BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Zhenbo Yang,Yilin Xie,Mengyang Li,Wenxian Chen,Changsheng Zhong,Jin Ju,Qin Deng,Huifang Wang,Ting Cheng,Lei Zhang,Weijie Du,Haihai Liang
Reperfusion stands as a pivotal intervention for ischemic heart disease. However, the restoration of blood flow to ischemic tissue always lead to further damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Ramelteon is an orally administered drug used to improve sleep quality, which is famous for its high bioadaptability and absence of notable addictive characteristics. However, the specific mechanism by which it improves MIRI is still unclear. Sirtuin-3 (Sirt3), primarily located in mitochondria, is crucial in mitigating many cardiac diseases, including MIRI. Based on the structure of Sirt3, we simulated molecular docking and identified several potential amino acid binding sites between it and ramelteon. Therefore, we propose a hypothesis that ramelteon may exert cardioprotective effects by activating the Sirt3 signaling pathway. Our results showed that the activation levels and expression level of Sirt3 were significantly decreased in MIRI tissue and H 2 O 2 stimulated H9C2 cells, while ramelteon treatment upregulated Sirt3 activity and expression. After treat with 3-TYP, a classic Sirt3 activity inhibitor, we constructed myocardial ischemia/reperfusion surgery in vivo and induced H9C2 cells with H 2 O 2 in vitro. The results showed that the myocardial protection and anti-apoptotic effects of ramelteon were antagonized by 3-TYP, indicating that the activation of Sirt3 is a key mechanism for ramelteon to exert myocardial protection. In summary, our results confirm a novel mechanism by which ramelteon improves MIRI by activating Sirt3 signaling pathway, providing strong evidence for the treatment of MIRI with ramelteon.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yijin Wu,Shaofeng Wang,Hui Huang,Jingling Yu,Jieren Liang,Hai Huang,Jianying Guo,Zhaoxin Tang,Jianzhao Liao
Background With the increasing application of copper nanoparticles (CuNPs) across various fields, its toxicity and hazards are gradually being confirmed. Hesperidin (Hes), a flavonoid compound with extensive antioxidant and anti-inflammatory effects, has recently attracted public attention. Methods Molecular docking was employed to investigate the potential binding sites between Hes and SIRT3. The activation of the SIRT3-FOXO3A signaling pathway by Hes was further validated through a series of experiments in vitro and vivo. Results The results indicate that exposure to CuNPs can cause pathological damage to liver. Compared with the control group, exposure to CuNPs induced the accumulation of reactive oxygen species and mitochondrial UPR mt in broiler liver, specifically manifested as an increase in reactive oxygen species and the gene and protein levels of UPR mt related proteins. The molecular docking results indicate that Hes and SIRT3 have potential binding sites. However, after treatment with Hes, pathological damage in liver was alleviated. At the same time, we found that the SIRT3-FOXO3A signaling pathway was activated, leading to a significant decrease in the expression levels of proteins and genes related to UPR mt . Conclusion Hes can ameliorate hepatic oxidative damage and UPR mt induced by exposure to CuNPs by activating the SIRT3-FOXO3A pathway.
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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纳米技术
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生物化学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Mingyue Tan,Yunfei Yin,Weixiang Chen,Jun Zhang,Yifeng Jin,Yue Zhang,Lei Zhang,Tingbo Jiang,Bin Jiang,Hongxia Li
Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia–reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.
