RESUMO
The Sirtuin family of NAD+-dependent enzymes assumes a pivotal role in orchestrating adaptive responses to environmental fluctuations and stress stimuli, operating at both genomic and metabolic levels. Within this family, SIRT7 emerges as a versatile player in tumorigenesis, displaying both pro-tumorigenic and tumor-suppressive functions in a context-dependent manner. While other sirtuins, such as SIRT1 and SIRT6, exhibit a similar dual role in cancer, SIRT7 stands out due to distinctive attributes that sharply distinguish it from other family members. Among these are a unique key role in regulation of nucleolar functions, a close functional relationship with RNA metabolism and processing -exceptional among sirtuins- and a complex multienzymatic nature, which provides a diverse range of molecular targets. This review offers a comprehensive overview of the current understanding of the role of SIRT7 in various malignancies, placing particular emphasis on the intricate molecular mechanisms employed by SIRT7 to either stimulate or counteract tumorigenesis. Additionally, it delves into the unique features of SIRT7, discussing their potential and specific implications in tumor initiation and progression, underscoring the promising avenue of targeting SIRT7 for the development of innovative anti-cancer therapies.
Assuntos
Neoplasias , Sirtuínas , Humanos , Sirtuínas/fisiologia , Carcinogênese/genética , Transformação Celular Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Aging is a chronic yet natural physiological decline of the body. Throughout life, humans are continuously exposed to a variety of exogenous and endogenous stresses, which engender various counteractive responses at the cellular, tissue, organ, as well as organismal levels. The compromised cellular and tissue functions that occur because of genetic factors or prolonged stress (or even the stress response) may accelerate aging. Over the last two decades, the sirtuin (SIRT) family of lysine deacylases has emerged as a key regulator of longevity in a variety of organisms. SIRT7, the most recently identified member of the SIRTs, maintains physiological homeostasis and provides protection against aging by functioning as a watchdog of genomic integrity, a dynamic sensor and modulator of stresses. SIRT7 decline disrupts metabolic homeostasis, accelerates aging, and increases the risk of age-related pathologies including cardiovascular and neurodegenerative diseases, pulmonary and renal disorders, inflammatory diseases, and cancer, etc. Here, we present SIRT7 as the seventh key to unlock the mystery of aging, and its specific manipulation holds great potential to ensure healthiness and longevity.
Assuntos
Envelhecimento , Sirtuínas , Humanos , Sirtuínas/fisiologiaRESUMO
Beyond its role on the conversion of nutrients into energy and biomass, cellular metabolism is actively involved in the control of many physiological processes. Among these, it is becoming increasingly evident that specific metabolic pathways are associated with the phenotype of several immune cell types and, importantly, are crucial in controlling their differentiation, proliferation, and effector functions, thus shaping the immune response against pathogens and tumors. In this context, data generated over the last decade have uncovered mammalian sirtuins as important regulators of cellular metabolism, immune cell function, and cancer. Here, we summarize our current knowledge on the roles of this family of protein deacylases on the metabolic control of immune cells and their implications on immune-related diseases and cancer.
Assuntos
Sistema Imunitário/metabolismo , Imunidade/fisiologia , Sirtuínas/fisiologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Metabolismo Energético/genética , Humanos , Sistema Imunitário/citologia , Imunidade/genética , Mitocôndrias/metabolismo , FenótipoRESUMO
Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.
Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Doença de Machado-Joseph/tratamento farmacológico , Sirtuínas/efeitos dos fármacos , Ácido Valproico/uso terapêutico , Acetilação , Animais , Animais Geneticamente Modificados , Ataxina-3/antagonistas & inibidores , Ataxina-3/genética , Ataxina-3/metabolismo , Autofagia/efeitos dos fármacos , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Genes Reporter , Células HEK293 , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Humanos , Peptídeos/genética , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Transdução de Sinais , Sirtuína 1/fisiologia , Sirtuínas/fisiologia , Natação , Expansão das Repetições de Trinucleotídeos , Ácido Valproico/farmacologia , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Osteoarthritis (OA) is the most common form of joint disease. The aim of this study was to explore the functions of SIRT3 on OA pathophysiology and the mechanism involved. Rat chondrocytes and destabilized medial meniscus (DMM) rat OA model were used as in vitro and in vivo models. In addition, lentivirus and plasmid were used to overexpress SIRT3, while siRNA was applied to establish SIRT3 knockdown. IL-1ß induced inflammation, apoptosis, mitochondrial dysfunction, and chondrocyte degeneration were inhibited by SIRT3 overexpression, which were enhanced in SIRT3-knockdown rat chondrocytes. Furthermore, overexpression of SIRT3 could restore IL-1ß-induced autophagy inhibition. We also found that IL-1ß-induced PI3K/Akt/mTOR signaling pathway activation was inhibited by SIRT3 overexpression, which was enhanced by SIRT3 knockdown. Last, intra-articular SIRT3 overexpression alleviated the severity of OA-induced rat joint damage. Our results demonstrated that SIRT3 is an important protective agent against OA pathophysiology via inhibiting PI3K/Akt/mTOR signaling.
Assuntos
Osteoartrite/metabolismo , Sirtuína 3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Inflamação/metabolismo , Articulação do Joelho/fisiologia , Masculino , Osteoartrite/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Sirtuína 3/fisiologia , Sirtuínas/metabolismo , Sirtuínas/fisiologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Sirtuins (SIRTs), enzymes from the family of NAD+-dependent histone deacetylases, play an important role in the functioning of the body at the cellular level and participate in many biochemical processes. The multi-directionality of SIRTs encourages scientists to undertake research aimed at understanding the mechanisms of their action and the influence that SIRTs have on the organism. At the same time, new substances are constantly being sought that can modulate the action of SIRTs. Extensive research on the expression of SIRTs in various pathological conditions suggests that regulation of their activity may have positive results in supporting the treatment of certain metabolic, neurodegenerative or cancer diseases or this connected with oxidative stress. Due to such a wide spectrum of activity, SIRTs may also be a prognostic markers of selected pathological conditions and prove helpful in assessing their progression, especially by modulating their activity. The article presents and discusses the activating or inhibiting impact of individual SIRTs modulators. The review also gathered selected currently available information on the expression of SIRTs in individual disease cases as well as the biological role that SIRTs play in the human organism, also in connection with oxidative stress condition, taking into account the progress of knowledge about SIRTs over the years, with particular reference to the latest research results.
Assuntos
Sirtuínas/metabolismo , Regulação da Expressão Gênica , Humanos , NAD/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Sirtuínas/fisiologiaRESUMO
In response to hypoxic-ischemic brain damage (HIBD), microglia activation and its mediated inflammation contribute to neuronal damage. Inhibition of over-activated microglia is deemed to be a potential therapeutic strategy. Our previous studies showed that gastrodin efficiently depressed the neuroinflammation mediated by activated microglia in HIBD neonatal rats. The underlying mechanisms through which gastrodin acts on activated microglia have not been fully elucidated. This study is designed to determine whether gastrodin would regulate the Notch signaling pathway and Sirtuin3 (Sirt3), which are implicated in regulating microglia activation. The present results showed that gastrodin markedly suppressed the expression of members of Notch signaling pathway (Notch-1, NICD, RBP-JK and Hes-1) in activated microglia both in vivo and in vitro. Conversely, Sirt3 expression was enhanced. In BV-2 microglia treated with a γ-secretase inhibitor of Notch pathway- DAPT, the expression of RBP-JK, Hes-1, and NICD was suppressed in activated microglia. Treatment with DAPT and gastrodin further decreased NICD and Hes-1 expression. Sirt3 expression was also decreased after DAPT treatment. However, Sirt3 expression in activated BV-2 microglia given a combined DAPT and gastrodin treatment was not further increased. In addition, combination of DAPT and Gastrodin cumulatively decreased tumor necrosis factor-α (TNF-α) expression. The results suggest that gastrodin regulates microglia activation via the Notch signaling pathway and Sirt3. More importantly, interference of the Notch signaling pathway inhibited Sirt3 expression, indicating that Sirt3 is a downstream gene of the Notch signaling pathway. It is suggested that Notch and Sirt3 synergistically regulate microglia activation such as in TNF-α production.
