Role of SIRT1 and Progesterone Resistance in Normal and Abnormal Endometrium

2021 ◽  
Author(s):  
Tae Hoon Kim ◽  
Steven L Young ◽  
Tsutomu Sasaki ◽  
Jeffrey L Deaton ◽  
David P Schammel ◽  
...  
Keyword(s):  
Cellular Response ◽  
Sirtuin 1 ◽  
Endometriotic Lesion ◽  
Mouse Uterus ◽  
Normal Endometrium ◽  
Sirt1 Expression ◽  
Progesterone Resistance ◽  
Sirt1 Inhibitor ◽  
Physiologic Role

Abstract Context Progesterone resistance, a known pathologic condition associated with a reduced cellular response to progesterone and heightened estrogen responses, appears to have a normal physiologic role in mammalian reproduction. The molecular mechanism responsible for progesterone resistance in normal and abnormal endometrium remains unclear. Objective To examine the roles of Sirtuin-1 (SIRT1) in normal endometrium as well as endometrium associated with infertility and endometriosis, as an epigenetic modulator associated with progesterone resistance. Methods SIRT1 expression was examined by Western blot, RT-qPCR and immunohistochemistry in mouse uterus and human endometrium. Mice with uterine specific Sirt1 overexpression were developed to examine SIRT1’s role in endometrial function and endometriosis development. EX-527, a SIRT1 inhibitor, and SRT1720, a SIRT1 agonist, were also used to evaluate SIRT1 effect on endometriosis. Results In normal healthy women, endometrial SIRT1 is expressed only during menses. SIRT1 was dramatically overexpressed in the endometrium from women with endometriosis in both the epithelium and strom. In mice, SIRT1 is expressed at the time of implantation between day 4.5 and 5.5 of pregnancy. Overexpression of SIRT1 (Sirt1  over) in the mouse uterus leads to subfertility due to implantation failure and decidualization defects and progesterone resistance. SIRT1 overexpression in endometriotic lesion promotes worsening endometriosis development. EX-527 (SIRT1 inhibitor) significantly reduced the number of endometriotic lesions in the mouse endometriosis model. Conclusions SIRT1 expression and progesterone resistance appears to play -roles in normal endometrial functions. Aberrant SIRT1 expression contributes to progesterone resistance and may participate in the pathophysiology of endometriosis. SIRT1 is a novel and targetable protein for the diagnosis as well as treatment of endometriosis and the associated infertility seen in this disease.

scholarly journals Role of SIRT1 in HIV-associated kidney disease

2020 ◽  
Vol 319 (2) ◽  
pp. F335-F344 ◽  
Author(s):  
Xuan Wang ◽  
Ruijie Liu ◽  
Weijia Zhang ◽  
Deborah P. Hyink ◽  
Gokul C. Das ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Drug Targets ◽  
Cell Injury ◽  
Kidney Diseases ◽  
Sirtuin 1 ◽  
Kidney Cells ◽  
Sirt1 Expression ◽  
Hiv 1

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

scholarly journals SIRT1 Expression and Regulation in the Primate Testis

2021 ◽  
Vol 22 (6) ◽  
pp. 3207
Author(s):  
Fazal Wahab ◽  
Ignacio Rodriguez Polo ◽  
Rüdiger Behr
Keyword(s):  
Germ Cells ◽  
Rhesus Macaques ◽  
Sirtuin 1 ◽  
Primate Species ◽  
Seminiferous Tubules ◽  
Sirt1 Expression ◽  
Protein Substrates ◽  
Development And Differentiation ◽  
Endocrine Factor

