Emerging roles of SIRT1 activator, SRT2104, in disease treatment

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 6, 2024

Abstract Silent information regulator 1 (SIRT1) is a NAD + -dependent class III deacetylase that plays important roles in the pathogenesis of numerous diseases, positioning it as prime candidate for therapeutic intervention. Among its modulators, SRT2104 emerges most specific small molecule activator SIRT1, currently advancing into clinical translation phase. The primary objective this review to evaluate emerging SRT2104, and explore potential agent various diseases. In present review, we systematically summarized findings from an extensive array literature sources including progress application disease treatment molecular mechanisms by reviewing published databases such PubMed, Web Science, World Health Organization International Clinical Trials Registry Platform. We focuses on strides made employing treatment, elucidating underpinnings based preclinical research data. reveal potent SIRT1 activator, holds considerable potential, particularly modulating metabolic longevity-related pathways. This establishes leading with significant promise.

Language: Английский

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Mechanism of Sirtuin1-Mediated Deacetylation of p65-Mediated Ferroptosis of Hippocampal Neurons in Cerebral Injury after Cardiopulmonary Resuscitation in Rats

Neurochemical Research, Journal Year: 2025, Volume and Issue: 50(1)

Published: Jan. 3, 2025

Language: Английский

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Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(6), P. 1760 - 1778

Published: April 24, 2024

Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, its risk increases with aging. Yet comprehensive insights into complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting globally or specifically RGCs led to RGC loss optic nerve during aging, despite normal intraocular pressure (IOP), resembling a phenotype normal-tension glaucoma. These detrimental effects were potentially mediated accelerated senescence through Caveolin-1 upregulation induction mitochondrial dysfunction. In mouse models high-tension glaucoma, level decreased after IOP elevation. Genetic overexpression significantly attenuated high tension-induced whereas partial RGC-specific deletion loss. Importantly, therapeutically targeting pharmacological activator AAV2-mediated gene delivery ameliorated IOP-induced degeneration. Together, our studies reveal critical role preventing aging setting stage for further exploration activation as potential therapy

Language: Английский

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Potential role of SIRT1 in cell ferroptosis

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 5, 2025

Ferroptosis is a novel form of cell death that uniquely requires iron and characterized by accumulation, the generation free radicals leading to oxidative stress, formation lipid peroxides, which distinguish it from other forms death. The regulation ferroptosis extremely complex closely associated with spectrum diseases. Sirtuin 1 (SIRT1), NAD + -dependent histone deacetylase, has emerged as pivotal epigenetic regulator potential regulate through wide array genes intricately metabolism, homeostasis, glutathione biosynthesis, redox homeostasis. This review provides comprehensive overview specific mechanisms SIRT1 regulates explores its therapeutic value in context multiple disease pathologies, highlighting significance SIRT1-mediated treatment strategies.

Language: Английский

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Role of sirtuins in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic potential

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 310, P. 143591 - 143591

Published: April 27, 2025

The high incidence and mortality rate of cardiac arrest (CA) establishes it as a critical clinical challenge in emergency medicine globally. Despite continuous advances advanced life support (ALS) technology, the prognosis for patients experiencing remains poor, with cerebral ischemia reperfusion injury (CIRI) being significant determinant adverse neurological outcomes increased mortality. Sirtuins (SIRTs) are class highly evolutionarily conserved NAD+-dependent histone deacylenzymes capable regulating expression various cytoprotective genes to play neuroprotective role CIRI. SIRTs mainly regulate levels downstream proteins such PGC 1-α, Nrf 2, NLRP 3, FoxOs, PINK 1 inhibit inflammatory response, attenuate oxidative stress, improve mitochondrial dysfunction, promote angiogenesis, apoptosis while reducing Natural active ingredients widely used protein level body because their multi-components, multi-pathway, multi-target, minimal toxic side effects. However, these naturally still face many challenges related drug targeting, pharmacokinetic properties, delivery. emergence vigorous development new delivery systems, nanoparticles, micromilk, exosomes, provide strong solving above problems. In context rapid molecular biology non-coding RNA (NcRNA), represented by miRNA LncRNA, offers great potential achieving gene-level precision medicine. multidisciplinary integration, combining biotechnology, omics technologies, artificial intelligence, material science will strongly deepening basic research expand application. This review describes major signaling pathways targeting mitigate CIRI, well current status Chinese Western medical means intervention SIRTs. Meanwhile, possible solutions application targeted drugs summarized. industrial crossover, direction future is discussed valuable reference researchers clinicians diagnosis treatment effects

Language: Английский

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GSK840 Alleviates Retinal Neuronal Injury by Inhibiting RIPK3/MLKL-Mediated RGC Necroptosis After Ischemia/Reperfusion

Investigative Ophthalmology & Visual Science, Journal Year: 2023, Volume and Issue: 64(14), P. 42 - 42

