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
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免疫治疗
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纳米技术
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细胞生物学
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分子生物学
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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.
研究领域:
肿瘤学
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药理学
·
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
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2018
·
IF 3.974
Peng Chen,Na Geng,Dong Zhou,Yiran Zhu,Yuliang Xu,Kangping Liu,Yongxia Liu,Jianzhu Liu
Hexavalent chromium (Cr(VI)) is a common environmental pollutant. Exposure of Cr(VI) can lead to cell autophagy, but the preventive measures for diminishing Cr(VI)-induced autophagy need further study. COX-2 can be induced by several heavy metals and can lead to endoplasmic reticulum (ER) stress and autophagy; thus, COX-2, ER stress, and autophagy may be related. This study mainly investigated the role of COX-2 in the eIF2α-ATF4 pathway, which is a major pathway in cell autophagy. In this study, Cr(VI) was used as a xenobiotic to determine changes in the parameters of ER stress, autophagy, and COX-2 levels. At the same time, a clear contrast was obtained by assigning positive and negative controls of ER stress and autophagy. The results showed that during Cr(VI) invasion, the parameters of ER stress and autophagy (such as BiP, PERK, p62, LC3-II, and mTOR) were enhanced, similarly to the positive control of ER stress and/or the autophagy controls. Such enhancement is a protective mechanism for cell survival. Additionally, the COX-2 levels increased. Moreover, when COX-2 was inhibited, the PERK level remained high, whereas the LC3-II level decreased. This finding suggests that COX-2 specifically affects the interaction between ER stress and autophagy. Notably, this study reveals that Cr(VI) can induce ER stress and autophagy in DF-1 cells and that COX-2 plays an essential role in the interaction between ER stress and autophagy.
研究领域:
毒理学
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细胞生物学
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环境科学
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DOI
PubMed
高影响因子
FEBS LETTERS
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2015
·Vol. 590
·期 1
·22-33
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IF 3.169
Xue Fu,Xingjie Gao,Lin Ge,Xiaoteng Cui,Chao Su,Wendong Yang,Xiaoming Sun,Wei Zhang,Zhi Yao,Xi Yang,Jie Yang
Malonate, a classic inhibitor of respiratory electron transport chain, induces mitochondrial stress. Stress granules (SGs) are a kind of dynamic foci structure during stress. The study on the connection of mitochondrial stress and SG assembly is still limited. Here, we demonstrated that malonate treatment leads to SG formation and translation inhibition, apart from mitochondrial stress, including enhanced ROS formation, reduced mitochondrial Δψ m and ATP level. The phosphorylation levels of eIF2α and 4EBP1 protein were affected upon mitochondrial dysfunction. However, knockdown of 4EBP1 affected SG formation, rather than eIF2α. In addition, an increase of ATP level under mitochondrial stress enhanced malonate-induced SG aggregation. Overall, malonate stimulation triggers mitochondrial stress and induces the assembly of non-canonical cellular SGs via 4EBP1 pathway.
研究领域:
细胞生物学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2023
·Vol. 42
·期 12
·711-719
·
IF 3.1
Shoudi He,Changsheng Huang,Ning Tan,Jianyong Zhang
Oridonin (ORI), derived from Chinese herbs Rabdosia rubescens, has anti-inflammatory, proapoptotic, anticancer effects. Previous studies have found that ORI induces apoptosis in rheumatoid arthritis fibroblast synovial cells (RA-FLSs), but this mechanism is not clear. We will investigate the apoptosis mechanism of ORI on RA-FLSs. RA-FLSs were treated with various concentrations of ORI (0, 5, 10, 15, 20, 25, and 30 μM) for 24 h. CCK8, LDH, and hochest/PI assay determined the viability, cytotoxicity, and death of ORI on RA-FLSs. The endoplasmic reticulum probe was used to observe structural changes of endoplasmic reticulum in RA-FLSs. RNA expression was detected with RNA sequencing analysis and quantitative real-time PCR. The PERK/eIF2α/CHOP pathway protein of the endoplasmic reticulum was verified with Western Blot. Our results show that ORI induced the apoptosis of RA-FLSs from CCK8, LDH, and Hochest/PI. The endoplasmic reticulum distribution was altered in RA-FLSs after being treated with ORI. Bioinformatics analysis of RNA sequencing data found that 1453 genes were elevated. The PERK/eIF2α/CHOP pathway of the endoplasmic reticulum was regulated from the Gene ontology and KEGG analysis. The results of quantitative real-time PCR and Western blot analysis verified the regulation of PERK/eIF2α/CHOP pathway in RA-FLSs. Our data imply that the endoplasmic reticulum's PERK/eIF2α/CHOP signaling pathway is certainly implicated in the induction of RA-FLS apoptosis by ORI. This study has important implications for the pharmacological effects of ORI and the treatment of RA.