The epigenetic mechanisms controlling germ cell development and differentiation are still not well understood. Sirtuin-1 (SIRT1) is a nicotinamide adenosine dinucleotide (NAD)-dependent histone deacetylase and belongs to the sirtuin family of deacetylases. It catalyzes the removal of acetyl groups from a number of protein substrates. Some studies reported a role of SIRT1 in the central and peripheral regulation of reproduction in various non-primate species. However, testicular SIRT1 expression and its possible role in the testis have not been analyzed in primates. Here, we document expression of SIRT1 in testes of different primates and some non-primate species. SIRT1 is expressed mainly in the cells of seminiferous tubules, particularly in germ cells. The majority of SIRT1-positive germ cells were in the meiotic and postmeiotic phase of differentiation. However, SIRT1 expression was also observed in selected premeiotic germ cells, i.e., spermatogonia. SIRT1 co-localized in spermatogonia with irisin, an endocrine factor specifically expressed in primate spermatogonia. In marmoset testicular explant cultures, SIRT1 transcript levels are upregulated by the addition of irisin as compared to untreated controls explants. Rhesus macaques are seasonal breeders with high testicular activity in winter and low testicular activity in summer. Of note, SIRT1 mRNA and SIRT1 protein expression are changed between nonbreeding (low spermatogenesis) and breeding (high spermatogenesis) season. Our data suggest that SIRT1 is a relevant factor for the regulation of spermatogenesis in primates. Further mechanistic studies are required to better understand the role of SIRT1 during spermatogenesis.

scholarly journals The Prognostic Role of SIRT1-Autophagy Axis in Gastric Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Guanglin Qiu ◽  
Xuqi Li ◽  
Chao Wei ◽  
Xiangming Che ◽  
Shicai He ◽  
...  
Keyword(s):  
Prognostic Indicator ◽  
Beclin 1 ◽  
Sirtuin 1 ◽  
Clinicopathological Parameters ◽  
Poor Survival ◽  
Free Survival ◽  
Sirt1 Expression ◽  
Transmission Electron ◽  
The Relationship

Aim. Sirtuin 1 (SIRT1) can induce autophagy through deacetylation of Beclin-1 and other autophagy mediators. However, the relationship between SIRT1 and autophagy in GC has not been defined. Therefore, the aim of this study was to confirm the prognostic value of SIRT1 and Beclin-1 and their relationship in GC patients. Methods. Transmission electron microscopy (TEM) was performed to examine the autophagy in GC patients. Immunohistochemistry was used to examine the expression of SIRT1, Beclin-1 in GC, and adjacent nonneoplastic mucosa. Results. In 7 out of 8 GC patients’ samples examined by TEM, more autophagic vesicles were observed in GC tissues compared to adjacent nonneoplastic mucosa tissue. A positive correlation between SIRT1 and Beclin-1 expression was observed. Furthermore, Beclin-1 or SIRT1 expression alone or their combined expression were significantly correlated with advanced clinicopathological parameters. High Beclin-1 and SIRT1 expression alone and their combined high expression predicted shorter overall survival and relapse-free survival. Both high Beclin-1 and SIRT1 expressions were independent prognostic factors for poor survival of GC. Conclusions. Based on our results we can conclude that SIRT1 and Beclin-1 expression alone or in combination can be used as prognostic indicator and may represent new therapeutic targets in GC.

scholarly journals PKCδ Mediates NF-κB Inflammatory Response and Downregulates SIRT1 Expression in Liver Fibrosis

2019 ◽  
Vol 20 (18) ◽  
pp. 4607 ◽  
Author(s):  
Lee ◽  
Kim ◽  
Lee ◽  
Kwon
Keyword(s):  
Inflammatory Response ◽  
Hepatic Cirrhosis ◽  
Regulatory Mechanism ◽  
Sirtuin 1 ◽  
Sirt1 Expression ◽  
Kinase C ◽  
Promising Target ◽  
Ccl4 Treatment ◽  
Fibrotic Diseases

