CELL BIOLOGY AND TOXICOLOGY
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2025
·Vol. 41
·期 1
·1-17
·
IF 5.9
Mao Shitao,Yu Na,Wang Wei,Mao Yikai,Du Ying,Zhao Qihe,Gu Xiu,Kang Jian
Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast activation and collagen deposition, is a progressive lung disease that lacks effective interventions. Ubiquitin-specific peptidase 10 (USP10) acts as a multifunctional player in inflammatory response and progression of cancers, the effect on pulmonary fibrosis is unknown. Here, we demonstrated downregulated expression of USP10 in fibrotic lung tissues of IPF patients. In the current study, lung tissues were collected at the end of weeks 1, 2, or 3 post bleomycin (BLM)-intratracheal delivery. Consistently, USP10 expression levels were reduced after BLM challenge in a time-dependent manner. Mice treated with lentivirus overexpressing USP10 exhibited mitigative lung injury and reduced collagen deposition. USP10 overexpression enhanced autophagy in BLM-treated mouse lungs. Interestingly, the protective effect of USP10 was attenuated as the pulmonary autophagy flux was blocked by autophagy inhibitor 3-methyladenine (3-MA). Primary human and mouse lung fibroblasts were treated with pro-fibrotic TGF-β1 to verify the role of USP10 in vitro. Mechanically, the deubiquitinating enzyme USP10 interacted with Sirtuin 6 (Sirt6) and inhibited its degradation. Furthermore, USP10 overexpression inhibited the activation of Sirt6-mediated AKT/mTOR pathway in both lung tissues and fibroblasts. Our findings suggest that USP10 might attenuate pulmonary fibrosis through the promotion of Sirt6/AKT/mTOR-mediated autophagy. These data prioritize USP10 as a therapeutic target for treating IPF. Graphical
研究领域:
医学
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分子生物学
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PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2022
·
IF 6.819
Gao Shuya,Yang Qingchen,Peng Yue,Kong Weixian,Liu Zekun,Li Zhe,Chen Jiawen,Bao Mengmeng,Li Xie,Zhang Yubin,Bian Xiaohong,Jin Liang,Zhang Hanwen,Zhang Yuexin,Sanchis Daniel,Yan Fangrong,Ye Junmei
The sirtuin 6 (SIRT6) participates in regulating glucose and lipid homeostasis. However, the function of SIRT6 in the process of cardiac pathogenesis caused by obesity-associated lipotoxicity remains to be unveiled. This study was designed to elucidate the role of SIRT6 in the pathogenesis of cardiac injury due to nutrition overload-induced obesity and explore the downstream signaling pathways affecting oxidative stress in the heart. In this study, we used Sirt6 cardiac-specific knockout murine models treated with a high-fat diet (HFD) feeding to explore the function and mechanism of SIRT6 in the heart tissue during HFD-induced obesity. We also took advantage of neonatal cardiomyocytes to study the role and downstream molecules of SIRT6 during HFD-induced injury in vitro, in which intracellular oxidative stress and mitochondrial content were assessed. We observed that during HFD-induced obesity, Sirt6 loss-of-function aggravated cardiac injury including left ventricular hypertrophy and lipid accumulation. Our results evidenced that upon increased fatty acid uptake, SIRT6 positively regulated the expression of endonuclease G (ENDOG), which is a mitochondrial-resident molecule that plays an important role in mitochondrial biogenesis and redox homeostasis. Our results also showed that SIRT6 positively regulated superoxide dismutase 2 (SOD2) expression post-transcriptionally via ENDOG. Our study gives a new sight into SIRT6 beneficial role in mitochondrial biogenesis of cardiomyocytes. Our data also show that SIRT6 is required to reduce intracellular oxidative stress in the heart triggered by high-fat diet-induced obesity, involving the control of ENDOG/SOD2.
