Science Advances
·
2019
·Vol. 5
·期 5
·
IF 12.804
Xin Xie,Hai-Lian Bi,Song Lai,Yun-Long Zhang,Nan Li,Hua-Jun Cao,Ling Han,Hong-Xia Wang,Hui-Hua Li
Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit β5i were significantly up-regulated in angiotensin II (Ang II)–treated cardiomyocytes and in the hypertrophic hearts. Knockout of β5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by β5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, β5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the β5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for β5i in the regulation of cardiac hypertrophy. The inhibition of β5i activity may provide a new therapeutic approach for hypertrophic diseases.
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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PubMed
高影响因子
International Journal of Biological Sciences
·
2024
·Vol. 20
·期 8
·2904-2921
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IF 8.2
Xiong Tianxin,Li Yi,Yang Molin,Huo Bo,Guo Xian,Liu Liyuan,Huang Yanxin,Zhu Xuehai,Hu Qinghua,Wei Xiang,Jiang Ding-Sheng,Yi Xin
Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the critical pathological mechanisms of pulmonary hypertension (PH), and therefore is gradually being adopted as an important direction for the treatment of PH. Metallothioneins (MTs) have been reported to be associated with PH, but the underlying mechanisms are not fully understood. Here, we demonstrated that the expression level of metallothionein 3 (MT3) was significantly increased in pulmonary arterioles from PH patients and chronic hypoxia-induced rat and mouse PH models, as well as in hypoxia-treated human PASMCs. Knockdown of MT3 significantly inhibited the proliferation of human PASMCs by arresting the cell cycle in the G1 phase, while overexpression of MT3 had the opposite effect. Mechanistically, we found that MT3 increased the intracellular zinc (Zn2+) concentration to enhance the transcriptional activity of metal-regulated transcription factor 1 (MTF1), which promoted the expression of autophagy-related gene 5 (ATG5), facilitating autophagosome formation. More importantly, MT3-induced autophagy and proliferation of human PASMCs were largely prevented by knockdown of MTF1 and ATG5. Therefore, in this study, we identified MT3-Zinc-MTF1-ATG5 as a novel pathway that affects PASMC proliferation by regulating autophagosome formation, suggesting that MT3 may be a novel target for the treatment of PH.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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病理生理学
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DOI
高影响因子
Journal of Functional Foods
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2023
·
IF 5.6
Qiang Yin,Ran Yan,Yan Wang,Jia Yu
Gatrodin is an active compound with cardio-protective potentials. In the current study, the mechanism underlying the effects of gastrodin was explored. Myocardial infarction was induced and handled with gastrodin. The role of miR-30a-5p and its downstream effector, ATG5, in the cardio-protective effects of gastrodin was verified. Gastrodin induced the dys-expresseion of 72 miRs in oxygen/glucose deprivation (OGD) cardiomyocytes and miR-30a-5p was selected as the potential therapeutic target. Gastrodin increased viability and suppressed autophagy in OGD cardiomyocytes, which was associated with the induction of miR-30a-5p and deactivation of ATG5. In rat models, gastrodin attenuated structure deterioration and dysfunction in heart, and suppressed autophagy. At molecular level, miR-30a-5p was induced and ATG5 were down-regulated. After the suppression of miR-30a-5p or the overexpression of ATG5, the cardio-protective effects of gastrodin were compromised. Gastrodin induced the expression of miR-30a-5p, which contributed to the attenuation of autophagy in infarcted heart tissues.
