ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Hong Zhang,Kai Ren,Xiaoting Ni,Liwang Lin,Longyu Li,Wenlei Zhang,Zengliang Gao,Shiao Ren,Lili Fan,Xin Hai
Arsenic (As), a widely recognized environmental pollutant, has been implicated in the pathogenesis of various neuropsychiatric disorders, including anxiety and depression. Trimethylamine N-oxide (TMAO), a microbiota-host co-metabolite derived from dietary quaternary amines (e.g., choline), has been associated with the progression of multiple neurological disorders. This study demonstrates that the gut microbiota-derived metabolite TMAO potentiates As-induced neurotoxicity. Using network toxicology, we identified genes targeted by As and TMAO in depression, revealing significant enrichment in pathways related to apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress. In C57BL/6 mice, a high-choline diet exacerbated As-induced depressive behaviors, hippocampal damage, and astrocyte depletion, which were mediated by elevated TMAO levels. High-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) analysis confirmed that TMAO enhanced arsenic accumulation in plasma and brain tissues. In vitro experiments further demonstrated that TMAO exacerbated As-induced oxidative stress, DNA damage, mitochondrial dysfunction, apoptosis, and ferroptosis. Mechanistically, TMAO upregulated the ER stress PERK/eIF2α/ATF4 signaling pathway in response to As exposure. Knockdown of PERK attenuated As- and TMAO-mediated apoptosis and ferroptosis in cultured cells. Collectively, these findings indicate that dietary choline exacerbates arsenic-induced depressive-like phenotypes by increasing TMAO levels and activating the PERK/eIF2α/ATF4 signaling pathway.
研究领域:
神经毒理学
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环境卫生
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分子生物学
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神经科学
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毒理学
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营养科学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Yinghan Guo,Lulu Jin,Zhipeng Shen,Linfeng Fan,Xian Yu,Yirui Kuang,Lingxin Cai,Jiayin Zhou,Zihang Chen,Feng Yan,Jianmin Zhang,Minfeng Tong,Jianlie Yuan,Zhengwei Mao,Gao Chen
The malignant interaction between tumor cells and immune cells is one of the important reasons for the rapid progression and refractoriness of glioblastoma (GBM). As an essential metabolic center of M2 macrophages, the inhibition of protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the reduction of M2 macrophages. Nevertheless, the restriction of the blood-brain barrier (BBB) and non-specific cell targeting hinder the application of PERK inhibitors in GBM. Herein, the optimal NP-M-M2pep is developed successfully, which has shown the capacity of BBB penetration and specific targeting of M2 microglia. In addition to inhibiting the polarization of M2 microglia, the administration of iPERK@NP-M-M2pep reprogrammed M2 microglia into M1 ones in vitro via PERK/HIF-1α/glycolysis pathway. Efficient brain accumulation of nanoparticles is achieved after tail vein injection, with effective inhibition of GBM progression after one course of treatment. The glioma-associated microglia and macrophages (GAM) with M2 type are induced to M1 and the immunosuppressive TME is remodeled by upregulating immunostimulatory cells and downregulating immunosuppressive cells. In summary, the biomimetic membrane vesicles (BMVs) specifically delivered iPERK to GAMs offer an inspiring strategy to reprogram microglia polarization, re-educate immunosuppressive TME, and inhibit the progression of GBM.
研究领域:
肿瘤学
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神经科学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Bosnian Journal of Basic Medical Sciences
·
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
Cell Death & Disease
·
2017
·Vol. 8
·期 10
·e3095
·
IF 5.965
Xu Junjie,Zheng Longbo,Chen Jiang,Sun Yin,Lin Hui,Jin Ren-an,Tang Minyue,Liang Xiao,Cai Xiujun
Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2 α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2 α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2 α , increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2 α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.
