Scientific Reports
·
2024
·Vol. 14
·期 1
·1-14
·
IF 3.8
Zheng Zihan,Liu YiZhen,Chen Danli,Yang Jianjun,Ren Lingxuan,Jin Zhen,Wang Weirong,Liu Xuyang,He Jianyu,Zheng Nanbo,Lin Rong
Background and purpose: Catalpol (CAT) has diverse pharmacological functions, including cellular homeostasis maintenance and anti-inflammatory effects. Sirtuin 5 (SIRT5) plays a considerable role in regulating cellular homeostasis in cardiac diseases. Our research explores the therapeutic potential of CAT against myocardial injury and its underlying mechanism. Methods: The H9c2 cells were pretreated with different CAT concentrations for 24 h, or CAT for 24 h followed by CoCl 2 stimulation. Cell viability was determined with MTT assay. Biochemical assays, western blotting, and quantitative real-time PCR (qRT-PCR), combined with bioinformatic analysis, were used to examine the impact of CAT on CoCl 2 -induced myocardial injury in H9c2 cells and further explore its molecular mechanisms. Results: CAT ameliorated levels of myocardial enzymes, increased nicotinamide adenine dinucleotide (NAD + /NADH) ratio and adenosine triphosphate (ATP), while inhibited lactic acid (LD), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 in CoCl 2 -induced H9c2 cells. Mechanistically, SIRT5 knockdown inhibited Lin28a expression and negated the effects of CAT on ATP level, LD content, and the expression of inflammatory factors in cells. CAT likely exerted its protective effects on myocardial function through the SIRT5-mediated signaling pathway. Conclusions: CAT regulates energy metabolism and inflammation via the SIRT5-mediated signaling pathway, exerting a protective effect in myocardial injury.
研究领域:
药理学
·
心脏病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Leilei Gong,Jinli Hou,Hongjun Yang,Xueyan Zhang,Jingxia Zhao,Lan Wang,Xiaojie Yin,Xin Feng,Chenghong Yin
Ethnopharmacological relevance Classical prescriptions are not only a primary method of clinical treatment in traditional Chinese medicine (TCM) but also represent breakthroughs in the inheritance and development of this field. Kuntai capsule (KTC), a formulation based on a classical prescription, comprises six TCMs: Rehmanniae Radix Praeparata, Coptidis Rhizoma , Paeoniae Radix Alba , Scutellariae Radix , Asini Corii Colla, and Poria . This formulation possesses various beneficial effects, such as nourishing yin and blood, clearing heat and purging fire, and calming the nerves and relieving annoyance. The investigation of the efficacy and mechanism of KTC in regulating anti-aging factors in the treatment of premature ovarian insufficiency (POI) is not only a prominent topic in classical prescription research but also a crucial issue in the treatment of female reproductive aging using TCM. Aim of the study To evaluate the therapeutic effect of KTC on POI and its underlying mechanism. Materials and methods Healthy and specific pathogen-free (SPF) female Kunming mice aged 6–8 weeks were selected. After acclimatization, the mice were randomly divided into a control, model, and high, middle, and low dose groups of KTC (1.6, 0.8, and 0.4 mg/kg, respectively). Except for the control group, the animals in the other groups were administered a single intraperitoneal injection of 120 mg/kg cyclophosphamide and 30 mg/kg Busulfan to induce the model of POI. After modeling, the mice were treated with the corresponding drugs for 7 days. Serum and ovarian tissues were collected, and the levels of serum follicle-stimulating hormone (FSH), estradiol (E2), and superoxide dismutase 2 (SOD2) were determined using enzyme-linked immunosorbent assay (ELISA). The chemical composition of KTC was characterized and analyzed using ultra-high-pressure liquid chromatography-linear ion trap-Orbitrap tandem mass spectrometry. A “drug-component-target-pathway-disease” network was constructed using network pharmacology research methods to identify the key active components of KTC in treating POI and to elucidate its potential mechanism. The protein expression of the FOXO3/SIRT5 pathway was detected by western blotting . Results Compared to the model group, the high-dose group of KTC showed a significant increase in ovarian index, significant increase in levels of E2 and SOD2, and a significant decrease in FSH levels. Through systematic analysis of the chemical constituents of KTC, 69 compounds were identified, including 7 organic acids, 14 alkaloids, 28 flavonoids , 15 terpenoids , 2 lignans , 2 phenylpropanoids, and 1 sugar. Based on network pharmacology research methods, it was determined that KTC exerts its therapeutic effect on POI through multiple components (paeoniflorin and malic acid), multiple targets (FOXO3 and SIRT5), and multiple pathways (prolactin signaling pathway, longevity regulating pathway, and metabolic pathways). The accuracy of the network pharmacology prediction was further validated by detecting the protein expression of SIRT5 and FOXO3a, which showed a significant increase in the middle and high-dose groups of KTC compared to the model group. Conclusions KTC may effectively treat POI through a multi-component, multi-target, multi-pathway approach, providing an experimental basis for using KTC based on classical prescriptions in the treatment of POI.