研究领域:
药理学
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心脏病学
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分子生物学
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高影响因子
DNA AND CELL BIOLOGY
·
2022
·Vol. 41
·期 12
·1038-1052
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IF 3.55
Qianyu Tang,Wenhui Liu,Xuefeng Yang,Yaying Tian,Jiacheng Chen,Yang Hu,Nian Fu
Despite activated autophagy ameliorating hepatocyte steatosis and metabolic associated fatty liver disease (MAFLD), mechanisms underlying the beneficial roles of autophagy in hepatic deregulation of lipid metabolism remain undefined. We explored whether autophagy can ameliorate oleic acid (OA)-induced hepatic steatosis by suppressing pyroptosis. Pyroptosis is involved in hepatocyte steatosis induced by OA. In addition, autophagy flux was blocked in OA-treated hepatocytes. Treatment with OA induced lipid accumulation in liver cell line L-02, which was attenuated by rapamycin (Rap), an autophagy agonist, while aggravated by autophagy inhibitor bafilomycin A1 (Baf A1). Inversely, treatment with pyroptotic agonist Nigericin aggravated OA-induced hepatic steatosis, while pyroptosis antagonist disulfiram ameliorated this effect. Mechanistically, treatment with Rap downregulated the expression of pyroptosis-related proteins, including NLRP3, Caspase-1, IL-18, GSDMD expression evoked by OA, thus improving pyroptosis in hepatic steatosis. Significantly, overexpression of ATG5 obviously downregulated cleaved caspase-1 expressions without altering the total caspase1 expressions in hepatic cell steatosis. Taken together, our studies strongly demonstrated that the activation of ATG5 inhibits pyroptosis to improve hepatic steatosis and suggest autophagy activation as a potential therapeutic strategy for pyroptosis-mediated MAFLD.
研究领域:
肝脏病学
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细胞生物学
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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
EXPERIMENTAL CELL RESEARCH
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2023
·
IF 3.7
Yuehao Tan,Can Li,Jiali Zhou,Fengmei Deng,Yilun Liu
Berberine (BBR) is an effective drug against liver fibrosis (LF). Autophagy is involved in the pathogenesis of LF; however, the mechanism linking BBR to autophagy in LF remains unresolved. To explore the underlying mechanism, we assessed the effects of BBR on autophagy and apoptosis of activated hepatic stellate cells (HSCs) in vitro and in a murine model of fibrosis. The decreased expression of the autophagy activation marker ATG5 , autophagosome formation, and autophagy flux in the HSC model confirmed that BBR inhibited autophagy in activated HSCs and in mice with liver fibrosis. Moreover, ATG5 was necessary for inducing autophagy and HSC activation. BBR suppressed ATG5 expression by upregulating miR-30a-5p expression, which affected the stability of ATG5 mRNA by binding to its 3′-untranslated region, an effect that was attenuated by treatment with a miR-30a-5p inhibitor. BBR also markedly induced HSC apoptosis, as indicated by the upregulated expression of the pro-apoptosis markers p53, BAX, and cleaved PARP and the downregulated expression of the anti-apoptosis marker BCL-2, effects that were reversed by ATG5 overexpression. In vivo, BBR improved mouse LF by decreasing collagen deposition, inflammatory cell infiltration , and expression of fibrosis markers hydroxyproline, α-smooth muscle actin, and collagen type 1-A1 and the autophagy marker LC3. BBR had a protective effect on mouse fibrotic livers and reduced serum aspartate aminotransferase and alanine aminotransferase levels . Collectively, these results reveal a novel mechanism of BBR-induced autophagy inhibition triggering apoptosis in HSCs, providing a reliable experimental and theoretical basis for developing BBR-based candidate drugs for LF.
