搜索到1926篇“ LYSOSOMAL“的相关文章
Nanomaterials-mediated lysosomal regulation:a robust protein-clearance approach for the treatment of Alzheimer’s disease
2025年
Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.
Mengqi HaoJianjian ChuTinglin ZhangTong YinYuankai GuWendanqi LiangWenbo JiJianhua ZhuangYan LiuJie GaoYou Yin
Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo
2025年
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
Zhimin LongChuanhua GeYueyang ZhaoYuanjie LiuQinghua ZengQing TangZhifang DongGuiqiong He
关键词:V-ATPASE
Lysosomal destabilization:A missing link between pathological calcification and osteoarthritis被引量:1
2024年
Calcification of cartilage by hydroxyapatite is a hallmark of osteoarthritis and its deposition strongly correlates with the severity of osteoarthritis.However,no effective strategies are available to date on the prevention of hydroxyapatite deposition within the osteoarthritic cartilage and its role in the pathogenesis of this degenerative condition is still controversial.Therefore,the present work aims at uncovering the pathogenic mechanism of intra-cartilaginous hydroxyapatite in osteoarthritis and developing feasible strategies to counter its detrimental effects.With the use of in vitro and in vivo models of osteoarthritis,hydroxyapatite crystallites deposited in the cartilage are found to be phagocytized by resident chondrocytes and processed by the lysosomes of those cells.This results in lysosomal membrane permeabilization(LMP)and release of cathepsin B(CTSB)into the cytosol.The cytosolic CTSB,in turn,activates NOD-like receptor protein-3(NLRP3)inflammasomes and subsequently instigates chondrocyte pyroptosis.Inhibition of LMP and CTSB in vivo are effective in managing the progression of osteoarthritis.The present work provides a conceptual therapeutic solution for the prevention of osteoarthritis via alleviation of lysosomal destabilization.
Tao YeChenyu WangJianfei YanZixuan QinWenpin QinYuxuan MaQianqian WanWeicheng LuMian ZhangFranklin R.TayKai JiaoLina Niu
关键词:OSTEOARTHRITIS
Role of lysosomal trafficking regulator in autophagic lysosome reformation in neurons:a disease perspective
2024年
Lysosomes are discrete organelles that act as recycling centers for extracellular and intracellular materials,playing a pivotal role in maintaining cellular homeostasis.Their acidic environment,maintained by numerous hydrolytic enzymes,facilitates substrate degradation.Dysfunction in lysosomal processes can lead to abnormal substrate degradation,significantly impacting cellular homeostasis.High energy-demanding cells,such as post-mitotic neurons,are especially vulnerable to these changes,often resulting in neurological diseases.Autophagy,a conserved catabolic process,requires extensive lysosomal utilization.It plays a key role in removing unnecessary intracellular components,ensuring cellular homeostasis,and promoting cell survival during stress conditions such as starvation,infection,or cellular damage.
Prashant SharmaJenny Serra-VinardellWendy J.IntroneMay Christine V.Malicdan
关键词:HOMEOSTASISLYSOSOMAL
Benzo[4,5]imidazo[1,2-a]pyrimidine-based structure-inherent targeting fluorescent sensor for imaging lysosomal viscosity and diagnosis of lysosomal storage disorders
2024年
Benzo[4,5]imidazo[1,2-a]pyrimidine-based derivatives play crucial roles in medicines,pesticides,tracers and photoelectric materials.However,their synthesis approach still needs to be optimized,and their fluorescent properties in intracellular microenvironment are unclear.Here,a Cu(II)-catalyzed cascade coupling cyclization reaction was successfully developed to synthesize benzo[4,5]imidazo[1,2-a]pyrimidine scaffold with mild reaction conditions,broad substrate scopes and high yields.After a system study,we found that compound 4aa displayed an optimal viscosity-specific response with remarkable fluorescence enhancement(102-fold)for glycerol at 490 nm.Particularly,4aa possessed excellent structure-inherent targeting(SIT)capability for lysosome(P=0.95)with high p H stability and large Stokes shift.Importantly,4aa was validated for its effectiveness in diagnosing lysosomal storage disorders(LSD)in living cells.The 4aa also showed its potential to map the micro-viscosity and its metabolism process in zebrafish.This work not only affords an efficient protocol to fabricate benzo[4,5]imidazo[1,2-a]pyrimidine derivatives,reveals this skeleton has excellent SIT features for lysosome,but also manifests that 4aa can serve as a practical tool to monitor lysosomal viscosity and diagnose LSD.
