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Pharmacological modulation of autophagy for Alzheimer's disease therapy:Opportunities and obstacles

Acta Pharmaceutica Sinica B 2022年第4期12卷 1688-1706页

作者： Zhiqiang Deng Yu Dong Xiaoting Zhou Jia-Hong Lu Zhenyu Yue State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China Department of Neurology the Friedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNY 10029USA Department of Geriatrics Xiangya HospitalCentral South UniversityChangsha 410008China

Alzheimer's disease(AD)is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloidβ(Aβ)plaques and neurofibrillary tangles(NFTs)in the brain.By far,the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease.autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles,pathogens,and disease-prone protein aggregates to lysosome for degradation.Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons.Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells.Finally,we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.

关键词： Alzheimer’s disease autophagy autophagy modulators Genetic modulation Neuronal autophagy Microglial autophagy LC3-associated phagocytosis Neuroinflammation

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Role of autophagy in cholangiocarcinoma:An autophagy-based treatment strategy

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World Journal of Gastrointestinal Oncology 2021年第10期13卷 1229-1243页

作者： Evangelos Koustas Eleni-Myrto Trifylli Panagiotis Sarantis Athanasios G Papavassiliou Michalis V Karamouzis Department of Biological Chemistry Medical SchoolNational and Kapodistrian University of AthensAthens 11527Greece

Cholangiocarcinomas(CCAs)are diverse biliary epithelial tumours involving the intrahepatic,perihilar and distal parts of the biliary tree.The three entirely variable entities have distinct epidemiology,molecular characteristics,prognosis and strategy for clinical management.However,many cholangiocarcinoma tu-mor-cells appear to be resistant to current chemotherapeutic agents.The role of autophagy and the therapeutic value of autophagy-based therapy are largely unknown in CCA.The multistep nature of autophagy offers a plethora of re-gulation points,which are prone to be deregulated and cause different human diseases,including cancer.However,it offers multiple targetable points for designing novel therapeutic strategies.Tumor cells have evolved to use auto-phagy as an adaptive mechanism for survival under stressful conditions such as energy imbalance and hypoxic region of tumors within the tumor microenvir-onment,but also to increase invasiveness and resistance to chemotherapy.The purpose of this review is to summarize the current knowledge regarding the interplay between autophagy and cholangiocarcinogenesis,together with some preclinical studies with agents that modulate autophagy in order to induce tumor cell death.Altogether,a combinatorial strategy,which comprises the current anti-cancer agents and autophagy modulators,would represent a positive CCA patient approach.

关键词： autophagy autophagy modulators Chemotherapy Cholangiocarcinoma

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