Targeting autophagy in ischemic stroke: From molecular mechanisms to clinical therapeutics

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 225, P. 107848 - 107848

Published: April 4, 2021

Language: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: April 30, 2021

Abstract Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major sensor that binds dsDNA to catalyze synthesis a special asymmetric cyclic-dinucleotide, 2′3′-cGAMP, secondary messenger bind and activate STING for subsequent production type I interferons other immune-modulatory genes. Hyperactivation signaling contributes autoimmune diseases but serves adjuvant anticancer immune therapy. On hand, inactivation causes deficiency sense clear viral bacterial infection creates tumor-prone microenvironment facilitate tumor evasion surveillance. Thus, activation tightly controlled. In this review, we summarize up-to-date multilayers regulatory mechanisms governing activation, including pre- post-translational regulations, cGAS-binding proteins, additional regulators such ions small molecules. We will also reveal pathophysiological function its product cGAMP human diseases. hope provide review recent research advances biology cGAS-targeted therapies

Language: Английский

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Mitophagy in cardiovascular diseases: molecular mechanisms, pathogenesis, and treatment

Trends in Molecular Medicine, Journal Year: 2022, Volume and Issue: 28(10), P. 836 - 849

Published: July 22, 2022

Language: Английский

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The multifaceted regulation of mitophagy by endogenous metabolites

Autophagy, Journal Year: 2021, Volume and Issue: 18(6), P. 1216 - 1239

Published: Sept. 29, 2021

Owing to the dominant functions of mitochondria in multiple cellular metabolisms and distinct types regulated cell death, maintaining a functional mitochondrial network is fundamental for homeostasis body fitness response physiological adaptations stressed conditions. The process mitophagy, which dysfunctional or superfluous are selectively engulfed by autophagosome subsequently degraded lysosome, has been well formulated as one major mechanisms quality control. To date, PINK1-PRKN-dependent receptors (including proteins lipids)-dependent pathways have characterized determine mitophagy mammalian cells. highly responsive dynamics endogenous metabolites, including iron-, calcium-, glycolysis-TCA-, NAD+-, amino acids-, fatty cAMP-associated metabolites. Herein, we summarize recent advances toward molecular details regulation We also highlight key regulations shed new light on bidirectional interplay between metabolisms, with attempting provide perspective insight into nutritional intervention metabolic disorders deficit.

Language: Английский

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The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Language: Английский

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Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 7, 2025

Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption homeostatic regulation, and abnormalities in dynamics. The escaped activates cytosolic sensors, especially cyclic gmp-amp synthase (cGAS) signalling inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating spectrum neurological pathologies. therapeutic promise targeting discussed detail, underscoring necessity for multifaceted strategy that encompasses preservation homeostasis, prevention leakage, reestablishment dynamics, inhibition activation sensors. Advancing our understanding complex interplay between neuroinflammation imperative developing precision interventions disorders.

Language: Английский

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cGAS-STING targeting offers novel therapeutic opportunities in neurological diseases

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: 105, P. 102691 - 102691

Published: Feb. 13, 2025

Language: Английский

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Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis

Acta Pharmacologica Sinica, Journal Year: 2021, Volume and Issue: 43(1), P. 39 - 49

Published: March 25, 2021

Language: Английский

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Mitophagy Receptors and Mediators: Therapeutic Targets in the Management of Cardiovascular Ageing

Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 62, P. 101129 - 101129

Published: July 22, 2020

Language: Английский

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