研究领域:
心脏病学
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药理学
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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
PHYTOTHERAPY RESEARCH
·
2025
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IF 6.3
Anpei Wang,Yi Li,Fei Zhao,Hai Fang,Chengxue Pan,Bo Wei
Cardioprotective formulations in traditional Chinese medicine often combine cold and hot herbs, with licorice frequently included to balance their properties and reduce adverse effects. However, the independent cardioprotective mechanisms of licorice in ischemic heart disease remain unclear. This study aimed to investigate the effects of licorice extract (GC) on myocardial ischemia (MI) and ischemia/reperfusion (MI/R) injury. Myocardial injury models were established using H 2 O 2 -induced H9c2 cardiomyocytes and left anterior descending coronary artery ligation in rats. Cardioprotective effects were evaluated through electrocardiography, echocardiography, and pharmacodynamic assessments. Network pharmacology and PCR were used to explore the anti-inflammatory mechanism, followed by investigation of the upstream inflammatory pathways using Western blotting, co-immunoprecipitation, immunofluorescence, and molecular docking. Metabolomics confirmed GC's impact on terminal metabolic disturbances. Pharmacodynamic evaluations demonstrated that GC exerted significant cardioprotective effects both in vitro and in vivo. Network pharmacology suggested anti-inflammatory potential, which was confirmed by PCR showing reduced levels of IL-1β, IL-6, and TNF-α. Expression analysis of seven Sirtuin and four NOD-like receptor family members revealed that GC's anti-inflammatory effect was mediated by upregulation of Sirt3, leading to inhibition of NLRP3 inflammasome activation, decreased Caspase-1 activity, and reduced secretion of IL-1β and IL-18. Additionally, GC modulated ischemia-induced metabolic disturbances, notably restoring disrupted amino acid and unsaturated fatty acid metabolism. In conclusion, GC exerted cardioprotective effects by suppressing inflammation through the Sirt3/NLRP3 axis and restoring metabolic homeostasis. These findings supported its traditional use and suggested its potential application in cardiovascular health.
研究领域:
心血管药理学
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分子生物学
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炎症免疫学
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代谢组学
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中药药理学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 2
·257-263
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IF 1.5
Qingzhi Wan,Lisha Tang,Kaili Jin,Xuanyi Chen,Yinghuan Li,Xiaofeng Xu
Granulosa cells are somatic cells located inside follicles that play a crucial role in the growth and development of follicles. Quercetin and tanshinone are two key monomers in traditional Chinese medicine that have antioxidant and anti-aging properties. The KGN cell apoptosis model caused by triptolide (TP) was employed in this work to investigate granulosa cell death and medication rescue. Quercetin and tanshinone therapy suppressed KGN cell death and oxidation while also regulating the expression of critical apoptosis and oxidation-related markers such as B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Further research revealed that the effects of Quercetin and Tanshinone were accomplished via deacetylation of FOXO3A in the cytoplasm and mitochondria via the SIRT1/SIRT3-FOXO3a axis. In summary, Quercetin and tanshinone protect KGN cells from apoptosis by reducing mitochondrial apoptosis and oxidation via the SIRT1/SIRT3-FOXO3a axis.
研究领域:
药理学
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细胞生物学
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中医药
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生殖生物学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2024
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IF 3.3
Jiemei Shi,Min Liu,Haohao Zhu,Chunhui Jiang
Oxidative stress in endothelial cells is pivotal in diabetic retinopathy (DR), with mitochondrial homeostasis being crucial to mitigate this stress. This study explored the roles of mitochondrial sirtuins (SIRTs) in high glucose (HG)-induced oxidative stress, related endothelial impairment, and mitochondrial homeostasis damage in rat retinal microvascular endothelial cells (RMECs). RMECs were cultured under HG or equivalent osmotic conditions. Cell viability was assessed using the Cell Counting Kit-8 assay, whereas cell death and survival were determined via calcein-AM/propidium iodide double staining. Reactive oxygen species (ROS) levels were measured using 2′,7′-dichlorofluorescein fluorescence. Expression of mitochondrial SIRTs3-5 and key mitochondrial homeostasis molecules was quantified by the quantitative real-time polymerase chain reaction and confirmed by western blotting. Mitochondrial morphology was evaluated using electron microscopy and the MitoTracker fluorescent probe. A SIRT3-overexpressing RMEC line was constructed to assess the role of SIRT3 in oxidative stress and mitochondrial dynamics. After 48 h of HG exposure, cell viability was significantly reduced, with a concomitant increase in cell death and ROS levels, alongside a marked decrease in SIRT3 expression and molecules associated with mitochondrial dynamics. SIRT3 overexpression reversed these effects, particularly increasing the mitochondrial fusion-related molecule, optic atrophy 1 (OPA1). However, the OPA1 inhibitor, MYLS22, blocked the protective effect of SIRT3, leading to more dead cells, a higher ROS level, and intensified mitochondrial fragmentation. These results suggest that SIRT3 is involved in HG-induced imbalanced mitochondrial dynamics of endothelial cells in DR, potentially through the OPA1 pathway.