Jiao ChenZihan ZhangGuojin SunYudi ChengAihua WuZefan WangWenwen JiangFulin ChenXiuying XieJianli Li
关键词:VISCOSITY
Advanced Strategies for Overcoming Endosomal/Lysosomal Barrier in Nanodrug Delivery
2024年
Nanocarriers have therapeutic potential to facilitate drug delivery,including biological agents,smallmolecule drugs,and nucleic acids.However,their efficiency is limited by several factors;among which,endosomal/lysosomal degradation after endocytosis is the most important.This review summarizes advanced strategies for overcoming endosomal/lysosomal barriers to efficient nanodrug delivery based on the perspective of cellular uptake and intracellular transport mechanisms.These strategies include promoting endosomal/lysosomal escape,using non-endocytic methods of delivery to directly cross the cell membrane to evade endosomes/lysosomes and making a detour pathway to evade endosomes/lysosomes.On the basis of the findings of this review,we proposed several promising strategies for overcoming endosomal/lysosomal barriers through the smarter and more efficient design of nanodrug delivery systems for future clinical applications.
Chong QiuFei XiaJunzhe ZhangQiaoli ShiYuqing MengChen WangHuanhuan PangLiwei GuChengchao XuQiuyan GuoJigang Wang
关键词:DRUGS
溶酶体贮积症及其治疗性替代酶类药物研究进展
2024年
溶酶体贮积症是由于体内溶酶体酶活性降低或丧失造成其作用底物在体内蓄积,进而导致机体多器官病变的一类疾病。目前已有报道的溶酶体贮积症约70余种,涉及多种溶酶体酶缺陷。溶酶体贮积症的治疗包括酶替代疗法、小分子药物疗法(底物减少疗法和分子伴侣等)以及基因疗法。其中应用最广泛的是酶替代疗法,即通过静脉注射的方式补充体内所缺失的溶酶体酶。截至目前共有19种治疗溶酶体贮积症的替代酶类药物经美国FDA批准上市。本文将对常见的溶酶体贮积症、已上市和在研的替代酶类药物等方面进行研究总结,旨在为此类药物的研发提供理论和实验借鉴。
杨可沁曹筠嵩马兰杨燕王伟
关键词:溶酶体贮积症酶替代疗法重组蛋白生物制剂
溶酶体半乳糖脑苷酯酶的作用机制及疾病
2024年
溶酶体贮积症(lysosomal storage diseases,LSD)是一类遗传性代谢障碍疾病,其发病机制主要源于溶酶体酸性水解酶的基因突变,导致酶的功能缺陷,进而触发生物大分子在溶酶体内的异常积累,继而对细胞、组织及器官功能造成显著损害。β-半乳糖脑苷酯酶(galactocerebrosidase,GALC)的突变或缺失导致鞘氨醇半乳糖苷(galactosylsphingosine)的累积,造成了进行性的脱髓鞘病变,诱发神经鞘脂贮积症-克拉伯病(Krabbe disease),其在疾病调控中的具体机制尚未完全阐明。目前,越来越多的有关GALC基因的致病突变被报道,结合GALC蛋白的三维结构解析,已逐渐了解GALC蛋白的突变造成克拉伯病的机制,这将为开发相关治疗药物提供有力的证据。此外,GALC在不同的肿瘤进程中扮演着双重角色,一些癌症中充当着抑癌因子的作用,而在另一些癌症中则发挥着致癌因子的作用,然而剖析GALC对癌症的影响仍需进一步深入的研究,这将为GALC作为潜在的肿瘤促进或抑制的靶点提供借鉴。GALC还与多种神经退行性疾病,包括阿尔茨海默病、帕金森氏病以及多发性硬化症有关。由于GALC作用机制的复杂性,目前,针对GALC缺乏所致的克拉伯病的治疗主要通过单一模式疗法(single-modality therapies)及多模式疗法(multi-modality therapies),但要开发出真正有效的治疗方法,仍需深入研究GALC基因缺陷导致的发病机制。本文综述了GALC的结构和功能特性,汇总并讨论了其在神经系统及肿瘤发生发展中的作用及相关研究的最新进展,旨在为未来深入探讨GALC的调控机制及开发治疗相关疾病的创新药物提供理论基础和参考。
沈畅尹秋媛孟明耀孙建伟
关键词:癌症
Hernandezine promotes cancer cell apoptosis and disrupts the lysosomal acidic environment and cathepsin D maturation
2024年
