PHARMACOLOGICAL RESEARCH
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2025
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IF 10.5
Binghui Kong,Xuehui Zheng,Yang Hu,Yuan Zhao,Jinghan Hai,Yun Ti,Peili Bu
Pathological myocardial remodelling is the initiation of pressure overload-induced heart failure, and its involvement in the associated molecular mechanisms remains to be fully elucidated. The aim of this study was to investigate whether Sirtuin3 (SIRT3) can affect pathological myocardial remodeling by regulating cellular cuproptosis and its potential mechanisms. In this study, we found that pressure overload induced pathologic myocardial remodeling in which cardiomyocytes showed a distinct cuproptosis signature accompanied by downregulation of SIRT3 expression. In vitro experiments demonstrated that copper ions reduced SIRT3 expression by 40% (p<0.01) via lysosomal degradation. In vivo validation showed that pressure overload reduced SIRT3 expression by 35% (p<0.01) in myocardial tissue. And SIRT3 knockdown increased pressure overload-induced pathological myocardial remodeling and cardiomyocyte apoptosis. In contrast, cardiomyocytes-specific overexpression of SIRT3 by adeno-associated virus vectors attenuated pressure overload-induced pathologic myocardial remodeling and was unaffected by circulating levels of copper ions and hepatic and renal impairment. Mechanistically, the reduction of SIRT3 induced cardiomyocytes to become copper ion-sensitive state cells by affecting the binding of copper ion transporter proteins to microtubule-associated protein 1a/1b-Light chain 3 (LC3) in cardiomyocytes. Disturbance of copper ion homeostasis in cardiomyocytes leads to accumulation of copper ions in cardiomyocytes and the development of cuproptosis. These findings elucidate a novel mechanism by which SIRT3 affects cardiomyocyte death in pressure overload-induced pathologic myocardial remodeling and suggest the great potential of SIRT3-regulated cuproptosis of cardiomyocytes in the prevention or treatment of pathologic myocardial remodeling.
研究领域:
心血管病学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
Science China-Life Sciences
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2021
·Vol. 65
·期 6
·1198-1212
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IF 6.038
Zhang Qi,Li Danyang,Dong Xue,Zhang Xiaowen,Liu Junwu,Peng Lili,Meng Bo,Hua Qi,Pei Xinyu,Zhao Lu,Hu Xiaoxi,Zhang Yang,Pan Zhenwei,Lu Yanjie,Yang Baofeng
Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. The molecular mechanisms of DCM remain to be fully elucidated. The intronic long noncoding RNA of DACH1 (lncDACH1) has been demonstrated to be closely associated with heart failure and cardiac regeneration. In this study, we investigated the role of lncDACH1 in DCM and the underlying molecular mechanisms. The expression of lncDACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes. Knockout of lncDACH1 reduced mitochondrial oxidative stress, cell apoptosis, cardiac fibrosis and hypertrophy, and improved cardiac function in DCM mice. Overexpression of lncDACH1 exacerbated mitochondria-derived reactive oxygen species (ROS) level and apoptosis, decreased activity of manganese superoxide dismutase (Mn-SOD); while silencing of lncDACH1 attenuated ROS production, mitochondrial dysfunction, cell apoptosis, and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose. LncDACH1 directly bound to sirtuin3 (SIRT3) and facilitated its degradation by ubiquitination, therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts. In addition, SIRT3 silencing abrogated the protective effects of lncDACH1 deficiency in cardiomyocytes. In summary, lncDACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts. Inhibition of lncDACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.
研究领域:
心脏病学
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分子生物学
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糖尿病
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DOI
PubMed
高影响因子
Food & Function
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2021
·Vol. 12
·期 10
·4582-4590
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IF 5.396
Xue-Yan Dai,Yi Zhao,Jing Ge,Shi-Yong Zhu,Mu-Zi Li,Milton Talukder,Jin-Long Li
Lycopene (Lyc) has been discussed as a potential effector in the prevention and therapy of various diseases. Di(2-ethylhexyl) phthalate (DEHP) is regarded as a universal environmental pollutant. To clarify the potential protective effect of Lyc on DEHP-induced splenic injury, 140 male mice were randomized into seven groups: control (distilled water), vehicle control (corn oil per day), Lyc (5 mg per kg BW per day), DEHP (500 or 1000 mg per kg BW per day), and DEHP combined Lyc group, respectively. All experimental animals were treated by oral gavage for 28 days. The results that showed DEHP exposure significantly up-regulated the mRNA and protein expression of the sirtuin family (except SIRT4-5), PGC-1α, OPA1, Drp1, MFN1/2, NRF1, TFAM, Parkin and PINK in DEHP-treated alone groups and the SOD2 and LC3-II protein expression were also in accordance with the above changes. These were accompanied with an increase of the number of inflammatory cells and rate of mitochondrial damage, and autophagosome formation in the spleen. Notably, Lyc supplementation facilitated all these changes to effectively return to the normal level, indicating that Lyc exerts protective effects against DEHP-induced splenic toxicity. Altogether, the protective effects of Lyc may be a strategy to ameliorate DEHP-induced spleen damage.
