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Hypoxia-induced signaling in the cardiovascular system: pathogenesis and Therapeutic targets

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Signal Transduction and Targeted Therapy 2023年第12期8卷 5727-5768页

作者： Yongchao Zhao Weidong Xiong Chaofu Li Ranzun Zhao Hao Lu Shuai Song You Zhou Yiqing Hu Bei Shi Junbo Ge Department of Cardiology Affiliated Hospital of Zunyi Medical UniversityZunyi 563000China Department of Cardiology Zhongshan HospitalFudan UniversityShanghai Institute of Cardiovascular DiseasesShanghai 200032China Key Laboratory of Viral Heart Diseases National Health CommissionShanghai 200032China Key Laboratory of Viral Heart Diseases Chinese Academy of Medical SciencesShanghai 200032China National Clinical Research Center for Interventional Medicine Shanghai 200032China Shanghai Clinical Research Center for Interventional Medicine Shanghai 200032China Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China

Hypoxia,characterized by reduced oxygen concentration,is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases.From the research history and milestone events related to hypoxia in cardiovascular development and diseases,The"hypoxia-inducible factors(HIFs)switch"can be observed from both temporal and spatial perspectives,encompassing the occurrence and progression of hypoxia(gradual decline in oxygen concentration),the acute and chronic manifestations of hypoxia,and the geographical characteristics of hypoxia(natural selection at high altitudes).Furthermore,hypoxia signaling pathways are associated with natural rhythms,such as diurnal and hibernation processes.In addition to innate factors and natural selection,it has been found that epigenetics,as a postnatal factor,profoundly influences the hypoxic response and progression within the cardiovascular system.Within this intricate process,interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established.Thus,it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more Therapeutic targets and make reasonable advancements in clinical research,including FDA-approved drugs and ongoing clinical trials,to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.

关键词： cardiovascular Therapeutic organs

Transcriptional co-activators: emerging roles in signaling pathways and potential Therapeutic targets for diseases

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Signal Transduction and Targeted Therapy 2023年第12期8卷 5686-5726页

作者： Priyanka Dey Talukdar Urmi Chatterji Cancer Research Laboratory Department of ZoologyUniversity of Calcutta35 Ballygunge Circular RoadKolkata 700019 West BengalIndia

Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators.Deregulation of these regulatory molecules is associated with cell state transitions,which in turn is accountable for diverse maladies,including developmental disorders,metabolic disorders,and most significantly,cancer.A decade back most transcription factors,the key enablers of disease development,were historically viewed as‘undruggable’;however,in the intervening years,a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators,their confederates in various physiological and molecular processes.These co-activators,along with transcription factors,have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions,whereby,deregulation of such interactions may foster tissue-specific disease phenotype.Hence,it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors.The proposed review attempts to elaborate an in-depth account of the transcription co-activators,their involvement in transcription regulation,and context-specific contributions to pathophysiological conditions.This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly Therapeutic strategies,where drugs targeting co-activators will have enhanced benefits and reduced side effects.Additional insights into currently available Therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced Therapeutic targets aiming for disease amelioration and good patient prognosis.

关键词： Therapeutic eventually potential

CD9 role in proliferation, rejuvenation, and Therapeutic applications

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Genes & Diseases 2024年第3期11卷 95-97页

作者： Sai Priyanka Kodam Neda Baghban Mujib Ullah Institutefor Immunityand Transplantation Stem Cell Biology and Regenerative MedicineSchool of MedicineMolecular Medicine Department of MedicineStanford UniversityPaloAltoCA94304USA

The CD9 gene,also known as the Tspan29 gene,codes for a protein called CD9,which is a member of the tetraspanin family of transmembrane proteins.^(1) The CD9 protein is involved in various cellular processes,including cell proliferation,differentiation,adhesion,and migration.^(1,2) CD9 has also been found to play a role in the regulation of stem cell proliferation and differentiation.

