Discovery of Effective Dual PROTAC Degraders for Neurodegenerative Disease-Associated Aggregates

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(5), P. 3448 - 3466

Published: Feb. 15, 2024

The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. targeted protein degradation (TPD) strategy has been studied the treatment NDs, but multitarget bifunctional molecules ignored. Herein, series effective dual PROTAC degraders were developed, could degrade α-Syn aggregates total simultaneously. effects evaluated vitro, results showed that T3 significantly knockdown efficiency with DC50 1.57 ± 0.55 4.09 0.90 μM, respectively. Further mechanistic exploration effect was mediated by ubiquitin–proteasome system (UPS). Additionally, therapeutic efficacy confirmed an MPTP-induced PD mouse model. Our suggest these PROTACs may provide potential for NDs.

Language: Английский

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Aging in Heart Failure

JACC Heart Failure, Journal Year: 2024, Volume and Issue: 12(5), P. 795 - 809

Published: April 8, 2024

Language: Английский

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The interplay of senescence and MMPs in myocardial infarction: implications for cardiac aging and therapeutics

Biogerontology, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 20, 2025

Language: Английский

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Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 23(1), P. 77 - 77

Published: Dec. 22, 2021

Atherosclerosis is a leading cause of cardiovascular diseases (CVD) worldwide and intimately linked to aging. This pathology characterized by chronic inflammation, oxidative stress, gradual accumulation low-density lipoproteins (LDL) particles fibrous elements in focal areas large medium arteries. These fibrofatty lesions the artery wall become progressively unstable thrombogenic heart attack, stroke or other severe ischemic syndromes. Elevated blood levels LDL are major triggering events for atherosclerosis. A cascade molecular cellular results atherosclerotic plaque formation, evolution, rupture. Moreover, senescence multiple cell types present vasculature were reported contribute progression destabilization. Classical therapeutic interventions consist lipid-lowering drugs, anti-inflammatory life style dispositions. targeting stress developing innovative antioxidant agents boosting systems also well-established strategy. Accumulation senescent cells (SC) another important feature atherosclerosis was detected various models. Hence, SCs appears as an emerging option, since senolytic favorably disturb plaques. In this review, we propose survey impact atherosclerosis; options, including thioredoxin-based approaches such anti-oxidant, anti-inflammatory, anti-atherogenic strategy with promising potential senomodulation.

Language: Английский

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The Role of Cytokines in Cholesterol Accumulation in Cells and Atherosclerosis Progression

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6426 - 6426

Published: March 29, 2023

Atherosclerosis is the most common cardiovascular disease and number one cause of death worldwide. Today, atherosclerosis a multifactorial chronic inflammatory with an autoimmune component, accompanied by accumulation cholesterol in vessel wall formation atherosclerotic plaques, endothelial dysfunction, inflammation. In process atherogenic lipids, cells immune system, such as monocytes, macrophages, dendritic cells, etc., play important role, producing and/or activating production various cytokines-interferons, interleukins, chemokines. this review, we have tried to summarize cytokines involved processes atherogenesis.

Language: Английский

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Senopathies—Diseases Associated with Cellular Senescence

Biomolecules, Journal Year: 2023, Volume and Issue: 13(6), P. 966 - 966

Published: June 8, 2023

Cellular senescence describes a stable cell cycle arrest state with characteristic phenotype. Senescent cells accumulate in the human body during normal aging, limiting lifespan and promoting aging-related, but also several non-related, pathologies. We propose to refer all diseases whose pathogenesis or progression is associated cellular as “senopathies”. Targeting senescent senolytics senomorphics likely mitigate these Examples of senopathies include cardiovascular, metabolic, musculoskeletal, liver, kidney, lung neurodegeneration. For pathologies, animal studies provide clear mechanistic evidence for connection between accumulation disease progression. The major persisting challenge developing novel senotherapies heterogeneity phenotypes, causing lack universal biomarkers difficulties discriminating from non-senescent cells.

Language: Английский

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Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging Target in Coronary Artery Disease

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(14), P. 4821 - 4821

Published: July 21, 2023

Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when healing process impaired due adverse left ventricular remodelling, be result so-called ischaemia/reperfusion injury (IRI), visualised by development intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation novel pharmacological strategies from preclinical studies target either IRI post MI have been largely unsuccessful. Anti-inflammatory therapies also carry risk affecting immune system. Fractalkine (FKN, CX3CL1) a unique chemokine, present as transmembrane protein on endothelium, following cleavage soluble ligand, attracting leukocyte subsets expressing corresponding receptor CX3CR1. We shown previously that fractalkine CX3CR1 associated with MVO patients undergoing primary PCI. Moreover, inhibition an allosteric small molecule antagonist (KAND567) rat model reduces acute infarct size, inflammation, IMH. Here we review cellular biology its receptor, along ongoing introduce future coronary artery disease, specifically infarction.

Language: Английский

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Modern Concepts in Cardiovascular Disease: Inflamm-Aging

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: May 18, 2022

The improvements in healthcare services and quality of life result a longer expectancy higher number aged individuals, who are inevitably affected by age-associated cardiovascular (CV) diseases. This challenging demographic shift calls for greater effort to unravel the molecular mechanisms underlying age-related CV diseases identify new therapeutic targets cope with ongoing aging "pandemic". Essential protection against external pathogens intrinsic degenerative processes, inflammatory response becomes dysregulated aging, leading persistent state low-grade inflammation known as inflamm-aging. Of interest, has been recently recognized key factor pathogenesis diseases, suggesting inflamm-aging possible driver afflictions plausible target this context. review discusses pathways their involvement disease. Moreover, potential several anti-inflammatory approaches context is also reviewed.

Language: Английский

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Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease

Biogerontology, Journal Year: 2023, Volume and Issue: 25(1), P. 71 - 82

Published: Sept. 25, 2023

Language: Английский

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Mechanistic Insights of the LEMD2 p.L13R Mutation and Its Role in Cardiomyopathy

Circulation Research, Journal Year: 2023, Volume and Issue: 132(2)

Published: Jan. 4, 2023

Nuclear envelope proteins play an important role in the pathogenesis of hereditary cardiomyopathies. Recently, a new form arrhythmic cardiomyopathy caused by homozygous mutation (p.L13R) inner nuclear membrane protein LEMD2 was discovered. The aim to unravel molecular mechanisms mutant cardiomyopathy.We generated Lemd2 p.L13R knock-in mouse model and corresponding cell via CRISPR/Cas9 technology investigated cardiac phenotype as well cellular subcellular rupture repair.Knock-in mice developed with predominantly endocardial fibrosis, left ventricular dilatation, systolic dysfunction. Electrocardiograms displayed pronounced arrhythmias conduction disease. A key finding cardiomyocytes on ultrastructural level significant increase invaginations decreased circularity. Furthermore, increased DNA damage premature senescence were detected underlying cause fibrotic inflammatory remodeling. As is located Lap2/Emerin/Man1 (LEM)-domain, we observed disrupted interaction between BAF (barrier-to-autointegration factor), which required initiate repair process. To mimic mechanical stress subsequent ruptures, HeLa-cells upon electrical stimulation stiffness. Here, demonstrated impaired capacity, cytoplasmic leakage factor KU80 along damage, recruitment cGAS (cyclic GMP-AMP synthase) micronuclei.We show for first time that recapitulates human dilated fibrosis severe arrhythmias. Impaired capacity resulted activation cGAS/STING/IFN pathway, promoting senescence. Hence, player inthe disease group laminopathies.

Language: Английский

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