研究领域:
心脏病学
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分子生物学
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肥胖研究
·
代谢
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PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2026
·
IF 3.2
Rongli Sun,Kai Xu,Xiaoqin Li,Jiawei Huang,Daqin Wang,Yuepu Pu,Juan Zhang
Benzene causes SIRT6 inhibition which enhances glycolysis and lactate accumulation. • The increased lactate thus drives DSBs and cellular senescence in benzene toxicity. • SIRT6 regulates PRMT5 lactylation at lysine 240 (K240) via enzymes TIP60 and HDAC1. • Blocking PRMT5 K240 lactylation mitigates BQ-caused DNA damage and senescence. Benzene exposure induces hematotoxicity, partially through disrupted DNA damage repair. SIRT6 is a key regulator of both DNA repair and metabolism. While its connection to metabolic reprogramming and novel lactylation modifications in benzene toxicity remains unknown. Herein, we found decreased SIRT6 expression in the peripheral WBCs of benzene-exposed workers. Furthermore, mediation analysis identified SIRT6, p16, and serum γ-H2AX levels as mediators of the inverse relationship between urinary S-PMA and WBC counts. In vitro , benzoquinone (BQ) suppressed SIRT6, enhanced glycolysis and lactate production, and induced DNA double-strand breaks (DSBs) and senescence. SIRT6-knockdown models confirmed that SIRT6 deficiency exacerbates benzene-induced increase in glycolysis and lactate accumulation. Crucially, lactate reduction with DCA attenuated DSBs and cellular senescence in bone marrow cells, mitigating hematopoietic damage. Mechanistically, we identified PRMT5 as a novel lactylation target of SIRT6 at lysine 240 (K240), a process that SIRT6 regulated through the lactyltransferase TIP60 and delactylase HDAC1. Functional studies in K240-mutant cells demonstrated that blocking lactylation at this site alleviated BQ-induced DSBs and senescence. Our findings establish that SIRT6 deficiency drives a lactate-fuelled lactylation of PRMT5 at K240, impairing DNA repair and promoting hematopoietic stem cell senescence caused by benzene. This work elucidates a previously unrecognized metabolic-epigenetic axis in benzene toxicity and highlights the therapeutic potential of targeting glycolytic flux or specific lactylation events to combat chemical-induced hematological damage. Download: Download high-res image (245KB) Download: Download full-size image
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高影响因子
JOURNAL OF ENDODONTICS
·
2013
·
IF 2.929
Hua Ling Sun,Yan Ru Wu,Cui Huang,Jia Wei Wang,Dong Jie Fu,Yin Chen Liu
Introduction The aim of this study was to investigate whether SIRT6 is expressed in human dental pulp as well as the effect of SIRT6 on proliferation and odontoblastic differentiation of human dental pulp cells (HDPCs). Methods Immunohistochemical and immunocytochemical assays were used to detect the expression of SIRT6 in human dental pulp tissue and HDPCs. To determine the effect of SIRT6 on odontoblast differentiation, HDPCs with loss (HDPCs SIRT6 knockdown) and gain (HDPCs SIRT6 overexpression) of SIRT6 function were developed, and their proliferation ability was examined. Odontogenic differentiation of HDPCs was determined by alkaline phosphatase (ALP) activity, ALP-positive cell staining, alizarin red staining, and von Kossa staining. Mineralization-related genes, including ALP, dentin sialophosphoprotein (DSPP), and dentin matrix acidic phosphoprotein 1 , were determined by real-time quantitative polymerase chain reaction. Western blot analysis was performed to detect the expression of DSPP protein. Results SIRT6 was found in the dental pulp tissue and HDPCs. SIRT6 knockdown decreased ALP activity in HDPCs; calcium nodule formation ability; and the expression of mineralization-related genes such as ALP, DSPP, and DMP1, whereas these were increased with the overexpression of SIRT6. Conclusions SIRT6 is expressed in human dental pulp and participates in the odontoblast differentiation of HDPCs.
研究领域:
牙科研究
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分子生物学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF HYPERTENSION
·
2023
·Vol. 41
·期 3
·393-401
·
IF 4.9
Tao Yafen,Wu Yue,Jiang Chuanyue,Wang Qianghua,Geng Xu,Chen Lei,Zhou Sihui,Wang Xuegu,Han Mingliang,Du Danli,Ding Biao,Li Xiang
Background:
This study aims to investigate the effects of saturated free fatty acid on calcification and SIRT6 expression in vascular smooth muscle cells (VSMCs) and the role of SIRT6 in regulating VSMC calcification.Methods:
Sprague–Dawley rats were randomly allocated to two groups: rats with normal diet (ND) and high-fat diet (HFD) from 4 to 12 weeks. At 12 weeks, part rats randomly selected from ND and HFD were administrated with vitamin D3 and nicotine
to establish a model of vascular calcification. Thoracic aortas were collected from treatment rats at 16 weeks for assaying vascular calcification and related protein expression. Primary VSMCs isolated from Sprague–Dawley rats were used for investigating the effects of palmitic
acid on VSMCs’ calcification, apoptosis and target protein expression.Results:
HFD-facilitated calcification in medial aorta, with decreased SIRT6 expression in VSMCs of aortas. Palmitic acid decreased SIRT6 expression while increased
calcification, apoptosis and protein expression of BMP2 and RUNX2 in primary VSMCs. Overexpression of SIRT6 could, partially or completely, rescue the palmitic acid-induced elevation of calcification, apoptosis and expression of BMP2 and RUNX2.Conclusion:
This
study demonstrated that vascular calcification induced by HFD was linked to the palmitic acid-induced downregulation of SIRT6. Overexpression of SIRT6 could decrease palmitic acid-induced calcification and apoptosis in VSMCs.