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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肝病学
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DOI
PubMed
高影响因子
Autophagy
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2022
·
IF 13.391
Jiawen Fu,Lin Zhao,Yu Pang,Heming Chen,Hayashi Yamamoto,Yuntong Chen,Zhaoran Li,Noboru Mizushima,Honglin Jia
In apicomplexan parasites, the macroautophagy/autophagy machinery is repurposed to maintain the plastid-like organelle apicoplast. Previously, we showed that in Toxoplasma and Plasmodium, ATG12 interacts with ATG5 in a non-covalent manner, in contrast to the covalent interaction in most organisms. However, it remained unknown whether apicomplexan parasites have functional orthologs of ATG16L1, a protein that is essential for the function of the covalent ATG12–ATG5 complex in vivo in other organisms. Furthermore, the mechanism used by the autophagy machinery to maintain the apicoplast is unclear. We report that the ATG12–ATG5-ATG16L complex exists in Toxoplasma gondii (Tg). This complex is localized on isolated structures at the periphery of the apicoplast dependent on TgATG16L. Inducible depletion of TgATG12, TgATG5, or TgATG16L caused loss of the apicoplast and affected parasite growth. We found that a putative soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) protein, synaptosomal-associated protein 29 (TgSNAP29, Qbc SNARE), is required to maintain the apicoplast in T. gondii. TgSNAP29 depletion disrupted TgATG8 localization at the apicoplast. Additionally, we identified a putative ubiquitin-interacting motif-docking site (UDS) of TgATG8. Mutation of the UDS site abolished TgATG8 localization on the apicoplast but not lipidation. These findings suggest that the TgATG12–TgATG5-TgATG16L complex is required for biogenesis of the apicoplast, in which TgATG8 is translocated to the apicoplast via vesicles in a SNARE -dependent manner in T. gondii.Abbreviations: AID: auxin-inducible degron; CCD: coiled-coil domain; HFF: human foreskin fibroblast; IAA: indole-3-acetic acid; LAP: LC3-associated phagocytosis; NAA: 1-naphthaleneacetic acid; PtdIns3P: phosphatidylinositol-3-phosphate; SNARE: soluble N-ethylmaleimide sensitive factor attachment protein receptor; UDS: ubiquitin-interacting motif-docking site; UIM: ubiquitin-interacting motif.
研究领域:
分子生物学
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细胞生物学
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寄生虫学
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微生物学
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DOI
PubMed
高影响因子
Journal of Advanced Research
·
2026
·
IF 17.1
Weichen Dong,Wenxin Zhang,Li Huang,Lulu Xiao,Yuanfei Luo,Linying Yuan,Yike Jiang,Anyu Liao,Hongting Zhao,Zhihui Liu,Jia Wang,Ying Zhao,Yulong Cai,Mengna Peng,Dong Yang,Yi Xie,Kuanyu Li,Wusheng Zhu
Introduction Cardiolipins (CLs) are mitochondria-specific phospholipids critically involved in neurological disorders. However, their role in cerebral ischemia/reperfusion (I/R) injury remains largely underexplored. Objectives This study aimed to characterize CL alterations following cerebral I/R injury, identify potential mechanisms underlying CL loss, and investigate the pathophysiological effects of these changes. Methods Ischemic stroke was modeled by using middle cerebral occlusion/reperfusion (MCAO/R) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro . CL alterations following cerebral I/R injury were evaluated through lipidomic analysis and fluorescent staining. The role of extracellular vesicles (EVs) in CL release was investigated. The effects of CL-targeting peptide SS-31 on CL release and homeostasis were assessed, and underlying mechanisms were explored by analyzing neuronal autophagy and ferroptosis. Plasma CL levels in stroke patients were also measured to elucidate clinical relevance. Results Significant CL depletion and acyl chain remodeling were observed in peri -infarct brain tissues. EV-mediated release was identified as one of the mechanisms of CL loss, and inhibiting EV release restored neuronal CL levels. SS-31 inhibits CL release, preserves CL content, and subsequently restores CL homeostasis. Restoring CL homeostasis attenuated cerebral I/R injury by suppressing neuronal ferroptosis. Mechanistically, SS-31 downregulated autophagy-associated genes, with ATG5 identified as the crucial target. Activating autophagy or overexpressing ATG5 reversed the protective effects of SS-31. Clinically, plasma CL levels in patients undergoing endovascular treatment correlated with 90-day functional outcomes. Conclusion Our findings establish CL preservation as a novel neuroprotective strategy, in which SS-31 mitigates I/R injury by restoring CL homeostasis and ameliorating ATG5-mediated autophagy-dependent neuronal ferroptosis, offering a novel therapeutic avenue for stroke.