关键词： migration. Therapeutic CD9

Expanding horizons in overcoming Therapeutic resistance in castration-resistant prostate cancer:targeting the androgen receptor-regulated tumor immune microenvironment

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癌症生物学与医学:英文版 2023年第8期20卷 568-574页

作者： Bisheng Cheng Hai Huang Department of Urology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China

Castration-resistant prostate cancer(CRPC)poses a major treatment challenge,because disease progression occurs despite androgen deprivation therapy(ADT)1.Overcoming Therapeutic resistance in CRPC remains a critical unmet need in clinical practice.The androgen receptor(AR)signaling pathway plays a critical role in prostate cancer development and progression,and is also involved in regulating the tumor immune microenvironment(TIME).

关键词： Therapeutic cancer resistance

Harnessing innate immune pathways for Therapeutic advancement in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1506-1564页

作者： Ankang Hu Li Sun Hao Lin Yuheng Liao Hui Yang Ying Mao Department of Neurosurgery Huashan HospitalFudan UniversityShanghaiP.R.China Institute for Translational Brain Research Shanghai Medical CollegeFudan University ShanghaiPR.China National Center for Neurological Disorders Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration Shanghai Clinical Medical Center of NeurosurgeryNeurosurgical institute of Fudan UniversityHuashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science Institutes of Brain ScienceShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)and Key Laboratory of Metabolism and Molecular Medicine(Ministry of Education)and Molecular and Cell Biology LabInstitutes of Biomedical SciencesShanghai Medical College of Fudan UniversityShanghaiP.R.China

The innate immune pathway is receiving increasing attention in cancer therapy.This pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal cells.Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical studies.However,to date,the clinical success of drugs targeting the innate immune pathway remains limited.Interestingly,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression.The uncertainty surrounding the Therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation.In this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell types.We propose that within the TME,the innate immune pathway exhibits multidimensional diversity.This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks.The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways.Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.

关键词： drugs Therapeutic innate

Lymphatic vessel:origin,heterogeneity,biological functions,and Therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 442-478页

作者： Zhaoliang Hu Xushi Zhao Zhonghua Wu Bicheng Qu Minxian Yuan Yanan Xing Yongxi Song Zhenning Wang Department of Surgical Oncology and General Surgery The First Hospital of China Medical UniversityKey Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors(China Medical University)Ministry of Education155 North Nanjing StreetHeping DistrictShenyang 110001China

Lymphatic vessels,comprising the secondary circulatory system in human body,play a multifaceted role in maintaining homeostasis among various tissues and organs.They are tasked with a serious of responsibilities,including the regulation of lymph absorption and transport,the orchestration of immune surveillance and responses.Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks.Lymphangiogenesis,as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins,is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo.However,abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases.Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis,to further modulate the progression of diseases.Actually,an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation.Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis,but improves the efficacy of diverse treatments.In conclusion,we present a comprehensive overview of lymphatic vessel development and physiological functions,and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases.Moreover,we summarize the targeting Therapeutic values of abnormal lymphangiogenesis,providing novel perspectives for treatment strategy of multiple human diseases.

关键词： Therapeutic origin specialized

Ischemia-reperfusion injury:molecular mechanisms and Therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 558-596页

作者： Meng Zhang Qian Liu Hui Meng Hongxia Duan Xin Liu Jian Wu Fei Gao Shijun Wang Rubin Tan Jinxiang Yuan The Collaborative Innovation Center Jining Medical UniversityJiningShandong 272067China Clinical Medical College Jining Medical UniversityJiningShandong 272067China Second Clinical Medical College Jining Medical UniversityJiningShandong 272067China Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghaiChina Institute of Zoology Chinese Academy of SciencesBeijingChina Department of Physiology Basic medical schoolXuzhou Medical UniversityXuzhou 221004China