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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PubMed
高影响因子
CLINICAL SCIENCE
·
2022
·Vol. 136
·期 22
·1711-1730
·
IF 6.876
Gao Shuya,Yang Qingchen,Liu Zekun,Kong Weixian,Chen Jiawen,Li Xie,Peng Yue,Bao Mengmeng,Bian Xiaohong,Zhang Yuexin,Jiang Qizhou,Li Zhe,Zhang Yubin,Yan Fangrong,Ye Junmei
Metformin is accepted as a first-line drug for the therapy of Type 2 diabetes (T2D), while its mechanism is still controversial. In the present study, by taking advantage of mouse model of high-fat-diet (HFD)-induced obesity and primary mouse hepatocytes (PMHCs) as well as human hepatocyte L02 cell line, we aimed to investigate the involvement of SIRTs during the application of metformin for the therapy of T2D. Our data evidenced that during HFD-induced obesity, there was elevation of nucleus protein acetylation. Analysis of liver tissue showed that among all SIRT members, SIRT6 expression was significantly down-regulated during HFD feeding, which was sustained to regular level with metformin administration. Our result also showed that SIRT6 suppressed intracellular oxidative stress upon FAs stimulation in PMHCs and L02 cells. Mechanistically, SIRT6, but not SIRT1 promoted PGC-1α expression. We further prove that ENDOG is downstream of PGC-1α. In addition, we evidenced that ENDOG protects hepatocytes from lipid-induced oxidative stress, and down-regulation of Endog blunted the protective role of metformin in defending against FAs-induced oxidative stress. Our study established a novel mechanism of metformin in counteracting lipid-induced hepatic injury via activating SIRT6/PGC-1α/ENDOG signaling, thus providing novel targets of metformin in the therapy of T2D.
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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细胞生物学
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高影响因子
EXPERIMENTAL AND MOLECULAR MEDICINE
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2026
·
IF 17.5
Chang Shujuan,Chen Wen,Zhu Wei,Liu Nana,Wang Yuhang,Li Jianguo,Kang Jiuhong
Fetal growth restriction (FGR), a major perinatal complication, is causally linked to lifelong cognitive deficits in offspring; however, its underlying mechanisms remain poorly defined. Here, the SIRT6–TDO2/KYNA–mTOR axis is identified as a critical mediator of synaptic dysfunction and cognitive deficits in FGR offspring. Hippocampal excitatory neurons in FGR mice exhibit markedly reduced SIRT6 expression, and SIRT6 conditional knockout in CaMKIIα⁺ neurons ( Sirt6 cKO) recapitulates FGR-induced synaptic and cognitive impairments. Mechanistically, SIRT6 governs synaptic plasticity and cognition via its histone deacetylase activity, independent of its ADP-ribosyltransferase function. SIRT6 deficiency increases histone H3K9 acetylation at the Tdo2 promoter, enhancing kynurenine pathway flux and leading to pathological accumulation of hippocampal kynurenic acid (KYNA). Elevated KYNA suppresses AKT/mTOR/p70S6K1 signaling, disrupting synaptic protein synthesis. Strikingly, pharmacological TDO2 blockade, neuronal TDO2 knockdown or mTOR activation reverses synaptic and cognitive deficits in Sirt6 cKO mice. Crucially, hippocampal SIRT6 overexpression in FGR mice normalizes KYNA levels, reactivates mTOR signaling, and restores synaptic plasticity and cognitive performance. These findings uncover a neurodevelopmental axis wherein neuronal SIRT6 deficiency dysregulates tryptophan metabolism to impair synaptic plasticity, identifying actionable targets for treating FGR-induced cognitive disorders. The alternative text for this image may have been generated using AI.
