Human & Experimental Toxicology

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ISSN / EISSN : 0960-3271 / 1477-0903
Published by: SAGE Publications (10.1177)
Total articles ≅ 4,470
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, , , A Karim, F Imam, M Raish, , M Noman
Human & Experimental Toxicology; https://doi.org/10.1177/09603271221102518

Abstract:
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with rising prevalence in developing countries, and limited success of current therapies, natural products have immense potential for therapy due to their “disease modifying and side-effect neutralizing” potential. Myrica salicifolia is traditionally used for gastrointestinal diseases and have reported antiinflammatory activities, but its use in IBD has not yet been studied. Therefore, in the present study, the effects of the root extract of M. salicifolia (Ms.Cr) were investigated using the acetic acid-induced UC model in rats. For 6 days, the rats were given either vehicle (10 mL/kg), lower (200 mg/kg), and higher (400 mg/kg) doses of Ms.Cr, or the positive control drug (prednisolone; 2 mg/kg) orally. A single dosage of 5% acetic acid (1.0 mL) was administered intrarectally to rats on day 6 to induce UC. Disease activity index (DAI), histological observations, the biochemical parameters related to oxidative stress, and specific cytokines such as interleukin-6 (IL-6) and the tumor necrosis factor-α (TNF-α) were determined to assess the effect of Ms.Cr. In comparison to the AA-induced colitis rats, Ms.Cr’s pretreatment significantly decreased DAI, colonic ulceration, and inflammatory score. Total glutathione levels and catalase activity were considerably recovered in the colitis group treated with Ms.Cr, whereas enhanced lipid peroxidation in colon tissues was significantly decreased. Moreover, Ms.Cr pretreatment also caused inhibition of the activation of IL-6 and TNF-α in the colonic tissues of respective groups. Based on these findings, Ms.Cr might be developed to treat UC in the future.
Hong-Yan Song, Jing-Sheng Xia, Yong-Gang Chen, Ling Chen
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271221080236

Abstract:
Objective: Cytochrome P450 3A5 ( CYP3A5) is a highly polymorphic gene and the encoded protein variants differ in catalytic activity, leading to inter-individual variation in metabolic ability. The aim of the current study was to investigate the effects of seven allelic variants on the ability of CYP3A5 to metabolize sorafenib in vitro and further explore the impacts of CYP3A5 polymorphism on the proliferation and apoptosis of hepatocellular carcinoma cell line (HepG2) induced by sorafenib. Methods: Wild-type and variant CYP3A5 enzymes were expressed in Spodoptera frugiperda insect cells using a baculovirus dual-expression system, and protein expression was checked by western blot. The enzymes were incubated with sorafenib at 37°C for 30 min, and formation of the major metabolite sorafenib N-oxide was assayed using ultra-performance liquid chromatography and tandem mass spectrometry. Intrinsic clearance values (V max/ K m) were calculated for each enzyme. Additionally, recombinant HepG2 cells transfecting with CYP3A5 variants were used to investigate the effects of sorafenib on the proliferation of HepG2 cells. Results: Intrinsic clearance of the six variants CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 was 26.41–71.04% of the wild-type ( CYP3A5*1) value. In contrast, the clearance value of the variant CYP3A5*6 was significantly higher (174.74%). Additionally, the decreased ATP levels and cell viability and the increased cell apoptosis in HepG2 cells transfected with CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 were observed, whereas, the increased ATP levels and cell viability and the reduced cell apoptosis in HepG2 cells transfected with CYP3A5*6 were also investigated when compared to CYP3A5*1. Conclusion: Our results suggest that CYP3A5 polymorphism influences sorafenib metabolism and pharmacotherapeutic effect in hepatic carcinomas . These data may help explain differential response to drug therapy for hepatocellular carcinoma, and they support the need for individualized treatment.
Fang-Chuan Chen, Cong-Ming Huang, Xiao-Wan Yu, Ya-Yu Chen
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271221080237