Assuntos
Álcoois Benzílicos/farmacologia , Glucosídeos/farmacologia , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Microglia/efeitos dos fármacos , Receptor Notch1/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/fisiologia , Animais , Animais Recém-Nascidos , Álcoois Benzílicos/farmacocinética , Artéria Carótida Primitiva , Células Cultivadas , Córtex Cerebral/patologia , Corpo Caloso/patologia , Diaminas/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/farmacocinética , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Ligadura , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptor Notch1/biossíntese , Receptor Notch1/genética , Sirtuínas/biossíntese , Sirtuínas/genética , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genéticaRESUMO
AIMS: Intracerebral hemorrhage (ICH) induces serious neuroinflammation and damage of blood-brain barrier. We aim to investigate the role of brown fat enriched lncRNA 1 (Blnc1) in the development of ICH in mice. METHODS: An ICH model was established with autologous blood injection in C57BL/6 mice, and Blnc1 siRNA was injected intracranially. Blnc1 levels were detected and brain injury was evaluated at day 3. Primary brain microvascular endothelial cells (BMVECs) were isolated from new born mice and gain- and loss-of-function experiments were performed to investigate the role of Blnc1. Then, ICH cell model was established by treating BMVECs with oxygen and glucose deprivation (OGD) plus hemin, and Blnc1 siRNA was transfected into the cells. BMVEC functions, including viability, invasion, apoptosis, permeability and secretion of inflammatory cytokines were analyzed. KEY FINDINGS: Blnc1 was upregulated in perihematomal edema, hematoma and microvessel in the brain of ICH mice. Blnc1 negatively regulated viability and migration, and facilitated apoptosis, permeability and inflammatory cytokine secretion in BMVECs. Silencing Blnc1 restrained OGD plus hemin-caused reduction of BMVEC viability and migration and the induction of apoptosis, permeability and inflammation response, and suppressed PPAR-γ/SIRT6-mediated FoxO3 activation, which could be reversed by T0070907 (PPAR-γ inhibitor). Downregulation of Blnc1 ameliorated ICH-induced nerve injury, brain edema, blood brain barrier destruction, inflammation response and hematoma. Moreover, Blnc1 levels were positively correlated with PPAR-γ levels, and Blnc1 interference suppressed PPAR-γ/SIRT6-mediated activation of FoxO3 signaling in ICH mice. SIGNIFICANCE: Silencing Blnc1 alleviated nerve injury and inflammatory response caused by ICH through activating PPAR-γ/SIRT6/FoxO3 pathway.
Assuntos
Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , RNA Longo não Codificante/genética , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Lesões Encefálicas/etiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/fisiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/metabolismo , PPAR gama/fisiologia , Permeabilidade/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo , Sirtuínas/fisiologiaRESUMO
PURPOSE OF REVIEW: Sirtuins are a family of nicotinamide adenine dinucleotide+-dependent enzymes catalyzing target protein deacetylation to modulate cellular metabolism, response to oxidative stress and inflammation, senescence, autophagy and apoptosis. In this review, we provide an overview of recent studies regarding the alterations and roles of sirtuins in a variety of renal and cardiovascular diseases. We are also going to highlight activators and inhibitors of sirtuins in the prevention of these diseases. This will help us to understand how this field may change in the future. RECENT FINDING: Recent studies have elucidated how physical or diseased conditions alter the expressions and enzyme activity of sirtuins and expounded sexual differences in sirtuins functions. In addition, interventions by targeting sirtuins have been applied in preclinical and clinical studies to prevent or slow the development of related diseases. SUMMARY: The advantages of female sex in renal and cardiovascular diseases are partially due to the expression and function of sirtuins. Estrogen activates sirtuins and in turn sirtuins promote estrogen receptor signaling. In addition, the hypoglycemic agents, sodium-glucose cotransporter 2 inhibitors protect against diabetic nephropathy at least in part via activating SIRT-1. Although several compounds targeted sirtuins are promising drug candidates in a variety of renal and cardiovascular diseases, well designed large clinical trials are still required to identify their efficacy and safety.