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高影响因子
MOLECULAR NEUROBIOLOGY
·
2021
·Vol. 59
·期 1
·429-444
·
IF 5.59
Zou Ying,Zhang Jiaqi,Liu Jingmin,Xu Jiawei,Fu Lanya,Ma Xinrui,Xu Yizhou,Xu Shuyi,Wang Xianghai,Guo Jiasong
Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Previous studies have been reported a pro-regenerative role of SIRT6 in central nervous system injury. However, the role of SIRT6 in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of SIRT6 steering Schwann cell dedifferentiation during Wallerian degeneration in injured peripheral nerve. Herein, we first examined the expression pattern of SIRT6 after peripheral nerve injury. Using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that SIRT6 inhibitor accelerates Schwann cell dedifferentiation as well as axonal and myelin degeneration, while SIRT6 activator attenuates this process. Moreover, in an in vitro Schwann cell dedifferentiation model, we found SIRT6 inhibitor promotes Schwann cell dedifferentiation through upregulating the expression of c-Jun. In addition, downregulation of c-Jun reverse the effects of SIRT6 inhibition on the Schwann cells dedifferentiation and axonal and myelin degeneration. In summary, we first described SIRT6 acts as a negative regulator for Schwann cells dedifferentiation during Wallerian degeneration and c-Jun worked as a direct downstream partner of SIRT6 in injured peripheral nerve.
研究领域:
神经科学
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分子生物学
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细胞生物学
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PubMed
高影响因子
Frontiers in Nutrition
·
2026
·
IF 5.5
Binhong Hu,Ling Yao,Xin Deng,Wei Zhao,Kuo Chen,Jiacheng Zhang,Zhiqiang Li,Jin-ping Li,Wei Jiang,Huabao Liu
AimsThis study aims to explore the potential therapeutic effect of Dendrobium officinale polysaccharide (DOP) on non-alcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD), and to elucidate the underlying mechanism involving the SIRT6/PGC-1α signaling axis and the regulation of the gut microbiota.MethodsWe extracted and characterized DOP. We established a rat model of NAFLD induced by HFD and evaluated the efficacy of DOP by integrating multi-omics techniques (transcriptomics, metabolomics) and 16S rRNA sequencing. To verify the specific role of SIRT6, we introduced the SIRT6 inhibitor OSS_128167 in the primary hepatocyte model induced by oleic acid/palmitic acid (OA/PA).ResultsDOP significantly alleviated liver steatosis, oxidative stress, and lipid metabolism disorders induced by HFD. Multi-omics analysis indicated that DOP regulated liver glycerophospholipid metabolism and restored intestinal microbiota homeostasis, significantly increasing the abundance of beneficial bacteria such as Lactobacillus. Mechanistically, DOP activated the liver SIRT6/PGC-1α signaling axis, thereby enhancing antioxidant defense and inhibiting lipogenesis. Crucially, in vitro experiments confirmed that the SIRT6 inhibitor OSS_128167 eliminated the protective effect of DOP on lipid accumulation, confirming that the effect of DOP depends on SIRT6.ConclusionDOP improves NAFLD through dual mechanisms of regulating the gut-liver axis homeostasis and directly activating the liver SIRT6/PGC-1α signaling pathway. The results of this study provide a theoretical basis for developing DOP as a drug for the treatment of NAFLD.
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高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2026
·
IF 12.2
Zhou Daqian,Wang Liquan,Zhou Yang,Lv Jiale,Song Chao,Mei Yongliang,Liu Tao,Wu Taotao,Yu Fei,Liu Zongchao
Intervertebral disc degeneration (IVDD) is a common and challenging chronic condition in orthopedics, primarily characterized by the aging of nucleus pulposus cells (NPC). Current treatment strategies for IVDD, particularly those targeting NPC senescence, remain underdeveloped. Research has shown that NPC senescence is closely associated with mitochondrial damage, leading to the accumulation of cytoplasmic reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). Mitochondrial autophagy, as a key mechanism of mitochondrial quality control, regulates ROS and mtDNA levels by eliminating dysfunctional and damaged mitochondria, thereby delaying cellular aging. Notably, mitophagy signaling associated with Sirtuin 6 (SIRT6) and PTEN-induced kinase 1 (PINK1)/Parkin has been implicated in this process. Traditional Chinese Medicine (TCM), with its holistic approach and unique theoretical system of syndrome differentiation and treatment, offers significant advantages in preventing and treating degenerative diseases such as IVDD. However, research into TCM formulations aimed at NPC senescence remains limited. In preliminary studies, we observed that Nodakenin, the primary active compound from the TCM formula Duhuo Jisheng decoction (DHJSD), exerts protective effects in a SIRT6-associated manner and appears to be associated with activation of PINK1/Parkin-related mitophagy signaling. In this study, we used single-cell analysis to construct human NPC senescence and rat IVDD models, assessing mitochondrial morphology, mitochondrial membrane potential, cell senescence, and autophagy-related gene expression. We further evaluated the effects of Nodakenin (Nod) on H 2 O 2 -induced NPC senescence and determined the optimal intervention concentration, followed by assessment of mitochondrial phenotypes and SIRT6- and PINK1/Parkin-associated markers. These findings provide new theoretical support for the clinical application of TCM in the treatment of IVDD.