研究领域:
肿瘤学
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药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NanoImpact
·
2020
·
IF 5.478
Tao Wang,Xiaozhen Wei,Yiru Sun,Yadong Hu,Jie Li,Xinyu Zhang,Shaowu Yin,Yonghai Shi,Yongxiang Zhu
Copper nanoparticles (CuNPs), a new pollutant in water environments, were widely used in various industrial and commercial applications. This study indicated that the presence of CuNPs exposure under environmental related concentration is an inducing factor that contributes to the fatty liver formation in Takifugu fasciatus . Furthermore, we explored the fatty liver formation mechanism. The results shown, (1) the cloned genes related to endoplasmic reticulum stress (ERS) ( GRP78, IRE-1α, PERK , and ATF-6α ) were highly expressed in the liver of T. fasciatus. (2) after 30-days exposure, CuNPs accumulated in the endoplasmic reticulum of liver and induced the appearance of ERS, then activated unfolded protein response (UPR) signaling pathway. Furthermore, the SREBP-1c pathway that plays a key role in lipid synthesis was activated. (3) by using 4-PBA and GSK inhibitors to respectively stimulate ERS and PKR-like ER kinase (PERK) through in vitro experiments, we confirmed that CuNPs induced the fatty liver formation in T. fasciatus triggered by the PERK-EIF2α pathway by activating the SREBP-1c pathway to promote fatty liver formation. This study provides a new perspective for identifying the pathogens of fatty liver formation, and adds to the knowledge of the ecological safety data service of CuNPs in water
研究领域:
环境科学
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分子生物学
·
水生毒理学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2024
·
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
·
细胞生物学
·
分子生物学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FISH PHYSIOLOGY AND BIOCHEMISTRY
·
2023
·
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
·
毒理学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Yi Zhao,Yuan-Hang Chang,Hao-Ran Ren,Ming Lou,Fu-Wei Jiang,Jia-Xin Wang,Ming-Shan Chen,Shuo Liu,Yu-Sheng Shi,Hong-Mei Zhu,Jin-Long Li
Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER–mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood–brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER–mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.
研究领域:
神经科学
·
毒理学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Huanhuan Xue,Peijie Li,Jing Guo,Tinggui Chen,Shifei Li,Liwei Zhang
Ulcerative colitis (UC) is an idiopathic, relapsing, and etiologically complicated chronic inflammatory bowel disease. Despite substantial progress in the management of UC, the outcomes of mucosal barrier repair are unsatisfactory. In this study, phillygenin (PHI) treatment alleviated the symptoms of chronic colitis in mice, including body weight loss, severe disease activity index scores, colon shortening, splenomegaly, oxidative stress, and inflammatory response. In particular, PHI treatment ameliorated the tight junction proteins (TJs) reduction, fibrosis, apoptosis, and intestinal stem cell activity, indicating that PHI exerted beneficial effects on the intestinal mucosal barrier in mice with chronic colitis. In the NCM460 cells damage model, dextran sulfate sodium triggered the sequential induction of TJs reduction, fibrosis, and apoptosis. Takeda G protein-coupled receptor-5 (TGR5) dysfunction mediated NCM460 cell injury. Moreover, PHI treatment enhanced TJs and suppressed fibrosis and apoptosis to maintain NCM460 cell function, depending on TGR5 activation. PHI promoted TGR5 activation and elevated intracellular cyclic adenosine monophosphate levels in HEK 293T cells transfected with TGR5 expression plasmids. Cellular thermal shift assay and molecular docking studies confirmed that PHI directly binds to TGR5, indicating that PHI is an agonist of TGR5. The process of PERK-eIF2α pathway-mediated endoplasmic reticulum Ca 2+ release was involved in NCM460 cell injury as well, which was associated with TGR5 dysfunction. When NCM460 cells were pretreated with PHI, the PERK-eIF2α pathway and elevated Ca 2+ levels were blocked. In conclusion, our study demonstrated a novel mechanism that PHI inhibited the PERK-eIF2α-Ca 2+ pathway through TGR5 activation to against DSS-induced TJs reduction, fibrosis, and apoptosis.
