NEUROMOLECULAR MEDICINE
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2022
·Vol. 25
·期 1
·53-63
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IF 4.103
Cheng Jing,Fan Yan-Qin,Zhang Wen-Fei,Zhang Guo,Zeng Kuo,Ye Zhang,Zhao Dan,Wu Li-Quan,Chen Zhi-Biao
Sirtuin-6 (SIRT6), a member of the sirtuins family of NAD ( +) dependent deacetylases, has been shown to have beneficial effects in ischemic stroke. However, the role of SIRT6 in intracerebral haemorrhage (ICH) has not reported. We observed that SIRT6 expression was down-regulated in human ICH patients and down-regulated in ICH-induced rat cortical neurons. We subsequently found that SIRT6 overexpression reduced brain tissue damage and increased neuronal survival in the ICH model of rats and hemin-induced cortical neurons. Our further study found that overexpression of SIRT6 can reduce inflammatory response by down-regulating the expression of NF-kB and thus promote the recovery of neurological function in ICH animals. In conclusion, SIRT6 can inhibit the expression of NF-kB and plays a neuroprotective role in ICH by inhibiting the NF-kB-mediated inflammatory response.SIRT6 could be a novel therapeutic target for ICH.
研究领域:
神经科学
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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
Iranian Journal of Basic Medical Sciences
·
2021
·
IF 2.699
Chuang Zhang,Suolin Li,Chi Sun,Lin Liu,Yanbin Fang,Xiaofeng Yang,Xingxin Pan,Ben Zhang
Objective(s): Vitexin, a natural flavonoid, is commonly found in many foods and traditional herbal medicines and has clear health benefits. However, the role of vitexin in cholestasis is presently unclear. This study investigated whether vitexin mitigated glycochenodeoxycholate (GCDC)-induced hepatocyte injury and further elucidated the underlying mechanisms. Materials and Methods: A cell counting kit-8 (CCK-8) assay was conducted to evaluate cell viability. The mitochondrial membrane potential (MMP, Δψm), reactive oxygen species (ROS) levels, and apoptosis rate of hepatocytes exposed to GCDC were detected by flow cytometry (FCM). We then measured the cytoprotective effects of vitexin against oxidative stress. The molecular signaling pathway was further investigated by using Western blotting and signaling pathway inhibitors. Results: Here, we showed that vitexin increased cell viability and reduced cell apoptosis, necroptosis, and oxidative stress in a dose-dependent manner in GCDC-treated hepatocytes. In addition, by using selective inhibitors, we further confirmed that inhibition of the JAK2/STAT3 pathway by vitexin was mediated by prolonged activation of Sirtuin 6 (SIRT6). Conclusion: Vitexin attenuated GCDC-induced hepatocyte injury via SIRT6 and the JAK2/STAT3 pathways.
研究领域:
药理学
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肝病学
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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
CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Shulin Wang,Xuan Zhang,Yanhong Hou,Yuliang Zhang,Jiamin Chen,Shuhan Gao,Huiying Duan,Shaoju Gu,Shanshan Yu,Yi Cai
The Sirtuins family, formally known as the Silent Information Regulator Factors, constitutes a highly conserved group of histone deacetylases. Recent studies have illuminated SIRT6's role in doxorubicin (DOX)-induced oxidative stress and apoptosis within myocardial cells. Nevertheless, the extent of SIRT6's impact on DOX-triggered myocardial cell aging and damage remains uncertain, with the associated mechanisms yet to be fully understood. In our research, we examined the influence of SIRT6 on DOX-induced cardiomyocyte senescence using β-galactosidase and γ-H2AX staining. Additionally, we gauged the mRNA expression of senescence-associated genes, namely p16, p21, and p53, through Real-time PCR. Employing ELISA assay kits, MDA, and total SOD activity assay kits, we measured inflammatory factors TNF-α, IL-6, and IL-1β, alongside oxidative stress-related indicators. The results unequivocally indicated that SIRT6 overexpression robustly inhibited DOX-induced cardiomyocyte senescence. Furthermore, we established that SIRT6 overexpression suppressed the inflammatory response and oxidative stress induced by DOX in cardiomyocytes. Conversely, silencing SIRT6 exacerbated DOX-induced cardiomyocyte injury. Our investigations further unveiled that SIRT6 upregulated the expression of genes CD36, CPT1, LCAD, MCAD associated with fatty acid oxidation through its interaction with PPARα, thereby exerting anti-aging effects. In vivo , the overexpression of SIRT6 was observed to restore DOX-induced declines in EF and FS to normal levels in mice. Echocardiography and HE staining revealed the restoration of cardiomyocyte alignment, affording protection against DOX-induced myocardial senescence and injury. The findings from this study suggest that SIRT6 holds significant promise as a therapeutic target for mitigating DOX-induced cardiomyopathy.
