{"title":"RNF216 inhibits ferroptosis in lung adenocarcinoma by promoting p53 ubiquitination.","authors":"Jiasheng Wu, Weiqiang Mo, Haiqin Wang, Jianping Jiang, Jing Zhao","doi":"10.1177/09603271251336793","DOIUrl":"https://doi.org/10.1177/09603271251336793","url":null,"abstract":"<p><p>PurposeLung adenocarcinoma (LUAD) is the most prevalent subtype of non-small cell lung cancer and a leading cause of cancer-related mortality worldwide. This study investigates the role of Ring Finger Protein 216 (RNF216) in LUAD progression.MethodsRNF216 expression was evaluated in LUAD tissues and cells. Functional assays evaluated cell viability, migration, invasion, and ferroptosis <i>in vitro</i>. Mechanistic investigations defined RNF216's role in regulating p53 ubiquitination and stability. <i>In vivo</i>, xenograft models evaluated tumor growth and ferroptosis.ResultsRNF216 was markedly overexpressed in LUAD tissues and cell lines. Functional studies demonstrated that silencing RNF216 suppressed LUAD cell proliferation, migration, and invasion while inducing ferroptosis, characterized by increased reactive oxygen species (ROS), lipid peroxidation (LPO), and intracellular Fe<sup>2+</sup> accumulation. Mechanistically, RNF216 knockdown stabilized p53 by reducing its ubiquitination, thereby promoting ferroptosis. These findings were corroborated <i>in vivo</i>, where RNF216 silencing significantly inhibited tumor growth and enhanced ferroptosis in xenograft models.ConclusionsOur results establish RNF216 as a pivotal oncogenic driver that accelerates LUAD progression by suppressing ferroptosis through p53 ubiquitination. Targeting RNF216 may represent a promising therapeutic strategy to induce ferroptosis and combat LUAD.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251336793"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuroinflammatory chemokine networks in transgenic models of Alzheimer's disease: A comparative multi-compartmental analysis.","authors":"Yangyan Sun, Xinhua Xie, Xiaoqin Zou, Futao Zhou","doi":"10.1177/09603271251348723","DOIUrl":"https://doi.org/10.1177/09603271251348723","url":null,"abstract":"<p><p>BackgroundAlzheimer's disease (AD) progression is critically modulated by neuroinflammatory cascades involving chemokine-mediated glial activation.ObjectiveThis study aimed to systematically compare compartment-specific chemokine signatures between two distinct AD mouse models (2×Tg-AD [APPswe/PS1dE9] and 3×Tg-AD [APPswe/PS1M146V/TauP301L]), hypothesizing that differential chemokine expression patterns would emerge in a model- and brain region-specific manner, correlating with glial activation profiles.ResultsUsing a Luminex liquid suspension chip assay, we quantified 22 chemokines in serum and brain tissues from transgenic and non-transgenic controls, complemented by Western blot analysis of microglial and astrocytic markers. Twenty-two chemokines were quantitatively analyzed with three key findings: First, serum analysis revealed elevated levels of (i) CCL11, CCL17, CCL24, CCL27, and CXCL12 in 3×Tg-AD versus non-Tg mice; (ii) CCL22 in 2×Tg-AD versus non-Tg mice; and (iii) CCL5, CCL11, CCL17, CCL24, CCL27, and CXCL12 in 3×Tg-AD versus 2×Tg-AD mice. Second, hippocampal changes showed upregulation of CCL3/CCL12 in 2×Tg-AD and CXCL16 in 3×Tg-AD mice, with cortical alterations demonstrating distinct CCL3/CCL12/CCL4 increases in 2×Tg-AD versus elevated CCL1/CXCL13 in 3×Tg-AD mice. Third, Western blot confirmed enhanced hippocampal microglial activation specifically in 3×Tg-AD mice. ConclusionOur findings establish model-specific chemokine signatures that differentially engage neuroinflammatory pathways, suggesting that 3×Tg-AD mice may better replicate human AD's complex chemokine-glia interactions. This compartmentalized profiling provides a framework for targeting chemokine networks in model-specific therapeutic development and biomarker discovery. Further studies are needed to determine whether elevated chemokine expression directly contributes to microglial activation.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251348723"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peng Bai, Caixia Li, Luwei Yin, Yao Li, Meng Ju, Laicang Wang