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PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 7
·859
·
IF 6
Ruifeng Wang,Anping Ding,Jiaye Wang,Jiaxue Wang,Yujie Zhou,Miao Chen,Shuang Ju,Mingpu Tan,Zengxu Xiang
Astragalin (AG), a typical flavonoid found inThesium chinenseTurcz (T. chinense), is abundant in various edible plants and possesses high nutritional value, as well as antioxidant and antibacterial effects. In this study, we initially predicted the mechanism of action of AG with two anti-aging and antioxidant-related protein targets (CD38 and IGFR) by molecular docking and molecular dynamics simulation techniques. Subsequently, we examined the anti-aging effects of AG inCaenorhabditis elegans(C. elegans), the antioxidant effects in zebrafish, and verified the related molecular mechanisms. InC. elegans, AG synergistically extended the lifespan ofC. elegansby up-regulating the expression ofdaf-16through inhibiting the expression ofdaf-2/IGFRand also activating the AMPK and MAPK pathways to up-regulate the expression ofsir-2.1,sir-2.4, andskn-1. In oxidatively damaged zebrafish embryos, AG demonstrated a synergistic effect in augmenting the resistance of zebrafish embryos to oxidative stress by up-regulating the expression levels ofSIRT1andSIRT6within the zebrafish embryos system via the suppression of CD38 enzymatic activity and then inhibiting the expression ofIGFRthrough high levels ofSIRT6. These findings highlight the antioxidant and anti-aging properties of AG and indicate its potential application as a supplementary ingredient in aquaculture for enhancing fish health and growth.
研究领域:
分子生物学
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老年医学
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营养科学
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水产养殖
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Zijun Zhou,Yinli Xu,Xiong Xiao,Tao Huang,Jikai Zhao,Yuting Huang,Guoxin Zhang,Bo Xing,Qiusheng Zhao,Zijun Cao,Zhishang Wang,Zongtao Yin,Liming Yu,Huishan Wang
Background and purpose Our previous clinical study showed that berberine could reduce the occurrence of postoperative atrial fibrillation (AF), but the underlying mechanism remains unknown. Additionally, the effect of SIRT6 in the pathogenesis of AF and whether the anti-arrhythmic effects of berberine are associated with SIRT6 regulation remain uncovered. This study aimed to investigate the role of SIRT6 in the occurrence of AF and the pharmacological effect of berberine on atrial remodeling and AF susceptibility with a focus on SIRT6-AMPK signaling. Methods Bioinformatics tools and human atrial sample analysis were conducted to investigate the potential mechanisms. Murine AF model was induced by angiotensin II (Ang II) infusion with or without the treatment of berberine and the adeno-associated virus carrying SIRT6 or SIRT6-specific short hairpin RNA. The protective effect and the underlying mechanisms were examined. Results NLRP3 inflammasome-mediated inflammatory signaling in atrial tissue was activated, and SIRT6 activity was inhibited in AF patients. Berberine dose-dependently improved atrial structural and electrical remodeling in Ang II-induced mice. Moreover, berberine enhanced atrial antioxidative stress capacity and reduced NLRP3 inflammasome activation. SIRT6 overexpression mimicked these actions. Berberine-mediated SIRT6-AMPK signaling activation was inhibited by SIRT6 knockdown, and berberine-mediated inhibition of NLRP3 inflammasome signaling was compromised. Conclusion These results demonstrate that activation of SIRT6-AMPK signaling protects against Ang II-induced atrial remodeling and AF susceptibility. Berberine prevents Ang II-induced atrial injury by inhibiting NLRP3 inflammasome activation through the SIRT6-AMPK signaling pathway. Its potential as a preventive or therapeutic agent warrants further clinical investigation.
研究领域:
心脏病学
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分子生物学
·
药理学
·
炎症研究
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PubMed
高影响因子
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