Current Research in Toxicology最新文献

{"title":"PPARγ activation ameliorates PM2.5-induced renal tubular injury by inhibiting ferroptosis and epithelial–mesenchymal transition","authors":"Chien-Hung Lin ,&nbsp;Wen-Sheng Liu ,&nbsp;Chuan Wan ,&nbsp;Hsin-Hui Wang","doi":"10.1016/j.crtox.2024.100189","DOIUrl":"10.1016/j.crtox.2024.100189","url":null,"abstract":"<div><p>Exposure to fine particulate matter (PM2.5) has been associated with the development and progression of renal disease. Peroxisome proliferator-activated receptor gamma (PPARγ), a key transcription factor involved in inflammation as well as lipid and glucose metabolism, helps maintain the integrity of tubular epithelial cells. However, the precise role of PPARγ in PM2.5-induced tubular injury remains unclear. In this study, we investigated the regulatory effects of PPARγ on PM2.5-induced ferroptotic stress and epithelial–mesenchymal transition (EMT) in tubular (HK-2) cells. We found that downregulation of PPARγ expression was correlated with EMT in PM2.5-exposed cells. Pretreatment with the PPARγ agonist 15d-PGJ2 protected the cells from EMT by reducing ferroptotic stress, whereas that with the PPARγ antagonist GW9662 promoted EMT. Furthermore, pretreatment with ferrostatin-1 (Fer-1) significantly prevented PM2.5-induced EMT and downregulation of PPARγ expression. Notably, overexpression of PPARγ blocked PM2.5-induced downregulation of E-cadherin and GPX4 expression and upregulation of α-SMA expression. This study highlights the complex associations of PPARγ with ferroptosis and EMT in PM2.5-exposed tubular cells. Our findings suggest that PPARγ activation confers protection against PM2.5-induced renal injury.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100189"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000422/pdfft?md5=902c1b7607a020f8948c7daf50b6eb1b&pid=1-s2.0-S2666027X24000422-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141852468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tocotrienol suppresses colitis-associated cancer progression through TLR4 signaling in a mouse model of colorectal cancer","authors":"Qian Li ,&nbsp;Shujing Zhang ,&nbsp;Qinghong Zhou ,&nbsp;Chenxi Gu ,&nbsp;Yinghua Liu ,&nbsp;Jing Zhang ,&nbsp;Jingshu Zhang","doi":"10.1016/j.crtox.2024.100196","DOIUrl":"10.1016/j.crtox.2024.100196","url":null,"abstract":"<div><div>This study aimed to evaluate the preventive efficacy of tocotrienol in inhibiting the nuclear factor-kappa B (NF-κB) mediated inflammation pathways in colorectal cancer. We utilized the azoxymethane (AOM) and dextran sulfate sodium salt (DSS) to induce colitis-associated colorectal cancer (CAC) mice model. In generating a CAC model, mice were intraperitoneally injected with AOM at a concentration of 10 mg/kg body weight. Seven days after the AOM injection, mice drinking water containing 3 % DSS for 1 week, followed by a 2-week period of regular water. This cycle of DSS treatment (1-week 3 % DSS+2-week water) was repeated for two additional cycles. Mice were randomly divided into five groups (n = 20/group), including Blank group, Model group, three different dosages tocotrienol groups (Low dose group [50 mg/kg], Medium dose group [75 mg/kg], and High dose group [100 mg/kg]). The protective effects of tocotrienol were assessed using histological, flow cytometry, western blot and mouse Luminex assay. Compared with the blank group, expressions of toll-like receptor 4 (TLR4), myeloid differentiation protein 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF-6), NF-κB, Interleukin (IL)-6 and tumor necrosis factor (TNF) −α were increased in model group, while IL-4 and IL-10 were decreased in model group (<em>P</em>&lt;0.05). Tocotrienol prevented carcinogenesis and decreased the IL-6, TNF-α, MyD88, TLR4, TRAF-6 and NF-κB expression levels, compared with the model group (<em>P</em>&lt;0.05). Compared with the model group, the expression of IL-10 was increased in medium dose group and high dose group (<em>P</em>&lt;0.05). The protective effects of tocotrienol may be related to the inhibition of TLR4 /MyD88 /NF-κB mediated inflammatory signaling pathways. Therefore, the use of tocotrienol can improve the abnormal expression of cytokines in a mouse model of colorectal cancer and inhibit the occurrence and development of colorectal cancer.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100196"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight on cytotoxic NHC gold(I) halide complexes evaluated in multifaceted culture systems","authors":"Vincenza De Gregorio ,&nbsp;Alessandra La Pietra ,&nbsp;Andrea Candela ,&nbsp;Carlo Oliviero ,&nbsp;Ida Ferrandino ,&nbsp;Diego Tesauro","doi":"10.1016/j.crtox.2024.100174","DOIUrl":"10.1016/j.crtox.2024.100174","url":null,"abstract":"<div><p>Gold complexes can be a useful system in the fight against cancer. Although many studies have been carried out on in vitro 2D cell culture models embryotoxic assays are particularly lacking. Embryotoxicity and DNA damage are critical concerns in drug development. In this study, the effects of a new N-Heterocyclic carbene (NHC)-Au compound (Bromo[1,3-di-4-methoxybenzyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I)) at different concentrations were explored using multifaceted approach, encompassing 2D cancer cell cultures, <em>in vivo</em> zebrafish and