研究领域:
药理学
·
中医妇科
·
信号传导
·
分析化学
·
整合药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 6
·
IF 7.7
Longchang Bai,Ruocen Liao,Yu Zhang,Yongshi Jia,Lei Shi,Hongen Xu,Liang Liang,Yu Feng,Chenfang Dong
Aberrant AKT1 activation is a hallmark of cancer, yet the molecular mechanisms regulating its activity remain incompletely understood. Here, we report that AKT1 undergoes glutarylation at evolutionarily conserved lysines K179 and K289. Mechanistically, AKT1 glutarylation is regulated by the metabolic enzymes GCDH and DHTKD1, which modulate glutaryl-CoA levels, and reversed by the deglutarylase SIRT5. Glutarylation at K179 disrupts the K179-E198 salt bridge and AKT1-ATP interactions, whereas K289 glutarylation perturbs ATP coordination and reduces PDK1-mediated phosphorylation, collectively inactivating AKT1. Functionally, AKT1 glutarylation inhibits cell proliferation and tumor growth, whereas GCDH promotes these oncogenic functions by suppressing glutarylation. Notably, pharmacological MYC inhibition, which downregulates GCDH and elevates AKT1 glutarylation, synergizes with the AKT inhibitor afuresertib to suppress gastric cancer cell growth, revealing a potential therapeutic vulnerability. These findings link lysine metabolism to AKT-driven cancer progression and suggest therapeutic strategies targeting glutarylation dynamics.
✓ 已验证
DOI
PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2026
·
IF 5.7
Qu Yinmeng,Liu Renjie,Chen Xuan,Wu Peifan,Zhao Yuhao
Diabetic-associated cognitive dysfunction (DACD) is a severe complication of diabetes characterized by mitochondrial failure in hippocampal neurons, yet its precise molecular drivers remain poorly understood. Here, hydroxysteroid dehydrogenase-like 2 (HSDL2) was identified as a key mitochondrial-related protein significantly upregulated in DACD models. Knockdown of HSDL2 alleviated cognitive impairment, synaptic loss, and neuronal apoptosis in DACD mice. Mechanistic investigations revealed that HSDL2 promoted mitochondrial dysfunction and neuronal apoptosis by downregulating TNF receptor-associated protein 1 (TRAP1). Furthermore, HSDL2 was identified as a novel substrate of the desuccinylase sirtuin 5 (SIRT5). SIRT5 mediated HSDL2 desuccinylation at the K42 site to stabilize its protein, leading to its upregulation. Importantly, SIRT5 was upregulated in DACD, and its knockdown mitigated hippocampal damage and cognitive dysfunction. This study unveiled a novel SIRT5/HSDL2/TRAP1 axis in DACD pathogenesis, wherein SIRT5 upregulation drove HSDL2 desuccinylation and stabilization, ultimately promoting mitochondrial dysfunction and cognitive decline via downregulation of TRAP1.
✓ 已验证
DOI
PubMed
高影响因子
LIVER INTERNATIONAL
·
2025
·Vol. 45
·期 12
·e70433
·
IF 5.2
Zekun Liu,Jie Hu,Yinan Lin,Chuang Ge,Yuru Shao,Mengmeng Bao,Mengjie Liu,Shilin Jia,Yating Li,Xiaozhi Xu,Ruiyan Li,Qizhou Jiang,Fangrong Yan,Fei Xiao,Junmei Ye
Background and Aims Obesity is one of the main factors that causes liver steatosis. While the mechanism remains to be elucidated. Methods SIRT5 was knocked down in male C57/BL6 mice via tail vein injection of adenovirus, which were then fed either normal chow or a high-fat diet. Glucose and lipid content was detected in the serum, and the liver tissue was harvested for further analysis. We also used primary rat hepatocytes and a hepatocyte cell line L02 cells to explore the role of SIRT5 in regulating lipid overload-induced hepatocyte injury. Finally, rAAV-induced SDHC knockdown was applied to investigate the role of SDHC in HFD-induced liver steatosis. Results High-fat diet results in upregulation of SIRT5 and causes desuccinylation of mitochondrial proteins including SDH. Adenovirus-driven SIRT5 knockdown of SIRT5 induces alleviated high-fat diet-induced hepatic injury and preserves mitochondrial function. We also show that SIRT5 knockdown reduces oxidative stress of hepatocytes both in vivo and in vitro. Mechanistically, SIRT5 in hepatocytes facilitates the desuccinylation of mitochondrial proteins including SDH, reducing SDH activity, which results in mitochondrial dysfunction. Furthermore, SIRT5 specifically inhibits the expression of SDHC at the post-transcriptional level, and SDHC knockdown deteriorates lipid overload-induced hepatic lipotoxicity. Conclusion and Implications Our findings underscore the critical role of SIRT5 in the progress of liver steatosis and provide novel insights into the regulation of SDH by SIRT5-mediated desuccinylation that affects mitochondrial function. Moreover, our results suggest that targeting SIRT5 may offer a therapeutic strategy for liver steatosis.