Abstract:
Background: Periodontal dressing is used to cover the gum surface and protect the wound after periodontal surgery. Nanomaterials have been widely applied in dentistry in recent years. Zinc oxide (ZnO) is one of the main components of periodontal dressing. Aim: This study aims to explore the toxicity ZnO nanoparticles (ZnO NPs) causes to human gingival fibroblast cells (HGF-1) and its effect on cell proliferation. Methods: First, we identified and analyzed HGF-1, including cell morphology, growth curve, and immunohistochemistry staining. Then, we treated HGF-1 with ZnO NP. Cell viability, the integrity of the cell membrane, oxidative damage, and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release assay, fluorescent probe, and flow cytometry. Furthermore, the expression of murine double minute 2 (MDM2) and p53 was determined by quantitative real-time polymerase chain reaction (qPCR) and Western blotting. We finally overexpressed MDM2 in HGF-1 to verify the relationship between MDM2 and cell proliferation. Results: Our research indicated ZnO NPs did not affect cell proliferation at low concentrations. However, high-concentration ZnO NP inhibited cell proliferation, destroyed the integrity of cell membranes, and induced oxidative stress and apoptosis. In addition, high concentration of ZnO NPs inhibited the proliferation of HGF-1 by regulating the expression of MDM2 and p53. Conclusion: High concentration of ZnO NP caused toxicity to HGF-1 cells and inhibited cell proliferation by regulating MDM2 and p53 expression.
Wenqi Chen, Shanshan Chen, Lifang Zhao, Mei Zhang, Hong Geng, Chuan Dong,
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271211061505

Abstract:
Background: The toxicological effects of fine particulate matter (PM2.5) on the cardiopulmonary and nervous systems have been studied widely, whereas the study of PM2.5 on systemic toxicity is not in-depth enough. Lipopolysaccharide (LPS) can cause multiple organ damage. The combined effects of co-exposure of PM2.5 plus LPS on the stomach, spleen, intestine, and kidney are still unclear. Purpose: This study was aimed to explore the toxicological effects of co-exposure of PM2.5 and LPS on the different organs of mice. Research Design and Study Sample Using a real-ambient PM2.5 exposure system and an intraperitoneal LPS injection mouse model, we investigated multiple organ damage effects on male BALB/c mice after co-exposure of PM2.5 plus LPS for 23 weeks in Linfen, a city with a high PM2.5 concentration in China. Data Collection: Eosin-hematoxylin staining, ELISA and the biochemical assay analysed the toxicological effects. Results: The pathological tissue injury on the four organs above appeared in mice co-exposed to PM2.5 plus LPS, accompanied by the body weight and stomach organ coefficient abnormality, and significant elevation of pro-inflammatory cytokines levels, oxidative stress in the spleen and kidney, and levels of kidney injury molecule (KIM-1) increase in the kidney. There were tissue differences in the pathological damage and toxicological effects on mice after co-exposure, in which the spleen and kidney were more sensitive to pollutants. In the PM2.5 + LPS group, the superoxide dismutase inhibition and catalase (CAT) activity promotion in the kidney or spleen of mice were significant relative to the PM2.5 group; the CAT and interleukin-6 (IL-6) levels in the spleen were raised considerably compared with the LPS group. Conclusions: These findings suggested the severity and sensitivity of multiple organ injuries in mice in response to PM2.5 plus LPS.
Pragati Singh, Sharmeen Ishteyaque, Ramanand Prajapati, Karan Singh Yadav, Rupali Singh, Akhilesh Kumar, Sharad Sharma, Tadigoppula Narender,
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271211061873

