Toxicology Research最新文献

{"title":"MitoQ alleviates carbon tetrachloride-induced liver fibrosis in mice through regulating JNK/YAP pathway.","authors":"Shulin Shan,&nbsp;Zhaoxiong Liu,&nbsp;Zhidan Liu,&nbsp;Cuiqin Zhang,&nbsp;Fuyong Song","doi":"10.1093/toxres/tfac062","DOIUrl":"https://doi.org/10.1093/toxres/tfac062","url":null,"abstract":"<p><strong>Background: </strong>Liver fibrosis is a pathological wound-healing response caused by chronic liver damage. Mitochondria regulate hepatic energy metabolism and oxidative stress. Accumulating evidence has revealed that increased mitochondrial oxidative stress contributes to the activation of fibrogenesis. However, the roles and underlying mechanisms of mitochondrial oxidative stress in liver fibrosis remain unknown.</p><p><strong>Methods and results: </strong>In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl₄ treatment for 8 weeks. Furthermore, intervention experiments were achieved by CCl₄ combined with the intraperitoneal injection of mitoquinone mesylate (mitoQ). We demonstrated that the chronic CCl₄ exposure resulted in severe hepatic fibrogenesis and significantly promoted the production of reactive oxygen species (ROS) and mitochondrial abnormalities. Besides, JNK/YAP pathway was also activated. By contrast, the administration of mitoQ markedly inhibited the expression of pro-fibrogenic transforming growth factor-β as well as type I collagen. The antifibrotic effects of mitoQ were also confirmed by hematoxylin and eosin staining and Sirius red staining. Moreover, mitoQ substantially reduced CCl₄-induced mitochondrial damage and the release of ROS. Further studies suggested that this protection against liver fibrosis was mechanistically related to the inhibition of phosphorylation of JNK and the nuclear translocation of YAP.</p><p><strong>Conclusion: </strong>In conclusion, these findings revealed that mitoQ attenuated liver fibrosis by inhibiting ROS production and the JNK/YAP signaling pathway. Selective targeting JNK/YAP may serve as a therapeutic strategy for retarding progression of chronic liver disease.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"852-862"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618106/pdf/tfac062.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10185158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silica exposure activates non-canonical inflammasome complex in intratracheal instilled rat model.","authors":"Yingmei Niu,&nbsp;Shuangli Yang,&nbsp;Xiumei Hu","doi":"10.1093/toxres/tfac061","DOIUrl":"https://doi.org/10.1093/toxres/tfac061","url":null,"abstract":"<p><strong>Background: </strong>Inhalation of silica crystals in occupational settings is a main cause of silicosis, a chronic irreversible pulmonary disorder. Our prior studies demonstrated the activation of inflammasome sensors AIM2 and NLRP3, effector protein caspase-1, and significant increase in IL-1β in silica exposed rats, suggesting that the canonical inflammasome activation may be associated with silica-induced tissue damage and inflammation.</p><p><strong>Aims and methods: </strong>In our current study using the same animal model system, we further evaluated the components of non-canonical inflammasome, including NEK7, caspase-11, and GSDMD following silica exposure.</p><p><strong>Results: </strong>We demonstrated sustained NEK7 elevation in the rat lung epithelial cells and macrophages following 1- and 3-day exposure. Enhanced NEK7 expression was also detected in lung homogenate by western blot. Similarly, caspase-11 expression was induced by silica exposure in lung sections and homogenate. Elevated GSDMD was observed both in lung sections by immunohistochemical staining and in lung tissue homogenate by western blot.</p><p><strong>Conclusion: </strong>In summary, our current study demonstrated increase in NEK7, caspase-11, and GSDMD in silica exposed rats, indicating activation of non-canonical inflammasome complex, thereby providing a broad inflammasome activation pathway caused by silica exposure.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"784-790"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618110/pdf/tfac061.