研究领域:
细胞生物学
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分子生物学
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糖尿病研究
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眼科学
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线粒体生物学
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DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 8
·1667
·
IF 4.6
Zenan Chen,Wei Li,Yan Zhao,Dingrui Liu,Jiahong Han,Enbo Cai
Tumorigenesis and progression are closely associated with apoptosis and primarily regulated by mitochondria, which are considered major targets for cancer therapy. In this study, twelve novel icaritin (ICT) derivatives were designed and synthesized, four of which were specifically targeted to mitochondria. Biological studies demonstrated that all compounds containing triphenylphosphine (TPP+) exhibited a substantial increase in antitumor activity compared to ICT and control compounds while also exhibiting notable selectivity for tumor cells over normal cells. Among these derivatives, Mito-ICT-4 exhibited the strongest antiproliferative effect, with an IC50value of 0.73 ± 0.06 μM for BEL-7402 cells, which is 29 times lower than that of ICT, and an IC50value of 67.11 ± 2.09 μM for HEK293 cells, indicating approximately 33-fold selectivity for tumor cells. High-performance liquid chromatography (HPLC) analysis revealed that Mito-ICT-4 significantly accumulated in the mitochondria of BEL-7402 cells, with the level of accumulation approximately 2.5 times greater than that of ICT. Further investigations demonstrated that upon entering the mitochondria of tumor cells, Mito-ICT-4 downregulated SIRT3 protein expression, disrupted intracellular redox homeostasis, and led to a substantial increase in mitochondrial ROS levels, abnormal CypD-dependent MPTP opening, mitochondrial membrane potential depolarization, and ROS release into the cytoplasm, ultimately triggering ROS-mediated apoptosis in BEL-7402 cells. Transcriptomic analysis identified differentially expressed genes and enriched pathways, highlighting the ROS-mediated p38-MAPK signaling pathway as a key mediator of Mito-ICT-4-induced mitochondria-dependent apoptosis. The effects of Mito-ICT-4 on the expression of key genes (SIRT3, CypD, P-MKK6, P-P38, and DDIT3) were further validated by qRT-PCR and Western blot analysis, with results aligning with transcriptomic data. The novel ICT derivatives synthesized in this study, with mitochondria-targeting functionality, provide a basis for the development of targeted antitumor drugs.