研究领域:
毒理学
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药理学
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分子生物学
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免疫学
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PubMed
高影响因子
Nutrients
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2025
·Vol. 17
·期 20
·3298
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IF 5
Bingsi Li,Yuxuan Gu,Libing Zhou,Rui Chen,Yiwei Liu,Zexuan Wan,Ziyi Liang,Yukang Wang,Renlei Ji,Zhian Liu
Background/Objective: Cellular senescence is increasingly recognized as a key mechanism underlying sarcopenia, an age-related muscle disorder with no effective therapeutic. 6,4′-Dihydroxy-7-methoxyflavanone (DMF), a flavonoid isolated from Dalbergia odorifera T. Chen, has shown anti-senescence potential. This study aimed to investigate the protective effects of DMF against myoblasts senescence and elucidate the underlying molecular mechanisms. Method: A cellular model of senescence was established in C2C12 myoblasts using D-galactose (D-gal). The effects of DMF pretreatment were evaluated by assessing senescence phenotypes, myogenic differentiation, and mitochondrial function. The role of Sirtuin3 (SIRT3) was confirmed using siRNA-mediated knockdown. Results: DMF Pre-treatment effectively attenuated D-gal-induced senescence, as indicated by restored proliferation, reduced senescence-associated β-galactosidase activity, decreased DNA damage, and the downregulation of p53, p21Cip1/WAF1and p16INK4a. Furthermore, DMF rescued myogenic differentiation capacity, enhancing the expression of Myoblast determination protein 1, Myogenin, Myosin heavy chain and Muscle-specific regulatory factor 4, and promoting myotube formation. Mechanistically, DMF was identified as a SIRT3 activator. It enhanced SIRT3 expression and activity, leading to the deacetylation and activation of the mitochondrial antioxidant enzyme superoxide dismutase 2. This consequently reduced mitochondrial reactive oxygen species, improved mitochondrial membrane potential and ATP production, and suppressed the NF-κB pathway by inhibiting IκBα phosphorylation and p65 acetylation/nuclear translocation. Crucially, all the beneficial effects of DMF—including oxidative stress reduction, mitochondrial functional recovery, anti-inflammatory action, and ultimately, the attenuation of senescence and improvement of myogenesis—were abolished upon SIRT3 knockdown. Conclusions: Our findings demonstrate that DMF alleviates myoblasts senescence and promotes myogenic differentiation by activating the SIRT3-SOD2 pathway, thereby reducing oxidative stress and NF-κB-driven inflammation responses. DMF emerges as a promising therapeutic candidate for sarcopenia.
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高影响因子
EBioMedicine
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2018
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IF 6.183
Aiyun Li,Qun Liu,Qiang Li,Baolin Liu,Yang Yang,Ning Zhang
Background Mitochondrial pyruvate import via mitochondrial pyruvate carrier (MPC) is a central step in hepatic gluconeogenesis. Berberine inhibits hepatic gluconeogenesis, but the mechanism is incompletely understood. This study aims to investigate whether berberine could reduce excessive hepatic glucose production (HGP) by limiting mitochondrial import of pyruvate through MPC1. Methods High-fat diet (HFD) feeding augmented HGP. The effects of berberine on hepatic fatty acid oxidation, sirtuin3 (SIRT3) induction and mitochondrial pyruvate carrier 1 (MPC1) function were examined. Findings HFD feeding increased hepatic acetyl coenzyme A (acetyl CoA) accumulation with impaired pyruvate dehydrogenase (PDH) activity and increased pyruvate carboxylase (PC) induction. Berberine reduced acetyl CoA accumulation by limiting fatty acid oxidation and prevented mitochondrial pyruvate shift from oxidation to gluconeogenesis through carboxylation. Upon pyruvate response, SIRT3 binded to MPC1 and stabilized MPC1 protein via deacetylation modification, facilitating mitochondrial import of pyruvate. Berberine preserved the acetylation of MPC1 by suppression of SIRT3 induction and impaired MPC1 protein stabilization via protein degradation, resultantly limiting mitochondrial pyruvate supply for gluconeogenesis. Interpretation Berberine reduced acetyl CoA contents by limiting fatty acid oxidation and increased MPC1 degradation via preserving acetylation, thereby restraining HGP by blocking mitochondrial import of pyruvate. These findings suggest that limitation of mitochondrial pyruvate import might be a therapeutic strategy to prevent excessive hepatic glucose production.
研究领域:
药理学
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代谢学
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肝病学
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分子生物学
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PubMed
高影响因子
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