Assuntos
Doenças Cardiovasculares , Nefropatias , Sirtuínas/fisiologia , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Pesquisa Biomédica/tendências , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Fenômenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Feminino , Fibrose/metabolismo , Fibrose/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Rim/metabolismo , Rim/fisiologia , Rim/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Estresse Oxidativo , Fatores Sexuais , Sirtuínas/biossíntese , Sirtuínas/metabolismoRESUMO
Colorectal cancer (CRC) is the leading cause of cancer death; however, targets with broad anti-CRC effects are limited. Sirtuin6 (SIRT6) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that is widely pathologically downregulated in CRC, but its pharmacological effect in CRC remains undefined due to the lack of small-molecule SIRT6 activators. We searched for a compound activating SIRT6 and investigated its anti-CRC effect in various models. Methods: We identified an allosteric SIRT6 activator, MDL-811. Its ability to enhance SIRT6 deacetylation at protein and cellular levels was evaluated by Fluor de Lys (FDL) and western blots. We assessed the proliferation of 26 CRC cell lines and patient-derived organoids (PDOs) treated with MDL-811. In vivo efficacy of MDL-811 was evaluated in HCT116 cell line- and patient-derived xenografts as well as a spontaneous CRC model. RNA sequencing and real-time quantitative PCR assays were performed to analyze gene expression changes in MDL-811-treated HCT116 cells. Along with controls in SIRT6-overexpressing HCT116 cells, the SIRT6-mediated histone H3 deacetylation at the Cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene locus was assessed by chromatin immunoprecipitation (ChIP) in MDL-811-treated HCT116 cells. A combination therapy against CRC based on the downstream gene of SIRT6 activation was evaluated in cells and mouse models. Results: MDL-811 significantly activated SIRT6 histone H3 deacetylation (H3K9Ac, H3K18Ac, and H3K56Ac) in vitro and had broad antiproliferative effects on diverse CRC cell lines and PDOs. More importantly, the in vivo anti-tumor efficacy of MDL-811 was demonstrated across cell line- and patient-derived xenografts and in the APCmin/+ spontaneous CRC model. Mechanically, we identified a new downstream target gene of SIRT6 in CRC, CYP24A1. Based on these findings, a combination drug strategy with MDL-811 to synergistically enhance the anti-CRC effect of vitamin D3 was validated in vitro and in vivo. Conclusions: Our data provide proof of concept that targeting SIRT6 using a small-molecule activator is an attractive therapeutic strategy for CRC and that MDL-811 could be a promising lead compound for further preclinical and clinical studies of treatments for CRC.
Assuntos
Colecalciferol/farmacologia , Neoplasias Colorretais/metabolismo , Sirtuínas/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colecalciferol/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Sirtuínas/farmacologia , Sirtuínas/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Diabetes-induced tissue injuries in target organs such as the kidney, heart, eye, liver, skin, and nervous system contribute significantly to the morbidity and mortality of diabetes. However, whether the lung should be considered a diabetic target organ has been discussed for decades. Accumulating evidence shows that both pulmonary histological changes and functional abnormalities have been observed in diabetic patients, suggesting that the lung is a diabetic target organ. Mechanisms underlying diabetic lung are unclear, however, oxidative stress, systemic inflammation, and premature aging convincingly contribute to them. Circadian system and Sirtuins have been well-documented to play important roles in above mechanisms. Circadian rhythms are intrinsic mammalian biological oscillations with a period of near 24 h driven by the circadian clock system. This system plays an important role in the regulation of energy metabolism, oxidative stress, inflammation, cellular proliferation and senescence, thus impacting metabolism-related diseases, chronic airway diseases and cancers. Sirtuins, a family of adenine dinucleotide (NAD+)-dependent histone deacetylases, have been demonstrated to regulate a series of physiological processes and affect diseases such as obesity, insulin resistance, type 2 diabetes (T2DM), heart disease, cancer, and aging. In this review, we summarize recent advances in the understanding of the roles of the circadian clock and Sirtuins in regulating cellular processes and highlight the potential interactions of the circadian clock and Sirtuins in the context of diabetic lung.
Assuntos
Relógios Circadianos/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Pulmão/fisiopatologia , Sirtuínas/fisiologia , Animais , Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Complicações do Diabetes/genética , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sirtuínas/genéticaRESUMO
OBJECTIVE: Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms. METHODS: For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated. RESULTS: Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons. CONCLUSIONS: Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance.