Ischemia-reperfusion(I/R)injury paradoxically occurs during reperfusion following ischemia,exacerbating the initial tissue damage.The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective Therapeutic interventions.The Wnt signaling pathway exhibits extensive crosstalk with various other pathways,forming a network system of signaling pathways involved in I/R injury.This review article elucidates the underlying mechanisms involved in Wnt signaling,as well as the complex interplay between Wnt and other pathways,including Notch,phosphatidylinositol 3-kinase/protein kinase B,transforming growth factor-β,nuclear factor kappa,bone morphogenetic protein,N-methyl-D-aspartic acid receptor-Ca2+-Activin A,Hippo-Yes-associated protein,toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β,and hepatocyte growth factor/mesenchymal-epithelial transition factor.In particular,we delve into their respective contributions to key pathological processes,including apoptosis,the inflammatory response,oxidative stress,extracellular matrix remodeling,angiogenesis,cell hypertrophy,fibrosis,ferroptosis,neurogenesis,and blood-brain barrier damage during I/R injury.Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery,while activation of the non-canonical Wnt pathways exacerbates injury.Moreover,we explore novel Therapeutic approaches based on these mechanistic findings,incorporating evidence from animal experiments,current standards,and clinical trials.The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction,to facilitate the development of innovative Therapeutic agents for I/R injury.

关键词： Therapeutic reperfusion damage

The role of inflammasomes in human diseases and their potential as Therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 479-508页

作者： Jing Yao Keenan Sterling Zhe Wang Yun Zhang Weihong Song The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053China Townsend Family Laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Key Laboratory of Neurodegenerative Diseases Ministry of EducationBeijingP.R.China Zhejiang Clinical Research Center for Mental Disorders Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and The Affiliated Kangning HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325000China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiang 325000China

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response.Each inflammasome complex has three major components:an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC.Inflammasome formation typically occurs in response to infectious agents or cellular damage.The active inflammasome then triggers caspase-1 activation,followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death.Aberrant inflammasome activation and activity contribute to the development of diabetes,cancer,and several cardiovascular and neurodegenerative disorders.As a result,recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation,as well as the potential of targeting inflammasomes to treat various diseases.Multiple clinical trials are currently underway to evaluate the Therapeutic potential of several distinct inflammasome-targeting therapies.Therefore,understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel Therapeutic strategies.In this article,we provide a summary of the biological and pathological roles of inflammasomes in health and disease.We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.

关键词： inflam Therapeutic potential

Activation of Wnt/β-catenin signaling in abdominal aortic aneurysm:A potential Therapeutic opportunity?

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Genes & Diseases 2023年第3期10卷 639-642页

作者： Lídia Puertas-Umbert Saray Varona Carme Ballester-Servera Judith Alonso Silvia Aguiló Mar Orriols Ernesto Martínez-Martínez Antonio Rodríguez-Sinovas JoséMartínez-González Cristina Rodríguez Institut de Recerca Hospital de la Santa Creu i Sant Pau(IRHSCSP) Barcelona 08025Spain Instituto de Investigación Biomédica Sant Pau Barcelona 08036Spain CIBER de Enfermedades Cardiovasculares ISCIIIMadrid 28029Spain Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas(IIBB-CSIC) Barcelona 08036Spain Facultad de Medicina Universidad Complutense de MadridInstituto de Investigación Sanitaria Gregorio MarañónMadrid 28040Spain Cardiovascular Diseases Research Group Vall d’Hebron Institut de RecercaVall d’Hebron Hospital UniversitariVall d’Hebron Barcelona Hospital CampusBarcelona 08035Spain

Abdominal aortic aneurysm (AAA) is a common degenerative vascular disease with a prevalence up to 8% in males over 60 years of age.1 This is a complex disorder characterized by permanent and focal dilation of abdominal aorta that exceeds at least 50% of the normal diameter. In these patients, the aortic diameter progressively expands boosted by smoking and aging as major risk factors. Unfortunately, aneurysm growth increases the risk of aortic rupture, a life-threatening emergency that carries a mortality rate of 80%. Despite the increasing effort of the scientific community to identify Therapeutic strategies for AAA, there are currently no pharmacological tools that ameliorate aneurysm expansion, while the underlying mechanisms involved in this disease are not completely understood.

关键词： aneurysm aortic Therapeutic