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Yi-xin Dong,Teng-hui Li,Shan-shan Wang,Yan-hong Hu,Yi Liu,Fan Zhang,Tian-shi Sun,Chu-jun Zhang,Qing-hong Du,Wei-hong Li
Ethnopharmacological relevance Bu-Zhong-Yi-Qi Decoction(BZYQD) is a traditional formula commonly used in China, known for its effects in tonifying Qi and raising Yang. It can relieve symptoms of cognitive impairment such as forgetfulness and lack of concentration caused by qi deficiency, which is common in aging and debilitating. However, much of the current research on BZYQD has been focused on its impact on the digestive system, leaving its molecular mechanisms in improving cognitive function largely unexplored. Aim of the study Cognitive decline in the aging central nervous system is intrinsically linked to oxidative damage. This study aims to investigate the therapeutic mechanism of BZYQD in treating mild cognitive impairment caused by qi deficiency, particularly through repair of mitochondrial oxidative damage. Materials and methods A rat model of mild cognitive impairment (MCI) was established by administering reserpine subcutaneously for two weeks, followed by a two-week treatment with BZYQD/GBE. In vitro experiments were conducted to assess the effects of BZYQD on neuronal cells using a H 2 O 2 -induced oxidative damage model in PC12 cells. The open field test and the Morris water maze test evaluated the cognitive and learning memory abilities of the rats. HE staining and TEM were employed to observe morphological changes in the hippocampus and its mitochondria. Mitochondrial activity, ATP levels, and cellular viability were measured using assay kits. Protein expression in the SIRT3/MnSOD/OGG1 pathway was analyzed in tissues and cells through western blotting. Levels of 8-OH-dG in mitochondria extracted from tissues and cells were quantified using ELISA. Mitochondrial morphology in PC12 cells was visualized using Mito Red, and mitochondrial membrane potential was assessed using the JC-1 kit. Results BZYQD treatment significantly improved cognitive decline caused by reserpine in rats, as well as enhanced mitochondrial morphology and function in the hippocampus. Our findings indicate that BZYQD mitigates mtDNA oxidative damage in rats by modulating the SIRT3/MnSOD/OGG1 pathway. In PC12 cells, BZYQD reduced oxidative damage to mitochondria and mtDNA in H 2 O 2 -induced conditions and was associated with changes in the SIRT3/MnSOD/OGG1 pathway. Conclusion BZYQD effectively counteracts reserpine-induced mild cognitive impairment and ameliorates mitochondrial oxidative stress damage through the SIRT3/MnSOD/OGG1 pathway.
研究领域:
民族药理学
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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
Journal of Functional Foods
·
2024
·
IF 3.8
Bobo Li,Jie Liu,Yuhui Sun,Mengmeng Song,Xiaoming Zhao,Yulan Sun
Metabolic disturbances associated with obesity increase the risk and advancement of various tumor forms, including postmenopausal lung cancer, in humans. Betaxanthin, a type of yellow-orange pigment found in certain plants, particularly in some flowers, fruits, and vegetables, can be utilized to inhibit the growth of tumors and lessen the metabolic dysfunctions brought on by obesity. However, the functional role of betaxanthin (BET) in suppressing lung cancer progression and its potential mechanisms are still not fully understood. In this study, we examined the regulation of BET in obese mice with postmenopausal lung cancer receiving a high-fat diet (HFD). Initially, we found that BET could significantly mitigate the metabolic dysfunction that a high-fat diet causes in mice. Improved histological changes in the mammary fat pad, lower hepatic lipid deposition, and improved glucose tolerance and insulin resistance demonstrated this. Following that, BET treatment inhibited the formation of lung neoplasms in in-situ cancer animal models that were stimulated by HFD. Furthermore, in a postmenopausal mouse model fed HFD, BET significantly reduced the growth of pre-existing lung tumors, as well as attenuating metabolic abnormalities. Notably, in vitro research revealed that BET co-culture significantly reduced the proliferation and migration of mouse lung cancer cells, whereas insulin exposure increased these processes. Research on animals verified that lung cancer progressed due to hyperinsulinemia; however, BET treatment might inhibit this condition in postmenopausal mice on a high-fat diet. BET could up-regulate sirtuin 3 (SIRT3) expression levels in tumor, liver, and mammary fat pad tissues in postmenopausal mice with HFD-induced obesity, according to a bioinformatic and molecular biology study. Crucially, eradicating SIRT3 expression completely eliminated BET’s inhibitory effects on insulin-stimulated cancer cell proliferation and migration. This suggests that increasing SIRT3 expression may be required for BET to perform its anti-tumor function against lung cancer in conditions of hyperinsulinemia. Our findings showed that by modifying SIRT3 signaling, BET consumption is probably effective in the prevention and treatment of obesity-related lung cancer.