in vitro bovine models, and compared with a consolidated similar complex (Bromo[1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I)). The results obtained from 2D cancer cell cultures revealed concentration-dependent effects of the gold compounds by estimating the cytotoxicity with MTT assay and cellular damage as indicated by LDH release. Selected concentrations of gold complexes demonstrated no adverse effects on zebrafish embryo development. However, in bovine embryos, these same concentrations led to significant impairments in the early developmental stages, triggering cell apoptosis and reducing blastocyst competence. These findings underscore the importance of evaluating drug effects across different model systems to comprehensively assess their safety and potential impact on embryonic development.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100174"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000276/pdfft?md5=734ebceb816cc928e98d56c5ae0b24b1&pid=1-s2.0-S2666027X24000276-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141143905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO","authors":"Umme Sabrina Haque ,&nbsp;Melissa Kohut ,&nbsp;Toshifumi Yokota","doi":"10.1016/j.crtox.2024.100182","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100182","url":null,"abstract":"<div><p>Duchenne Muscular Dystrophy (DMD) is a devastating X-linked genetic disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. This results in the absence or dysfunction of the dystrophin protein, leading to muscle weakness, loss of ambulation, respiratory issues, and cardiac complications, often leading to premature death. Recently, antisense oligonucleotide (ASO)-mediated exon skipping has emerged as a promising therapeutic strategy for DMD. Notably, the FDA has conditionally approved four ASO therapies for DMD, with numerous others in various stages of clinical development, indicating the growing interest and potential in this field. To enhance ASO-based therapies, researchers have explored the novel concept of conjugating peptides to the phosphorodiamidate morpholino backbone (PMO) of ASOs, leading to the development of peptide-conjugated PMOs (PPMOs). These PPMOs have demonstrated significantly improved pharmacokinetic profiles, potentially augmenting their therapeutic effectiveness. Despite the optimism surrounding ASOs and PPMOs, concerns persist regarding their efficacy and safety. To comprehensively evaluate these therapies, it is imperative to expand patient populations in clinical trials and conduct thorough investigations into the associated risks. This article provides a comprehensive review and discussion of the available data pertaining to adverse reactions and toxicology associated with FDA-approved ASO drugs for DMD. Furthermore, it offers insights into the emerging category of peptide-conjugated ASO drugs those are clinical and preclinical trials, shedding light on their potential benefits and challenges.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100182"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000355/pdfft?md5=0ee155e7dc6de2577482f5fe36a61d0b&pid=1-s2.0-S2666027X24000355-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sublethal effects of early-life exposure to common and emerging contaminants in birds","authors":"Jacquelyn Grace ,&nbsp;Elena Duran ,&nbsp;Mary Ann Ottinger ,&nbsp;Terri Maness","doi":"10.1016/j.crtox.2024.100190","DOIUrl":"10.1016/j.crtox.2024.100190","url":null,"abstract":"<div><p>The plight of wild birds is becoming critical due to exposure to environmental contaminants. Although laboratory studies have provided insights into the developmental effects of chemical exposures, less is known about the adverse effects of environmental chemicals in developing wild birds. Early life stages are critical windows during which long-term organization of physiological, behavioral, and neurological systems can occur. Thus, contaminant exposure at early life stages can directly influence survival and reproductive success, with consequences for population stability and resilience in wild species. This review synthesizes existing knowledge regarding both short- and long-term effects of early-life exposure to widespread contaminants in birds. We focus especially on wild birds and on contaminants of concern within the Gulf of Mexico as an example of a habitat under anthropogenic stress from exposure to a complex mixture of chemicals and changing land uses that exacerbate existing vulnerabilities of wildlife in this region. Chemical contaminants for discussion in this review are based on avian mortality records from the Wildlife Health Information Sharing Partnership (WHISPers) database and on additional review of the literature regarding avian contaminants of concern for the northern Gulf of Mexico, and include oil and associated polycyclic aromatic hydrocarbons, dioxin and dioxin-like compounds, flame retardants, pesticides, heavy metals, and plastics. We provide an overview of effects in bird species at both the pre-hatching and post-hatching early life stages, discuss differences in sensitivities by route of exposure, life stage, and life history, and provide recommendations for future research. We find that additional research is needed on altricial species, post-hatching early-life exposure, long-term effects, and on ecologically relevant contaminant concentrations and routes of exposure. Given the increasing frequency and intensity of anthropogenic stressors encountered by wild animals, understanding both lethal and sublethal impacts of contaminants on the health of individuals and populations will be critical to inform restoration, management, and mitigation efforts.