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2020
·Vol. 42
·期 2
·290-300
·
IF 5.064
Yu Xiao-xuan,Zhu Meng-yuan,Wang Jia-rong,Li Hui,Hu Po,Qing Ying-jie,Wang Xiang-yuan,Wang Hong-zheng,Wang Zhan-yu,Xu Jing-yan,Guo Qing-long,Hui Hui
Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC 50 values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP 3 R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP 3 R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.
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PubMed
高影响因子
PeerJ
·
2024
·
IF 2.3
Lingmin Zhang,Jianguo Zhang,Yingying Zhou,Qingqing Xia,Jing Xie,Bihong Zhu,Yang Wang,Zaixing Yang,Jie Li
Background Cadmium (Cd) is hazardous to human health because of its cytotoxicity and long biological half-life. Azoramide is a small molecular agent that targets the endoplasmic reticulum (ER) and moderates the unfolded protein response. However, its role in Cd-induced cytotoxicity remains unclear. This study was performed to investigate the protective effect of azoramide against Cd-induced cytotoxicity and elucidate its underlying mechanisms. Methods Inductively coupled plasma‒mass spectrometry was used to measure Cd concentrations in each tissue of ICR male mice. The human proximal tubule epithelial cell line HK-2 and the human retinal pigment epithelial cell line ARPE-19 were used in the in vitro study. Cell apoptosis was determined by DAPI staining, JC-1 staining, and annexin V/propidium iodide double staining. Intracellular oxidative stress was detected by MitoSOX red staining, western blot, and quantitative real-time PCR. Moreover, ER stress signaling, MAPK cascades, and autophagy signaling were analyzed by western blot. Results The present data showed that Cd accumulated in various organs of ICR mice, and the concentrations of Cd in the studied organs, from high to low, were as follows: liver > kidney > testis > lung > spleen > eye. Our study demonstrated that azoramide inhibited ER stress by promoting BiP expression and suppressing the PERK-eIF2α-CHOP pathway. Additionally, we also found that azoramide significantly decreased ER stress-associated radical oxidative species production, attenuated p38 MAPK and JNK signaling, and inhibited autophagy, thus suppressing apoptosis in HK-2 and ARPE-19 cells. Conclusion Our study investigated the effect of azoramide on Cd-induced cytotoxicity and revealed that azoramide may be a therapeutic drug for Cd poisoning.
研究领域:
毒理学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Hongwen Liu,Lei Xu,Yiyang Zhang,Yiqiong Xie,Lishan Wang,Yue Zhou,Zhangding Wang,Yani Pan,Wenying Li,Lu Xu,Xinyun Xu,Ting Wang,Kui Meng,Jian He,Yudong Qiu,Guifang Xu,Weihong Ge,Yun Zhu,Lei Wang
Chemotherapy-induced adaptive resistance is a significant factor that contributes to low therapeutic efficacy in tumor cells. The unfolded protein response (UPR) is a key mechanism in the development of drug resistance and serves as a critical reactive system for endoplasmic reticulum stress. Cu(II) can reduce the abundance of 60S ribosomal subunits and inhibit rRNA processing, leading to a decrease in the translation efficiency of the GRP78/BiP mRNA, which serves as a primary sensor for UPR activation. In this study, CuET-Lipid@Cela, composed of CuET and tripterine (Cela), demonstrates a significant synergistic antitumor effect on cholangiocarcinoma (CCA) cells. RNA-Seq is used to investigate the underlying mechanism, which suggests that the transmembrane protein 2 (TMX2) gene may be crucial in Cu(II) regulation of UPR by inhibiting the activation of GRP78/BiP and PERK/eIF2 α . The synergistic antitumor efficacy of CuET-Lipid@Cela via inhibition of TMX2 is also confirmed in a myrAKT/YapS127A plasmid-induced primary CCA mouse model, providing new insights into the reversal of acquired chemotherapy-induced resistance in CCA.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-12
·
IF 3.8
Hu Deliang,Yang Yuqing,Fang Lei,Fan Shijie,Lin Ling,Luo Puying,Xiong Yuanhuan,Su Yufang
