JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Li Mou,Daguang Sun,Jiayuan Qu,Xiaoyin Tan,Suli Wang,Qiang Zeng,Changjiang Liu
Iodoacetic acid (IAA) is an emerging unregulated iodinated disinfection byproduct with high toxicity and widespread exposure. IAA has potential reproductive toxicity and could damage male reproduction. However, the underlying mechanisms and toxicological targets of IAA on male reproductive impairment are still unclear, and thus Sprague-Dawley rats and Leydig cells were used in this work to decode these pending concerns. Results showed that after IAA exposure, the histomorphology and ultrastructure of rat testes were abnormally changed, numbers of Leydig cells were reduced, the hypothalamic-pituitary-testis (HPT) axis was disordered, and testosterone biosynthesis was inhibited. Proteomics analyses displayed that oxidative stress, endoplasmic reticulum stress, and steroid hormone biosynthesis were involved in IAA-caused reproductive injury. Antioxidant enzymes were depleted, while levels of ROS, MDA, 8-OHdG, and γ-H2A.X were increased by IAA. IAA triggered oxidative stress and DNA damage, and then activated the GRP78/IRE1/XBP1s and cGAS/STING/NF-κB pathways in Leydig cells. The two signaling pathways constructed an interactive network by synergistically regulating the downstream transcription factor CHOP, which in turn directly bound to and negatively modulated steroidogenic StAR, finally refraining testosterone biosynthesis in Leydig cells. Collectively, IAA as a reproductive toxicant has anti-androgenic effects, and the GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP facilitates IAA-mediated testosterone decline.
研究领域:
生殖毒理学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Linhao Xu,Yuxin Jiang,Yanli Bi,Senwen Zheng,Yirong Wu,Yihao Wu,Yizhou Xu,Jian Chen
Chinese herbs have been used to treat small-cell lung cancer (SCLC) due to their low toxicity and significant efficacy. This study focused on oridonin, a natural compound extracted from Rabdosia rubescens, and aimed to investigate its potential antitumor activity on SCLC and to evaluate the synergistic effect of combining oridonin with other small molecules. In this study, oridonin exhibited a dual effect. At lower concentrations, it suppressed the cell viability of SCLC cells (H1688 and H446). At high concentrations, oridonin induced SCLC cell apoptosis, damaged HBE cells in vitro and compromised the function of the liver and heart in vivo . The lower concentration of oridonin induced autophagy by enhancing the expression of p62 and the LC3B-II/LC3B-I ratio. This phenomenon might be associated with the activation of the protein kinase RNA-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/growth arrest and DNA damage-inducible gene 153 (CHOP/GAD153) pathway. Therefore, the combined effect of oridonin with GSK2606414 or 3- methyladenine increased apoptosis in SCLC cells and reduced tumor growth. A similar phenomenon was observed after oridonin was combined with p62 or CHOP RNA interference treatment. Simultaneously, the combination of oridonin and GSK2606414 exhibited therapeutic efficacy without manifesting adverse effects. Our findings suggest that oridonin at lower concentrations can induce autophagy by activating the PERK/eIF2α/CHOP signaling pathway. The inhibition of the PERK/eIF2α/CHOP pathway could enhance oridonin therapeutic responses by triggering apoptosis. The novel therapeutic approach of combining oridonin with a PERK inhibitor is promising as a strategy for the treatment of SCLC.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
·
2022
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IF 5.011
Xijie Yu,Xiaoxiao Xu,Wei Dong,Chang Yang,Yao Luo,Ying He,Chenxi Jiang,Yanru Wu,Jiawei Wang
Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response related to multiple diseases, including temporomandibular joint (TMJ) cartilage-related diseases. Recent studies have indicated that DDIT3/CHOP (a downstream transcription factor of ER stress) is an important effector in mediating ER stress to inhibit chondrogenesis . However, the underlying mechanism by which DDIT3 regulates chondrogenesis remains unclear. In this study, tunicamycin (an ER stress agonist)-induced ER stress inhibited chondrocyte differentiation and matrix synthesis in vitro and led to an osteoarthritis-like phenotype in mouse TMJ cartilage. Meanwhile, DDIT3 expression in chondrocytes was robustly upregulated. Loss-of-function experiments validated the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Mechanistically, the inhibiting effect was attributed to the direct and indirect regulatory effect of DDIT3 on SIRT1 (sirtuin1, silent mating type information regulation protein type 1, a member of NAD+ dependent class III histone deacetylases). On one hand, DDIT3 directly promoted the transcription of SIRT1. On the other hand, DDIT3 indirectly increased the expression of SIRT1 by promoting AMPKα phosphorylation and activation. Furthermore, activation of AMPKα or SIRT1 with the corresponding agonist AICAR or resveratrol in the DDIT3-knockdown cells partially restored the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Collectively, these novel findings indicate that DDIT3 regulates the inhibitory effect of ER stress on chondrocyte differentiation and matrix synthesis partially via the AMPKα-SIRT1 pathway. A thorough understanding of ER stress in regulating chondrocyte homeostasis and its role in the onset of osteoarthritis may be promising to develop therapeutic targets and prevent condyle cartilage destruction.
