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Peficitinib suppresses diffuse-type tenosynovial giant cell tumor by targeting TYK2 and JAK/STAT signaling

Science China Life Sciences 2025年

作者： Shan Lu Chenxi Cao Wenjia Zhang Jiayi Li Jingli Yang Zisheng Huang Zhijun Wu Baitao Liu Hongjie Huang Haijun Wang Yongjian Wang Dingge Liu Zhihua Zhang Kaiping Liu Gang Yang Xi Gong Hui Dai Yingjia Li Erdan Dong Xin Zhang Yan Zhang Haihe Laboratory of Cell Ecosystem Institute of cardiovascular Diseases The First Affiliated Hospital of Dalian Medical University Institute of cardiovascular Sciences School of Basic Medical Sciences Peking University Health Science Center Department of Cardiology and Institute of Vascular Medicine Peking University Third HospitalState Key Laboratory of Vascular Homeostasis and Remodeling Peking University Department of Sports Medicine Peking University Third Hospital Institute of Sports Medicine of Peking University Beijing Key Laboratory of Sports Injuries Engineering research Center of Sports Trauma Treatment Technology and Devices Ministry of Education State Key Laboratory of Membrane Biology Institute of Molecular Medicine College of Future Technology Peking University Peking University Health Science Centre Peking University Department of Immunology School of Basic Medical Sciences NHC Key Laboratory of Medical Immunology Peking University research Center for Cardiopulmonary Rehabilitation University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital) School of Health and Life Sciences University of Health and Rehabilitation Sciences research unit of Medical Science research Management/Basic and Clinical research of metabolic cardiovascular Diseases Chinese Academy of Medical Sciences

Diffuse-type tenosynovial giant cell tumor(dTGCT) is a destructive but rare benign proliferative synovial neoplasm. Although surgery is currently the main treatment modality for dTGCT, the recurrence risk is up to 50%. Therefore, there is a great need for effective drugs against dTGCT with minor side effects. The Janus kinase(JAK)/signal transducer and activator of transcription(STAT) signaling plays a central role in rheumatoid arthritis(RA), a disease with similar characteristics as dTGCT, but its function in dTGCT remains *** fibroblast-like synoviocytes(FLS) and macrophages were isolated from 10 synovial tissue samples from dTGCT patients for the screening and validation of the five clinically approved JAK inhibitors to treat RA against dTGCT. Cell viability, cell death, inflammation and the activity of the JAK family members of cultured dTGCT FLS(both 2-D and 3-D) and macrophages were investigated for the efficacy of the JAK inhibitors. Here, we found that similar to RA, JAK/STAT signaling was markedly activated in the dTGCT synovium. Of the 5 JAK inhibitors, peficitinib was shown to have the most potency in addressing some of the pathological responses of dTGCT FLS and *** potency of peficitinib was much higher than pexidartinib, which is the only FDA-approved drug for dTGCT. Mechanistically, peficitinib inhibited tyrosine kinase 2(TYK2), a JAK family member necessary for the pathological progression of dTGCT FLS and macrophages. In summary, we not only revealed JAK/STAT(especially TYK2) signaling as the major mechanism underlying dTGCT, but also identified peficitinib as a promising drug against dTGCT.

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Dietary carbohydrate intake and risk of type 2 diabetes:a 16-year prospective cohort study

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Science China Life Sciences 2025年

作者： Lu Gan Yi Yang Bin Zhao Kai Yu Kehua Guo Fang Fang Zhiguang Zhou Demetrius Albanes Jiaqi Huang Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University CSU-Sinocare Research Center for Nutrition and Metabolic Health Xiangya School of Public Health Central South UniversityFurong Laboratory Division of Cancer Epidemiology and Genetics National Cancer Institute NIH Department of Health and Human Services School of Computer Science and Engineering Central South University Institute of Environmental Medicine Karolinska Institute National Clinical research Center for metabolic Diseases Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University