The precise mechanism of hepatic cirrhosis remains largely unclear. In particular, a potential regulatory mechanism by which protein kinase C-delta (PKCδ ) affects profibrogenic gene expression involved in hepatic cirrhosis has never been explored. In the present study, we investigated whether PKCδ activation is involved in liver inflammatory fibrosis in both lipopolysaccharide (LPS)-treated RAW 264.7 and CCl4-treated mice. PKCδ was strongly activated by LPS or CCl4 treatment and consequently stimulated nuclear factor (NF)-κB inflammatory response. Interestingly, the activation of PKCδ negatively regulated sirtuin-1 (SIRT1) expression, whereas PKCδ suppression by PKCδ peptide inhibitor V1-1 or siRNA dramatically increased SIRT1 expression. Furthermore, we showed that the negative regulation of PKCδ leads to a decrease in SIRT1 expression. To our knowledge, these results are the first demonstration of the involvement of PKCδ in modulating NF-κB through SIRT1 signaling in fibrosis in mice, suggesting a novel role of PKCδ in inflammatory fibrosis. The level of NF-κB p65 in the nucleus was also negatively regulated by SIRT1 activity. We showed that the inhibition of PKCδ promoted SIRT1 expression and decreased p65 levels in the nucleus through deacetylation. Moreover, the inactivation of PKCδ with V1-1 dramatically suppressed the inflammatory fibrosis, indicating that PKCδ represents a promising target for treating fibrotic diseases like hepatic cirrhosis.

scholarly journals Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-α production in cultured macrophage cell lines

2009 ◽  
Vol 296 (5) ◽  
pp. G1047-G1053 ◽  
Author(s):  
Zheng Shen ◽  
Joanne M. Ajmo ◽  
Christopher Q. Rogers ◽  
Xiaomei Liang ◽  
Lisa Le ◽  
...  
Keyword(s):  
Cell Lines ◽  
Proinflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Sirtuin 1 ◽  
Class Iii ◽  
Macrophage Cell ◽  
Tnf Α ◽  
Sirt1 Inhibitor ◽  
Factor Α

Dysregulation of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of alcoholic liver injury. Sirtuin 1 (SIRT1) is an NAD+-dependent class III protein deacetylase that is known to be involved in regulating production of proinflammatory cytokines including TNF-α. In the present study, we examined the role of SIRT1 signaling in TNF-α generation stimulated by either lipopolysaccharide (LPS), acetaldehyde (AcH), or acetate (two major metabolites of ethanol) in two cultured macrophage cell lines. In both rat Kupffer cell line 1 (RKC1) and murine RAW 264.7 macrophages, treatment with either LPS, AcH, or acetate caused significant decreases in SIRT1 transcription, translation, and activation, which essentially demonstrated an inverse relationship with TNF-α levels. LPS, AcH, and acetate each provoked the release of TNF-α from RKC1 cells, whereas coincubation with resveratrol (a potent SIRT1 agonist) inhibited this effect. Conversely, addition of sirtinol (a known SIRT1 inhibitor) or knocking down SIRT1 by the small silencing SIRT1 plasmid (SIRT1shRNA) augmented TNF-α release, suggesting that impairment of SIRT1 may contribute to TNF-α secretion. Further mechanistic studies revealed that inhibition of SIRT1 by LPS, AcH, or acetate was associated with a marked increase in the acetylation of the RelA/p65 subunit of nuclear transcription factor (NF-κB) and promotion of NF-κB transcriptional activity. Taken together, our findings suggest that SIRT1-NF-κB signaling is involved in regulating LPS- and metabolites-of-ethanol-mediated TNF-α production in rat Kupffer cells and in murine macrophages. Our study provides new insights into understanding the molecular mechanisms underlying the development of alcoholic steatohepatitis.

scholarly journals D-Galactosamine/Lipopolysaccharide-Induced Hepatotoxicity Downregulates Sirtuin 1 in Rat Liver: Role of Sirtuin 1 Modulation in Hepatoprotection

2014 ◽  
pp. 615-623
Author(s):  
M. K. KEMELO ◽  
L. WOJNAROVÁ ◽  
N. KUTINOVÁ CANOVÁ ◽  
H. FARGHALI
Keyword(s):  
Protein Expression ◽  
Wistar Rats ◽  
Sirtuin 1 ◽  
Dramatic Decrease ◽  
Cytotoxic Effects ◽  
Male Wistar Rats ◽  
Sirt1 Inhibitor ◽  
Lps Treatment ◽  
Sirt1 Activator