Abstract:
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and insulin resistance. 4-hydroxyisoleucine (4-HIL) is a non-proteinogenic amino acid isolated from the fenugreek seeds and has enormous pharmacological activities. The present study was undertaken to investigate the antihyperglycemic effect of 4-HIL in streptozotocin (STZ)-induced diabetic rats. Moreover, its toxicity was evaluated in vitro and in vivo employing human embryonic kidney cells (HEK-293) and healthy rats, respectively. In experiment 1, STZ-induced diabetic male rats were subjected to an oral treatment of 4-HIL (100 mg/kg), while experiment 2 deals with the effects of 4-HIL on healthy male and female rats following oral administration. The treatment (experiment 1) declined the elevated blood glucose level, feed intake, and increased body weight(s). Additionally, blood glucose impairment was improved as observed by OGTT and IPGT tests. Pancreatic histopathology revealed mild changes in the 4-HIL group. Moreover, experiment 2 showed increased body weight, normal blood glucose levels (male—106.06 ± 7.49 mg/dl and female—100.06 ± 14.69 mg/dL), hematological parameters, and histopathological profiles in the treatment group. 4-HIL did not affect the viability of HEK-293 cells, and no signs of toxicity were observed in healthy rats. Therefore, the study concludes that 4-HIL has potential antihyperglycemic activity without any toxic effects.
Diana M Paredes-Céspedes, Yael Yvette Bernal-Hernández, , Aurora Elizabeth Rojas-García, Irma Martha Medina-Díaz, Cyndia A González-Arias,
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271211063161

Abstract:
The INK4 -ARF locus includes the CDKN2B and CDKN2A genes and is functionally relevant in the regulation of both cell proliferation and senescence. Studies have reported modifications of DNA methylation in this locus by exposure to environmental contaminants including pesticides; however, until now, specific methylation profiles have not been reported in genetically conserved populations exposed to occupational pesticides. The aim of this study was to determine the methylation profiles of the CDKN2B and CDKN2A genes in a genetically conserved population exposed to pesticides. A cross-sectional and analytical study was carried out in 190 Huichol indigenous persons. Information related to pesticide exposure, diet and other variables were obtained through the use of a structured questionnaire. Blood and urine samples were collected for methylation test and dialkylphosphates (DAP) determination, respectively. DNA methylation was measured by the pyrosequencing of bisulfite-treated DNA and DAP concentrations by gas chromatography-tandem mass spectrometry (GC/MS). The most frequent metabolite in the population was dimethylthiophosphate. The farmer group presented a higher methylation percentage of CDKN2B than the non-farmer group, but no differences in CDKN2A were observed between groups. A positive correlation between methylation of CpG site 3 of CDKN2B and time working in the field was observed in the farmer group. An association between methylation percentage of CDKN2B and age was also observed in the non-farmer group. These results suggest that pesticide exposure and exposure time in Huichol indigenous individuals could modify the methylation pattern of the CDKN2B gene.
Shaochun Wang, Chengcheng Zhang, Ruilin Chen
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271211062854

Abstract:
Background: Lung cancer is the most common malignancy, and its mortality ranks first among malignancies. Non-small cell lung carcinoma (NSCLC) is the most common pathological subtype of lung cancer. It is reported that circular RNAs (circRNAs) feature prominently in the occurrence and metastasis of NSCLC. Purpose: This study aims to decipher the biological functions of circ_0006220 in NSCLC and the underlying mechanism. Methods: The microarray data (GSE101586) were downloaded from the Gene Expression Omnibus database, and differentially expressed circRNAs in NSCLC tissues were screened using the GEO2R tool. Quantitative real-time polymerase chain reaction was used for detecting the expression of circ_0006220, miR-203-3p, and regulator of G-protein signaling 17 (RGS17) mRNA in NSCLC tissues and cells. The connection between circ_0006220 expression and clinicopathological indicators was analyzed through the chi-square test. EdU and cell counting kit-8 assays were carried out to detect cell growth. Cell migration and invasion were detected by transwell assays. Bioinformatics was used to predict, and RNA immunoprecipitation assay and dual-luciferase reporter gene assay were conducted for verifying, the targeted relationship among circ_0006220, miR-203-3p, and RGS17. Results: The expression of circ_0006220 was elevated in NSCLC cells and tissues, and high circ_0006220 expression was significantly associated with unfavorable clinicopathological indicators. In addition, it was revealed that circ_0006220 overexpression facilitated NSCLC cell growth, migration, and invasion, whereas knocking down circ_0006220 had contrary effects. Furthermore, miR-203-3p was identified as a downstream target of circ_0006220, and circ_0006220 could sponge miR-203-3p; RGS17 was identified as a downstream target of miR-203-3p and was positively modulated by circ_0006220. Conclusions: Circ_0006220 up-regulates RGS17 expression by adsorbing miR-203-3p to promote NSCLC development.
, Magdalena Łukasik-Głębocka, Barbara Zielińska-Psuja
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271211061502