研究领域:
细胞生物学
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分子生物学
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骨科
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病理学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
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IF 6.9
Zefeng Jiang,Xiaowei Wen,Qin Mao,Gang Wang,Zhuo Wang,Yu Yan,Shan Gao,Xiaoqian Sun,Miao Zhang,Jiajing Liu,Rong Zhang,Baofeng Yang
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and endoplasmic reticulum stress (ERS) and mitochondrial Ca 2+ overload have been involved in apoptotic cardiomyocyte death during MI. 13-Methylpalmatine (13-Me-PLT) is a natural isoquinoline alkaloid isolated from Coptis chinensis and has not been systematically studied for their potential pharmacological effects in cardiovascular diseases. We conducted the present study to elucidate whether 13-Me-PLT modulates MI pathology in animal MI and cellular hypoxic models, employing state-of-the-art molecular techniques. The results demonstrated that 13-Me-PLT preserved post-ischemic cardiac function and alleviated cardiomyocyte apoptosis. 13-Me-PLT decreased ERS and the communication between ER and mitochondria, which serves as a protective mechanism against mitochondrial Ca 2+ overload and structural and functional injuries to mitochondria. Our data revealed mitigating mitochondrial Ca 2+ overload and apoptosis by inhibiting CHOP-mediated Ca 2+ transfer between inositol 1,4,5-trisphosphate receptor (IP 3 R) in ER and VDAC1 in mitochondria as an underlying mechanism for 13-Me-PLT action. Furthermore, 13-Me-PLT produced superior effects in alleviating cardiac dysfunction and apoptosis post-MI to diltiazem and palmatine. Collectively, our research suggests that the CHOP/IP 3 R/VDAC1 signaling pathway mediates ER-mitochondrial Ca 2+ transfer and 13-Me-PLT activates this axis to maintain cellular and organellar Ca 2+ homeostasis, protecting against ischemic myocardial injury. These findings may offer an opportunity to develop new agents for the therapy of ischemic heart disease.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Biomedical Research
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2018
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IF 0
Li-xing Wu,Yu-yu Xu,Zhi-jian Yang,Qing Feng
Myocardial infarction triggers massive biochemical changes, even cardiac cell death. Endoplasmic reticulum stress is involved in the pathology of myocardial infarction-mediated apoptosis. In the present study, myocardial cell line H9c2 cells were treated with cobalt chloride (CoCl 2 ) to induce hypoxia. Isoproterenol was used for two successive days to induce myocardial infarction in SD rats. The cardioprotective effect of olive leaf extract (OLE) and its main constituent hydroxytyrosol and the underlying mechanisms were evaluated. The results showed that hydroxytyrosol markedly protected H9c2 cells against CoCl 2 -induced apoptosis. Hydroxytyrosol could reduce the mRNA and protein expression of GRP78 and CHOP induced by CoCl 2 in vitro . In vivo , the decreased ejection fraction and fractional shortening, increased heart weight/body ratio, the formation of infarction, disordered cardiac muscle fibers and infiltration of inflammatory cells induced by isoproterenol could be significantly ameliorated by pretreatment with OLE for a month. Similarly, OLE could also reverse the increase of GRP78 and CHOP expression induced by isoproterenol. Therefore, OLE and hydroxytyrosol exert a cardioprotective effect through endoplasmic reticulum stress, which could be a new target for the prevention and treatment of cardiovascular diseases.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
Bosnian Journal of Basic Medical Sciences
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2018
·
IF 1.432
Jing Chen,Guo Zheng,Hu Guo,Zhong-nan Shi,Jiao Jiang,Xiao-yu Wang,Xiao Yang,Xian-yu Liu
Status epilepticus (SE) is defined as continuous seizure activity lasting more than 5 minutes. It results in neuronal cell death, mediated by endoplasmic reticulum (ER) stress response. Previously, metformin demonstrated neuroprotective effects in primary cortical neurons. In this study, we analyzed the effect of metformin on ER stress via the pro-apoptotic protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. SE was induced in rats by pentylenetetrazole. Following SE, the rats were treated with salubrinal, GSK2656157, or metformin. In a control group (normal saline) SE was not induced. CHOP, eIF2α, and PERK expression was determined by Western blot; apoptosis was analyzed by TUNEL assay. CHOP expression was significantly increased at 6 and 24 hours following SE. At both time points, eIF2α and PERK levels were also increased. At 6 hours, CHOP expression was significantly reduced in salubrinal, GSK2656157 and metformin groups versus SE group. eIF2α and PERK levels were decreased in metformin compared to SE group. eIF2α expression was markedly decreased in salubrinal versus SE group, while PERK expression was markedly reduced in GSK2656157 versus SE group. At 6 and 24 hours, the apoptosis rate was significantly increased in SE versus control group, while it was significantly reduced in salubrinal, GSK2656157, and metformin groups compared to SE group. The apoptosis rate also decreased in salubrinal group at 24 hours, although not to the extent observed in metformin group. Overall, CHOP expression and apoptosis induced by SE in rats were reduced with metformin. Further studies are required to evaluate the clinical relevance of metformin for patients with SE.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