D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

Use of riboflavinum and magnesium citrate in obstetrics and gynecology

GYNECOLOGY ◽  
2018 ◽  
Vol 20 (6) ◽  
pp. 60-66
Author(s):  
O A Gromova ◽  
I Yu Torshin ◽  
N K Tetruashvili
Keyword(s):  
Thrombus Formation ◽  
Sirtuin 1 ◽  
Obstetrics And Gynecology ◽  
Inflammatory Factor ◽  
Vitamin B2 ◽  
Magnesium Citrate ◽  
Fetal Malformations ◽  
Folate Cycle ◽  
Pro Inflammatory Cytokines

Low provision of cells with vitamin B2 and magnesium leads to a decrease in the activity of the sirtuin-1 deacetylase and an increase in the activity of the pro-inflammatory factor NF-kB, a decrease in the levels of glutathione, an increase in the levels of homocysteine, thrombus formation, the activity of mitochondria, the development of migraine, convulsions and miscarriage. The role of riboflavin in the regulation of the folate cycle in the genotype MTHFR 677TT for the prevention of folatresistant fetal malformations, the advantages of an aqueous solution of riboflavin and magnesium citrate is considered. The data on titanium dioxide, which increases the level of pro-inflammatory cytokines IL-1b, IL-4, IL-5, IL-6, G-CSF, CCL-2, CCL-3, CCL-4, are presented.

scholarly journals Deconjugation of bilirubin-IX alpha glucuronides: a physiologic role of hepatic microsomal beta-glucuronidase.

1993 ◽  
Vol 268 (31) ◽  
pp. 23197-23201
Author(s):  
J.F. Whiting ◽  
J.P. Narciso ◽  
V Chapman ◽  
B.J. Ransil ◽  
R.T. Swank ◽  
...  
Keyword(s):  
Physiologic Role

scholarly journals Oxidized LDLs as Signaling Molecules

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1184
Author(s):  
Jean-Marc Zingg ◽  
Adelina Vlad ◽  
Roberta Ricciarelli
Keyword(s):  
Free Radicals ◽  
Cellular Response ◽  
Vascular System ◽  
Signaling Molecules ◽  
Scavenger Receptors ◽  
Physiological Relevance ◽  
Reactive Radicals ◽  
Accumulation Of Lipids

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

scholarly journals Role of miRNAs in Normal Endometrium and in Endometrial Disorders: Comprehensive Review

2021 ◽  
Vol 10 (16) ◽  
pp. 3457
Author(s):  
Kamila Kolanska ◽  
Sofiane Bendifallah ◽  
Geoffroy Canlorbe ◽  
Arsène Mekinian ◽  
Cyril Touboul ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mirna Expression ◽  
Expression Patterns ◽  
Mirna Regulation ◽  
Rigorous Analysis ◽  
Sexual Hormones ◽  
Physiological Mechanisms ◽  
Normal Endometrium ◽  
Gynecological Disorders

The molecular responses to hormonal stimuli in the endometrium are modulated at the transcriptional and post-transcriptional stages. Any imbalance in cellular and molecular endometrial homeostasis may lead to gynecological disorders. MicroRNAs (miRNAs) are involved in a wide variety of physiological mechanisms and their expression patterns in the endometrium are currently attracting a lot of interest. miRNA regulation could be hormone dependent. Conversely, miRNAs could regulate the action of sexual hormones. Modifications to miRNA expression in pathological situations could either be a cause or a result of the existing pathology. The complexity of miRNA actions and the diversity of signaling pathways controlled by numerous miRNAs require rigorous analysis and findings need to be interpreted with caution. Alteration of miRNA expression in women with endometriosis has been reported. Thus, a potential diagnostic test supported by a specific miRNA signature could contribute to early diagnosis and a change in the therapeutic paradigm. Similarly, specific miRNA profile signatures are expected for RIF and endometrial cancer, with direct implications for associated therapies for RIF and adjuvant therapies for endometrial cancer. Advances in targeted therapies based on the regulation of miRNA expression are under evaluation.

Sign in / Sign up

Export Citation Format

Share Document