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CCM3 and cerebral cavernous malformation disease

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Stroke & vascular Neurology 2019年第2期4卷 67-70页

作者： Kang Wang Huanjiao Jenny Zhou Min Wang Interdepartmental program in vascular biology and Therapeutics Department of PathologyYale University School of MedicineNew HavenConnecticutUSA

Cerebral cavernous malformations(CCMs)are vascular lesions characterised by enlarged and irregular structure of small blood vessels in the brain,which can result in increased risk of stroke,focal neurological defects and *** different genes,CCM1/Krev/Rap1 Interacting Trapped 1,CCM2/MGC4607 and CCM3/PDCD10,are associated with the CCMs’progression,and mutations in one of three CCM genes cause CCM *** three CCM proteins have similar function in maintaining the normal structure of small blood ***,CCM3 mutation results in a more severe form of the disease which may suggest that CCM3 has unique biological function in the *** current review focuses on the signalling pathways mediated by CCM3 in regulating endothelial cell junction,proliferation,migration and *** findings may offer potential therapeutic strategies for the treatment of CCMs.

关键词： cerebral malformation finding

Cardiovascular care for older adults： hypertension and stroke in the older adult

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Journal of Geriatric Cardiology 2016年第5期13卷 373-379页

作者： Andrew P Miller Ann M Navar Gary S Roubin Suzanne Oparil Cardiovascular Associates Birmingham Alabama USA Duke Clinical Research Institute Durham North Carolina USA vascular biology & Hypertension program Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham Alabama USA

1 Introduction Hypertension and cerebrovascular disease incidence and prevalence rise dramatically with age, owing to longer exposure time to age-associated alterations in vascular function and structure and cardiovascular risk factors. This chapter is aimed at connecting age-related alterations in vascular function and structure to the resultant target organ damage, and to raise awareness of unique presentations and treatment strategies for hypertension and stroke in older adults.

关键词： Aging Cerebrovascular disease Clinical trials Hypertension Stroke

Cell-specific mineralocorticoid receptors:future therapeutic targets for stroke?

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Neural Regeneration Research 2016年第8期11卷 1230-1231页

作者： Quynh N.Dinh Grant R.Drummond Christopher G.Sobey Sophocles Chrissobolis vascular biology & Immunopharmacology Group Cardiovascular Disease Program and Department of PharmacologyBiomedicine Discovery InstituteMonash University Department of Pharmaceutical and Biomedical Sciences Raabe College of PharmacyOhio Northern University

The mineralocorticoid receptor（MR）,well known to be expressed in renal epithelial cells where it is important in fluid and electrolyte homeostasis,has aldosterone as one of its main *** research in the last 10–15 years indicates that MRs are also expressed outside of the kidney,including in the brain,vasculature and heart,where they contribute to the pathophysiology of disease（Dinh et al.,2012;]aisser and Farman, 2016）.

关键词： aldosterone homeostasis electrolyte outside inflammation deletion neurological protective infarct remodeling

Endothelial mechanosensors: the gatekeepers of vascular homeostasis and adaptation under mechanical stress

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Science China(Life Sciences) 2014年第8期57卷 755-762页

作者： DENG QiuPing HUO YingQing LUO JinCai Laboratory of vascular biology Institute of Molecular MedicineBeijing Key Laboratory of Cardiometabolic Molecular MedicinePeking University

Endothelial cells(ECs)not only serve as a barrier between blood and extravascular space to modulate the exchange of fluid,macromolecules and cells,but also play a critical role in regulation of vascular homeostasis and adaptation under mechanical stimulus via intrinsic ***,with the dissection of microdomains responsible for cellular responsiveness to mechanical stimulus,a lot of mechanosensing molecules(mechanosensors)and pathways have been identified in *** addition,there is growing evidence that endothelial mechanosensors not only serve as key vascular gatekeepers,but also contribute to the pathogenesis of various vascular *** review focuses on recent findings in endothelial mechanosensors in subcellular microdomains and their roles in regulation of physiological and pathological functions under mechanical stress.