Assuntos
Leptina/metabolismo , Neurônios/metabolismo , Sirtuínas/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Composição Corporal , Peso Corporal , Encéfalo/metabolismo , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Leptina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Transdução de Sinais/fisiologia , Sirtuínas/fisiologiaRESUMO
Molecular alterations within the hematopoietic system influence cellular longevity and development of age-related myeloid stem-cell disorders like acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). A reduced SIRT7-expression in aged murine hematopoietic stem cells (HSC) resulted in reduced longevity and increased proliferation. In this study we investigated age-related changes of SIRT7-expression in healthy humans and relevant pathomechanisms in AML and CML. SIRT7-expression in leukocytes of healthy people decreased in an age-dependent manner. Low SIRT7 mRNA levels were also detected in AML and CML patients. With positive treatment response, SIRT7-expression increased, but showed reduction when patients progressed or relapsed. Pharmacologic inhibition of driver mutations in AML (FLT3-ITD) or CML (BCR-ABL) also restored SIRT7 levels in cell lines and patient samples. Furthermore, SIRT7-expression increased with time during PMA-mediated monocyte differentiation of THP-1 cells. SIRT7-overexpression in THP-1 cells resulted in increased expression of differentiation markers. BCR-ABL, FLT3-ITD, and differentiation-associated SIRT7-expression in general were positively regulated by C/EBPα, -ß, and -ε binding to two different C/EBP-binding sites within the SIRT7 promoter. SIRT7 is important in human hematopoietic cell aging and longevity. It might act as tumor suppressor and could potentially serve as general biomarker for monitoring treatment response in myeloid stem-cell disorders.
Assuntos
Envelhecimento Saudável , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Leucemia Mieloide Aguda/etiologia , Sirtuínas/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Mutação , Sirtuínas/genética , Células THP-1 , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Mammalian sirtuins (SIRTs 1-7) are a family of NAD+-dependent deacetylases with distinct subcellular localization and biological functions that regulate various important cellular processes. Among these, SIRTs -3, -4 and -5 are located in the mitochondria and have been implicated in caloric restriction, oxidative stress, aging and various human diseases. Emerging evidence has found dysregulation of mitochondrial sirtuins in multiple dermatological conditions, including responses to ultraviolet radiation (UVR), suggesting their importance in maintaining skin health. In this review, we discuss the roles and implications of mitochondrial sirtuins in cutaneous cellular processes, and their emerging potential as a target for the management of skin diseases, including skin cancer. Among mitochondrial sirtuins, SIRT3 is the most studied and linked to multiple skin conditions and diseases (keratinocyte differentiation, wound healing, chronological aging, UVR and ozone response, systemic sclerosis, melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). SIRT4 has been connected to keratinocyte differentiation, chronological aging, UVR response, alopecia, BCC and SCC. Further, SIRT5 has been associated with keratinocyte differentiation, melanoma, BCC and SCC. Overall, while there is compelling evidence for the involvement of mitochondrial sirtuins in skin, additional detailed studies are needed to understand their exact roles in skin and skin cancers.
Assuntos
Mitocôndrias/metabolismo , Sirtuínas/metabolismo , Neoplasias Cutâneas/metabolismo , Pele/metabolismo , Diferenciação Celular/fisiologia , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Ozônio/toxicidade , Sirtuínas/fisiologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Envelhecimento da Pele , Neoplasias Cutâneas/patologia , Raios UltravioletaRESUMO
Fusaric acid (FA) is a ubiquitous yet neglected mycotoxin. The toxicity of FA is associated with mitochondrial dysfunction and oxidative stress. Sirtuins (SIRTs) are key mediators of cell stress responses through deacetylation of antioxidant, mitochondrial maintenance and energy metabolism proteins. Dietary bioactive compounds have profound effects on SIRT activity, however little is known regarding common foodborne toxins and SIRTs. In this study the interaction of FA with mitochondrial SIRTs - SIRT3 and SIRT5, were firstly studied by molecular docking. Thereafter we substantiated the in silico findings by investigating the effect of FA on expression profiles of SIRT3 and SIRT5, and transcriptional and post-transcriptional regulators, PGC-1α and miRNA-30c using western blots and qPCR in vitro. FA was predicted to bind to the active site of SIRT3 and SIRT5 having implications for biological activity. Furthermore, protein expression of SIRT3 and SIRT5 was down-regulated despite elevated mRNA levels. Further experimentation revealed post-transcriptional regulation of both SIRTs as evidenced by elevated miRNA-30c despite induction of PGC-1α. This study highlights the potential of a diet contaminated with FA to dysregulate mitochondrial specific proteins that can lead to initiation and progression of sirtuin related diseases including cancer and insulin resistance.