{"title":"Rhynchophylline promotes microglia phenotypic transformation and repair of cerebral ischaemic injury through the JAK2/STAT3 pathway.","authors":"Peng Bai, Caixia Li, Luwei Yin, Yao Li, Meng Ju, Laicang Wang","doi":"10.1177/09603271251324582","DOIUrl":"10.1177/09603271251324582","url":null,"abstract":"<p><strong>Background: </strong>Rhynchophylline (RIN) is an alkaloid known for its ability to effectively block signal transduction related to various neurodegenerative diseases. However, the specific mechanism by which RIN regulates microglial activation and cerebral ischemia remains unexplored. This study aims to investigate the function and molecular pathways through which RIN activates the JAK2/STAT3 signaling cascade, promoting the transformation of microglial phenotypes that contribute to recovery from cerebral ischemic injury.</p><p><strong>Methods: </strong>By establishing a microglia oxygen glucose deprivation/reoxygenation (OGD/R) model and a middle cerebral artery occlusion animal model, we assessed changes in the expression of phenotype-specific marker factors for M1 and M2 microglia, as well as key proteins in the JAK2/STAT3 pathway, utilizing ELISA and Western blot techniques. Histological examination, including HE staining, TUNEL assay, and immunofluorescence, was employed to evaluate pathological changes in brain tissue, along with cell apoptosis and proliferation.</p><p><strong>Results: </strong>The results indicated that microglial activity was significantly reduced and shifted towards the M1 phenotype following OGD/R. However, RIN treatment reversed these changes. When JAK2/STAT3 inhibitors were combined with RIN, it inhibited RIN's protective effect. Animal studies have shown that RIN reduces histopathological changes associated with cerebral ischemia. Additionally, RIN inhibited microglial proliferation in ischemic cortical tissue and increased the expression of M2-type marker proteins, as well as the levels of phosphorylated JAK2 and STAT3 in the ischemic tissue.</p><p><strong>Conclusion: </strong>In conclusion, this study indicates that RIN may protect against cerebral ischemic injury by activating the JAK2/STAT3 pathway, which promotes the transition of microglia to the M2 phenotypic.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251324582"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KLF9 mediates NLRP3 inflammasome and reactive oxygen species to mediate pyroptosis in trophoblasts.","authors":"Qian Li, Min Chen","doi":"10.1177/09603271251324702","DOIUrl":"10.1177/09603271251324702","url":null,"abstract":"<p><p>IntroductionThe objective of this study was to explore the effect of KLF9 on oxidative stress (OS) and NLRP3-mediated inflammation in preeclampsia (PE).MethodsLipopolysaccharide (LPS)+adenosine triphosphate (ATP)-induced HTR-8/SVneo cells were used as an <i>in vitro</i> PE inflammation cell model. shRNA was used to interfere with KLF9 expression (sh-KLF9) to assess the transfection efficiency and the effect of KLF9 on cell proliferation, migration, and invasion. ELISA was performed to detect OS-related factors and inflammatory cytokines. Reactive oxygen species (ROS) levels and pyroptosis were analyzed using DCFH-DA and TUNEL staining. LPS and ATP induced HTR-8/SVneo cells were co-transfected with sh-PRDX6/sh-KLF9 to explore the potential regulatory effect of KLF9 on PRDX6.ResultsLPS+ATP stimulation increased KLF9 expression in the PE cell model. Specifically, reducing KLF9 levels alleviated morphological damage and enhanced proliferation, migration, and invasion in the <i>in vitro</i> PE cell models. Moreover, inhibiting KLF9 expression decreased protein expression of NLRP3, GSDMD-N, cleaved caspase-1, and cleaved-IL-1β, suppressing cell death in LPS+ATP-induced HTR-8/SVneo cells. Analysis of OS indicators revealed that downregulating KLF9 expression restrained intracellular ROS production, decreased MDA expression, and increased SOD and CAT levels. KLF9 regulated the transcription of PRDX6 to attenuate OS and pyroptosis. Knockdown of PRDX6 partially abolished the effect of KLF9 downregulation on OS and pyroptosis of LPS+ATP-induced HTR-8/SVneo cells, as evidenced by the inhibition of cell proliferation, migration, and invasion, as well as the enhanced activity of the NLRP3 inflammasome.ConclusionDownregulation of KLF9 enhances trophoblast cell invasion and reduces OS and NLRP3 inflammasome activation-mediated pyroptosis.