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10074493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of quercetin against phthalates induced hepatotoxicity in rats.","authors":"Ling-Zi Xia,&nbsp;Ming-Zhe Jiang,&nbsp;Li-Lan Liu,&nbsp;Yi Wu,&nbsp;Yi-Lin Zhang,&nbsp;Li-Xia Yang,&nbsp;Xin-Yue Shen,&nbsp;Qiu-Yu Zhang,&nbsp;Min Lin,&nbsp;Hai-Tao Gao","doi":"10.1093/toxres/tfac060","DOIUrl":"https://doi.org/10.1093/toxres/tfac060","url":null,"abstract":"<p><p>Humans are increasingly exposed to ubiquitous phthalates (PEs), e.g. butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), and di(2-ethylhexyl) phthalate (DEHP), which are widely used plasticizers in polymer products. This study was aimed to investigate the effect of phytochemical quercetin (Que) on hepatotoxicity caused by the mixture of the 3 commonly used PEs (MPEs), and further to explore the underlying mechanism. Forty male Sprague-Dawley rats were randomly divided into control group, MPEs group, and MPEs combined Que at Low-, Median-, and High-dose groups; rats in MPEs group were orally administered with 900 mg/kg/d MPEs, whereas rats in MPEs combined Que groups were simultaneously treated with 900 mg/kg/d MPEs and respectively 10, 30, and 90 mg/kg/d Que. The intervention last 30 days. Compared with control group, serum ALT, AST, LDH and AKP, and hepatic MDA, SOD, CAT and GPx were significantly increased, whereas, serum albumin and total protein were significantly decreased in MPEs group (<i>P</i> < 0.05); hepatic histopathological observation showed numerous inflammatory cells infiltration, hepatocyte ballooning degeneration, and numerous residual erythrocytes in the central vein in MPEs group. Western-blot analysis showed that hepatic Keap1 was downregulated, whereas Nrf2 and HO-1 were upregulated in MPEs group (<i>P</i> < 0.05). However, the alterations of these parameters were alleviated in MPEs combined Que at Median- and High-dose groups. The results indicated that MPEs-induced hepatic oxidative stress, and caused hepatic injuries; whereas, Que inhibited MPEs' hepatotoxicity, which might relate to Que's ability of quenching free radicals directly, and restored the regulation of Nrf2 signaling pathway.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"863-871"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618111/pdf/tfac060.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10266067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A bioactive component of <i>Portulaca Oleracea</i> L., HM-chromanone, improves palmitate-induced insulin resistance by inhibiting mTOR/S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells.","authors":"Jae Eun Park,&nbsp;Ji Sook Han","doi":"10.1093/toxres/tfac055","DOIUrl":"https://doi.org/10.1093/toxres/tfac055","url":null,"abstract":"<p><p>Increased free fatty acid levels in the blood are common in obesity and cause insulin resistance associated with type 2 diabetes in the muscles. Previous studies have confirmed the antidiabetic and anti-obesity potential of (<i>E</i>)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone). However, it is unknown how HM-chromanone alleviates obesity-related insulin resistance in L6 skeletal muscle cells. Palmitate induced insulin resistance and reduced glucose uptake, whereas HM-chromanone significantly increased glucose uptake. In palmitate-treated L6 skeletal muscle cells, HM-chromanone stimulated liver kinase B1 (LKB1) and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. The AMPK inhibitor compound C, and the LKB1 inhibitor radicicol blocked the effects of HM-chromanone. Furthermore, HM-chromanone significantly inhibited mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase 1 (S6K1) activation, but there was no change in protein kinase C θ (PKC θ) expression. When pAMPK was inhibited with compound C, the effect of HM-chromanone on the inhibition of mTOR and S6K1 was significantly diminished. This indicates that HM-chromanone inhibits mTOR and S6K1 activation through pAMPK activation. Inhibition of mTOR and S6K1 by HM-chromanone significantly reduced IRS-1_Ser307 and IRS-1_Ser632 phosphorylation, leading to insulin resistance. This resulted in an increase in PM-GLUT4 (glucose transporter 4) expression, thereby stimulating glucose uptake in insulin-resistant muscle cells. HM-chromanone can improve palmitate-induced insulin resistance by inhibiting mTOR and S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells. These results show the therapeutic potential of HM-chromanone for improving insulin resistance in type 2 diabetes.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"774-783"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618117/pdf/tfac055.