Assuntos
Ácido Fusárico/toxicidade , Mitocôndrias/efeitos dos fármacos , Micotoxinas/toxicidade , Sirtuínas/efeitos dos fármacos , Animais , Carcinoma Hepatocelular , Células Hep G2 , Humanos , Neoplasias Hepáticas , Simulação de Acoplamento Molecular , Estresse Oxidativo , Sirtuínas/fisiologiaRESUMO
BACKGROUND: Neuronal apoptosis plays a critical event in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). This study investigated the roles of Tauroursodeoxycholic acid (TUDCA) in attenuate neuronal apoptosis and underlying mechanisms after SAH. METHODS: Sprague-Dawley rats were subjected to model of SAH and TUDCA was administered via the internal carotid injection. Small interfering RNA (siRNA) for TGR5 were administered through intracerebroventricular injection 48 h before SAH. Neurological scores, brain water content, Western blot, TUNEL staining and immunofluorescence staining were evaluated. RESULTS: TUDCA alleviated brain water content and improved neurological scores at 24 h and 72 h after SAH. TUDCA administration prevented the reduction of SIRT3 and BCL-2 expressions, as well as the increase of BAX and cleaved caspase-3.Endogenous TGR5 expression were upregulated after SAH and treatment with TGR5 siRNA exacerbated neurological outcomes after SAH and the protective effects of TUDCA at 24 h after SAH were also abolished by TGR5 siRNA. CONCLUSIONS: Our findings demonstrate that TUDCA could attenuated neuronal apoptosis and improve neurological functions through TGR5/ SIRT3 signaling pathway after SAH. TUDCA may be an attractive candidate for anti-apoptosis treatment in SAH.
Assuntos
Animais , Masculino , Ratos , Hemorragia Subaracnóidea/tratamento farmacológico , Ácido Tauroquenodesoxicólico/uso terapêutico , Apoptose , Sirtuínas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Neurônios/patologia , Ratos Sprague-Dawley , Neurônios/efeitos dos fármacosRESUMO
Tumor cells undergo a metabolic shift in order to adapt to the altered microenvironment, although the underlying mechanisms have not been fully explored. HnRNP A1 is involved in the alternative splicing of the pyruvate kinase (PK) mRNA, allowing tumor cells to specifically produce the PKM2 isoform. We found that the acetylation status of hnRNP A1 in hepatocellular carcinoma (HCC) cells was dependent on glucose availability, which affected the PKM2-dependent glycolytic pathway. In the glucose-starved HCC cells, SIRT1 and SIRT6, members of deacetylase sirtuin family, were highly expressed and deacetylated hnRNP A1 after direct binding. We identified four lysine residues in hnRNP A1 that were deacetylated by SIRT1 and SIRT6, resulting in significant inhibition of glycolysis in HCC cells. Deacetylated hnRNP A1 reduced PKM2 and increased PKM1 alternative splicing in HCC cells under normal glucose conditions, thereby reducing the metabolic activity of PK and the non-metabolic PKM2-ß-catenin signaling pathway. However, under glucose starvation, the low levels of acetylated hnRNP A1 reduced HCC cell metabolism to adapt to the nutrient deficiency. Taken together, sirtuin-mediated hnRNP A1 deacetylation inhibits HCC cell proliferation and tumorigenesis in a PKM2-dependent manner. These findings point to the metabolic reprogramming induced by hnRNP A1 acetylation in order to adapt to the nutritional status of the tumor microenvironment.
