ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
·
IF 6.1
Jiayi He,Zuqing Hu,Zhenjie Gao,Renyi Liu,Zhujun Kang,Shuyi Lan,Yang Wang,Shanshan He,Hongyi Xian,Fatoumata Diallo,Yunxia Jiang,Jiguo Wu,Suli Huang,Ziquan Lv,Dalin Hu
Lead is an important heavy metal material and also an omnipresent environmental pollutant, which poses extensive hazards to human health, including its nephrotoxicity. However, there are still many unknowns regarding its toxic mechanism and intervention strategy. Here, we revealed that lead exposure promoted the activation of PERK in HK - 2 cells (p - PERK and the ratio of p - PERK / PERK increased), enhanced the expression of its molecular chaperone binding immunoglobulin protein (BIP) and its downstream signaling molecule CCAAT / enhancer - binding protein homologous protein (CHOP). This indicated that lead exposure resulted in the occurrence of the unfolded protein response (UPR) in HK - 2 cells. Further, lead induced significant DNA damage, oxidative stress and apoptosis in HK-2 cells. Especially, when human umbilical cord mesenchymal stem cell - derived exosomes (hucMSC - exos) were ingested by HK-2 cells, all the levels of p - PERK, p - PERK / PERK ratio, BIP and CHOP were significantly down - regulated, which suggested that the UPR was significantly alleviated. Simultaneously, the above-mentioned toxic effects of lead were significantly reduced. Moreover, when GSK2606414 was employed to block the phosphorylation of PERK, the toxic effects of lead were also significantly alleviated. Hence, we conclude that hucMSC - exos can alleviate the toxicity of lead to HK-2 cells via interfering with the UPR, in which PERK plays a crucial role, and it may be a promising target for intervening in the toxicity of lead.
研究领域:
毒理学
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细胞生物学
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环境卫生
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干细胞研究
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Xiuya Guan,Mengkai Lu,Xinhai Cui,Dawei Zhang,Lei Zhang,Lin Lin,Yuan Li,Yuanlong Hu,Chao Li
Atherosclerosis is a chronic inflammatory disease driven by senescent vascular smooth muscle cells (VSMCs). Salvianolic acid A (SAA) exhibits cardiovascular protective effects; however, its role in atherosclerosis remains unclear. This study aimed to investigate the effects and targets of SAA in atherosclerosis. In vitro studies were performed in senescent VSMCs with heat shock protein 90 alpha (HSP90α) overexpression or knockdown, with or without SAA treatment. In vivo, ApoE −/− mice fed a high‐fat diet were treated with SAA and adeno‐associated virus‐mediated VSMC‐specific HSP90α overexpression or knockdown. SAA promoted apoptosis in senescent VSMCs by inhibiting HSP90α. This inhibition promoted ubiquitin‐proteasome‐dependent degradation of protein kinase B (AKT) and activation of PRKR‐Like Endoplasmic Reticulum Kinase (PERK) signaling. SAA increased endoplasmic reticulum‐mitochondrial contacts and mitochondrial calcium uptake. These effects were reversed by HSP90α overexpression. In ApoE −/− mice, SAA reduced the burden of senescent VSMCs, decreased the size of plaque, and increased the stability of the fibrous cap. VSMC‐specific HSP90α knockdown mimicked the protective effects of SAA, whereas HSP90α overexpression reversed SAA‐mediated effects on disease. SAA reduces the burden of senescent VSMCs in atherosclerosis by inhibiting the scaffold function of HSP90α which maintains the AKT‐PERK interaction, to reactivate PERK signaling, thereby alleviating disease progression. Salvianolic acid A (SAA) selectively induces senescent vascular smooth muscle cell apoptosis, alleviating atherosclerosis. Mechanistically, SAA targets heat shock protein 90 alpha (HSP90α) to disrupt the protein inase B (AKT)‐PRKR‐Like Endoplasmic Reticulum Kinase (PERK) scaffold, driving ubiquitin‐proteasome‐dependent AKT degradation. This pathway reactivates PERK signaling, enhances endoplasmic reticulum‐mitochondria contact area, and increases mitochondrial calcium uptake, offering a promising senolytic approach for cardiovascular protection.