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100190"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000434/pdfft?md5=87270839d476de9548652c2bdce46fa7&pid=1-s2.0-S2666027X24000434-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141963231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicology study profile of Nicotinamide mononucleotide after acute and 90-day sub chronic dosing in Wistar rats and mutagenicity tests","authors":"Jianjun Yu,&nbsp;Qiang Shen,&nbsp;Jiayan Li","doi":"10.1016/j.crtox.2024.100171","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100171","url":null,"abstract":"<div><p>Nicotinamide mononucleotide (NMN) is an intermediate in biosynthesis pathway of Nicotinamide adenine dinucleotide (NAD+), an essential cofactor in all living cells involved in fundamental biological processes. Evidence stemming from recent studies have unveiled numerous roles of NAD+ metabolism on aging, longevity, delaying the progression of age-related diseases. A three-study genetic toxicity (genetox) battery (bacterial mutagenesis, in vitro cytogenetics, and in vivo mammalian test) is usually required to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time.</p><p>The acute oral LD50 of NMN was greater than 2000 mg/kg body weight with 5000 mg/kg body weight as LD50 cut-off value and was classified under “Category 5 or Unclassified” as per Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Based on 90 days repeated dose toxicity test the NOAEL was considered to be NLT 800 mg NMN/kg body weight in Wistar rats. The bacterial reverse mutation test, the in vitro and in vivo chromosomal aberration test, found NMN to be non-mutagenic. In the mammalian bone marrow chromosomal aberration test, it was concluded that NMN is non clastogenic at and up to 2,000 mg/kg body weight in all the animals tested to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100171"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000240/pdfft?md5=d2d93c1852cab16f8d024b14ecbbfef2&pid=1-s2.0-S2666027X24000240-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140906755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of inflammatory mechanisms induced by croton oil in mouse ear","authors":"Ganming Mao ,&nbsp;Dalon Douglas ,&nbsp;Milankumar Prajapati ,&nbsp;Trishaal Janardhanam Raghavendra Rao ,&nbsp;Haiyan Zheng ,&nbsp;Caifeng Zhao ,&nbsp;Blase Billack","doi":"10.1016/j.crtox.2024.100184","DOIUrl":"10.1016/j.crtox.2024.100184","url":null,"abstract":"<div><p>Croton oil is liquid at room temperature, with a pale-yellow color and spicy odor. It is commonly used in combination with phenol as a chemical peeling agent in dermatology, which reveals its caustic exfoliating effects. Topical use of croton oil at a high dose produces skin irritation, inflammation, swelling, pain, and even tumors. Therefore, croton oil has been widely used for inflammation, pain, and tumor related research, with different animal models having been established. However, mechanistic studies through which croton oil induces skin swelling, injury and activates tissue repair/regeneration are limited. The present study used croton oil to induce mouse ear edema and examined tissue responses 4 h after exposure. To this end, croton oil was applied to the ventral side of mouse ears, followed by tissue collection. Samples were analyzed by hematoxylin and eosin (H&amp;E) staining, toluidine blue staining, and immunohistochemistry staining for myeloperoxidase (MPO) and matrix metalloproteinase-9 (MMP-9). Western blotting and ELISA were also carried out for MMP-9 together with unbiased proteomic analysis using mass-spectrometry. Results from our study demonstrated that as soon as 4 h of exposure to 2.5 % croton oil, the expression levels of MPO and MMP-9 in the dermis significantly increased compared to acetone-treated (vehicle) control ears, as did other inflammatory reactions such as swelling and neutrophil aggregation and infiltration. Subsequently, proteomic analysis confirmed that croton oil treatment resulted in significant upregulation of proteins such as myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9), and matrix metalloproteinase-8 (MMP-8) in the ear skin. Interestingly, mouse ears treated with acetone vehicle showed differential expression of 2,478 proteins relative to naïve tissues; among those differentially expressed in acetone-treated samples were members of the phosphatidylinositol-glycan biosynthesis class N, T and U proteins (PIGN, PIGT, and PIGU). Overall, this work confirms the presence of neutrophil-derived MPO and MMP-9 and extends the body of knowledge to show that MMP-8 is also present during croton oil-mediated skin inflammation in the mouse ear; moreover, we find that acetone vehicle is not inert and has effects on the skin that should be considered moving forward.