Hernandezine(Her),a bisbenzylisoquinoline alkaloid extracted from Thalictrum flavum,is recognized for its range of biological activities inherent to this herbal medicine.Despite its notable properties,the anti-cancer effects of Her have remained largely unexplored.In this study,we elucidated that Her significantly induced cytotoxicity in cancer cells through the activation of apoptosis and necroptosis mechanisms.Furthermore,Her triggered autophagosome formation by activating the AMPK and ATG5 conjugation systems,leading to LC3 lipidation.Our findings revealed that Her caused damage to the mitochondrial membrane,with the damaged mitochondria undergoing mitophagy,as evidenced by the elevated expression of mitophagy markers.Conversely,Her disrupted autophagic flux,demonstrated by the upregulation of p62 and accumulation of autolysosomes,as observed in the RFP-GFP-LC3 reporter assay.Initially,we determined that Her did not prevent the fusion of autophagosomes and lysosomes.However,it inhibited the maturation of cathepsin D and increased lysosomal pH,indicating an impairment of lysosomal function.The use of the early-stage autophagy inhibitor,3-methyladenine(3-MA),did not suppress LC3II,suggesting that Her also induces noncanonical autophagy in autophagosome formation.The application of Bafilomycin A1,an inhibitor of noncanonical autophagy,diminished the recruitment of ATG16L1 and the accumulation of LC3II by Her,thereby augmenting Her-induced cell death.These observations imply that while autophagy initially plays a protective role,the disruption of the autophagic process by Her promotes programmed cell death.This study provides the first evidence of Her’s dual role in inducing apoptosis and necroptosis while also initiating and subsequently impairing autophagy to promote apoptotic cell death.These insights contribute to a deeper understanding of the mechanisms underlying programmed cell death,offering potential avenues for enhancing cancer prevention and therapeutic strategies.
FENG QianwenSUN LuMuhammad Jibran SualehZHAO QingliZHAO SongjiCUI ZhengguoINADERA Hidekuni
关键词:APOPTOSISMITOPHAGYLYSOSOME
泛素-蛋白酶体系统、自噬-溶酶体系统与代谢性疾病
2024年
泛素-蛋白酶系统(ubiquitin-protease system,UPS)和自噬-溶酶体系统(autophagy-lysosomal system,ALS)是两种清理系统,负责清除功能失调/错误折叠的蛋白质,从而充当真核细胞中蛋白质稳态的关键调节因子。代谢性疾病是全球性的健康挑战,研究其病理生理机制是从根本上解决该类疾病的关键。在代谢性疾病中,由于UPS、ALS功能障碍而导致蛋白质稳态丧失,从而引起受损蛋白质过分累积是引起机体代谢功能障碍的重要原因之一。因此,本文重点阐述了UPS和ALS的基本过程及两者相互调控的机制,为开发新的药物作用靶点及研发新药物开辟新的途径。
宋幸奇邱燕燕
关键词:泛素-蛋白酶体系统代谢性疾病胰岛素抵抗2型糖尿病

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