly studied and displays the lowest pick-up rate. We used whole exome sequencing (WES) to investigate pathogenic and likely pathogenic (PLP) variants in 34 novel human-mouse orthologs HI genes, in 40 individuals from Cameroon and South Africa diagnosed with non-syndromic hearing impairment (NSHI), and compared the data to WES data of 129 ethnically matched controls. In addition, protein modeling for selected PLP gene variants, gene enrichment, and network analyses were performed. A total of 4/38 murine genes, d6wsu163e, zfp719, grp152 and minar2, had no human orthologs. WES identified three rare PLP variants in 3/34 human-mouse orthologs genes in three unrelated Cameroonian patients, namely: OCM2, c.227G>C p.(Arg76Thr) and LRGI1, c.1657G>A p.(Gly533Arg) in a heterozygous state, and a PLP variant MCPH1, c.2311C>G p.(Pro771Ala) in a homozygous state. In silico functional analyses suggest that these human-mouse ortholog genes functionally co-expressed interactions with well-established HI genes: GJB2 and GJB6. The study found one homozygous variant in MCPH1, likely to explain HI in one patient, and suggests that human-mouse ortholog variants could contribute to the understanding of the physiology of hearing in humans.Impact statementDespite, human and murine hearing system being very similar, the contribution of variants in relevant mouse-ortholog genes to hearing impairment (HI) has not been fully investigated. The contribution of variants in the known non-syndromic hearing impairment (NSHI) genes among Africans is poorly studied, suggesting that the novel gene(s) and mutations are yet to be discovered in NSHI in the African populations. Using whole exome sequencing (WES), this study identified rare candidate pathogenic and likely pathogenic (PLP) variants in 3/34 novel human-mouse ortholog genes in 3/40 individuals, with one homozygous variant, MCPH1, c.2311C>G p.(Pro771Ala), likely to explain HI in one patient. In silico functional analyses suggest that these human-mouse ortholog genes could contribute to the understanding of the physiology of hearing in humans and thus the variants identified in those genes deserve additional investigations.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-30T09:58:00Z
      DOI: 10.1177/1535370220960388
  • Recent developments in autophagy-targeted therapies in cancer
    • Authors: Manasi P Jogalekar, Anurag Veerabathini, Prakash Gangadaran
      First page: 207
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Autophagy plays a crucial role in cellular development and differentiation as well as in the maintenance of homeostasis in healthy cells. Autophagy is well documented in neurodegenerative disorders, aging, and infectious diseases. However, recognizing its significance in cancer has always been challenging due to its tumor-promoting and suppressive attributes. Various modulators targeting key components of autophagy machinery directly or indirectly have been developed over the years, and have shown promising results in preclinical models. Some of these compounds are even being tested in clinical trials for safety and efficacy. A detailed review of strategies used to target autophagy in cancer is presented including our opinion on developing better therapies and outstanding issues.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-11-10T07:02:48Z
      DOI: 10.1177/1535370220966545
  • Histone deacetylases in modulating cardiac disease and their clinical
           translational and therapeutic implications
    • Authors: Zhengke Wang, Yu Tina Zhao, Ting C Zhao
      First page: 213
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Cardiovascular diseases are the leading cause of mortality and morbidity worldwide. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of genetic transcription in response to stress or pathological conditions. HDACs interact with a complex co-regulatory network of transcriptional regulators, deacetylate histones or non-histone proteins, and modulate gene expression in the heart. The selective HDAC inhibitors have been considered to be a critical target for the treatment of cardiac disease, especially for ameliorating cardiac dysfunction. In this review, we discuss our current knowledge of the cellular and molecular basis of HDACs in mediating cardiac development and hypertrophy and related pharmacologic interventions in heart disease.Impact statementHistone deacetylases (HDACs) have recently been recognized as one of the most important regulated mechanism(s) in mediating cardiovascular development, myocardial injury, and hypertrophy. This detailed review of the functional role(s) and molecular mechanism(s) of histone deacetylase will provide the current view by which HDACs induce different biological signaling in the regulation of cardiac physiology and disease. More importantly, HDACs could be targeted to develop a new therapeutic strategy in treating cardiovascular disorders. Further studies of the specific roles and targets of HDACs will extend our knowledge of the biological impact and clinical implications of HDACs.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-07-30T06:17:23Z
      DOI: 10.1177/1535370220944128
  • H2S attenuates oxidative stress via Nrf2/NF-κB signaling to regulate
           restenosis after percutaneous transluminal angioplasty
    • Authors: Ken Ling, Wei Zhou, Yi Guo, Guofu Hu, Jie Chu, Fen Xie, Yiqing Li, Weici Wang
      First page: 226