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251324702"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Acute exposure and histopathological effects of drilling fluid in rats.","authors":"Arstan Mamyrbayev, Kuanysh Baitenov, Zhanat Komekbay, Abdiraman Kaliev, Saule Bermagambetova, Svetlana Sakhanova, Kulyan Shayakhmetova, Gulsim Karashova","doi":"10.1177/09603271251377601","DOIUrl":"https://doi.org/10.1177/09603271251377601","url":null,"abstract":"<p><p>IntroductionThis study aimed to assess the acute toxic properties of drilling fluid (DF), a multicomponent substance extensively utilized in oil extraction, through a single intragastric administration in mature male rats, to better understand its potential health risks.MethodsAcute toxicity was evaluated in mature male rats via a single intragastric administration of DF at doses of 300, 600, 1200, 2400, and 4800 mg/kg. Mortality, body weight changes, and relative organ weights were monitored throughout the study. Biochemical enzyme activities, including ALT, AST, ALP, and LDH, were assessed. Behavioral responses were recorded, and histological examinations of the liver, kidneys, and heart were conducted to evaluate tissue-level effects.ResultsAdministration of DF caused significant toxic effects including mortality (2 deaths at 2400 mg/kg; 3 deaths at 4800 mg/kg), changes in body weight, and relative weights of liver (control: 7.12 ± 0.53; 2400 mg/kg: 7.89 ± 0.51; 4800 mg/kg: 9.68 ± 0.67; <i>p</i> < 0.001) and heart (control: 1.24 ± 0.17; 2400 mg/kg: 0.97 ± 0.21; 4800 mg/kg: 0.84 ± 0.08; <i>p</i> < 0.001). Activities of cytolytic enzymes ALT (control: 78.65 ± 4.28; 4800 mg/kg: 89.47 ± 2.62; <i>p</i> < 0.001) and AST (control: 226.18 ± 31.66; 4800 mg/kg: 322.73 ± 8.02; <i>p</i> < 0.001), as well as ALP and LDH, were significantly altered. Behavioral activity was markedly reduced. Histological changes were observed in the liver, kidneys, and heart tissues.DiscussionThese findings demonstrate that DF exhibits marked acute toxicity and causes significant physiological and histopathological damage in mammals, indicating a potential hazard.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251377601"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The safety assessment of N-<i>trans</i>-feruloyltyramine using <i>In vitro</i> genotoxicity studies and 90-day toxicity study in rats.","authors":"Sungwon Lee, Srinivas Seekallu, Suresh Babu Venkataramaiah, Chandrashekar Mataguru Doreswamy, Mohan Cheluru Umesh, Sandeep Malleshappa, Sajeev Justin Dev, Ganadhal Puttaramaiah Chethankumara, Nagaraju Lohith, Gajanan Rajpal Deshmukh, Brian Premkumar, Brinda Mahadevan","doi":"10.1177/09603271251334452","DOIUrl":"https://doi.org/10.1177/09603271251334452","url":null,"abstract":"<p><p>IntroductionN-<i>trans</i>-feruloyltyramine (NFT) is a bioactive compound present in many plant sources. The purpose of the studies was to investigate adverse effects, if any, of NFT produced through precision fermentation.MethodsAn <i>in vitro</i> Ames test was performed with NFT using bacterial strains at concentrations up to 1580 µg/plate with and without S9. The <i>in vitro</i> micronucleus assay was performed in human peripheral blood cells in culture, with and without, metabolic activation at three different doses. In the subchronic toxicity study, adult Sprague Dawley rats (10/sex/group) were fed diets prepared with target doses of 0, 5000, 10,000 or 20,000 ppm of NFT for 90 days.ResultsIn the Ames assay, there were no NFT-related or concentration dependent increases in revertant colony numbers in any of the tester strains. In the <i>in vitro</i> micronucleus assay, there was no statistically significant increase in the number of binucleated cells with micronuclei compared to the vehicle control. NFT was found to be non-genotoxic when evaluated in the <i>in vitro</i> Ames and micronucleus assays. In the 90-day rodent study, NFT was well tolerated, with no related adverse findings observed at any of the dose levels tested. There were no NFT related adverse histopathological changes observed in the high dose group of both the sexes.ConclusionThe No observed adverse effect level of NFT was determined as 1474 mg/kg body weight/day in males and 1958 mg/kg body weight/day in females based on the actual intake at the dose levels tested and under the experimental conditions employed.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251334452"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Establishment and validation of an <i>in vitro</i> liver model based extracellular matrix for hepatotoxicity prediction.","authors":"Yue Yu, Haodong Zhong, Qianyi Niu, Manman Zhao, Bo Li, Xiaobing Zhou","doi":"10.1177/09603271251350797","DOIUrl":"https://doi.org/10.1177/09603271251350797","url":null,"abstract":"<p><p>IntroductionThree-dimension (3D) cell culture presents a promising alternative of drug-induced liver injury (DILI). To advance preclinical toxicology research, we developed an <i>in vitro</i> liver model using HepG2 for toxic evaluation.MethodsThe model was constructed based on the extracellular matrix. We assessed its long-term stability by monitoring the morphological change and anabolic capacity for 2 weeks, with functional analyses including albumin/urea production, lipid accumulation