ENVIRONMENTAL TOXICOLOGY
·
2023
·Vol. 38
·期 7
·1756-1767
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IF 4.5
Lin Zhao,Liyuan Wang,Han Wang,Tao Xi,Sijia Liu,Yang Li,Jianping Ruan,Yongqing Huang
Fluoride induces endoplasmic reticulum (ER) stress in ameloblasts, which is responsible for enamel mineralization disorder. Fluoride induces autophagy in ameloblasts, but the molecular mechanisms through which ameloblasts respond to fluoride-induced cellular stress and autophagy remain unclear. This study investigated ER stress-induced autophagy and the regulatory role of the ER molecular chaperone GRP78 in fluoride-induced autophagy in ameloblast LS8 cells. To explore the relationship between fluoride-induced ER stress and autophagy, we assessed changes in fluoride-induced autophagy in LS8 cells following overexpression and/or silencing of the ER stress molecular chaperone GRP78. We found that autophagy induced by fluoride was further increased after GRP78 overexpression in LS8 cells. Fluoride-induced autophagy was reduced in GRP78-silenced LS8 cells. Furthermore, we found that ER stress can regulate autophagy in fluoride-treated ameloblasts (LS8 cells) and that the GRP78/IRE1/TRAF2/JNK pathway is involved in the underlying regulation. Our study suggests that ER stress plays a role in fluoride-induced damage by inducing ameloblast autophagy.
研究领域:
口腔生物学
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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
Food Bioscience
·
2023
·
IF 5.2
Jiaxin Li,Hengju Ge,Yang Xu,Jiahong Xie,Naymul Karim,Fujie Yan,Jianling Mo,Wei Chen
Chlorogenic acid (CGA) is a phenylpropanoid compound in chrysanthemum, which has a variety of biological activities. Nevertheless, CGA has not yet been studied concerning oxidative stress in hepatocytes. Our research aims to investigate whether chlorogenic acid can improve hepatic oxidative stress, and further illustrated its detailed mechanism. The results of free radicals measurement and Western blot showed that CGA suppressed the activation of JNK (c-Jun NH2-teminal kinase) signaling pathway by ameliorating endoplasmic reticulum stress in H 2 O 2 -treated hepatocytes, thereby eliminating excess intracellular free radicals. In addition, through RT-qPCR, we found that miR-199a-5p down-regulated in H 2 O 2 -induced L02 cells, which was restored by CGA. By inhibiting the expression of miR-199a-5p to promote the transcription of GRP78 gene, the antioxidant capacity of CGA was greatly weakened in hepatocytes. Our findings suggest that CGA treatment alleviated the H 2 O 2 -induced oxidative stress by targeting miR-199a-5p, thereby ameliorating ER stress and inhibiting JNK phosphorylation for antioxidant capacity enhancement. Based on our available results, CGA may be an alternative compound to mitigate hepatic oxidative damage through the miR-199a-5p/GPR78 axis.
研究领域:
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
高影响因子
CELLULAR SIGNALLING
·
2023
·
IF 4.8
Jinmiao Tian,Lichao Zhang,Xiaoqin La,Xiaxia Fan,Aiping Li,Changxin Wu,Yuxuan An,Shuning Yan,Xiushan Dong,Haitao Wu,Zhuoyu Li
Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism , which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination . Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.
研究领域:
肿瘤学
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免疫学
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细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
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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产品关联
DOI
PubMed
高影响因子
FISH PHYSIOLOGY AND BIOCHEMISTRY
·
2023
·
IF 2.9
Shen Yuedong,Zhao Wenli,Bao Yangguang,Zhu Jiayun,Jiao Lefei,Duan Xuemei,Pan Tingting,Monroig Óscar,Zhou Qicun,Jin Min
Glucose-regulated protein 78 ( grp78 ) and activating transcription factor 6α ( atf6α ) are considered vital endoplasmic reticulum (ER) molecular chaperones and ER stress (ERS) sensors, respectively. In the present study, the full cDNA sequences of these two ERS-related genes were first cloned and characterized from black seabream ( Acanthopagrus schlegelii ). The grp78 cDNA sequence is 2606 base pair (bp) encoding a protein of 654 amino acids (aa). The atf6α cDNA sequence is 2168 base pair (bp) encoding a protein of 645 aa. The predicted aa sequences of A. schlegelii grp78 and atf6α indicated that the proteins contain all the structural features, which were characteristic of the two genes in other species. Tissues transcript abundance analysis revealed that the mRNAs of grp78 and atf6α were expressed in all measured tissues, but the highest expression of these two genes was all recorded in the gill followed by liver/ brain. Moreover, in vivo experiment found that fish intake of a high lipid diet (HLD) can trigger ERS by activating grp78 /Grp78 and atf6α/ Atf6α. However, it can be alleviated by dietary betaine supplementation, similar results were also obtained by in vitro experiment using primary hepatocytes of A. schlegelii . These findings will be beneficial for us to evaluate the regulator effects of HLD supplemented with betaine on ERS at the molecular level, and thus provide some novel insights into the functions of betaine in marine fish fed with an HLD.
研究领域:
分子生物学
·
水产养殖
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营养学
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DOI
PubMed
高影响因子
Journal of Biomedical Research
·
2018
·
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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产品关联
DOI
PubMed
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.