研究领域:
胃肠病学
·
药理学
·
细胞生物学
·
炎症性肠病
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2023
·
IF 5.6
Ritian Jin,Jude Juventus Aweya,Rong Lin,Wuyin Weng,Jiaqi Shang,Dangfeng Wang,Yiling Fan,Shen Yang
VLATSGPG (VLA) was a DPP-IV inhibitory peptide isolated from salmon ( Salmo Salar ) skin. Here, we demonstrated that VLA inhibited the activation of PERK through the AKT signaling pathway. Furthermore, we investigated the effect of VLA on free fatty acid (FFA)-induced lipid accumulation disorder and inflammation in HepG2 cells, elucidating the potential regulatory mechanism in this nonalcoholic fatty liver disease cell model. VLA reduced the mRNA expression of adipogenic factors FAS, ACC, and SCD-1 through the PERK/eIF2α pathway and the level of apolipoprotein B-100 secretion. These may contribute to the reducing FFA-induced lipid accumulation in cells and reducing intracellular lipid levels. In addition, VLA increased IκBα mRNA expression via the PERK/IκBα pathway, inhibited the NF-κB p65 activation, and thus inhibited cell inflammation.
研究领域:
分子生物学
·
细胞生物学
·
药理学
·
生物化学
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产品关联
DOI
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Xiaoli Feng,Tian Lin,Dong Chen,Zhiyang Li,Qiuping Yang,Huiting Tian,Yao Xiao,Mingzhen Lin,Min Liang,Weihong Guo,Peng Zhao,Zhaoze Guo
Chemodynamic therapy (CDT) can effectively induce immunogenic cell death (ICD) in tumours and is thus a promising strategy for boosting the efficacy of immunotherapy. However, the mechanism by which CDT enhances ICD and lowers ICD efficiency is unknown and this restricts its clinical application. In this study, a second near-infrared (NIR-II) window irradiation-triggered hydrogen peroxide (H 2 O 2 ) self-supplying nanocomposite ((Cu 2 Se-CaO 2 )@LA) was constructed. The modified lauric acid was melted by the heat energy of the NIR-II irradiation, to expose the CaO 2 nanoparticles, and they then reacted with water to produce H 2 O 2 and Ca 2+ . H 2 O 2 was then converted to hydroxyl radicals by the photothermal-enhanced CDT process of the Cu 2 Se nanocubes. Notably, the CDT and Ca 2+ overload was found to induce sequential damage to the mitochondria and endoplasmic reticulum (ER), which upregulated the PERK-mediated eIF2α phosphorylation pathway and caused subsequent ICD. NIR-II irradiation of the (Cu 2 Se-CaO 2 )@LA also increased reactive oxygen species (ROS) formation and this was sufficient to increase dendritic cell maturation, attracting cytotoxic T lymphocytes, and suppressing tumour growth in vivo. Overall, we demonstrated that an enhanced CDT strategy under NIR-II exposure and H 2 O 2 self-supply can induce extensive ICD by inducing mitochondria-associated ER stress, which represents a highly effective and promising strategy for ICD amplification and tumour immunotherapy. Statement of significance In this study, a second near-infrared window (NIR-II) irradiation-triggered and H 2 O 2 self-supplying nanocomposite (named (Cu 2 Se-CaO 2 )@LA) was constructed and tested both in vitro and in vivo . These nanoparticles demonstrated promising antitumor activity as designed. Mechanistically, the nanoparticles could damage mitochondria and upregulate the PERK-mediated eIF2αphosphorylation pathway, further causing endoplasmic reticulum stress, and inducing immunogenic cell death through dendritic cell maturation and cytotoxic T lymphocyte recruitment augmented activity. This system represents a highly effective and promising strategy for enhancing tumor immunotherapy and provides new insights for future studies and design refinements.
研究领域:
癌症研究
·
免疫治疗
·
纳米技术
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）