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
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Shanshan Song,Xina Yu,Changming Xie,Zhanhua Li,Ying Zhang,Yan Liu,Zhongjue Qiu,Tiantian Wang,Hongna Su,Hui Huang,Pei Luo
Panaxynol (PA), a bioactive compound found in carrots and other Apiaceae plants, holds promise for managing diabetes-related vascular complications. This study investigated the long-term effects of PA on diabetes-induced vascular calcification (DVC) in db/db mice for up to 9 weeks. The impact of PA on DVC was evaluated both in vivo and in vitro using immunohistochemical staining, Western blotting, micro-computed tomography, and other analytical techniques. Results demonstrated that PA significantly attenuated arterial calcification and collagen hyperplasia in the aorta. Additionally, PA elevated levels of the lipid signaling molecule 14,15-EET, which preserved the vascular structure and function by reducing inflammatory macrophage infiltration in perivascular adipose tissue. This protective effect was partially attributed to the PA-mediated inhibition of soluble epoxide hydrolase (sEH) through Sirt6 activation. These findings highlight PA as a potential natural therapeutic strategy for mitigating diabetic vascular complications and offer an alternative to conventional pharmacological approaches.
研究领域:
生物学
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医学
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药理学
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PubMed
高影响因子
Food & Function
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2022
·Vol. 13
·期 13
·7302-7319
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IF 6.317
Li-Ming Yu,Xue Dong,Ning Li,Hui Jiang,Ji-Kai Zhao,Yin-Li Xu,Deng-Yue Xu,Xiao-Dong Xue,Zi-Jun Zhou,Yu-Ting Huang,Qiu-Sheng Zhao,Zhi-Shang Wang,Zong-Tao Yin,Hui-Shan Wang
Polydatin has attracted much attention as a potential cardioprotective agent against ischemic heart disease and diabetic cardiomyopathy. However, the effect and mechanism of polydatin supplementation on alcoholic cardiomyopathy (ACM) are still unknown. This study aimed to determine the therapeutic effect of polydatin against ACM and to explore the molecular mechanisms with a focus on SIRT6–AMP-activated protein kinase (AMPK) signaling and mitochondrial function. The ACM model was established by feeding C57/BL6 mice with an ethanol Lieber–DeCarli diet for 12 weeks. The mice received polydatin (20 mg kg−1) or vehicle treatment. We showed that polydatin treatment not only improved cardiac function but also reduced myocardial fibrosis and dynamin-related protein 1 (Drp-1)-mediated mitochondrial fission, and enhanced PTEN-induced putative kinase 1 (PINK1)–Parkin-dependent mitophagy in alcohol-treated myocardium. Importantly, these beneficial effects were mimicked by SIRT6 overexpression but abolished by the infection of recombinant serotype 9 adeno-associated virus (AAV9) carrying SIRT6-specific small hairpin RNA. Mechanistically, alcohol consumption induced a gradual decrease in the myocardial SIRT6 level, while polydatin effectively activated SIRT6–AMPK signaling and modulated mitochondrial dynamics and mitophagy, thus reducing oxidative stress damage and preserving mitochondrial function. In summary, these data present new information regarding the therapeutic actions of polydatin, suggesting that the activation of SIRT6 signaling may represent a new approach for tackling ACM-related cardiac dysfunction.