Despite considerable research underscoring the importance of carbohydrate intake in relation to the risk of type 2 diabetes(T2D), a comprehensive assessment of this relationship is currently lacking. We aimed to examine the associations of various types and food sources of dietary carbohydrate intake with the risk of T2D, to evaluate potential effect modification by other factors, including genetic susceptibility,and to explore the potential mediators for such associations. The present study included 161,872 participants of the UK Biobank who were free of prevalent cancer, cardiovascular disease, or diabetes, and had at least one validated 24-h dietary recall assessment. Multivariableadjusted age-stratified Cox proportional hazard regression models were applied to estimate hazard ratios(HRs) and 95% confidence intervals(CI) for the associations of various types and food sources of dietary carbohydrate intake with risk of T2D. During a median follow-up of13.6 years, 4,176 incident cases of T2D were identified. In the multivariable-adjusted models, a greater intake of fiber, carbohydrates from whole grains, and carbohydrates from non-starchy vegetables was significantly associated with a lower risk of T2D(highest vs. lowest quantile, HR [95% CI]=0.70 [0.62–0.79], 0.74 [0.67–0.82], and 0.83 [0.75–0.92], respectively, all P for trend <0.005). In contrast, a higher intake of starch and carbohydrate from starchy vegetables was associated with an increased risk of T2D(highest vs. lowest quantile, HR [95%CI]=1.31 [1.16–1.48] and 1.19 [1.09–1.31], respectively, both P for trend <0.005). Replacing one serving of refined grains or starchy vegetables with an equal amount of whole grains or non-starchy vegetables was associated with 4% to 10% lower risk of T2D(all P values <0.001).The observed associations were generally similar across population subgroups, including individuals with different genetic susceptibility to T2D. Mediation analyses of the inverse association between T

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Exercise training attenuates angiotensinⅡ-induced cardiac fibrosis by reducing POU2F1 expression

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Journal of Sport and Health Science 2023年第4期12卷 464-476页

作者： Na Feng Haiyi Yu Yueshen Wang Youyi Zhang Han Xiao Wei Gao Department of Cardiology and Institute of Vascular Medicine Peking University Third HospitalNational Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesKey Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijing Key Laboratory of Cardiovascular Receptors ResearchBeijing 100191China research unit of Medical Science research Management/Basic and Clinical research of metabolic cardiovascular Diseases Chinese Academy of Medical SciencesBeijing 100191China

Background:Exercise training protects against heart ***,the mechanism underlying the protective effect of exercise training on angiotensinⅡ(AngⅡ)-induced cardiac fibrosis remains ***:An exercise model involving C57BL/6N mice and 6 weeks of treadmill training was ***Ⅱ(1.44 mg/kg/day)was administered to induce cardiac *** sequencing and bioinformatic analysis were used to identify the key factors mediating the effects of exercise training on cardiac *** adult mouse cardiac fibroblasts(CFs)were used in ***-associated virus serotype 9 was used to overexpress POU domain,class 2,transcription factor 1(POU2F1)in ***:Exercise training attenuated AngⅡ-induced cardiac fibrosis and reversed 39 gene expression *** transcription factor regulating the largest number of these genes was *** to controls,POU2F1 was shown to be signififcantly upregulated by AngⅡ,which is itself reduced by exercise *** vivo,POU2F1 overexpression nullified the benefits of exercise training on cardiac *** CFs,POU2F1 promoted cardiac *** enhancer-binding proteinβ(C/EBPβ)was predicted to be the transcription factor of POU2F1and verified using a dual-luciferase reporter *** vivo,exercise training activated AMP-activated protein kinase(AMPK)and alleviated the increase in C/EBPβinduced by AngⅡ.In CFs,AMPK agonist inhibited the increase in C/EBPβand POU2F1 induced by Ang II,whereas AMPK inhibitor reversed this ***:Exercise training attenuates AngⅡ-induced cardiac fibrosis by reducing *** training inhibits POU2F1 by activating AMPK,which is followed by the downregulation of C/EBPβ,the transcription factor of POU2F1.

关键词： AMPK C/EBPβ Cardiac fibrosis Exercise POU2F1

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Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction

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World Journal of Gastroenterology 2018年第16期24卷 1748-1765页

作者： Michelle L Boland Stephanie Oldham Brandon B Boland Sarah Will Jean-Martin Lapointe Silvia Guionaud Christopher J Rhodes James L Trevaskis cardiovascular and metabolic Diseases MedImmune LLC Pathology MedImmune Ltd. Pathology Drug Safety and MetabolismIMED Biotech UnitAstraZeneca

AIM To comprehensively evaluate mitochondrial(dys) function in preclinical models of nonalcoholic steatohepatitis(NASH).METHODS We utilized two readily available mouse models of nonalcoholic fatty liver disease(NAFLD) with or without progressive fibrosis: Lep^(ob)/Lep^(ob)(ob/ob) and FATZO mice on high trans-fat, high fructose and high cholesterol(AMLN) diet. Presence of NASH was assessed using immunohistochemical and pathological techniques, and gene expression profiling. Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence, and function was assessed by measuring oxidative capacity in primary hepatocytes, and respiratory control and proton leak in isolated mitochondria. Oxidative stress was measured by assessing activity and/or expression levels of Nrf1, Sod1, Sod2, catalase and 8-OHdG. RESULTS When challenged with AMLN diet for 12 wk, ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia. NASH development was associated with hepatic mitochondrial abnormalities, similar to those previously observed in humans, including mitochondrial accumulation and increased proton leak. AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice. Despite similar mitochondrial phenotypes, we found that ob/ob mice developed more advanced hepatic fibrosis. Activity of superoxide dismutase(SOD) was increased in ob/ob AMLN mice, whereas FATZO mice displayed increased catalase activity, irrespective of diet. Furthermore, 8-OHd G, a marker of oxidative DNA damage, was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice. Therefore, antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57 BL6 J control mice, but significantly perturbed in ob/ob mice. CONCLUSION Oxidative stress, and/or the capacity to compensate for increased oxidative stress, in the setting of mitochondrial dysfunction, is