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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.
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产品关联
DOI
高影响因子
BRAIN RESEARCH BULLETIN
·
2024
·
IF 3.5
Yuqian Zhang,Shenghan Gao,Shengnan Xia,Haiyan Yang,Xinyu Bao,Qingxiu Zhang,Yun Xu
Due to various factors, there is still a lack of effective neuroprotective agents for ischemic stroke in clinical practice. Neuroinflammation and neuronal apoptosis mediated by endoplasmic reticulum stress are some of the important pathological mechanisms in ischemic stroke. Linarin has been reported to have anti-inflammation, antioxidant, and anti-apoptotic effects in myocardial ischemia, osteoarthritis, and kidney disease. Whether it exerts neuroprotective functions in ischemic stroke has not been investigated. The results showed that linarin could reduce the infarct volume in cerebral ischemia animal models, improve the neurological function scores and suppress the expression of inflammatory factors mediating the NF-κB. Meanwhile, it could protect the neurons from OGD/R-induced-apoptosis, which was related to the PERK-eIF2α pathway. Our results suggested linarin could inhibit neuronal inflammation and apoptosis induced by endoplasmic reticulum stress. Furthermore, the neuroprotective effect of linarin may be related to the inhibition of AKR1B1. Our study offers new insight into protecting against ischemia-reperfusion injury by linarin treatment in stroke.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2021
·
IF 5.858
Xiaohua Lu,Ge Yan,Sabine M. Klauck,Edmond Fleischer,Anette Klinger,Yoshikazu Sugimoto,Letian Shan,Thomas Efferth
After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G 2 M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.
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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.
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产品关联
DOI
PubMed
高影响因子
Advanced Therapeutics
·
2024
·Vol. 7
·期 8
·2400045
·
IF 3.7
Shanshan Wang,Zhiqiang Bi,Tianming Lu,Ruoning Qian,Jie Yu,Qiang Zhang,Hao Yang,Wenli Lu,Yuanyuan Guo,Xiaoqing Xin,Yong Bian,Ruogu Qi
Colorectal cancer (CRC) stands out as one of the most prevalent gastrointestinal cancers. Current treatment strategies for CRC are significantly hindered by systemic toxicity and suboptimal therapeutic efficacy. This study aims to overcome these limitations by developing a robust tumor-targeting chemo-photothermal strategy, combining Bortezomib (BTZ) as a proteasome inhibitor, IR780 iodide as a near-infrared dye, and Photothermal Therapy (PTT) agent, with hyaluronic acid (HA) serving as the shell for tumor targeting, denoted as HA/PB@IR780. The investigations reveal the impressive tumor-targeting affinity of HA/PB@IR780, leading to a synergistic chemo-photothermal therapeutic effect both in vitro and in vivo. Additionally, this material demonstrates the capability for drug release triggered by low pH conditions. Moreover, HA/PB@IR780 induced the generation of reactive oxygen species (ROS), triggered cells apoptosis via the PERK-CHOP-Bcl-2 pathway, and induced Immunogenic Cell Death (ICD) in CT26 cells. Importantly, HA/PB@IR780 selectively targets tumor sites, mitigating systemic toxic side effects and significantly extending the survival of CT26 tumor-bearing mice. In conclusion, this designed tumor-targeting nanocarrier represents a promising and potentially effective platform for the precise treatment of CRC.
研究领域:
肿瘤学
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纳米技术
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药理学
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细胞生物学
·
治疗学
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产品关联
DOI
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-16
·
IF 39.3
Cui Bopei,Song Lifang,Wang Qian,Li Kelei,He Qian,Wu Xing,Gao Fan,Liu Mingchen,An Chaoqiang,Gao Qiushuang,Hu Chaoying,Hao Xiaotian,Dong Fangyu,Zhou Jiuyue,Liu Dong,Song Ziyang,Yan Xujia,Zhang Jialu,Bai Yu,Mao Qunying,Yang Xiaoming,Liang Zhenglun
With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.
研究领域:
肿瘤学
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病毒学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
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