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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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Yingya Zhou,Meng Feng,Hongyan Hai,Xinmeng Teng,Xinxin Zhou,Yong Gao,Yanhua Zhong,Changhui Liu
Background : Due to the absence of disease-modifying treatments and mysterious molecular causes, metabolic dysfunction-associated steatotic liver disease (MASLD) poses an urgent and unmet clinical need. The active ingredient in Fructus gardenia , geniposidic acid (GPA), has anti-inflammatory, antioxidant, and hepato-protective properties. However, its effects on MASLD are still unknown. Purpose : This study aimed to determine how diet-induced hepatic steatosis in mice is affected by GPA. Methods : Dietary induction developed the mouse model of hepatic steatosis. The influence of GPA on hepatic steatosis, inflammation, and fibrosis were examined using the mouse primary hepatocyte lipid overload model. The mechanism of GPA in preventing and treating MASLD was explored through RNA-seq, and the activation of the SIRT6 signal by GPA was verified by molecular docking, pull-down, etc. Hepatocyte-specific Sirt6 -deletion mice were established, and cellular and animal studies were performed to assess SIRT6 functions in inhibiting and treating MASLD by GPA. Results : GPA therapy significantly enhanced hepatic fat accumulation, oxidative stress, inflammatory infiltration, and fibrosis in mice subjected to high fat diet (HFD) and methionine choline deficient (MCD) diets. In the meantime, GPA can reduce oxidative stress in hepatocyte metabolic stress and fat buildup brought on by oleic acid (OA) and palmitic acid (PA). RNA sequencing revealed that GPA exerts its protective effects against MASLD primarily by stimulating SIRT6 and triggering the downstream PPARα signaling cascade. Furthermore, GPA was found to interact directly with SIRT6 through specific binding sites. This interaction enables SIRT6 activation under both normal and disease conditions. However, without SIRT6, the liver-protective benefits of GPA under metabolic stress are lost. Conclusion : It was found that GPA binds directly to SIRT6 and enhances its activity, thereby inhibiting the progression of diet-induced MASLD. The findings suggest the potential of GPA as a therapeutic target for treating MASLD.
研究领域:
药理学
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分子生物学
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肝病学
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营养学
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药物研发
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PubMed
高影响因子
Acta Physiologica
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2020
·Vol. 231
·期 4
·e13602
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IF 5.542
Yi Cai,Shan Shan Yu,Yang He,Xue Ying Bi,Si Gao,Ting Dong Yan,Guo Dong Zheng,Ting Ting Chen,Jian Tao Ye,Pei Qing Liu
Aim Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, exerts multiple protective effects against cardiovascular diseases, including cardiac hypertrophy. However, the molecular mechanism underlying its anti-hypertrophic effect has not been clarified. This study revealed that EGCG could inhibit pressure overload-induced cardiac hypertrophy by regulating the PSMB5/Nmnat2/SIRT6-dependent signalling pathway. Methods Quantitative real-time polymerase chain reaction and western blotting were used to determine the expression of mRNA and protein respectively. A fluorometric assay kit was used to determine the activity of SIRT6, a histone deacetylase. Luciferase reporter gene assay and electrophoretic mobility shift assay were employed to measure transcriptional activity and DNA binding activity respectively. Results EGCG could significantly increase Nmnat2 protein expression and enzyme activity in cultured neonatal rat cardiomyocytes stimulated with angiotensin II (Ang II) and heart tissues from rats subjected to abdominal aortic constriction. Nmnat2 knockdown by RNA interference attenuated the inhibitory effect of EGCG on cardiac hypertrophy. EGCG blocked NF-κB DNA binding activity induced by Ang II, which was dependent on Nmnat2 and the subsequent SIRT6 activation. Moreover the activation of PSMB5 (20S proteasome subunit β-5, chymotrypsin-like) was required for EGCG-induced Nmnat2 protein expression. Additionally, we demonstrated that EGCG might interact with PSMB5 and inhibit the activation of the proteasome. Conclusions These findings serve as the first evidence that the effect of EGCG against cardiac hypertrophy may be, at least partially, attributed to the modulation of the PSMB5/Nmnat2-dependent signalling pathway, suggesting the therapeutic potential of EGCG in the prevention and treatment of cardiac hypertrophy.