关键词： endothelial cells mechanotransduction mechanosensors vascular adaptation vascular pathogenesis

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

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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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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

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Bone Research 2018年第2期6卷 167-176页

作者： Babita Madan Mitchell J.McDonald Gabrielle E.Foxa Cassandra R.Diegel Bart O.Williams David M.Virshup program in Cancer and Stem Cell biology Duke-NUS Medical School Center for Cancer and Cell biology and program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute Department of Pediatrics Duke University

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine（PORCN） that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159（ETC-159） had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably,simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family,mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN *** of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

关键词： Wnt ETC Bone loss Wnt inhibition mitigated concurrent alendronate therapy

Prohibitin regulates mTOR pathway via interaction with FKBP8

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Frontiers of Medicine 2021年第3期15卷 448-459页

作者： Jiahui Zhang Yanan Yin Jiahui Wang Jingjing Zhang Hua Liu Weiwei Feng Wen Yang Bruce Zetter Yingjie Xu Department of Biochemistry and Molecular and Cell biology Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Obstetrics and Gynecology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China vascular biology program Boston Children’s HospitalHarvard Medical SchoolBostonMA 02115USA

The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of *** activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor *** PI3K-Akt-mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer ***,it is also one of the most commonly attempted targets for cancer ***506 binding protein 8(FKBP8)is an intrinsic inhibitor of mTOR kinase that also exerts an anti-apoptotic *** aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a“switch”type *** identified through immunoprecipitation--mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1(PHB1)specifically interacts with ***,the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway,whereas the FKBP8 level in the mitochondria was substantially ***,concomitant with these changes,the interaction between FKBP8 and mTOR substantially increased in the absence of ***,our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role.

关键词： prohibitin 1 FKBP8 mTOR cell proliferation cancer

Smooth muscle cell differentiation： Mechanisms and models for vascular diseases

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Frontiers in biology 2017年第6期12卷 392-405页

作者： Yujie Deng Caixia Lin Huanjiao Jenny Zhou Wang Min Center for Translational Medicine The First Affiliated Hospital Sun Yat-Sen University Guangzhou 510080 China Department of Pathology and the vascular biology and Therapeutics program Yale University Sehool of Medicine New Haven CT 06520USA

vascular smooth muscle cells (VSMCs) are mature cells that play critical roles in both normal and aberrant cardiovascular conditions. In response to various environmental cues, VSMCs can dedifferentiate from a contractile state to a highly proliferative synthetic state through the so-called ‘phenotypic switching’ process. Changes in VSMC phenotype contribute to numerous vascular-related diseases, including atherosclerosis, calcification, and restenosis following angioplasty. Adventitial VSMC progenitor cells also contribute to formation of the neointima. Herein, we review both, the roles of VSMC differentiation in vascular diseases, and the in vitro models used to investigate the molecular mechanisms involved in the regulation of VSMC differentiation and phenotype modulation. A comprehensive understanding of VSMC behavior in vascular diseases is essential to identify new therapeutic targets for the prevention and treatment of cardiovascular diseases.

关键词： vascular smooth muscle cells progenitor differentiation transcription factor cardiovascular disease

A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

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Neural Regeneration Research 2023年第10期18卷 2141-2146页

作者： Angelina S.Bortoletto Ronald J.Parchem Center for Cell and Gene Therapy Stem Cell and Regenerative Medicine CenterDepartment of NeuroscienceDepartment of Molecular and Cellular BiologyTranslational Biology and Molecular Medicine ProgramMedical Scientist Training ProgramBaylor College of MedicineHoustonTXUSA

Type 2 diabetes mellitus patients have a markedly higher risk of developing *** multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes *** amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are *** this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of *** discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced *** are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at ***,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating *** such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

关键词： Alzheimer’s disease amylin amyloid dementia diabetes human islet amyloid polypeptide islet amyloid polypeptide protofibrils type 2 diabetes mellitus vascular dementia