Molecular & Cellular Toxicology
·
2023
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IF 1.7
Hou Xiaochao,Jiang Yujie,Xu Guiping
Background Colon cancer is a malignancy from digestive tract and remains the third most common cancer worldwide. Dexmedetomidine (DEX) can be used for postoperative analgesia in patients with colon cancer and also has biological activities such as anti-oxidative stress, anti-inflammation, and anti-cancer. Objective This study was designed to explore the functions and mechanism of DEX in regulating colon cancer cell proliferation, apoptosis, and autophagy. Results Dex reduced LoVo and HCT116 cell viability in a time- and dose-dependent way. Additionally, DEX suppressed colon cancer cell proliferation while promoting cell apoptosis and autophagy. Moreover, chloroquine (a compound used for inhibition of autophagy) reversed the promoting effect of DEX on colon cancer cell apoptosis. Furthermore, DEX activated the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/activating transcription factor 4 (ATF4) signaling pathway. PERK silencing inhibited DEX-induced cell apoptosis and autophagy. Conclusion This work revealed the anti-cancer effect of DEX treatment by inhibiting colon cancer cell proliferation while promoting cancer cell apoptosis and autophagy via the PERK/eIF2α/ATF4 pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
高影响因子
Molecular Medicine Reports
·
2017
·Vol. 16
·期 6
·9189-9196
·
IF 1.692
Xin Wang,Dalin Jia,Juncheng Zhang,Wei Wang
The aim of the present study was to observe the protective effect of grape seed proanthocyanidins (GSPs) against endoplasmic reticulum (ER) stress‑mediated apoptosis caused by hypoxia/reoxygenation (H/R) injury in H9C2 cardiomyocytes along with its potential mechanisms. H9C2 cardiomyocytes underwent hypoxia for 3 h followed by reoxygenation for 3 h. Different doses of GSPs (50, 100 and 200 µg/ml) were administered 30 min before hypoxia. Cell viability was assessed, as well as lactic dehydrogenase (LDH) activity, cell apoptosis rate, expression levels of glucose‑regulated protein 78 (GRP78), C/EBP‑homologous protein (CHOP), protein kinase RNA‑like ER kinase (PERK), and eukaryotic translation initiation factor‑2 (eIF2α) mRNA and protein. The results revealed that GSPs improved cell viability, reduced LDH activity and reduced the apoptosis rate in cells subjected to H/R, and that the protective effect was most significant when 100 µg/ml in GSPs was administered. GSPs treatment also decreased mRNA and protein expression of GRP78, CHOP, eIF2α and the level of the phosphorylated form of PERK. Furthermore, GSPs displayed a similar protective effect to that of established ER stress inhibitor 4‑phenyl butyric acid. In conclusion, the findings of this study suggest that GSPs may protect H9C2 cardiomyocytes from H/R injury by decreasing ER stress‑mediated apoptosis through the suppression of the PERK/eIF2α signaling pathway.
研究领域:
心脏病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
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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
Frontiers in Endocrinology
·
2025
·
IF 4.6
Congrong Wu,Maomao Sun,Yue He,Jie Jiang,Luran Wang,Yanni Wang,Yonghui Yu
Background: Clinical research has identified a correlation between hypertensive disorders of pregnancy (HDP) and subclinical hypothyroidism during gestation. But the potential influence of HDP on thyroid hormone synthesis remains undetermined.Aims: This study aims to elucidate the impact of HDP on thyroid hormone synthesis and to delineate the underlying mechanisms.Methods: 20 pregnancy SD rats were stratified at random into the HDP group and the Control group. The HDP group was subjected to NG-Nitro-L-arginine-methylester administration from gestational days 13 to 20, while the Control group received saline. Subsequent assessments encompassed serum FT4, FT3, and TSH concentrations, morphological examination of the thyroid, as well as quantification of essential proteins pivotal to thyroid hormone synthesis and markers indicative of endoplasmic reticulum stress.Results: The HDP group exhibited a statistically significant augmentation in serum TSH concentrations (p<0.05), while FT3 and FT4 levels manifested no discernible statistical variations. H&E staining highlighted a pronounced hyperplasia of the follicular epithelial cells and a diminution in the follicle lumen area. Electron microscopy unveiled pronounced endoplasmic reticulum markedly swelling and expansion within the HDP group. Molecular evaluations revealed a decrement in Tg expression within thyroid tissue, concomitant with an upregulated expression of p-PERK, P-eIF2α, and ATF4.Conclusion: This investigation suggests that HDP might modulate Tg expression within thyroid tissue, possibly mediated through the PERK/eIF2α signaling cascade. This perturbation may compromise thyroid hormone synthesis, thereby predisposing pregnant rats to subclinical hypothyroidism.