关键词： Nonalcoholic steatohepatitis Steatosis Fibrosis Mitochondrial function Oxidative stress

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The mechanism and therapy of aortic aneurysms

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Signal Transduction and Targeted Therapy 2023年第3期8卷 963-982页

作者： Jianing Gao Huanhuan Cao Gaofei Hu Yufei Wu Yangkai Xu Hongtu Cui Hong S.Lu Lemin Zheng The Institute of cardiovascular Sciences and Institute of Systems Biomedicine School of Basic Medical SciencesKey Laboratory of Molecular Cardiovascular Science of Ministry of EducationNHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesBeijing Key Laboratory of Cardiovascular Receptors ResearchHealth Science CenterPeking University100191 BeijingChina Department of Cardiology and Institute of Vascular Medicine Peking University Third HospitalNHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesKey Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijing Key Laboratory of Cardiovascular Receptors ResearchResearch Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular DiseasesChinese Academy of Medical Sciences100191 BeijingChina Department of Physiology Saha Cardiovascular Research CenterUniversity of KentuckySouth LimestoneLexingtonKY 40536-0298USA

Aortic aneurysm is a chronic aortic disease affected by many *** it is generally asymptomatic,it poses a significant threat to human life due to a high risk of *** of its strong concealment,it is difficult to diagnose the disease in the early *** present,there are no effective drugs for the treatment of *** intervention and endovascular treatment are the only *** current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm,the specific mechanisms remain *** are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and *** better understand aortic aneurysm,this review elaborates on the discovery history of aortic aneurysm,main classification and clinical manifestations,related molecular mechanisms,clinical cohort studies and animal models,with the ultimate goal of providing insights into the treatment of this devastating *** underlying problem with aneurysm disease is weakening of the aortic wall,leading to progressive *** not treated in time,the aortic aneurysm eventually *** aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic *** disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.

关键词： aortic diagnosis drugs treatment

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Mitochondria as therapeutic targets for cancer stem cells

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World Journal of Stem Cells 2015年第2期7卷 418-427页

作者： In Sung Song Jeong Yu Jeong Seung Hun Jeong Hyoung Kyu Kim Kyung Soo Ko Byoung Doo Rhee Nari Kim Jin Han National research Laboratory for Mitochondrial Signaling Department of PhysiologyCollege of MedicineCardiovascular and Metabolic Disease CenterInje University

Cancer stem cells(CSCs) are maintained by theirsomatic stem cells and are responsible for tumor initiation, chemoresistance, and metastasis. Evidence for the CSCs existence has been reported for a number of human cancers. The CSC mitochondria have been shown recently to be an important target for cancer treatment, but clinical significance of CSCs and their mitochondria properties remain unclear. Mitochondriatargeted agents are considerably more effective compared to other agents in triggering apoptosis of CSCs, as well as general cancer cells, via mitochondrial dysfunction. Mitochondrial metabolism is altered in cancer cells because of their reliance on glycolytic intermediates, which are normally destined for oxidative phosphorylation. Therefore, inhibiting cancer-specific modifications in mitochondrial metabolism, increasing reactive oxygen species production, or stimulating mitochondrial permeabilization transition could be promising new therapeutic strategies to activate cell death in CSCs as well, as in general cancer cells. This review analyzed mitochondrial function and its potential as a therapeutic target to induce cell death in CSCs. Furthermore, combined treatment with mitochondriatargeted drugs will be a promising strategy for the treatment of relapsed and refractory cancer.

关键词： Cancer stem cells Mitochondria Relapsedand refractory cancer Therapeutic target Mitochondrialenergy metabolism

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Cyclooxygenase 2 in liver dysfunction and carcinogenesis: Facts and perspectives

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World Journal of Gastroenterology 2017年第20期23卷 3572-3580页

作者： Paloma Martín-Sanz Marta Casado Lisardo Boscá Department of Metabolism and Cell Signaling Institute of Biomedical Research Alberto Sols Biomedical Network Center for the Study of Hepatic and Digestive Disease and Cardiovascular Diseases metabolic Experimental Pathology unit Biomedical Institute of ValenciaJaume Roig 11

The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver *** are the enzymes involved in the first step of the biosynthesis of these lipid mediators and selective inhibitors for these isoenzymes as well as pharmacological analogues of prostaglandins have been developed and are currently applied *** we discuss the implications of these enzymes in the onset of metabolic and lipid disorders in the liver and their potential role in the progression of the diseases towards fibrosis and hepatocellular carcinogenesis.

