RESUMO
Menopause causes important bodily and metabolic changes, which favor the increased occurrence of cardiovascular diseases, obesity, diabetes, and osteoporosis. Resveratrol exerts proven effects on body metabolism, improving glucose and lipid homeostasis and reducing inflammation and oxidative stress in various organs and tissues. Accordingly, this study evaluates the effects of resveratrol supplementation on the expression of markers associated with thermogenesis in brown adipose tissue, and on the body, metabolic and hormonal parameters of female mice submitted to bilateral oophorectomy. Eighteen female mice were randomized into three groups: G1: control (CONTROL), G2: oophorectomy (OOF), and G3: oophorectomy + resveratrol (OOF + RSV); the animals were kept under treatment for twelve weeks, being fed a standard diet and treated with resveratrol via gavage. Body, biochemical, hormonal, and histological parameters were measured; in addition to the expression of markers associated with thermogenesis in brown adipose tissue. The results showed that animals supplemented with resveratrol showed reduced body weight and visceral adiposity, in addition to glucose, total cholesterol, and triglyceride levels; decreased serum FSH levels and increased estrogen levels were observed compared to the OOF group and mRNA expression of PRDM16, UCP1, and SIRT3 in brown adipose tissue. The findings of this study suggest the important role of resveratrol in terms of improving body, metabolic, and hormonal parameters, as well as modulating markers associated with thermogenesis in brown adipose tissue of female mice submitted to oophorectomy.
Assuntos
Tecido Adiposo Marrom , Suplementos Nutricionais , Ovariectomia , Resveratrol , Termogênese , Proteína Desacopladora 1 , Animais , Resveratrol/farmacologia , Resveratrol/administração & dosagem , Feminino , Termogênese/efeitos dos fármacos , Termogênese/genética , Camundongos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Administração Oral , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo , Peso Corporal/efeitos dos fármacos , Hormônios/sangueRESUMO
To assess and validate the gene expression profile of SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7) in relation to the pathogenesis and prognostic progression of Myelodysplastic neoplasm (MDS). Eighty bone marrow samples of patients with de novo MDS were diagnosed according to WHO 2022 and IPSS-R criteria. Ten bone marrow samples were obtained from elderly healthy volunteers and used as control samples. Gene expression levels of all SIRTs were assessed using RT-qPCR assays. Downregulation of SIRT2 (p = 0.009), SIRT3 (p = 0.048), SIRT4 (p = 0.049), SIRT5 (p = 0.046), SIRT6 (p = 0.043), and SIRT7 (p = 0.047) was identified in MDS patients compared to control individuals. Also, we identified that while SIRT2-7 genes are typically down-regulated in MDS patients compared to normal controls, there are relative expression variations among MDS patient subgroups. Specifically, SIRT4 (p = 0.029) showed increased expression in patients aged 60 or above, and both SIRT2 (p = 0.016) and SIRT3 (p = 0.036) were upregulated in patients with hemoglobin levels below 8 g/dL. SIRT2 (p = 0.045) and SIRT3 (p = 0.033) were highly expressed in patients with chromosomal abnormalities. Different SIRTs exhibited altered expression patterns concerning specific MDS clinical and prognostic characteristics. The downregulation in SIRTs genes (e.g., SIRT2 to SIRT7) expression in Brazilian MDS patients highlights their role in the disease's development. The upregulation of SIRT2 and SIRT3 in severe anemia patients suggests a potential link to manage iron overload-related complications in transfusion-dependent patients. Moreover, the association of SIRT2/SIRT3 with genomic instability and their role in MDS progression signify promising areas for future research and therapeutic targets. These findings underscore the importance of SIRT family in understanding and addressing MDS, offering novel clinical, prognostic, and therapeutic insights for patients with this condition.