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高影响因子
Autophagy
·
2018
·
IF 11.1
Li Yang,Bing Han,Yuan Zhang,Ying Bai,Jie Chao,Gang Hu,Honghong Yao
Endothelial-mesenchymal transition (EndoMT) is associated with damage to blood-brain barrier (BBB) integrity. Circular RNAs (circRNAs) are highly expressed in the brain and are involved in brain diseases; however, whether circRNAs regulate the EndoMT in the brain remains unknown. Our study demonstrated that circHECW2 regulated the EndoMT by directly binding to MIR30D, a significantly downregulated miRNA from miRNA profiling, which subsequently caused an increased expression of ATG5. These findings shed new light on the understanding of the noncanonical role of ATG5 in the EndoMT induced by methamphetamine (Meth) or lipopolysaccharide (LPS). The in vivo relevance was confirmed as microinjection of circHecw2 siRNA lentivirus into the mouse hippocampus suppressed the EndoMT induced by LPS. These findings provide novel insights regarding the contribution of circHECW2 to the nonautophagic role of ATG5 in the EndoMT process in the context of drug abuse and the broad range of neuroinflammatory disorders.
研究领域:
神经科学
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分子生物学
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药理学
·
炎症
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DOI
PubMed
高影响因子
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
·
2015
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IF 2.415
Haibo Mu,Qianjin Liu,Hong Niu,Dongdong Wang,Jiangjiang Tang,Jinyou Duan
Toxic DNA–protein crosslinks (DPCs) can result from exposure to radiation or chemotherapeutic agents. DPCs can also accumulate during aging or stress. However, the cellular mechanisms underlying clearance of DPCs remain largely unknown. Here, we have identified an important role of autophagy in the processing of DPCs induced by three representative agents: formaldehyde, a chemical used widely in industry; UV light; and camptothecin, a cytotoxic anticancer drug. Autophagy inhibitors, 3-methyladenine (3-MA) or chloroquine (CQ), promoted the accumulation of DPCs in damaged cells and injured organs. siRNA-mediated silencing of Atg5 or Atg7, two essential components for the formation of the autophagosome, gave similar results. In contrast, the autophagy inducer rapamycin (RAP) attenuated DPCs in vitro and in vivo . Our findings reveal the importance of autophagy in controlling the level of DPCs, and may open up a new avenue for understanding the formation and clearance of this detrimental DNA adduct.
研究领域:
细胞生物学
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分子生物学
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癌症研究
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衰老研究
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Sijia Weng,Hongmei Chen,Junli Wang,Jianjun Yang,Shuoyu Qiu,Yufeng Liu,Tongbo Zhu
Over the past four decades, efforts to improve the prognosis of pancreatic cancer have yielded limited progress, largely due to the complex genetic mutations, a desmoplastic tumor microenvironment, and the rapid metabolic rewiring that enables pancreatic cancer cells to adapt to cellular stress. Recent studies have demonstrated the critical reliance of pancreatic cancer cells on autophagy for survival, fitness, and the development of resistance to various clinical therapies. These findings position autophagy as a potential therapeutic vulnerability for the development of novel neoadjuvant treatments. However, conventional autophagy inhibition often leads to the accumulation of p62, which activates p62-dependent pathways that promote tumor growth and metastasis, thereby limiting the efficacy of autophagy-targeting therapies. In this study, we demonstrate that the atypical protein kinase C isoform zeta (PKCζ) plays a pivotal role in maintaining intracellular homeostasis in pancreatic ductal adenocarcinoma (PDAC) cells. Inhibition of PKCζ downregulates BCL-2-associated athanogene 3 (BAG3), reduces the expression of key autophagy-related proteins, autophagy related 5 (ATG5) and Beclin-1, and attenuates autophagic flux. Notably, PKCζ-mediated autophagy suppression does not result in p62 accumulation, circumventing the pro-tumorigenic effects associated with conventional autophagy inhibition. Furthermore, PKCζ inhibition enhances the anti-tumor efficacy of other chemotherapeutic agents, such as mitogen-activated protein kinase kinase (MEK) inhibitors, in PDAC. These findings identify PKCζ as a promising therapeutic target and provide a foundation for the development of innovative treatment strategies for pancreatic cancer.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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肿瘤学