研究领域:
肿瘤学
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代谢学
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药理学
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分子生物学
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生物信息学
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产品关联
DOI
高影响因子
INFLAMMATION RESEARCH
·
2024
·
IF 4.8
Tan Min,Mao Jing,Zheng Jianxiong,Meng Yu,Li Jun,Hao Jiayao,Shen Haili
Background Mammalian STE20-like kinase 1 (MST1) is involved in the occurrence of cancer and autoimmune diseases by regulating cell proliferation, differentiation, apoptosis and other functions. However, its role and downstream targets in rheumatoid arthritis (RA) remain unclear. Methods The model of RA fibroblast-like synoviocytes (RA-FLSs) overexpressing MST1 was constructed by lentiviral transfection in vitro and analyzed the effects of MST1 on apoptosis, migration, invasion, and inflammation of RA-FLSs. The effect of MST1 on joint synovial membrane inflammation and bone destruction was observed in vivo by establishing a rat model of arthritis with complete Freund’s adjuvant. Results MST1 is down-regulated in RA-FLSs, and up-regulation of MST1 inhibits the survival, migration, invasion and inflammation of RA-FLSs. Mechanistically, MST1 inhibits SIRT3/mTOR-signaling pathway, inducing decreased mitochondrial autophagy and increased mitochondrial fission, resulting in mitochondrial morphological abnormalities and dysfunction, and ultimately increased apoptosis. We have observed that activation of MST1 alleviates synovial inflammation and bone erosion in vivo. Conclusions MST1 reduces the survival, migration, invasion and inflammation of FLSs by inhibiting the SIRT3/mTOR axis to reduce mitochondrial autophagy and promote mitochondrial division, thereby achieving the potential role of relieving rheumatoid arthritis.
研究领域:
免疫学
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风湿病学
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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
Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-17
·
IF 40.8
Peng Fu,Liao Minru,Jin Wenke,Liu Wei,Li Zixiang,Fan Zhichao,Zou Ling,Chen Siwei,Zhu Lingjuan,Zhao Qian,Zhan Gu,Ouyang Liang,Peng Cheng,Han Bo,Zhang Jin,Fu Leilei
Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD + )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
研究领域:
心血管药理学
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分子生物学
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细胞生理学
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DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Shan Yang,Cheng Chen,Yang Xiong,Jiaxiu Ling,Lijuan Chen,Chunxia Wang,Xiaoyu Zhang,Jixiu Yi,Wenzhen Deng,Xiaohui Liao
Objective Pirfenidone (PFD) has been used to treat kidney fibrosis. However, the effects of PFD on obesity-related kidney injury and the underlying mechanisms are still poorly understood. Methods Male C57BL/6 J mice were fed a high-fat diet (HFD) for 20 weeks to induce kidney injury, and PFD was added to the feed of the mice in the PFD group beginning at 8 weeks. The controls were fed a normal control diet (NCD), and half of the mice were similarly treated with PFD. Indicators associated with lipid metabolism and kidney injury were assessed in vivo. Furthermore, human proximal tubular epithelial (HK−2) cells and human primary renal proximal tubule epithelial cells (PTECs) were incubated with palmitate (PA) and PFD, to investigate the effect of PFD on tubule cell injury in vitro. Single-cell sequencing analysis, molecular docking, and coimmunoprecipitation were subsequently used to explore the mechanisms of PFD action. Results PFD ameliorated metabolic abnormalities, inflammatory responses and oxidative stress induced by an HFD. PFD alleviated renal fatty acid oxidation and injury indicators in the HFD-fed mice and PA-treated renal tubular cells. PFD reversed the HFD/PA-induced decrease in SIRT3 protein expression. Moreover, transfection with si-SIRT3 abolished the beneficial effects of PFD on kidney injury and lipid metabolism in HK-2 cells. Conclusion In summary, our data revealed that PFD could mitigate obesity-related kidney injury in a SIRT3-dependent manner.
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PubMed
高影响因子
危险品化学品经营许可证（带存储）