Abstract:
Ethylene glycol (EG), in addition to its neurotoxic and nephrotoxic effects, evokes oxidative stress. The aim of this study was to assess the influence of the ethylene glycol on the biochemical indicators and oxidoreductive balance of patients treated for acute poisoning. The total study group consisted of 56 persons including 26 alcoholics who took EG as a substitute for ethyl alcohol in the course of alcohol dependence syndrome and 30 controls. Severity of poisoning, results of acid-base parameters, biochemical, and toxicological tests as well as biomarkers of the oxidative stress in blood were analyzed during the patients’ hospitalization. The key issue was to assess the oxidative stress and biochemical disturbances caused by EG and the type of treatment applied in the course of poisoning. Significant changes in some parameters were found both at time of diagnosis and after treatment initiation (ethanol as an antidote and hemodialysis). The most important differences included the activity of hepatic parameters (aspartate aminotransferase, AST) and oxidative stress markers like catalase (CAT); correlation of the lipid peroxidation products level (TBARS) with urea concentration has been shown. On the last day of the hospitalization, in some cases, the mutual correlation between the evaluated markers were observed, for example, between alanine transaminase (ALT) and glutathione reductase (GR), and urea concentration and glutathione level (GSH/GSSG). The concentration of ions (H+) had a major impact on the oxidoreductive balance, correlating with the elevated GR and GSH/GSSG levels.
Yu-Juan Li, Kun Yang, Xue-Ming Long, Gang Xiao, Si-Juan Huang, Zi-Yue Zeng, Zhao-Ying Liu,
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271211062857

Abstract:
Background: Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth ( G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. Objective: This study aimed to analyse the toxicity characteristics of gelsenicine. Methods: Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. Results: In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood–brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. Conclusions: Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine -related poisoning and its toxicity mechanisms.
Zongyang Wu, Jinbo Wang, Jiye Feng, Liping Ying
Human & Experimental Toxicology, Volume 41; https://doi.org/10.1177/09603271221084672

Abstract:
Liver fibrosis is a wound-healing response and the activation of the hepatic stellate cell (HSC) is the core of hepatic fibrosis. MicroRNAs (miRNAs) participate in the development of fibrosis. It is reported that histone deacetylases (HDAC2) tyrosine phosphorylation by cellular-Abelsongene (c-Abl) induces malignant growth of cells. Here, we investigated the effect of miR-122-5p on the proliferation and apoptosis of HSCs. Normal human HSC line LX-2 and LX-2 cells stimulated by transforming growth factor (TGF)-β1 for 24 h were cultured and assigned into the blank group and the TGF-β1 group. The miR-122-5p inhibitor and its negative control were transfected into LX-2 cells and miR-122-5p mimic and its negative control were transfected into LX-2 cells stimulated by TGF-β1. The result showed that miR-122-5p expression was decreased in TGF-β1-stimulated LX-2 cells. miR-122-5p overexpression reduced the mRNA and protein levels of collagen I and α-smooth muscle actin, inhibited cell proliferation, and accelerated cell apoptosis. miR-122-5p targeted c-Abl. Meanwhile, miR-122-5p overexpression inhibited HSC activation by suppressing the c-Abl/HDAC2 pathway. In summary, miR-122-5p overexpression exerted anti-fibrosis effect and inhibited HSC activation by suppressing the c-Abl/HDAC2 pathway.
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