研究领域:
分子生物学
·
代谢性疾病
·
细胞生物学
·
内分泌学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Stem Cell Research & Therapy
·
2025
·Vol. 16
·期 1
·691
·
IF 7.3
Gu Hongji,Liu Buhan,An Yue
Background Bone marrow mesenchymal stem cells (BMSCs) play a crucial role in bone repair and regeneration. The sirtuin family member sirtuin 5 (SIRT5) has been implicated in various cellular processes, including the regulation of osteogenic differentiation. This study aimed to investigate the role of SIRT5 in osteogenic differentiation of BMSCs and its impact on fracture healing. Methods BMSCs were characterized and induced to undergo osteogenic and adipogenic differentiation. The effects of SIRT5 modulation on osteogenic differentiation were assessed through alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, and osteogenic genes expression analysis. The role of SIRT5 in regulating bone morphogenetic protein 2 (BMP2) succinylation and stability was explored using Western blot, immunoprecipitation, and co-immunoprecipitation. A rat tibial fracture model was used to evaluate the in vivo effects of SIRT5 and BMP2 modulation on fracture healing, assessed by Micro-CT and histological analysis. Results SIRT5 overexpression enhanced osteogenic differentiation of BMSCs, as evidenced by increased ALP activity and mineralization. It also upregulated the expression of osteogenic markers such as osteopontin (OPN), runt-related transcription factor 2 (RUNX2), osterix (OSX), and BMP2. Conversely, SIRT5 knockdown inhibited these processes. Mechanistically, SIRT5 was found to regulate BMP2 succinylation, affecting its stability and function. In vivo, overexpression of SIRT5 in a rat tibial fracture model significantly improved bone volume fraction, trabecular number, and thickness, while reducing trabecular separation. The beneficial effects of SIRT5 overexpression were counteracted by BMP2 knockdown, highlighting the importance of BMP2 in mediating SIRT5’s actions on bone healing. Conclusion SIRT5 promotes osteogenic differentiation of BMSCs and enhances fracture healing by modulating BMP2 succinylation. These findings suggest that SIRT5 could be a potential therapeutic target for the treatment of bone fractures and other skeletal disorders.
研究领域:
分子生物学
·
干细胞研究
·
骨再生医学
·
翻译后修饰
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARDIOVASCULAR DRUGS AND THERAPY
·
2025
·
IF 3.1
Li Yuanbin,Feng Chuanping,Lin Hui,Li Hui,Zeng Wei,Dong Xiaoyan,Chen Zhuang
Purpose While reperfusion is essential for restoring blood flow, it can paradoxically exacerbate myocardial injury by disrupting energy metabolism, leading to cell necrosis, apoptosis, and structural damage. Despite the significance of ischemia–reperfusion (I/R) injury, effective treatments remain scarce, highlighting the need for a deeper understanding of its underlying mechanisms to develop targeted therapies. Methods A rat model of myocardial I/R injury and a H9c2 cell-based hypoxia/reoxygenation (H/R) model were utilized for primary validation. HOXB5 was overexpressed several days prior to I/R or H/R induction. Gene and protein expression were assessed by RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. Cell viability and apoptosis were evaluated using CCK-8 and flow cytometry. Mitochondrial function and ferroptosis were analyzed by commercial kits. The regulatory relationship among Lin28a, HOXB5, and Sirt5 was examined using RIP, ChIP-PCR, and dual-luciferase assays. Results HOXB5 expression was significantly reduced in infarcted myocardial tissue following I/R injury, of which overexpression attenuated H/R-trigged apoptosis to motivate H9c2 cell survival. Meanwhile, HOXB5 overexpression decreased mitochondrial ROS production, improved mitochondrial respiration, mitochondrial complexes (I, II, III, and V) activity, and reduced mitophagy under H/R conditions in H9c2 cells. Mechanistically, Lin28A was identified as a regulator of HOXB5, which in turn transcriptionally activated Sirt5. Furthermore, the protective effects of HOXB5 overexpression on myocardial histological damage and cardiac function through modulating ferroptosis in rats' I/R injury was abrogated by Sirt5 knockdown. Conclusion Our study reveals the crucial role of HOXB5 in maintaining mitochondrial homeostasis and regulating mitophagy, which in turn protects cardiomyocytes from I/R injury through Sirt5. These findings underscore the HOXB5-Sirt5 pathway as a promising therapeutic target for mitigating I/R injury.