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2022
·
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
ACS Nano
·
2022
·
IF 18.027
Jing-Jie Ye,Wuyang Yu,Bo-Ru Xie,Ke Li,Miao-Deng Liu,Xue Dong,Zhao-Xia Chen,Jun Feng,Xian-Zheng Zhang
Conventional cancer targeting methodology needs to be reformed to overcome the intrinsic barriers responsible for poor targeting efficiency. This study describes a concept of self-reinforced cancer targeting (SRCT) by correlating targeting with therapy in a reciprocally enhancing manner. SRCT is achieved on the basis of two prerequisites: (1) target molecules have to be expressed on cancer cell membranes but not on normal cells, and (2) notably, their expression on cancer cells must be actively upregulated in response to cellular attack by cancer treatments. As a proof-of-concept, a GRP78-targeting nanovehicle for chemotherapy was designed. Resultant data showed that chemotherapeutic drugs could effectively elevate GRP78 expression on the plasma membranes of cancer cells while having minimal influence on normal cells. DOX pretreatment of cancer cells and tumor tissues can greatly increase the targeting efficacy and therapeutic performance of the prepared GRP78-targeting nanomedicine while somewhat disfavoring the nontargeting counterpart. In vivo and in vitro results demonstrated that this GRP78-targeting nanomedicine could accurately target cancer cells to not only implement chemotherapy but also induce GRP78 upregulation on cancer cells, eventually benefiting continuous cancer-cell-targeted attack by the nanomedicines remaining in the blood circulation or administered in the next dose. The GRP78-targeting nanomedicine displays much better antitumor performance compared with the nontargeting counterpart. SRCT is expected to advance cancer-targeted therapy based on the positive dependency between targeting and therapeutic modalities.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
PLoS One
·
2018
·Vol. 13
·期 5
·e0197934
·
IF 2.766
Xi Chen,Long-Yun Li,Jin-Lan Jiang,Kai Li,Zhen-Bo Su,Fu-Qiang Zhang,Wen-Jing Zhang,Guo-Qing Zhao
In this study, we investigated the relationship between propofol and autophagy and examined whether this relationship depends on ER stress, production of ROS (reactive oxygen species), and disruption of calcium (Ca 2+ ) homeostasis. To this end, we measured C2C12 cell apoptosis in vitro , along with Ca 2+ levels; ROS production; and expression of proteins and genes associated with autophagy, Ca 2+ homeostasis, and ER stress, including LC3 (microtubule-associate protein 1 light chain 3), p62, AMPK (adenosine 5’-monophosphate (AMP)-activated protein kinase), phosphorylated AMPK, mTOR (the mammalian target of rapamycin), phosphorylated mTOR, CHOP (C/BEP homologous protein), and Grp78/Bip (78 kDa glucose-regulated protein). We found that propofol treatment induced autophagy, ER stress, and Ca 2+ release. The ratio of phosphorylated AMPK to AMPK increased, whereas the ratio of phosphorylated mTOR to mTOR decreased. Collectively, the data suggested that propofol induced autophagy in vitro through ER stress, resulting in elevated ROS and Ca 2+ . Additionally, co-administration of an ER stress inhibitor blunted the effect of propofol.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2023
·
IF 4.7
Xiaojing Li,Yichen Bai,Yanju Bi,Qian Wu,Shiwen Xu
Chlorpyrifos (CPF) has caused large-scale pollution worldwide and posed a threat to non-target organisms. Baicalein (BAI) is a flavonoid extract with anti-oxidant and anti-inflammatory activities. The gills are the mucosal immune organ and the first physical barrier of fish. However, it is not clear whether BAI counteracts organophosphorus pesticide CPF exposure-caused gill damage. Therefore, we established the CPF exposure and BAI intervention models by adding 23.2 μg/L CPF in water and/or 0.15 g/kg BAI in feed for 30 days. The results showed that CPF exposure could cause gill histopathology lesions. Moreover, CPF exposure led to endoplasmic reticulum (ER) stress, caused oxidative stress and Nrf2 pathway activation, and triggered NF-κB-mediated inflammation reaction and necroptosis in carp gills. BAI adding effectively relieved the pathological changes, and lighten inflammation and necroptosis involving in the elF2α/ATF4 and ATF6 pathways through binding to GRP78 protein. Moreover, BAI could ease oxidative stress, but did not affect Nrf2 pathway in carp gills under CPF exposure. These results suggested that BAI feeding could alleviate necroptosis and inflammation against chlorpyrifos toxicity through elF2α/ATF4 and ATF6 axis. The results partially explained the poisoning effect of CPF, and showed BAI could be act as an antidote for organophosphorus pesticides.
研究领域:
环境毒理学
·
水生生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
NEOPLASIA
·
2026
·
IF 4.8
Hongming Teng,Yuxin Guo,Xinran Chen,Anlian Fan,Chengfei Zhang,Ting Zhang,Yuanyuan Luo,Lin Huang
Colorectal cancer (CRC) progression could be fueled by the activation of the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress. The proline-rich Akt1 substrate of 40 kDa (PRAS40) is implicated in cancer progression, but its role in the UPR remains unclear. Herein, we demonstrate that PRAS40 promotes the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis-dependent UPR in driving CRC progression. Mechanistically, PRAS40 interacts with ER chaperone glucose-regulated protein 78 (GRP78) and enhances its N-glycosylation. Moreover, PRAS40 improves the interaction between GRP78 and ST6 β-galactoside α-2, 6-sialyltransferase 1 (ST6Gal1), leading to increased α-2, 6-sialylation of GRP78 and the UPR triggered by ER stress. Furthermore, we identified the natural compound β-sitosterol as a novel ST6Gal1 inhibitor, which attenuated PRAS40-triggered tumor growth. Collectively, these findings unveil a PRAS40-ST6Gal1-GRP78 axis that drives CRC progression through activating the IRE1α-XBP-1-mediated UPR and nominate ST6Gal1 as a promising therapeutic target.
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DOI
高影响因子
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