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IF 6.1
Qing Zhao,Lingling Zhai,Yangyang Song,Mujiao Li,You Yang,Jian Zhao
The toxic effect of Polystyrene Microplastics (PS-MPs) on leydig cells were found in male mice, but the toxic mechanism was not clear. The PS-MPs exposure mice model and cell model were established in this study to explore the leydig cells toxic mechanism. In vivo study, the leydig cells toxicity in male mice was evaluated exposed to PS-MPs for 28 days. And found that the sperm density, mobility and testosterone (T) level decreased, and the sperm malformation rate and malondialdehyde level increased. PS-MPs exposure impaired the function of male reproduction. The results also showed that the levels of testosterone-producing proteins (StAR, P450scc,3β-HSD and CYP17A1) decreased, apoptosis signaling pathways (Bax/Bcl-2, Caspase-8 and Caspase-12) were activated and endoplasmic reticulum stress (GRP78/p-PERK/CHOP) occurred in male mice exposed to PS-MPs. In vitro study, TM3 cells (leydig cells) were treated with 50, 100 and 200 μg/mL of PS-MPs for 24 h. And we found that PS-MPs exposure reduced the cell viability and the level of T, increased reactive oxygen species (ROS) level in TM3 cells. PS-MPs exposure impaired the function of the leydig cells. Further testing revealed that PS-MPs could activate GRP78/p-PERK/CHOP pathway, aggrandized endoplasmic reticulum stress in the leydig cells, then increased apoptosis level, and induced testosterone synthase protein reduction. These could be reversed when exposed to ROS inhibitor or endoplasmic reticulum stress inhibitor. In conclusion, PS-MPs exposure induced the high level of ROS, activated the GRP78/p-PERK/CHOP signaling pathway, enhanced endoplasmic reticulum stress in leydig cells, then apoptosis level increased, which impaired the leydig cell function.
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高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2024
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IF 4.4
Junjie Chen,Weibin Fan,Jing Fan,Jiao Xie,Yan Wang,Yinhui Wang,Nengming Lin,Bin Lin
The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB-induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB-induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB-induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB-induced nephrotoxicity in an in vitro model of PMB-induced cell injury. Moreover, we demonstrated that THC effectively protected HK-2 cells from PMB-induced apoptosis by using cell counting kit-8 and flow cytometry assay. THC could also suppress PMB-induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB-induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB-induced nephrotoxicity by inhibiting the ER stress-mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB-induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment.
研究领域:
药理学
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细胞生物学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2022
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IF 5.572
Yuqi Wang,Yilei Zhang,Xinyue Sun,Xu Shi,Shiwen Xu
With the widespread use of plastics, microplastics (MPs) and di(2-ethylhexyl) phthalate (DEHP) have become emerging environmental pollutants. The combined toxicity of MPs and DEHP on the mouse pancreas and the specific mechanism of toxicity remain unclear. To establish in vitro and in vivo models to address these questions, mice were continuously exposed to 200 mg/kg/d DEHP and 10 mg/L MPs for 4 weeks. In vitro, MIN-6 cells were treated with 200 μg/mL MPs and 200 μM DEHP for 24 h. Based on toxicity assessed using CCK8 of the equivalent TU binary mixture, the IC50 of the TU-mix of DEHP and MPs 0.692 < 0.8, indicating a synergistic effect of the two toxicants. Meanwhile, our data revealed that compared to the control group, MPs and DEHP combined treatment increased ROS levels, inhibited the activity, and enhanced the expression of GRP78 , and CHOP. Simultaneously, activated CHOP decreased the expression of Bcl-2, and increased the expression of Bax. In conclusion, DEHP and MPs synergistically induce oxidative stress , and activate the GRP78/CHOP/Bcl-2 pathway to induce pancreatic apoptosis in mice. Our finding provides a new direction for the research on the specific mechanism of MPs and DEHP combined toxicity.