Assuntos
Acetiltransferases/metabolismo , Carcinoma Hepatocelular/patologia , Glicólise , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Neoplasias Hepáticas/patologia , Sirtuína 1/fisiologia , Sirtuínas/fisiologia , Células A549 , Acetilação , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Glicólise/genética , Células HCT116 , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Pessoa de Meia-Idade , Prognóstico , Processamento de Proteína Pós-Traducional/genética , Hormônios Tireóideos/fisiologia , Microambiente Tumoral/genética , Proteínas de Ligação a Hormônio da TireoideRESUMO
SIRT7 is an NAD+-dependent histone/non-histone deacetylase, which is highly expressed in different types of cancer including thyroid cancer; however, its biological function in thyroid cancer is still undiscovered. In this study, we found that SIRT7 expression was elevated in papillary thyroid cancers (PTCs), and demonstrated that SIRT7 knockdown dramatically inhibited the proliferation, colony formation, migration and invasion of thyroid cancer cells, and induced thyroid cancer cell cycle arrest and apoptosis. Conversely, SIRT7 re-expression markedly enhanced thyroid cancer cell growth, invasiveness and tumorigenic potential in nude mice. Further studies revealed that SIRT7 exerted an oncogenic function in thyroid tumorigenesis by phosphorylation of Akt and p70S6K1. Mechanistically, SIRT7 binds to the promoter of deleted in breast cancer-1 (DBC1), an endogenous inhibitor of SIRT1, and represses its transcription via deacetylation of H3K18Ac. This results in enhanced interactions between SIRT1 and Akt or p70S6K1, thereby promoting deacetylation and subsequent phosphorylation of Akt and p70S6K1 through a SIRT1-dependent manner. Altogether, our results show that DBC1 is a downstream target of SIRT7, and first uncover that SIRT7 promotes thyroid tumorigenesis through phosphorylation and activation of Akt and p70S6K1 via the modulation of DBC1/SIRT1 axis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Carcinoma Papilar/metabolismo , Proteínas de Neoplasias/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirtuína 1/metabolismo , Sirtuínas/fisiologia , Neoplasias da Glândula Tireoide/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Carcinoma Papilar/patologia , Ciclo Celular , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Transformação Celular Neoplásica , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Camundongos , Camundongos Nus , Fosforilação , Ligação Proteica , Mapeamento de Interação de Proteínas , Transdução de Sinais , Neoplasias da Glândula Tireoide/patologia , Ensaio Tumoral de Célula-TroncoRESUMO
In recent years, the key role of sirtuins in the regulation of the most important cellular processes has been established. Sirtuins are involved in histone deacetylation, regulation of fat and glucose metabolism. Violations of their synthesis and secretion can induce carcinogenesis, aging and cell death. The wide range of processes in which sirtuins are involved indicates their possible role in the pathogenesis of many diseases including metabolic syndrome, neurodegenerative diseases, inflammation associated diseases and tumor growth. All of these diseases are associated with aging. In this article, we analyze the existing data on sirtuins and their role in the pathogenesis of aging, as well as their possible verification as markers for the diagnosis of age-related diseases and as targets of geriatric therapy and prevention.
Assuntos
Envelhecimento , Sirtuínas/fisiologia , Humanos , Inflamação/patologia , Síndrome Metabólica/patologia , Neoplasias/patologia , Doenças Neurodegenerativas/patologiaRESUMO
Rolipram is a selective phosphodiesterase 4 (PDE4) inhibitor that exerts a variety of effects, including anti-inflammatory, immunosuppressive, and anti-tumor effects. The aim of this study was to investigate the effect of rolipram on metabolic disorder and its underlying mechanisms. Metabolic disorder was induced in 8-week-old wild type BABL/c mice by administration of D-galactose for 4 weeks. Simultaneously the mice were administered vehicle or rolipram. Alternatively, beginning at 3 or 21 months, the mice were administered db-cAMP for 3 months, with or without a high-fat-diet (HFD) to induce metabolic disorder. In both models, better metabolic function was observed in rolipram-treated mice. Rolipram reduced adipose deposition and inflammation and reserved metabolic disorder. Treatment with rolipram increased the AMPK phosphorylation and SIRT6 levels in the liver and kidney while reducing NF-κB acetylation. In vitro, these effects were blocked by suppression of SIRT6 expression using specific siRNA. Increased cAMP levels reduced excessive adipose deposition, and improved adipose distribution in presenile mice. These findings provide a promising strategy for the treatment of aging-related metabolic dysfunctions and suggest that selective PDE4 inhibitors may be useful agents for the treatment of aging-related metabolic diseases.