Isoliquiritigenin (ISL), a naturally occurring flavonoid derived from licorice root, exhibits antioxidant, anticancer, anti-inflammatory, and anti-allergic properties, and is frequently detected in both environmental and human samples. Previous studies from our lab have demonstrated that ISL exposure can lead to developmental deformities and aberrant immune responses. However, the molecular mechanisms underlying ISL toxicity in zebrafish embryos remain incompletely elucidated. Therefore, this study aimed to elucidate the effects of ISL exposure on endoplasmic reticulum (ER) stress in zebrafish embryos by assessing the expression levels of ER stress markers HSPA5 and CHOP , along with associated apoptosis factors, under various ISL concentrations, with tunicamycin (TM) serving as a positive control. Furthermore, targeted analyses of ER stress-related pathways were conducted using RNA transcriptome sequencing, and the up-regulated gene was verified by western blot. The results revealed that ISL exposure significantly elevated the expression levels of HSPA5 and CHOP , concomitantly activating ER stress pathways, including pPERK-eIF2α-ATF4 and ATF6 pathways in zebrafish embryos. These findings suggest that the activation of endoplasmic reticulum stress signaling pathways may contribute to the developmental deformities observed in zebrafish embryos following ISL exposure, thereby highlighting the potential ecological risks associated with ISL usage.
研究领域:
毒理学
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发育生物学
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分子生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Nianxiu Tian,Yanbin Gao,Xiaolei Wang,Xiaoming Wu,Dawei Zou,Zhiyao Zhu,ZheJi Han,Tao Wang,Yimin Shi
Background Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown.Aim This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK–eIF2α pathway.Methods KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopathology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time PCR were used to detect gene and protein expression both in vivo and in vitro.Results The results showed that emodin treatment ameliorated urine albumin, serum creatinine, and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes apoptosis and endoplasmic reticulum stress markers (GRP78) were significantly reduced upon emodin treatment. Furthermore, emodin treatment decreased the expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (P-PERK), phosphorylated P-eIF2α, ATF4, and CHOP. In vitro, emodin treatment was further found to decrease the GRP78 level induced by high glucose or tunicamycin (TM). Besides, emodin and PERK knockdown inhibited the apoptosis of podocytes cultured in high glucose by counteracting the upregulation of phosphorylated PERK, phosphorylated eIF2α, ATF4, and CHOP.Conclusion Overall, the findings indicate that emodin mitigates podocytes apoptosis by inhibiting the PERK-eIF2α signaling pathway in vivo and in vitro, and, therefore, exerts a protective action on podocytes in DN.
研究领域:
药理学
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肾病学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
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
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Jing Cong,Yuehui Zhang,Xinming Yang,Yu Wang,Hui He,Mengying Wang
Polycystic ovary syndrome (PCOS) is a complicated endocrinopathy affecting women at reproductive age. Increasing evidence has shown the anti-PCOS effect of electroacupuncture (EA), a modified approach of traditional Chinese medical therapy “acupuncture”. However, the underlying mechanism of EA-alleviated PCOS waits further explored. In this study, experimental PCOS were induced in rats by dehydroepiandrosterone (DHEA) injection. Testosterone (T)-induced human ovarian granulosa cell (GC) line KGN was used to mimic PCOS in vitro . EA significantly alleviated histological changes and hormone disruption in PCOS rats. Besides, EA inhibited cell apoptosis, autophagy and the activation of endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4/CHOP signaling in ovaries of PCOS rats. More interestingly, intermedin (IMD), a member of calcitonin gene-related peptide (CGRP), was evidently up-regulated in ovarian GCs after EA treatment, and its main bioactive form IMD 1-53 suppressed cell apoptosis, autophagy and PERK/eIF2α/ATF4/CHOP signaling in T-induced KGN cells. Consistent with IMD 1-53 , ER stress inhibitor 4-PBA exerted an inhibitory effect on T-induced cell apoptosis and autophagy in KGN cells. Collectively, this study validates the protective effect of EA on DHEA-induced PCOS, and proposes that IMD relieved apoptosis and autophagy in T-induced granulosa cells via inhibiting ER stress.
研究领域:
生殖医学
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内分泌学
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分子生物学
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中医学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）