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10429049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Morinda umbellata</i> active fraction inhibits lipopolysaccharide induced proinflammatory cytokines by downregulating <i>NF-κB</i> activation.","authors":"Neenthamadathil Mohandas Krishnakumar,&nbsp;Kuttapetty Manikantan,&nbsp;Somasekharan Nair Rajam Suja,&nbsp;Panickamparambil Gopalakrishnan Latha,&nbsp;Stanislaus Antony Ceasar","doi":"10.1093/toxres/tfac063","DOIUrl":"https://doi.org/10.1093/toxres/tfac063","url":null,"abstract":"<p><p><i>Morinda umbellata</i> L. is a woody climber or liana distributed in south East Asia. It is a traditional medicinal plant with excellent curative effects against diarrhea, dysentery, and other stomach disorders. The present study was aimed to assess the effect of <i>M. umbellata</i> active fraction (MUAF) on various inflammatory mediators using lipopolysaccharide (LPS) induced <i>in vivo</i> model in Wistar rats. The effect of MUAF on secretion of TNF-α, IL-1β, and IL-6 were evaluated in LPS-induced experimental animals. The expression of <i>TNF-</i>α<i>, IL-1β, IL-6, iNOS, COX-2</i>, and <i>nuclear factor NF-κB</i> genes were also evaluated. The gas chromatography-mass spectrometry (GC-MS) analysis of the active fraction was carried out to identify the active compounds present in MUAF. The results of oral acute toxicity suggested the non-toxic nature of MUAF. GC-MS analysis of the MUAF leaves revealed the presence of 8 compounds. The study demonstrated that the proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 were significantly inhibited by MUAF in a dose-dependent manner. Moreover, MUAF down-regulated the expression of <i>TNF-</i>α<i>, IL-1β, IL-6, iNOS, COX-2</i>, and <i>NF-κB</i> genes. Our research findings suggest that the presence of anti-inflammatory compounds in MUAF can effectively inhibit LPS-induced proinflammatory cytokines TNF-α, IL-β, and IL-6 <i>in vivo</i>. It also suppressed the over expression of <i>TNF-</i>α, <i>IL-1β</i>, <i>IL-6</i>, <i>iNOS</i>, and <i>COX-2</i> possibly via downregulating <i>NF-κB</i> activation.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"841-851"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618104/pdf/tfac063.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10185162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ameliorative impact of herbal formulation -Majoon-Dabeed-ul-ward and Sharbat-e-Deenar against CCl₄ induced liver toxicity via regulation of antioxidant enzymes and oxidative stress.","authors":"Arvind Kumar Shakya,&nbsp;Neetu Sharma,&nbsp;Monika Bhadauria,&nbsp;Satendra Kumar Nirala,&nbsp;Sadhana Shrivastava,&nbsp;Sangeeta Shukla","doi":"10.1093/toxres/tfac052","DOIUrl":"https://doi.org/10.1093/toxres/tfac052","url":null,"abstract":"<p><p>Polyherbal Unani formulations have been used in the treatment of liver diseases for a long time. (Ibrahim M, Khaja MN, Aara A, Khan AA, Habeeb MA, Devi YP, Narasu ML, Habibullah CM. Hepatoprotective activity of <i>Sapindus mukorossi</i> and <i>Rheum emodi</i> extracts: <i>in vitro</i> and <i>in vivo</i> studies. <i>World J Gastroenterol</i>. 2008:<b>14</b>:2566-2571.) The aim of the present study was to investigate comparative hepatoprotective potential of Majoon-e-Dabeed-ul-ward (MD) and Sharbat-e-Deenar (SD) against CCl₄ induced subchronic hepatic toxicity. In vivo study, albino rats were divided into 5 groups. Group I was control; Group II was experimental control treated with CCl₄ (0.15 mL/kg, i.p. for 21 days); Groups III-IV treated with SD (2 mL/kg, p.o.) and MD (1,000 mg/kg, p.o.) for 5 days following CCl₄ intoxication as in group 2 respectively; and Group V was positive control treated with silymarin (50 mg/kg, p.o.). In vitro hepatoprotective activity of SD and MD (25, 50, and 100 μg/mL) was assessed by SRB assay and flow cytometry analysis. CCl₄ exposure significantly elevated the release of hepatic enzymes i.e. AST, ALT, LDH, and SALP in serum and lipid peroxidation in liver tissue which all these parameters were reversed after SD and MD administration. Therapy for 5 days also normalized the levels of antioxidant enzymes i.e. catalase, SOD, GPx, GR, tissue GSH, and aniline hydroxylase in CCl₄ treated group. DNA damage and histological alterations caused by CCl₄ were restored towards normal group. In vitro study showed protective effect of SD and MD against CCl₄ treated HepG2 cell lines and rat hepatocytes. The results suggested that MD has a significant hepatoprotective potential and regulatory effect on oxidative stress than SD against CCl₄ induced hepatotoxicity, and that this effect may be related to its antioxidant activity.