研究领域:
心脏病学
·
分子生物学
·
线粒体生物学
·
细胞死亡机制
·
基因调控
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PLoS Pathogens
·
2026
·Vol. 22
·期 2
·e1013975
·
IF 4.9
Huijie Hu,Naiyuan Jiang,Juxiong Liu,Junlong Bi,Xuanting Liu,Bin Xu,Yu Cao,Wenjin Guo,Shoupeng Fu
Staphylococcus aureus ( S. aureus )–driven senescence of bovine mammary epithelial cells is a key determinant of mammary gland health, yet its molecular basis remains poorly defined. Sirtuin 5 (SIRT5), a mitochondria-localized desuccinylase, may play an important regulatory role in this process. This study aimed to elucidate the mechanisms by which S. aureus drives cellular senescence and to define the contribution of the SIRT5–mitochondrial axis to delaying senescence. We found pronounced oxidative stress and cellular senescence in mammary tissues from cows with S. aureus mastitis, accompanied by marked downregulation of SIRT5. In an S. aureus -infected epithelial cell model, infection induced mitochondrial stress characterized by excessive mitochondrial fragmentation, loss of membrane potential, and increased mitochondrial superoxide, along with oxidative damage and cellular senescence. Mechanistically, S. aureus toxins and the toxin-induced inflammatory response cooperatively drove mitochondrial stress, which in turn increased intracellular bacterial burden and exacerbated cell death. During infection, SIRT5 protein abundance was significantly reduced. Mass spectrometry and co-immunoprecipitation analyses indicated that infection upregulated the ubiquitin-conjugating enzyme ubiquitin C (UBC), enhanced its interaction with SIRT5, and promoted ubiquitin-mediated degradation of SIRT5. Loss of SIRT5 increased succinylation of dynamin-related protein 1 (DRP1), inhibited its ubiquitin-mediated degradation, and led to its excessive accumulation on the outer mitochondrial membrane, thereby promoting excessive mitochondrial fission. Functionally, SIRT5 overexpression markedly alleviated mitochondrial stress, oxidative damage, and senescence phenotypes. When mitochondrial fission was forcibly enhanced, the cytoprotective effect of SIRT5 was substantially weakened, confirming that SIRT5 acts through a pathway dependent on mitochondrial integrity. Collectively, S. aureus infection releases toxins and induces inflammatory injury, during which UBC-mediated SIRT5 degradation activates DRP1-dependent mitochondrial hyper-fragmentation, aggravating mitochondrial stress, oxidative stress, and mammary epithelial cell senescence. These findings identify SIRT5 as a critical regulator of redox and mitochondrial homeostasis in mammary epithelial cells and a potential therapeutic target for mitigating oxidative damage associated with bovine mastitis.
Staphylococcus aureus ( S. aureus ) is a leading cause of bovine mastitis, an intramammary infection that reduces milk yield, increases antibiotic use, and results in substantial economic loss. One way this bacterium damages the udder is by driving bovine mammary epithelial cells into premature senescence, but how infection triggers this process has not been fully understood. Here, we show that S. aureus infection induces an inflammatory response via its secreted toxins, which in turn provokes mitochondrial stress. We identify the mitochondrial enzyme Sirtuin 5 (SIRT5) as a key defender in this context. During infection, the host ubiquitin-conjugating enzyme ubiquitin C (UBC) targets SIRT5 for degradation. Loss of SIRT5 leads to accumulation of the mitochondrial fission protein dynamin-related protein 1 (DRP1), causing excessive mitochondrial fragmentation, enhanced oxidative damage, increased intracellular bacterial burden, and aggravated cellular senescence. Restoring SIRT5 helps to preserve mitochondrial integrity and reduces oxidative injury and senescence; however, this protection is weakened when mitochondrial fission is forcibly maintained at a high level. Together, our findings reveal that the UBC–SIRT5–DRP1 pathway links S. aureus infection to mitochondrial damage and cellular senescence, and they highlight SIRT5 as a potential therapeutic target to protect the bovine mammary gland (S1 Fig).
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）