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Restenosis after angioplasty of peripheral arteries is a clinical problem involving oxidative stress. Hydrogen sulfide (H2S) participates in oxidative stress regulation and activates nuclear factor erythroid 2-related factor 2 (Nrf2). This study investigated the effect of H2S and Nrf2 on restenosis-induced arterial injury. Using an in vivo rat model of restenosis, we investigated whether H2S inhibits restenosis after percutaneous transluminal angioplasty (PTA) and the oxidative stress-related mechanisms implicated therein. The involvement of Nrf2 was explored using Nrf2-shRNA. Neointimal formation and the deposition of elastic fibers were assessed histologically. Inflammatory cytokine secretion and the expression of proteins associated with oxidative stress and inflammation were evaluated. The artery of rats subjected to restenosis showed increased arterial intimal thickness, with prominent elastic fiber deposition. Sodium hydrosulfide (NaHS), an H2S donor, counteracted these changes in vivo. Restenosis caused a decrease in anti-oxidative stress signaling. This phenomenon was inhibited by NaHS, but Nrf2-shRNA counteracted the effects of NaHS. In terms of inflammation, inflammatory cytokines were upregulated, whereas NaHS suppressed the induced inflammatory reaction. Similarly, Nrf2 downregulation blocked the effect of NaHS. In vitro studies using aortic endothelial and vascular smooth muscle cells isolated from experimental animals showed consistent results as those of in vivo studies, and the participation of the nuclear factor-kappa B signaling pathway was demonstrated. Collectively, H2S played a role in regulating post-PTA restenosis by alleviating oxidative stress, modulating anti-oxidant defense, and targeting Nrf2-related pathways via nuclear factor-kappa B signaling.Impact statementThis work advances the field of vascular pharmacology as it addresses the issue of neointimal hyperplasia, which is a severe problem that results in restenosis after percutaneous transluminal angioplastic surgery. The effectiveness of vascular surgery is impacted negatively because of this phenomenon, and a solution is urgently needed. Here, we report in a rat model of angioplasty-induced vessel injury that hydrogen sulfide (H2S) counteracts post-percutaneous transluminal angioplasty neointimal formation and inflammation. Importantly, we demonstrated that the action of H2S requires Nrf2 signaling and is associated with the regulation of oxidative stress and inflammation via the nuclear factor-kappa B signaling pathway. Notably, our findings offer a potential strategy to address post-vascular surgery restenosis, which remains a clinical problem.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-09-30T10:28:36Z
      DOI: 10.1177/1535370220961038
  • Direct conversion of adult human retinal pigmented epithelium cells to
           neurons with photoreceptor properties
    • Authors: Bo Li, Houbo Jiang, Hong Li, Boyang Zhang, Malcolm Slaughter, Zhen Yan, Jian Feng
      First page: 240
      Abstract: Experimental Biology and Medicine, Ahead of Print.
      Degeneration of photoreceptors is a major cause of blindness. Identifying new methods for the generation of photoreceptors offers valuable options for a cell replacement therapy of blindness. Here, we show that primary adult human retinal pigmented epithelium (hRPE) cells were directly converted to postmitotic neurons with various properties of photoreceptors by the neurogenic transcription factor ASCL1 and microRNA124. At Day 8 after the induction of ASCL1 and miRNA124 expression in hRPE cells, 91% of all cells were Tuj1+, and 83% of all cells were MAP2+ neurons. The cone photoreceptor marker L/M-opsin, the rod photoreceptor marker rhodopsin, and the generic photoreceptor marker recoverin were expressed in 76%, 86%, and 92% of all cells, respectively. Real-time quantitative PCR measurements showed significant and continuous increases in the expression of photoreceptor markers phosducin and recoverin, rod cell markers phosphodiesterases 6 b and arrestin S-antigen, and cone cell markers L/M-opsin and S-opsin in three independent lines of primary hRPE cells at different days of transdifferentiation. Transmission electron microscopy of converted neurons showed disc-like structures similar to those found in photoreceptors. While the converted neurons had voltage-dependent Na+, K+, and Ca2+ currents, light-induced change in membrane potential was not detected. The study demonstrates the feasibility of rapid and efficient transdifferentiation of adult hPRE cells to neurons with many properties of photoreceptors. It opens up a new possibility in cell replacement therapy of blindness caused by photoreceptor degeneration.Impact statementThe degeneration of photoreceptors is a leading cause of blindness. Retinal pigment epithelium (RPE) cells are mitotic cells that support the function of photoreceptors. We found that lentivirus-mediated overexpression of ASCL1 and microRNA124 directly converted primary adult human RPE cells to postmitotic neurons with many properties of photoreceptors. This study identifies a new method toward the generation of human photoreceptors and provides a new avenue in cell-based therapies for blindness caused by photoreceptor degeneration.
      Citation: Experimental Biology and Medicine
      PubDate: 2020-10-19T04:13:56Z
      DOI: 10.1177/1535370220963755
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