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"819-830"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618100/pdf/tfac052.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10488308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of cilostazol and verapamil against thioacetamide-induced hepatotoxicity in rats may involve Nrf2/GSK-3β/NF-κB signaling pathway.","authors":"Alaa E Elsisi,&nbsp;Esraa H Elmarhoumy,&nbsp;Enass Y Osman","doi":"10.1093/toxres/tfac045","DOIUrl":"https://doi.org/10.1093/toxres/tfac045","url":null,"abstract":"<p><strong>Background: </strong>Verapamil (VER) and cilostazol (Cilo) are mostly used as cardiovascular drugs; they have beneficial effects on different organs toxicities.</p><p><strong>Aim: </strong>we investigated whether the Nuclear factor erythroid 2-related factor 2 (Nrf2), Glycogen synthase kinase-3β (GSK-3β), and Nuclear factor-kappa B (NF-κB) pathway involved in the protective role of these drugs against Thioacetamide (TAA) induced hepatotoxicity.</p><p><strong>Method: </strong>male rats were randomized divided into five groups, each group (<i>n</i> = 10): control, TAA, VER+TAA, Cilo+TAA, and VER+Cilo+TAA groups. Hepatotoxicity induced in rats by TAA injection once on the 7th day of the experiment.</p><p><strong>Results: </strong>TAA-induced hepatotoxicity indicated by a significant elevated in serum markers (Alanine aminotransferases (ALT), Aspartate aminotransferases (AST), and bilirubin), oxidative stress markers (Malondialdehyde (MDA), and Nitric oxide (NO)), and protein levels markers (NF-κB, and S100 calcium-binding protein A4 (S100A4)). Also, TAA decreased Nrf2, and increased GSK-3β genes expression. Histopathological alterations in the liver also appeared as a response to TAA injection. On the other hand VER and/or Cilo significantly prevented TAA-induced hepatotoxicity in rats through significantly decreased in ALT, AST, bilirubin, MDA, NO, NF-κB, and S100A4 protein levels. Also, they increased Nrf2 and decreased GSK-3β genes expression which caused improvement in the histopathological changes of the liver.</p><p><strong>Conclusion: </strong>the addition of verapamil to cilostazol potentiated the hepatoprotective activity, and inhibited the progression of hepatotoxicity caused by TAA through the Nrf2/GSK-3β/NF-κBpathway and their activity on oxidative stress, inflammation, and NF-κB protein expression.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"718-729"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618097/pdf/tfac045.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10333922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential protective effect of escin from <i>Aesculus hippocastanum</i> extract against cyclophosphamide-induced oxidative stress on rat tissues.","authors":"İsmail Küçükkurt,&nbsp;Erten Akbel,&nbsp;Sinan İnce,&nbsp;Damla Arslan Acaröz,&nbsp;Hasan Hüseyin Demirel,&nbsp;Fahriye Kan","doi":"10.1093/toxres/tfac059","DOIUrl":"https://doi.org/10.1093/toxres/tfac059","url":null,"abstract":"<p><p>Cyclophosphamide (CP)-also known as cytophosphan-is an alkylating agent that has many side effects in humans and rats. Rats were divided into 5 different groups to evaluate the protective effect of escin (ES) obtained from the horse-chestnut plant (<i>Aesculus hippocastanum</i>) against acute damage induce by CP. Groups: control group, ethanol group, ES group (100 mg/kg body weight (bw) ES for 14 days by gastric gavage), ES + CP group (100 mg/kg bw ES for 14 days by gastric gavage and 75 mg/kg bw CP i.p. on 14th day), and CP group (75 mg/kg bw CP i.p. on 14th day). After the experiment was completed, blood and tissue samples (liver, kidney, heart, brain, lung, and testis) were taken from the rats under anesthesia. When the CP group was compared with the control group, an increase was observed in the level of Malondialdehyde (MDA) in blood and all tissues except the lung, but when it was given together with escin, there was a decrease except kidney and lung (<i>P</i> < 0.05). Glutathione (GSH) level decreased in the blood and all tissues when CP was given, whereas an increase was observed in the heart, brain, and lung when given with escin (<i>P</i> < 0.05). There was no statistical change in the activities of superoxide dismutase and catalase enzymes in all tissues. ES reduced CP-induced damage in all tissues except the kidney. As a result, it was determined that ES had a protective effect against CP-induced tissue damage in rats due to its antioxidant properties.