关键词： Cyclooxygenase-2 NAS Prostaglandin Non-alcoholic steatohepatitis Hepatocellular carcinoma

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Serum Alanine Aminotransferase Is Associated with metabolic Syndrome and 10-year Risk of cardiovascular Disease

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Biomedical and Environmental Sciences 2019年第2期32卷 121-125页

作者： MA Li Na DU Rui CHENG Di LIN Lin WU Xue Yan HU Chun Yan DAI Meng XU Yu XU Min JIANG Lei LI Mian LU Jie Li BI Yu Fang WANG Wei Qing NING Guang Rui Jin Hospital Shanghai Jiao Tong University School of Medicine Shanghai Institute of Endocrine and metabolic Diseases

metabolic syndrome(MetS) is a cluster of metabolic disorders including obesity, hypertension, hyperglycemia, elevated triglyceride levels, and low high-density lipoprotein cholesterol(HDL-C) levels. In recent years, t... 详细信息

关键词： ALT HDL CVD LDL SBP BMI

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Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion

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World Journal of Gastrointestinal Pathophysiology 2017年第4期8卷 161-175页

作者： Benjamin S Maciejewski Tara B Manion Claire M Steppan Pfizer Worldwide research and Development Cardiovascular and Metabolic Diseases Research Unit Pfizer Inc.

AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and *** The standard experimental paradigm utilized to evaluate the incretin response was a lipid *** a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 *** hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then *** impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT ***,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological *** further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were *** DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were *** response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype ***,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid *** treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active *** contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was *** further explore this observation,GPR119 knockout mice were *** response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and ***,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype ***

关键词： Glucagon-like peptide-1 Peptide tyrosinetyrosine Glucose independent insulinotropic peptide Acyl-CoA diacylglycerol acyltransferase-1 Incretin

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Galectin-3-centered paracrine network mediates cardiac inflammation and fibrosis upon β-adrenergic insult

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Science China(Life Sciences) 2023年第5期66卷 1067-1078页

作者： Guomin Hu Jimin Wu Huijun Gu Xiangning Deng Wenli Xu Shan Feng Shuaixing Wang Yao Song Zhengda Pang Xiuling Deng Aleksandr E.Vendrov Nageswara R.Madamanchi Marschall S.Runge Xinyu Wang Youyi Zhang Han Xiao Erdan Dong Department of Cardiology and Institute of Vascular Medicine Peking University Third HospitalNHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesKey Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijing Key Laboratory of Cardiovascular Receptors ResearchResearch Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular DiseasesChinese Academy of Medical SciencesBeijing 100191China Department of Physiology and Pathophysiology Cardiovascular Research CenterSchool of Basic Medical SciencesXi’an Jiaotong University Health Science CenterXi’an 710061China Department of Internal Medicine Frankel Cardiovascular CenterUniversity of MichiganAnn ArborMI48109USA Academy for Advanced Interdisciplinary Studies Peking UniversityBeijing 100087China

Rapid over-activation of β-adrenergic receptors (β-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18),however,the process of inflammation cascades has not been fully *** present study aimed to determine the mechanisms of cardiac inflammatory amplification following acute sympathetic *** bioinformatics analysis,galectin-3 was identified as a potential key downstream effector of β-AR and IL-18 *** serum level of galectin-3 was positively correlated with norepinephrine or IL-18 in patients with chest *** the heart of mice treated with β-AR agonist isoproterenol (ISO,5 mg kg^(-1)),galectin-3 expression was upregulated markedly later than IL-18 activation,and Nlrp3^(-/-)and Il18^(-/-)mice did not show ISO-induced galectin-3 *** was further revealed that cardiomyocyte-derived IL-18 induced galectin-3 expression in macrophages following ISO ***,galectin-3deficiency suppressed ISO-induced cardiac inflammation and fibrosis without blocking ISO-induced IL-18 *** with a galectin-3 inhibitor,but not a β-blocker,one day after ISO treatment effectively attenuated cardiac inflammation and *** conclusion,galectin-3 is upregulated to exaggerate cardiac inflammation and injury following acute β-AR activation,a galectin-3 inhibitor effectively blocks cardiac injury one day after β-AR insult.

关键词： galectin-3 interleukin-18 β-adrenergic receptor macrophage inflammation fibrosis

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