研究领域:
心血管疾病
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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
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Xiaowei Zhang,Liang Zhao,Shixie Xiang,Yiran Sun,Pan Wang,Jenny Jie Chen,Brian Sheng-Xian Teo,Zhishen Xie,Zhenqiang Zhang,Jiangyan Xu
Ethnopharmacological relevance Yishen Tongluo formula (YSTLF) is formulated based on traditional Chinese medicine theory for the treatment of Diabetic kidney disease (DKD) and has been shown to be effective in improving the symptoms of DKD according to the clinical observation. Aim of the study To explore the effect of YSTLF on DKD and figure out whether its effects were due to the regulation Sirt6/TGF-β1/Smad2/3 pathway and promoting degradation of TGF-β1. Materials and methods The extract of YSTLF at 1, 2.5 and 5 g/kg was orally administered to C57BLKS/J ( db/db ) mice for 8 weeks and db/db mice were given valsartan as a positive control. The littermate db/m and db/db mice were given vehicle as the control and model group, respectively. Blood urea nitrogen and serum creatinine were detected and the urinary albumin excretion, urea albumin creatinine ratio was calculated. The histopathological change of renal tissues in each group was determined. Simultaneously, the levels of fibrosis-related proteins and messenger RNA (mRNA) in kidney and high glucose (HG)-induced SV40-MES-13 cells were detected. The roles of YSTLF in regulating of Sirt6/TGF-β1/Smad2/3 signaling pathway were investigated in HG-stimulated SV40-MES-13 cells and validated in db/db mice. Furthermore, the effect of YSTLF on TGF-β1 degradation was investigated in HG-stimulated SV40-MES-13 cells. Results YSTLF significantly improved the renal function in DKD mice. YSTLF dose-dependently attenuated pathological changes and suppressed the expression of type I collagen , alpha smooth muscle actin , type IV collagen , and fibronectin in vitro and in vivo , resulting in ameliorating of renal fibrosis . YSTLF positively regulated Sirt6 expression, while inhibited the activating of TGF-β1/Smad2/3 signaling pathway. TGF-β1 was steady expressed in HG-stimulated SV40-MES-13 cells, whereas was continuously degraded under YSTLF treatment. Conclusions YSTLF significantly ameliorates renal damages and fibrosis may via regulating Sirt6/TGF-β1/Smad2/3 signaling pathway as well as promoting the degradation of TGF-β1.
研究领域:
药理学
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内分泌学
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分子生物学
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中医
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 12
·e18407
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IF 4.3
Zijun Zhou,Qiusheng Zhao,Yuting Huang,Shan Meng,Xin Chen,Guoxin Zhang,Yanbang Chi,Dengyue Xu,Zongtao Yin,Hui Jiang,Liming Yu,Huishan Wang
Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH-induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH-induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno-associated virus 9 (AAV9) carrying SIRT6 or SIRT6-specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK-FOXO3a signalling. BBR dose-dependently ameliorated cardiac injury in CIH-induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6-specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6-AMPK-FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1-Parkin-mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH-induced cardiac dysfunction. BBR attenuates CIH-induced myocardial injury by improving mitochondrial biogenesis and PINK1-Parkin-dependent mitophagy via the SIRT6-AMPK-FOXO3a signalling pathway.
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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PubMed
高影响因子
INFLAMMATION
·
2020
·Vol. 43
·期 5
·1751-1758
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IF 3.212
Zhaohui Chen,Shuihua Wu
Accumulating evidence supports that Sirtuin 6 (SIRT6) may play a vital role in the pathogenesis of spinal cord injury. The current study was designed to investigate the specific effects of SIRT6 on spinal cord injury (SCI). HE and Nissl staining were performed for pathological analysis in SCI rats. SIRT6 expression was detected by RT-qPCR. CCK8 assay was applied for the detection of cell viability of LPS-injured PC12 cells. TNF-a, IL-1β, IL-6, MCP-1 levels and ROS, MPO, SOD levels were assessed to evaluate inflammation and oxidative stress in spinal cord injury. Cell apoptosis were evaluated by morphological examination using AO/EB fluorescent staining methods and key proteins related to apoptosis were explored via western blot. HE staining revealed increased cavity involving the dorsal white matter and central gray matter, and Nissl staining discovered the loss of motor neurons in the ventral horn in SCI rats. SIRT6 had lower expression in SCI rats. Lipopolysaccharide (LPS) exposure induced cell apoptosis and reduced the expression of SIRT6. Mechanistically, we revealed that up-regulation of SIRT6 alleviated inflammation and oxidative stress and inhibited cell apoptosis in spinal cord injury. Together, our findings indicated that SIRT6 attenuated spinal cord injury by suppressing inflammation, oxidative stress, and cell apoptosis. This study demonstrates that SIRT6 may represent a protective effect against spinal cord injury.
