Why Is Longevity Still a Scientific Mystery? Sirtuins—Past, Present and Future

International Journal of Molecular Sciences, Год журнала: 2022, Номер 24(1), С. 728 - 728

Опубликована: Дек. 31, 2022

The sirtuin system consists of seven highly conserved regulatory enzymes responsible for metabolism, antioxidant protection, and cell cycle regulation. great interest in sirtuins is associated with the potential impact on life extension. This article summarizes latest research activity their role aging process. effects compounds that modulate were discussed, numerous studies, effectiveness was demonstrated. Attention paid to a caloric restriction risks influence careless modulation organism. It has been shown low modulators' bioavailability/retention time crucial problem optimal regulation studied pathways. Therefore, detailed understanding modulator structure reactivity silico studies should precede vitro vivo experiments. achievements nanobiotechnology make it possible create promising molecules, but many them remain sphere plans concepts. seems solving mystery longevity will have wait new scientific discoveries.

Язык: Английский

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Activation and inhibition of sirtuins: From bench to bedside

Medicinal Research Reviews, Год журнала: 2024, Номер unknown

Опубликована: Авг. 31, 2024

Abstract The sirtuin family comprises seven NAD + ‐dependent enzymes which catalyze protein lysine deacylation and mono ADP‐ribosylation. Sirtuins act as central regulators of genomic stability gene expression control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, aging. As a result, all sirtuins play critical roles in cellular homeostasis organism wellness, their dysregulation has been linked to metabolic, cardiovascular, neurological diseases. Furthermore, have shown dichotomous cancer, acting context‐dependent tumor suppressors or promoters. Given role different attracted increasing research interest aimed at developing both activators inhibitors. Indeed, modulation may therapeutic effects many age‐related diseases, diabetes, cardiovascular neurodegenerative disorders, cancer. Moreover, isoform selective modulators increase our knowledge biology aid develop better therapies. Through this review, we provide insights into pharmacology illustrate enzymatic activities biological functions. outline the most relevant terms modes action, structure–activity relationships, pharmacological effects, clinical applications.

Язык: Английский

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Advancements in understanding the role and mechanism of sirtuin family (SIRT1-7) in breast cancer management

Biochemical Pharmacology, Год журнала: 2025, Номер 232, С. 116743 - 116743

Опубликована: Янв. 4, 2025

Язык: Английский

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Sirtuins and Resveratrol in Cardiorenal Diseases: A Narrative Review of Mechanisms and Therapeutic Potential

Nutrients, Год журнала: 2025, Номер 17(7), С. 1212 - 1212

Опубликована: Март 30, 2025

Aging is a very complex process, and it has been linked with Sirtuins. Sirtuin enzymes are family of deacetylases that related to caloric restriction aging by modulating energy metabolism, genomic stability, stress resistance. Up now, seven sirtuins have recognized. This narrative review aimed analyze the literature produced between January 2005 March 2025 evaluate role in chronic kidney disease and, as heart diseases strictly interrelated, explore their cardio-renal cross-talk. A reciprocal relationship CKD seems exist since may contribute premature biological different organ systems. SIRTs involved pathophysiology renal diseases; activation can delay progression several diseases. Notably, an increasing number studies CVDs. affect production mitochondrial reactive oxygen species (ROS) function. The imbalance SIRT levels increase vulnerability pathophysiological mechanisms HFpEF (heart failure preserved ejection fraction) through signaling pathways. Fibrosis linkage mechanism development Current on sirtuins, resveratrol, cardiorenal highlight potential therapeutic benefits regulating blood pressure, function, lipid profiles, inflammation, making them promising area investigation for improving cardiovascular health outcomes. However, significant gaps remain. limited availability highly selective potent sirtuin modulators hampers clinical translation, most existing compounds exhibit poor bioavailability suboptimal pharmacokinetic properties.