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药理学
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信号转导
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2023
·
IF 3.4
Saijuan Li,Fangge Wu,Pengcheng Gao,Can Jin,Yuyong Wang,Wenfeng Liao,Kan Ding
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aβ clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycane on Aβ 42 secretion and the underlying mechanism. Briefly, we extracted a novel peptidoglycan named SA02C using hot water extraction and alcohol precipitation with the Mw of 13.72 kDa. SA02C contains 73.33% carbohydrate and 27.83% protein. The structure characterization revealed that its glycan part might mainly composed of galacturonic acid with minor rhamnose in backbone, and branched with glucose, galactose, arabinose, xylose and galacturonic acid. The protein or peptide moiety in SA02C was bonded to the polysaccharide via threonine. Bioactivities test showed that SA02C could reduce Aβ 42 production in a dose dependent manner with no obvious cytotoxicity. Mechanism study demonstrated that SA02C could modulate APP processing by upregulating the expression of ADAM10, sAPPα and downregulating BACE1, sAPPβ. Furthermore, SA02C also could stimulate autophagy by promoting the expression of the markers of autophagy such as LC3B and ATG5, resulting in the promotion of Aβ 42 phagocytosis.
研究领域:
药理学
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神经科学
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分子生物学
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植物化学
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PubMed
高影响因子
Stem Cells International
·
2026
·Vol. 2026
·期 1
·6997518
·
IF 3.6
Fengshan Gan,Fan Zheng,Qingzhu Zhou,Boyan Liu,Bin Yang,Lianzhu Ou,Wenli Huang,Xinxin Yang,Zhuo Gong,Yunyu Xiong,Xian Zhao,Jia He
Background Soft tissue defects refer to defects in or damage to human soft tissue, which may affect the appearance, function, and health of the human body and cause physical and psychological distress to the patient. Hyaluronic acid (HA), a fillable material in the field of plastic medicine, could play a crucial role in reconstructing soft tissues and enhancing the adipogenic differentiation of adipose-derived stem cells (ADSCs). Methods We isolated ADSCs from human subcutaneous adipose tissue and cultured them in HA hydrogel at a density of 2.1 × 10 6 /mL, followed by subcutaneous injections of ADSCs (0.2 mL, 1 × 10 7 cells/mL with 0.2 mL of DMEM) and HA hydrogel (0.2 mL) into the dorsal side of nude mice. The expression of related genes and proteins was detected using RT‒qPCR and western blotting. The adipogenic differentiation of ADSCs and adipogenesis in nude mice were assessed using CCK-8, Oil Red O, and HE staining. Results The results revealed an increase in the levels of miR-181a-5p and adipocyte differentiation-related proteins (PPARγ, C/EBPα, FABP4, and adiponectin) and a decrease in the levels of autophagy-related proteins (LC3II/I, Beclin-1, and ATG5) in ADSCs cocultured with HA hydrogel. The adipogenic differentiation ability of ADSCs was enhanced. From a mechanistic standpoint, HA hydrogel inhibited the expression of ATG5 by promoting the expression of miR-181a-5p, thus inhibiting autophagy, promoting the adipogenic differentiation of ADSCs, and promoting the formation of adipose tissue in vivo. Conclusions Our findings suggest that a combined culture of ADSCs and HA hydrogel may be a new method to enhance the adipogenic differentiation of ADSCs.
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PubMed
高影响因子
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