Drug Target and Biomarker: SIRT1 (sirtuin-1) in various biological processes and has potential therapeutic relevance

Target Name: SIRT1

NCBI ID: G23411

Drug Target and Biomarker: SIRT1 (sirtuin-1) in various biological processes and has potential therapeutic relevance

SIRT1 activation:
- SIRT1 is activated by resveratrol (RSV) and plays a role in reducing retinal neurodegeneration, apoptosis, and inflammation in diabetic retinopathy.
- RSV stimulates mitochondrial activity through the AMPK-PGC1alpha pathway, which reduces apoptosis.
- SIRT1 activation by RSV inhibits the MAP kinase pathway and reduces oxidative-osmotic nitrosative stress, contributing to the pathophysiology of diabetic cataract.

Therapeutic strategies:
- Increasing SIRT1 activity is a potential therapeutic approach, and various pharmacologic and non-pharmacologic interventions are being explored.

Tumor-related effects:
- SIRT1 has both tumor suppressing and tumor promoting activities.
- It can influence the development of tumors by deacetylating specific transcription targets, such as tumor suppressor genes (p53, HIC1, Rb) or tumor-promoting genes (Ras, Myc).

Vascular endothelial function and preeclampsia:
- Downstream targets of SIRT1 are related to vascular endothelial function and pathways implicated in the pathophysiology of preeclampsia (PE).
- Functional enrichment analysis revealed pathways associated with the pathophysiology of PE, and SIRT1 plays a role in regulating these pathways.

Hepatic steatosis and inflammation:
- SIRT1 is involved in the regulation of hepatic steatosis and inflammation.
- DHA (docosahexaenoic acid) treatment increases the expression of SIRT1 and inhibits NF-kappaB activation, leading to reduced inflammation and improved hepatic steatosis.

The provided context information highlights various roles and implications of SIRT1 in different biological processes, including retinopathy, tumor development, vascular endothelial function, preeclampsia, and hepatic steatosis. SIRT1 activation and modulation may have therapeutic relevance in these areas.
Based on the provided context information, several key genes, such as SIRT1, are differentially expressed in female and male magpies, with SIRT1 being upregulated in males. SIRT1 is known for its role in stress resistance and longevity. Additionally, SIRT1 is associated with AMPK signaling and energy metabolism, with females enhancing AMPK and G6Pase to regulate energy metabolism. In terms of the immune system, females upregulate MHC II, JNK, and SMADs to promote the differentiation of Th1/Th2 and Th17 cells, while males inhibit the differentiation of Th17 cells through Th1 cells. Moreover, genes encoding JNK and SIRT1 are significantly enriched in the FOXO signaling pathway, which is related to oxidative stress resistance, longevity, apoptosis, cell-cycle control, and glucose metabolism. In another study, SIRT1 expression was enhanced via NRF2-mediated p53 suppression, leading to the maintenance and regulation of MSC stemness. Furthermore, SIRT1 interacts with HDAC4 to facilitate SUMOylation of a specific lysine residue. The stabilization of SIRT1 by Hsp90 is proposed to involve regions beyond its catalytic core, and reduction in Hsp90 capacity can induce SIRT1 destabilization and degradation. Finally, the effects of NAM and SRT1720 on SIRT1 activation and cellular processes were compared, with SRT1720 leading to upregulation of mitophagy and mitochondrial turnover, while NAM enhanced glycolysis and decreased electron transfer to Complex I.

Protein Name: Sirtuin 1

Functions: NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metabolism, apoptosis and autophagy (PubMed:11672523, PubMed:12006491, PubMed:14976264, PubMed:14980222, PubMed:15126506, PubMed:15152190, PubMed:15205477, PubMed:15469825, PubMed:15692560, PubMed:16079181, PubMed:16166628, PubMed:16892051, PubMed:16998810, PubMed:17283066, PubMed:17290224, PubMed:17334224, PubMed:17505061, PubMed:17612497, PubMed:17620057, PubMed:17936707, PubMed:18203716, PubMed:18296641, PubMed:18662546, PubMed:18687677, PubMed:19188449, PubMed:19220062, PubMed:19364925, PubMed:19690166, PubMed:19934257, PubMed:20097625, PubMed:20100829, PubMed:20203304, PubMed:20375098, PubMed:20620956, PubMed:20670893, PubMed:20817729, PubMed:20955178, PubMed:21149730, PubMed:21245319, PubMed:21471201, PubMed:21504832, PubMed:21555002, PubMed:21698133, PubMed:21701047, PubMed:21775285, PubMed:21807113, PubMed:21841822, PubMed:21890893, PubMed:21947282, PubMed:22274616, PubMed:24415752, PubMed:24824780, PubMed:29765047, PubMed:30409912). Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression (PubMed:15469825). Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively (PubMed:15152190, PubMed:14980222, PubMed:14976264). Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction (PubMed:15205477). Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT) (By similarity). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes (PubMed:18485871). The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus (PubMed:18485871, PubMed:21504832). Deacetylates 'Lys-266' of SUV39H1, leading to its activation (PubMed:21504832). Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1 (PubMed:19188449). Deacetylates H2A and 'Lys-26' of H1-4 (PubMed:15469825). Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression (PubMed:20375098). Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting (By similarity). Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1 (PubMed:15469825, PubMed:18004385). Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2 (PubMed:18004385, PubMed:21504832). This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response (PubMed:18004385, PubMed:21504832). Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence (PubMed:11672523, PubMed:12006491). Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I (By similarity). Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability (PubMed:19364925, PubMed:21807113). Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation (PubMed:14980222, PubMed:14976264, PubMed:21841822). Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis (PubMed:15126506). Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing (PubMed:21947282). Deacetylates RELA/NF-kappa-

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