Published: Nov. 28, 2023

Purpose: This study aimed to explore the impact of GSK840 on retinal neuronal injury after ischemia/reperfusion (IR) and its associated mechanism. Methods: We established an in vivo mouse model IR vitro oxygen glucose deprivation/reoxygenation (OGDR) primary ganglion cells (RGCs). GSK840, a small-molecule compound, was used specifically inhibit RIPK3/MLKL-dependent necroptosis. Retinal structure function evaluation performed by using hematoxylin eosin staining, optical coherence tomography, electroretinography. Propidium Iodide (PI) staining for detection necroptotic cell death, whereas Western blot analysis immunofluorescence were assess necroptosis-related proteins inner neurons. Results: necroptosis rapidly activated RGCs following or OGDR. helped maintain relatively normal thickness preserving neurons, particularly RGCs. Meanwhile, ameliorated IR-induced visual dysfunction, as evidenced improved amplitudes photopic negative response, a-wave, b-wave, oscillatory potentials. And treatment significantly reduced population PI+ injury. Mechanistically, RGC inhibiting RIPK3/MLKL pathway. Conclusions: exerts protective effects against RIPK3/MLKL-mediated may represent strategy degeneration ischemic retinopathy.

Language: Английский

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Epigenetic modifications and emerging therapeutic targets in cardiovascular aging and diseases

Pharmacological Research, Journal Year: 2024, Volume and Issue: unknown, P. 107546 - 107546

Published: Dec. 1, 2024

Language: Английский

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Setanaxib mitigates oxidative damage following retinal ischemia-reperfusion via NOX1 and NOX4 inhibition in retinal ganglion cells

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 170, P. 116042 - 116042

Published: Dec. 20, 2023

Glaucoma, a prevalent cause of permanent visual impairment worldwide, is characterized by the progressive degeneration retinal ganglion cells (RGCs). NADPH oxidase (NOX) 1 and NOX4 are pivotal nodes in various diseases. Setanaxib, potent highly selective inhibitor NOX1 NOX4, can impede progression This study investigated efficacy setanaxib ameliorating ischemia-reperfusion (I/R) injury elucidated its underlying mechanisms. The model I/R induced acute intraocular hypertension oxygen-glucose deprivation/reoxygenation (OGD/R) primary RGCs were established. By suppressing expression RGCs, mitigated I/R-induced neuronal loss, structural disruption, dysfunction. Setanaxib reduced TUNEL-positive cells, upregulated Bcl-2, inhibited Bax, Bad, cleaved-caspase-3 overexpression after vitro vivo. Moreover, also significantly cellular senescence, as demonstrated downregulating SA-β-gal-positive p16-INK4a expression. Furthermore, suppressed ROS production, Hif-1α FOXO1 upregulation, NRF2 downregulation damaged RGCs. These findings highlight that effectively thereby regulating production redox signal activation. inhibition further prevents activation apoptosis senescence related factors ultimately protecting them against injury. Consequently, exhibits promising potential therapeutic intervention for glaucoma.

Language: Английский

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Senolytic and senomorphic secondary metabolites as therapeutic agents in Drosophila melanogaster models of Parkinson’s disease

Frontiers in Neurology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 28, 2023

Drosophila melanogaster is a valuable model organism for wide range of biological exploration. The well-known advantages D. include its relatively simple biology, the ease with which it genetically modified, low financial and time costs associated their short gestation life cycles, large number offspring they produce per generation. has facilitated discovery many significant insights into pathology Parkinson’s disease (PD) served as an excellent preclinical PD-related therapeutic discovery. In this review, we provide overview major models PD, each unique PD-relevant targets. These are discussed in context past, current, future potential use studying utility secondary metabolites agents PD. Over last decade, senolytics have garnered exponential interest ability to mitigate broad spectrum diseases, including Therefore, emphasis placed on senolytic senomorphic properties metabolites. It expected that will continue be critical effort understand improve treatment involvement translational studies focused

Language: Английский

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Anesthetic effects on electrophysiological responses across the visual pathway

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 13, 2024

Anesthetics are widely used in electrophysiological tests to assess retinal and visual system functions avoid experimental errors caused by movement stress animals. To determine the most suitable anesthetic for tests, excluding ketamine chloral hydrate due regulatory side effect concerns, this study investigated effects of ethyl carbamate (EC), avertin (AR), pentobarbital sodium (PS) on signal conduction retina primary cortex. Assessments included flash electroretinogram (FERG), pattern (PERG), evoked potentials (PVEP), (FVEP), FERG FVEP were evaluate responses cortex stimuli, respectively, while PERG PVEP assessed stimuli. The research showed that AR demonstrates least disruption pathway, as evidenced consistently high characteristic peaks group across various tests. In contrast, mice given EC exhibited lowest peak values both FVEP, subjects anesthetized with PS suppressed oscillatory responses. Notably, substantial observed only AR. Consequently, among three anesthetics tested, is studies.

Language: Английский

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