Язык: Английский

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Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(14), С. 9622 - 9641

Опубликована: Июль 13, 2023

The mitochondrial SIRT3 modulates several biological pathways such as cancer, metabolism, and hypoxia-related diseases. Recently, we discovered new 1,4-dihydropyridines, compounds 2 3, the latter being a SIRT3-specific activator. In present work, novel 2- 3-related small series of have been developed, with 3c displaying strongest binding activation, KD 29 μM 387% enzyme activation. Differently, 3d was best in enhancing glutamate dehydrogenase activity deacetylating K68- K122-acMnSOD triple-negative MDA-MB-231 breast cancer cells. Tested CAL-62 thyroid cells, displayed time- dose-dependent reduction cell viability clonogenicity at single-digit micromolar level, along death, both normoxia hypoxia conditions. Moreover, downregulated not only hypoxia-induced factors, HIF-1α, EPAS-1, CA-IX, but also epithelial–mesenchymal transition master regulators extracellular matrix components SNAIL1, ZEB1, SLUG, COL1A2, MMP2, MMP9, markedly hampering migration.

Язык: Английский

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Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

Cancers, Год журнала: 2023, Номер 15(15), С. 4013 - 4013

Опубликована: Авг. 7, 2023

Perilipins (PLINs) are the most abundant proteins in lipid droplets (LD). These LD-associated responsible for upgrading LD from inert storage structures to fully functional organelles, fundamentally integrated metabolism. There five distinct perilipins (PLIN1–5), each with specific expression patterns and metabolic activation, but all capable of regulating activity lipases on LD. This plurality creates a complex orchestrated mechanism that is directly related healthy balance between lipogenesis lipolysis. Given essential role PLINs modulation metabolism, these can become interesting targets treatment lipid-associated diseases. Since reprogrammed metabolism recognized cancer hallmark, obesity known risk factor other comorbidities, could either improve existing treatments or create new opportunities Even though have not been, so far, considered pharmacological interventions, there many established drugs modulate activity. Therefore, aim this study assess involvement diseases dysregulation whether be viewed as potential therapeutic obesity.

Язык: Английский

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Biochemical Characterization and Inhibitor Discovery for PfSir2A – New Tricks for An Old Enzyme

RSC Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Pf Sir2A controls the var virulence gene expression in malaria parasites. Inhibitors targeting are potential antimalarial agents. In current study, 3-TYP and NR identified as lead compounds for further inhibitor development.

Язык: Английский

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The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 7, 2025

Язык: Английский

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Role of Sirtuins in Physiology and Diseases of the Central Nervous System

Biomedicines, Год журнала: 2022, Номер 10(10), С. 2434 - 2434

Опубликована: Сен. 29, 2022

Silent information regulators, sirtuins (SIRTs), are a family of enzymes which take part in major posttranslational modifications proteins and contribute to multiple cellular processes, including metabolic energetic transformations, as well regulation the cell cycle. Recently, SIRTs have gained increased attention object research because their multidirectional activity possible role complex pathomechanisms underlying human diseases. The aim this study was review current literature evidence SIRTs’ physiology pathology central nervous system (CNS). been demonstrated be crucial players crosstalk between neuroinflammation, neurodegeneration, alterations. elucidation background various CNS diseases offers chance define relevant markers progression promising candidates for novel therapeutic targets. Possible diagnostic implications from SIRTs-related investigations discussed, future directions associated challenges.

Язык: Английский

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Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging

Current Stem Cell Research & Therapy, Год журнала: 2023, Номер 19(1), С. 15 - 32

Опубликована: Янв. 16, 2023

Abstract: Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks necessity of providing a sufficient number MSCs achieve clinically efficient outcomes, prolonged vitro cultivation is indisputable. However, either long-term expansion or aging elderly individuals, face cellular senescence. Senescent undergo an impairment function capacities secrete degenerative factors negatively affect young MSCs. To this end, designing novel investigations further elucidate senescence pave way toward finding new strategies reverse highly demanded. In review, we will concisely discuss current progress on detailed mechanisms MSC various inflicted changes MSC. We shed light examined underlying monitoring reversing bypass comprised efficacy senescent

Язык: Английский

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