研究领域:
内分泌学
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生殖医学
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分子生物学
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DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
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2025
·
IF 3.9
Chuang Cui,Hao Liu,Yun-Fei Zhang,Ling-Ke Liu,Hai-Peng Liu
As obligate intracellular pathogens, viruses rely on the endoplasmic reticulum (ER) of host cells for viral protein synthesis and processing, leading to increased ER loading, which in turn triggers ER stress and activates the unfolded protein response (UPR). And this process is intricately linked to both viral infection and the host's immune response. White spot syndrome virus (WSSV) is one of the most detrimental viral pathogens affecting farmed crustaceans such as shrimp and crayfish, but the interaction between WSSV-induced ER stress and viral infection has not been comprehensively investigated. Here, we demonstrated that WSSV infection activated all three UPR pathways, including IRE1 pathway, ATF6 pathway and PERK-eIF2α pathway in crayfish hematopoietic tissue cells. In contrast to the promoted WSSV infection by IRE1 pathway and ATF6 pathway, the activated PERK-eIF2α pathway exhibited an inhibitory effect on viral infection, which was achieved via attenuation of global protein translation of host cells mediated by phosphorylation of eIF2α. Whereas, the continuous expression of WSSV proteins appeared to bypass this translational repression. Collectively, these results emphasized the key role of the PERK-eIF2α pathway, activated by WSSV-induced ER stress, in regulating viral infection, which might constitute an important aspect of the host cell's immune response to viral infection.
研究领域:
病毒学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2023
·Vol. 299
·期 5
·
IF 4.8
Danxue He,Lei Tao,Binxiang Cai,Xiangjun Chen,Yan Wang,Shiying Li,Chunyan Liao,Yuling Chen,Jingmeng Chen,Zuguo Liu,Yalin Wu
Dry age-related macular degeneration (AMD) and recessive Stargardt’s disease (STGD1) lead to irreversible blindness in humans. The accumulation of all-trans-retinal (atRAL) induced by chaos in visual cycle is closely associated with retinal atrophy in dry AMD and STGD1 but its critical downstream signaling molecules remain ambiguous. Here, we reported that activation of eukaryotic translation initiation factor 2α (eIF2α) by atRAL promoted retinal degeneration and photoreceptor loss through activating c-Jun N-terminal kinase (JNK) signaling-dependent apoptosis and gasdermin E (GSDME)-mediated pyroptosis. We determined that eIF2α activation by atRAL in photoreceptor cells resulted from endoplasmic reticulum homeostasis disruption caused at least in part by reactive oxygen species production, and it activated JNK signaling independent of and dependent on activating transcription factor 4 and the activating transcription factor 4/transcription factor C/EBP homologous protein (CHOP) axis. CHOP overexpression induced apoptosis of atRAL-loaded photoreceptor cells through activating JNK signaling rather than inhibiting the expression of antiapoptotic gene Bcl2. JNK activation by eIF2α facilitated photoreceptor cell apoptosis caused by atRAL via caspase-3 activation and DNA damage. Additionally, we demonstrated that eIF2α was activated in neural retina of light-exposed Abca4−/−Rdh8−/− mice, a model that shows severe defects in atRAL clearance and displays primary features of human dry AMD and STGD1. Of note, inhibition of eIF2α activation by salubrinal effectively ameliorated retinal degeneration and photoreceptor apoptosis in Abca4−/−Rdh8−/− mice upon light exposure. The results of this study suggest that eIF2α is an important target to develop drug therapies for the treatment of dry AMD and STGD1.
研究领域:
眼科学
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分子生物学
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细胞生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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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
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 Stem Cell
·
2022
·
IF 25.269
Changzheng Li,Binghuo Wu,Yishan Li,Jie Chen,Zhitao Ye,Xiaobin Tian,Jin Wang,Xi Xu,Shuai Pan,Yucan Zheng,Xiongwei Cai,Linjia Jiang,Meng Zhao
Summary Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD + precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.
研究领域:
血液学
·
干细胞生物学
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代谢
·
蛋白质合成调控
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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
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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
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药理学
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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
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