研究领域:
环境毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2021
·
IF 4.374
Xiaohui Tan,Dunpeng Cai,Na Chen,Sihao Du,Dongfang Qiao,Xia Yue,Tao Wang,Jia Li,Weibing Xie,Huijun Wang
Methamphetamine (METH) is a highly addictive amphetamine-type drug that has caused persistent harm to society and human health in recent years. Most studies have shown that METH severely damages the central nervous system, and this drug has been found to be toxic to the cardiovascular system in recent years. Therefore, we hypothesized that METH may also damage vascular smooth muscle. We examined the expression of the apoptosis-related proteins Caspase 3 and PARP after METH treatment in vivo and in vitro and detected the expression of endoplasmic reticulum stress-related proteins. After treatment with the endoplasmic reticulum stress inhibitor 4-PBA, changes in the above indicators were examined. C/EBP homologous protein (Chop) expression was also detected, and the relationship between endoplasmic reticulum stress and apoptosis was further determined by siRNA silencing of Chop. The results indicated that METH can induce apoptosis of vascular smooth muscle cells (VSMCs) and upregulate the expression of Chop and endoplasmic reticulum stress-related proteins. Chop inhibits protein kinase B phosphorylation and further inhibits forkhead box class O3a (Foxo3a) dephosphorylation, resulting in increased p53 upregulated molecular of apoptosis (PUMA) transcription. Increased PUMA induces apoptosis through the mitochondrial pathway. These results indicate that Chop is involved in the METH-induced endoplasmic reticulum stress and apoptosis in VSMCs and may be a potential therapeutic target for METH-induced VSMC injury.
研究领域:
药理学
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心血管科学
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细胞生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
FISH PHYSIOLOGY AND BIOCHEMISTRY
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2023
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IF 2.9
Pan En-Zhuang,Xin Yue,Li Xue-Qing,Wu Xin-Yu,Tan Xue-Lian,Dong Jing-Quan
The aim of this study was to investigate the splenic tissue damage of environmental biological drug avermectin to freshwater cultured carp and to evaluate the effect of silybin on the splenic tissue damage of carp induced by avermectin. A total of 60 carp were divided into 4 groups with 15 carp in each group, including the control group fed with basic diet, experimental group fed with basal diet and exposed to avermectin (avermectin group), experimental group fed with basal diet supplement silybin (silybin group), and experimental group fed with basal diet supplement silybin and exposed to avermectin (silybin + avermectin group). The whole test period lasted for 30 days, and spleen tissue was collected for analysis. In this study, H&E staining, mitochondrial purification and membrane potential detection, ATP detection, DHE staining, biochemical tests, qPCR, immunohistochemistry, and apoptosis staining were used to evaluate the biological processes of spleen tissue injury, mitochondrial function, oxidative stress, apoptosis, and endoplasmic reticulum stress. The results show that silybin protected carp splenic tissue damage caused by chronic avermectin exposure, decreased mitochondrial membrane potential, decreased ATP content, ROS accumulation, oxidative stress, apoptosis, and endoplasmic reticulum stress. Silybin may ameliorate the splenic tissue damage of cultured freshwater carp caused by environmental biopesticide avermectin by alleviating mitochondrial dysfunction and inhibiting PERK-ATF4-CHOP-driven mitochondrial apoptosis. Adding silybin into the diet becomes a feasible strategy to resist the pollution of avermectin and provides a theoretical basis for creating a good living environment for freshwater carp. Graphical Abstract
研究领域:
水产养殖
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毒理学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FUNDAMENTAL & CLINICAL PHARMACOLOGY
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2020
·Vol. 34
·期 5
·559-570
·
IF 2.754
Siyuan Lv,Ning Wu,Qiang Wang,Li-Hua Yang
The aim of this study was to estimate whether methotrexate (MTX) promotes cognitive impairment via increased ER stress and disrupted H 2 S signaling in the hippocampus and whether H 2 S may alleviate MTX-induced cognitive impairment by inhibiting ER stress through CHOP and caspase-12. Cognitive impairment behaviors were observed by Morris water maze test, and the apoptosis of neurons was assessed by TUNEL assay. The production of neurons was analyzed by DCX and Ki67 immunohistochemistry. The expressions of CHOP and caspase-12 in the hippocampus were determined by Western blot and immunohistochemistry. MTX increased the expression of CHOP and caspase-12 and the number of TUNEL-positive cells in the hippocampus by inhibiting endogenous H 2 S-induced neuronal pyknosis in the hippocampal CA1 region. MTX decreased the number of DCX- and Ki67-positive cells in the hippocampal DG region. The results of Morris water maze showed that MTX could damage the spatial memory of rats. The changes of MTX-induced Morris water maze test in mice and H 2 S levels in serum and hippocampus, as well as the expression of CHOP and caspase-12 and the number of CHOP and caspase-12-positive neurons in the hippocampus, indicated that H 2 S could alleviate the cognitive impairment induced by methotrexate through CHOP and caspase-12.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
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