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 5","pages":"812-818"},"PeriodicalIF":2.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618105/pdf/tfac059.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10488313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screen identifies fasudil as a radioprotector on human fibroblasts.","authors":"Yanling Yao,&nbsp;Chen Chen,&nbsp;Zuchao Cai,&nbsp;Guochao Liu,&nbsp;Chenxia Ding,&nbsp;David Lim,&nbsp;Dong Chao,&nbsp;Zhihui Feng","doi":"10.1093/toxres/tfac042","DOIUrl":"https://doi.org/10.1093/toxres/tfac042","url":null,"abstract":"<p><strong>Background: </strong>Radioprotectors safeguard biological system exposed to ionizing radiation (IR) by protecting normal cells from radiation damage during radiotherapy. Due to the toxicity and limited clinical utility of the present radioprotectors, it prompts us to identify novel radioprotectors that could alleviate IR-induced cytotoxicity of normal tissues.</p><p><strong>Aims and methods: </strong>To identify new radioprotectors, we screened a chemical molecular library comprising 253 compounds in normal human fibroblasts (HFs) or 16HBE cells upon IR by CCK-8 assays and clonogenic survival assays. Fasudil was identified as a potential effective radioprotector.</p><p><strong>Results: </strong>The results indicated that Fasudil exerts radioprotective effects on HFs against IR-induced DNA double-strand breaks (DSBs) through the regulation of DSB repair. Fasudil increased homologous recombination (HR) repair by 45.24% and decreased non-homologous end-joining (NHEJ) by 63.88% compared with untreated cells, without affecting changes to cell cycle profile. We further found that fasudil significantly facilitated the expression and foci formation of HR core proteins such as Rad51 and BRCA1 upon IR, and decreased the expression of NHEJ-associated proteins such as DNA-PKcs at 24 h post-IR.</p><p><strong>Conclusion: </strong>Our study identified fasudil as a novel radioprotector that exert radioprotective effects on normal cells through regulation of DSB repair by promoting HR repair.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 4","pages":"662-672"},"PeriodicalIF":2.1,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9424713/pdf/tfac042.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9854652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIN1-mediated ROS production is involved in antagonism of N-acetyl-L-cysteine against arsenic-induced hepatotoxicity.","authors":"Huijie Zhang,&nbsp;Zhixin He,&nbsp;Ping Deng,&nbsp;Muxue Lu,&nbsp;Chao Zhou,&nbsp;Lingling Yang,&nbsp;Zhengping Yu","doi":"10.1093/toxres/tfac040","DOIUrl":"https://doi.org/10.1093/toxres/tfac040","url":null,"abstract":"<p><p>Arsenic, a widely existing environmental contaminant, is recognized to be toxic to multiple organs. Exposure to arsenic results in liver damage via excessive production of reactive oxidative species (ROS). PIN1 regulates the levels of ROS. N-acetyl-L-cysteine (NAC) is an ROS scavenger that protects the hepatic functions. Whether PIN1 plays a regulatory role in NAC-mediated antagonism against arsenic hepatotoxicity remains largely unknown. In our study, the protective effects of NAC against arsenic (NaAsO₂)-induced hepatotoxicity were evaluated in vitro and in vivo. Arsenic exposure induced cytotoxicity by increasing the intracellular ROS production, impairing mitochondrial function and inducing apoptosis in L02 hepatocytes. Overexpression of PIN1 markedly protected against arsenic cytotoxicity, decreased ROS levels, and mitigated mitochondrial dysfunction and apoptosis in L02 cells. However, loss of PIN1 further aggravated arsenic-induced cytotoxicity and abolished the protective effects of NAC in L02 cells. An in vivo study showed that pretreatment with NAC rescued arsenic-induced liver injury by restoring liver function and suppressing hepatic oxidative stress. Overexpression of PIN1 in mice transfected with AAV-<i>Pin1</i> relieved arsenic-induced liver dysfunction and hepatic oxidative stress. Taken together, our study identified PIN1 as a novel intervention target for antagonizing arsenic-induced hepatotoxicity, highlighting a new pharmacological mechanism of NAC targeting PIN1 in antagonism against arsenic toxicity.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":"11 4","pages":"628-643"},"PeriodicalIF":2.1,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9424717/pdf/tfac040.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9762292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}