研究领域:
神经科学
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分子生物学
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病理学
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PubMed
高影响因子
STEM CELLS
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2014
·Vol. 32
·期 7
·1943-1955
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IF 7.133
Sun Hualing,Wu Yanru,Fu Dongjie,Liu Yinchen,Huang Cui
Sirtuin 6 (SIRT6) is a NAD-dependent deacetylase involved in lifespan regulation. To evaluate the effect of SIRT6 on osteogenesis, rat bone marrow mesenchymal stem cells (rBMSCs) with enhanced or reduced SIRT6 function were developed. We observed that SIRT6 knockdown significantly reduced the mRNA levels of several key osteogenic markers in vitro, including alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), and osteocalcin, while overexpression of SIRT6 enhanced their expression. Additionally, SIRT6 knockdown activated nuclear factor-κB (NF-κB) transcriptional activity and upregulated the expression of acetyl-NF-κB p65 (Lys310). The decreased osteogenic differentiation ability of rBMSCs could be partially rescued by the addition of NF-κB inhibitor BAY 11–7082. Furthermore, SIRT6 overexpression in rBMSCs combined with the use of collagen/chitosan/hydroxyapatite scaffold could significantly boost new bone formation in rat cranial critical-sized defects, as determined by microcomputed tomography and histological examination. These data confirm that SIRT6 is mainly located in the nuclei of rBMSCs and plays an essential role in their normal osteogenic differentiation, partly by suppressing NF-κB signaling. Stem Cells 2014;32:1943–1955
研究领域:
干细胞生物学
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骨再生
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Shuai Chen,Jie Jin,Ziqing Xu,Huawei Han,Lan Wu,Zhiwei Li
Background Catalpol , a major active component of the Chinese herb Rehmannia glutinosa , possesses various pharmacological benefits, including anti-inflammatory, antidiabetic , and antitumor properties. Recent studies have reported that catalpol can attenuate bone loss and enhance bone formation. Nevertheless, the molecular mechanisms underlying its effects on osteoporosis pathogenesis remain unclear. Purpose We investigated whether catalpol had a protective effect against postmenopausal osteoporosis (PMOP) and explored its exact mechanism of action. Methods Seventy-two rats were randomly divided into six groups: sham, model, low-dose catalpol (5 mg/kg/day), medium-dose catalpol (10 mg/kg/day), high-dose catalpol (20 mg/kg/day), and positive control (alendronate, 2.5 mg/kg). In this experiment, a ovariectomy was performed to establish a female rat model of PMOP. After 12 weeks of gavage, micro-computed tomography (micro-CT) and histochemical staining were performed to evaluate bone mass, bone microstructure and histological parameters. Furthermore, RAW 264.7 cells were induced by RANKL to form mature osteoclasts to investigate the effect of catalpol on osteoclast differentiation and apoptosis in vitro . Additionally, the osteoclast apoptosis-related proteins of Sirt6 , ERα, FasL , NFATc1, cleaved-caspase 8, cleaved-caspase 3, and Bax were assessed using western blotting . The expressions of NFATc1, Ctsk, Oscar , and Trap were quantified using RT-qPCR. The apoptotic rate of the osteoclasts was determined using flow cytometry. Sirt6 knockdown was performed using siRNA gene silencing in experiments to investigate its role in catalpol-mediated osteoclast apoptosis. The deacetylation of ERα in osteoclasts was tested via co-immunoprecipitation. Results Catalpol (10 and 20 mg/kg) and alendronate (2.5 mg/kg) could significantly improve bone mineral density (BMD) and microstructure and decrease osteoclast density in ovariectomized (OVX) rats. In addition, catalpol (10 and 20 mg/kg) upregulated the expression of Sirt6, ERα, FasL, cleaved-caspase 8, cleaved-caspase 3, Bax, and downregulated the expression of NFATc1, Ctsk, Oscar, Trap both in vivo and in vitro . Catalpol also promoted ERα deacetylation and stabilized ERα protein to enhance the expression of FasL. In addition, Sirt6 knockdown by siRNA prevented ERα deacetylation and eliminated catalpol-mediated osteoclast apoptosis. Conclusions The present study demonstrated that catalpol prevents estrogen deficiency-induced osteoporosis by promoting osteoclast apoptosis via the Sirt6-ERα-FasL axis. These findings revealed a novel molecular mechanism underpinning the impact of catalpol in the progression of osteoporosis and provided novel insights into the treatment of osteoporosis.
研究领域:
药理学
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骨骼生物学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
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