Assuntos
Proteínas Mitocondriais , Síndromes Mielodisplásicas , Sirtuína 3 , Sirtuínas , Humanos , Sirtuínas/genética , Sirtuínas/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Prognóstico , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismo , Adulto , Idoso de 80 Anos ou mais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica/métodos , Estudos de Casos e ControlesRESUMO
During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent hallmark. As a result, our objective was to examine the expression of genes associated with mitophagy and mitochondrial biogenesis in the brain exposed to the HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections of 100 ng of HIV-1 Tat into the hippocampus of Sprague-Dawley rats, followed by immunoneuromagnetic cell isolation. Subsequently, we assessed the gene expression of Ppargc1a, Pink1, and Sirt1-3 in neurons using RT-qPCR. Additionally, to understand the role of Tert in telomeric dysfunction, we quantified the activity and expression of Tert. Our results revealed that only Ppargc1a, Pink1, and mitochondrial Sirt3 were downregulated in response to the presence of HIV-1 Tat in hippocampal neurons. Interestingly, we observed a reduction in the activity of Tert in the experimental group, while mRNA levels remained relatively stable. These findings support the compelling evidence of dysregulation in both mitophagy and mitochondrial biogenesis in neurons exposed to HIV-1 Tat, which in turn induces telomeric dysfunction.
Assuntos
Infecções por HIV , HIV-1 , Transtornos Neurocognitivos , Sirtuína 3 , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Animais , Ratos , Produtos do Gene tat/metabolismo , Infecções por HIV/metabolismo , HIV-1/metabolismo , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/virologia , Neurônios/metabolismo , Biogênese de Organelas , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Sirtuína 3/genética , Sirtuína 3/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de PeroxissomoRESUMO
Studying the evolutionary history of gene families is a challenging and exciting task with a wide range of implications. In addition to exploring fundamental questions about the origin and evolution of genes, disentangling their evolution is also critical to those who do functional/structural studies to allow a deeper and more precise interpretation of their results in an evolutionary context. The sirtuin gene family is a group of genes that are involved in a variety of biological functions mostly related to aging. Their duplicative history is an open question, as well as the definition of the repertoire of sirtuin genes among vertebrates. Our results show a well-resolved phylogeny that represents an improvement in our understanding of the duplicative history of the sirtuin gene family. We identified a new sirtuin gene family member (SIRT3.2) that was apparently lost in the last common ancestor of amniotes but retained in all other groups of jawed vertebrates. According to our experimental analyses, elephant shark SIRT3.2 protein is located in mitochondria, the overexpression of which leads to an increase in cellular levels of ATP. Moreover, in vitro analysis demonstrated that it has deacetylase activity being modulated in a similar way to mammalian SIRT3. Our results indicate that there are at least eight sirtuin paralogs among vertebrates and that all of them can be traced back to the last common ancestor of the group that existed between 676 and 615 millions of years ago.
Assuntos
Sirtuína 3 , Sirtuínas , Animais , Sirtuínas/genética , Sirtuína 3/genética , Evolução Molecular , Vertebrados/genética , Filogenia , MamíferosRESUMO
CONTEXT: The sirtuins (SIRT1 to SIRT7) constitute a family of highly conserved nicotinamide adenine dinucleotide-dependent proteins. When activated, sirtuins control essential cellular processes to maintain metabolic homeostasis, while lack of expression of sirtuins has been related to chronic disease. OBJECTIVE: The aim of this systematic review is to analyze the role of fat consumption as a modulator of human sirtuins. DATA SOURCES: This review was conducted according to PRISMA guidelines. Studies were identified by searches of the electronic databases PubMed/MEDLINE, Scopus, and Web of Science. STUDY SELECTION: Randomized clinical trials assessing the effect of fatty acid consumption on sirtuin mRNA expression, sirtuin protein expression, or sirtuin protein activity were eligible for inclusion. DATA EXTRACTION: Two authors screened and determined the quality of the studies; disagreements were resolved by the third author. All authors compared the compiled data. RESULTS: Seven clinical studies with 3 different types of interventions involving healthy and nonhealthy participants were selected. Only SIRT1 and SIRT3 were evaluated. Overall, the evidence from clinical studies to date is insufficient to understand how lipid consumption modulates sirtuins in humans. The best-characterized mechanism highlights oleic acid as a natural activator of SIRT1. CONCLUSION: These results draw attention to a new field of interest in nutrition science. The possible activation of sirtuins by dietary fat manipulation may represent an important nutritional strategy for management of chronic and metabolic disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42018114456.