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100184"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000379/pdfft?md5=065ccacf3dd535d6119a2638ba46a403&pid=1-s2.0-S2666027X24000379-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruptive consequences of monosodium glutamate on male reproductive function: A review","authors":"David Tolulope OLUWOLE ,&nbsp;Oladipupo`Samuel EBIWONJUMI ,&nbsp;Lydia Oluwatoyin AJAYI ,&nbsp;Olubunmi Dupe ALABI ,&nbsp;Victor AMOS ,&nbsp;Grace AKANBI ,&nbsp;Wale Johnson ADEYEMI ,&nbsp;Ayodeji Folorunsho AJAYI","doi":"10.1016/j.crtox.2024.100148","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100148","url":null,"abstract":"<div><p>Monosodium glutamate (MSG) is one of the most extensively used flavour enhancers worldwide. Although it is widely regarded as a safe food additive with no recommended daily dosage, its over-consumption has been associated with notably pathophysiological events in various tissues and organs of the body. Previous studies have reported of the neuro- cardio- and hepato- toxic effects of its excessive exposure. Moreover, the food additive instigates metabolic dysfunction. It has been established that MSG damages male reproductive accessory organs like prostate glands and epididymis. In addition, it impairs serum enzymatic activities and serum levels of testosterone, gonadotropin-releasing hormone, luteinizing hormone and cholesterol. Reduced sperm count, sperm motility, sperm morphology, and sperm viability, imbalances in male reproductive hormones, alongside alteration in the histoarchitecture of the testes and other male reproductive tissues have also been connected with excessive exposure to MSG. Literature reports affirm the link between the over-consumption of MSG and reproductive organ weight and male sexual behaviour. This review article addresses the multi-systemic effects of exposure to MSG and the possible mechanism of action of the compound with a focus on the negative implications of the food additive on male reproductive functions and the possible role of natural antioxidants in male reproductive functions. carefully selected keywords were used during the literature search to gather credible and up-to-date information about the subject matter.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100148"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X2400001X/pdfft?md5=44f680ca120bc4503db1bb33cb5420a5&pid=1-s2.0-S2666027X2400001X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139434489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of oxidative stress/JNK/ERK signals in paraquat-triggered hepatic apoptosis","authors":"Kuan-I Lee ,&nbsp;Kai-Min Fang ,&nbsp;Chun-Ying Kuo ,&nbsp;Chun-Fa Huang ,&nbsp;Shing-Hwa Liu ,&nbsp;Jui-Ming Liu ,&nbsp;Wei-Cheng Lai ,&nbsp;Kai-Chih Chang ,&nbsp;Chin-Chuan Su ,&nbsp;Ya-Wen Chen","doi":"10.1016/j.crtox.2024.100155","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100155","url":null,"abstract":"<div><p>Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1–2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome <em>c</em> release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant <em>N</em>-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100155"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000082/pdfft?md5=e145215fad560b32c819d99cb92a7fe9&pid=1-s2.0-S2666027X24000082-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139737551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A wide survey of heavy metals-induced in-vitro DNA replication stress characterized by rate-limited replication","authors":"Qidong Ren ,&nbsp;Xuejun Guo ,&nbsp;Dong Yang ,&nbsp;Chuanfang Zhao ,&nbsp;Xiangyuan Zhang ,&nbsp;Xinghui Xia","doi":"10.1016/j.crtox.2024.100152","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100152","url":null,"abstract":"<div><p>Heavy metals (HMs) are environmental pollutants that pose a threat to human health and have been accepted to cause various diseases, including cancer and developmental disorders. DNA replication stress has been identified to be associated with such diseases. However, the effect of HMs exclusively on DNA replication stress is still not well understood. In this study, DNA replication stress induced by thirteen HMs was assessed using a simplified <em>in-vitro</em> DNA replication model. Two parameters, <em>Ct_e/Ct_c</em> reflecting the cycle threshold value alteration and <em>K_e/K_c</em> reflecting the linear phase slope change, were calculated based on the DNA replication amplification curve to evaluate the rate of exponential and linear phases. These parameters were used to detect the replication rate reflecting <em>in-vitro</em> DNA replication stress induced by tested HMs. According to the effective concentrations and rate-limiting degree, HMs were ranked as follows: Hg, Ce &gt; Pb &gt; Zn &gt; Cr &gt; Cd &gt; Co &gt; Fe &gt; Mn, Cu, Bi, Sr, Ni. Additionally, EDTA could relieve the DNA replication stress induced by some HMs. In conclusion, this study highlights the potential danger of HMs themselves on DNA replication and provides new insight into the possible links between HMs and DNA replication-related diseases.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100152"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000057/pdfft?md5=f119fe5f30e69c128acda54cd1a6475d&pid=1-s2.0-S2666027X24000057-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139674448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}