with Nile red staining, bile secretion with CLF signal, and transporter/enzyme expression including PGP, MRP2, BSEP, and CYP3A4.ResultsThe model could be maintained for at least 10 days with enhanced hepatic synthetic functions indicated by albumin and urea nitrogen. Compared with the two-dimensional (2D) cultures, 3D culture exhibited enhanced lipid accumulation and biliary excretion. Key hepatic transporters PGP, MRP2, and BSEP and the metabolic enzyme cytochrome P450 3A4 were expressed between day 5 and 7. Single-exposure induced measurable apoptosis, mitochondrial disfunction and viability assays, while repeated treatment replicated impaired bile acid transport by reduced CLF intensity, and cytotoxicity with elevated AST, ALT, and decreased survival.DiscussionOur 3D model surpasses conventional 2D systems in culture duration and functional complexity. It is suitable for DILI prediction after single- and repeated- treatment, which makes it particularly valuable for preclinical drug screening.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251350797"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Human health risk assessment of heavy metals in different compartments of vegetables from Erbil City-Iraq.","authors":"Bashdar Abuzed Sadee","doi":"10.1177/09603271251351421","DOIUrl":"https://doi.org/10.1177/09603271251351421","url":null,"abstract":"<p><p>IntroductionThe consumption of vegetables is a key route for increasing the content of potentially toxic heavy metals in the food chain. This article aimed to quantify the concentrations of As, Se, Cd, Cr, Co, Cu, Ni, and Pb in different parts of vegetables harvested from Erbil city.MethodologyThe total concentrations of As, Cd, Cr, Co, Cu, Ni, and Pb in various vegetable parts were pursued by ICP-MS analysis.ResultsThe values of heavy metals in different parts of the analyzed vegetables ranged from 0.052 to 2.106 mg/kg for As, 0.024 to 5.899 mg/kg for Se, 0.014 to 0.753 mg/kg for Cd, 0.441 to 89.400 mg/kg for Cr, 0.052 to 2.693 mg/kg for Co, 0.737 to 39.120 mg/kg for Cu, 0.301 to 63.880 mg/kg for Ni, and 0.032 to 1.782 mg/kg for Pb. The Hazard Quotient (HQ) values for As, Cr, Cu, and Ni in the edible parts of most vegetables exceeded one, while those for Se, Co, Cd, and Pb were below one.DiscussionIn contrast to Se, Co, Cd, and Pb, the HQ values for As, Cr, and Pb indicate a potential health risk when consuming these edible parts of the vegetables. The Hazard Index (HI) for all edible parts of the analyzed vegetable samples exceeded one. The cancer risk (CR) of As, Cd, Cr and Ni were higher than 1.0 × 10<sup>-4</sup> which indicating carcinogenic risk. As a result, regular consumption of these vegetables is regarded as unsafe and not advisable.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251351421"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical characteristics and the risk factors analysis in patients with delayed encephalopathy after acute carbon monoxide poisoning.","authors":"Ziang Han, Sumeng Shi, Yan Zhang, Ding Yuan, Zhigao Xu, Yanxia Gao","doi":"10.1177/09603271251332234","DOIUrl":"10.1177/09603271251332234","url":null,"abstract":"<p><p>IntroductionAcute carbon monoxide poisoning (ACMP) remains a leading cause of morbidity and mortality from fatal inhaled poisoning. Delayed encephalopathy after ACMP (DEACMP) has become one of the most complex and serious complications.MethodsIn this research, an observational study was performed from January 2016 to December 2019 to investigate the potential relevant risk factors of DEACMP with data collected from Level 3 medical facilities located in Northern China. Within the 4-year data collection period, the final study cohort consisted of 240 (117 males, 123 females).ResultsUni-variable analysis identified older age, medical history of cerebrovascular accident, basic disease of diabetes, and longer duration of loss of consciousness as relevant factors for DEACMP; while multivariable logistic regression revealed that the older age (OR, 1.45; 95% CI, 1.25-1.69; <i>P</i> < 0.01), longer duration of loss of consciousness (OR, 1.39; 95% CI, 1.36-1.45; <i>P</i> < 0.01), and cerebrovascular accidents occurring (OR, 1.23; 95% CI, 1.03-1.47; <i>P</i> = 0.04) were independent predictors for DEACMP.DiscussionFurthermore, additional research is needed to testify to the relevance and to elucidate the potential pathogenesis, consequently determining the clinical guideline and approving the best prevention and treatment strategy for DEACMP.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"44 ","pages":"9603271251332234"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}