Assuntos
Ácidos Graxos/administração & dosagem , Sirtuína 1/genética , Sirtuína 3/genética , Adulto , Idoso , Gorduras na Dieta/administração & dosagem , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Sirtuína 1/metabolismo , Sirtuína 3/metabolismo , Adulto JovemRESUMO
INTRODUCTION: Sirtuins regulate energy metabolism and insulin sensitivity through their ability to act as energy sensors and regulators in several metabolic tissues. AIM: To evaluate the expression levels of sirtuin genes SIRT1, SIRT2, SIRT3 and SIRT6 and their target genes (PPAR-α, PGC1-α, NRF1, DGAT1, PPAR-γ and FOXO3a) in subcutaneous adipose tissue collected from individuals with normoweight, overweight and obesity. METHODS: Adipose tissue samples, obtained by lipoaspiration during liposuction surgery, were processed to obtain RNA, which was reverse-transcribed to cDNA. Then, we measured the expression levels of each gene by qPCR. RESULTS: We found differences in the mRNA expression of SIRT1, SIRT2, SIRT3 and SIRT6 and their target genes (PPAR-α, PGC1-α, NRF1, DGAT1, PPAR-γ and FOXO3a) in adipose tissue from overweight or obese subjects when compared to normoweight subjects. All genes analyzed, except SIRT2, showed correlation with BMI. CONCLUSIONS: Our findings in human subcutaneous adipose tissue show that increased body mass index modifies the expression of genes encoding sirtuins and their target genes, which are metabolic regulators of adipose tissue. Therefore, these could be used as biomarkers to predict the ability of adipose tissue to gain mass of adipose tissue.
Assuntos
Tecido Adiposo/fisiologia , Obesidade/genética , Sirtuína 1/genética , Sirtuína 2/genética , Sirtuína 3/genética , Sirtuínas/genética , Adulto , Índice de Massa Corporal , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/metabolismo , Sirtuína 1/biossíntese , Sirtuína 2/biossíntese , Sirtuína 3/biossíntese , Sirtuínas/biossíntese , Adulto JovemRESUMO
Sirtuins 1-7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1-7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.
Assuntos
Adenoma/metabolismo , Neoplasias Hipofisárias/metabolismo , Sirtuínas/metabolismo , Adenoma/genética , Adenoma/patologia , Adulto , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sirtuínas/genéticaRESUMO
Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that catalyze the hydrolysis of acetyl-lysine residues. They play an important role in many physiological and pathophysiological processes, such as the regulation of lifespan and the prevention of metabolic diseases. In this study, we analyzed the effect of resveratrol on the gene expression levels of SIRT1, SIRT3, SIRT4, PGC1α, and NAMPT, as well as its effect on NAD(+) and NADH levels, in the liver of non stressed or non impaired wild-type zebrafish. Semiquantative RT-PCR assays showed that resveratrol did not change the mRNA levels of SIRT1 and PGC1α but decreased the expression levels of the SIRT3, SIRT4, and NAMPT genes. The decrease in NAMPT mRNA levels was accompanied by an increase in NADH levels, thereby decreasing the NAD(+)/H ratio. Taken together, our results suggest that resveratrol plays a modulatory role in the transcription of the NAMPT, SIRT3, and SIRT4 genes. Zebrafish is an interesting tool that can be used to understand the mechanisms of SIRTs and NAMPT metabolism and to help develop therapeutic compounds. However, further investigations using healthy experimental animals are required to study the modulation of the SIRT and NAMPT genes by resveratrol before it is used as a nutraceutical compound in healthy humans.