Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation / 医学前沿

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD+/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.

Therapeutic potential of targeting SIRT1 for the treatment of Alzheimer's disease / 生理学报

Silent information regulator 1 (SIRT1) is one of the seven mammalian proteins of the sirtuin family of NAD+-dependent deacetylases. SIRT1 plays a pivotal role in neuroprotection and ongoing research has uncovered a mechanism by which SIRT1 may exert a neuroprotective effect on Alzheimer's disease (AD). Growing evidence demonstrates that SIRT1 regulates many pathological processes including amyloid-β precursor protein (APP) processing, neuroinflammation, neurodegeneration, and mitochondrial dysfunction. SIRT1 has recently received enormous attention, and pharmacological or transgenic approaches to activate the sirtuin pathway have shown promising results in the experimental models of AD. In the present review, we delineate the role of SIRT1 in AD from a disease-centered perspective and provides an up-to-date overview of the SIRT1 modulators and their potential as effective therapeutics in AD.

Immunofluorescent distribution of SIRT1, SIRT2, SIRT6 protein in the skin of SKH1 mouse after ultraviolet B irradiation for 10 Weeks / Distribución inmunofluorescente de la proteína SIRT1, SIRT2, SIRT6 en la piel del ratón SKH1 después de la irradiación ultravioleta B durante 10 semanas

SUMMARY: The skin, located on the outermost part of the body, is always exposed to external stimuli such as sunlight. The exposure of skin to ultraviolet B (UVB) radiation from sunlight is known to be a major environmental factor in inducing photoaging. After exposure to UVB, an increase in reactive oxygen species can affect the expression and activity of many critical proteins depending on the duration and dose of the UVB radiation. Mammalian sirtuins (SIRTs), which are nicotinamide dinucleotide-dependent protein deacetylases, are well known for playing a role in cellular longevity. However, little is known about SIRT protein alterations in keratinocytes upon UVB irradiation according to SIRT subtypes. Therefore, in this study, the distribution of non-mitochondrial SIRT1, SIRT2, and SIRT6 proteins was investigated by immunofluorescence (IF) staining of the skin of SKH-1 mice (n=12) after UVB irradiation for 10 weeks. After UVB irradiation for 10 weeks, the IF of both SIRT1 and SIRT6 was significantly increased in the UVB-irradiated mice group (UG), but the difference in SIRT2 IF was not statistically significant between the control group (CG) and the UG. The translocation of both SIRT1 and SIRT6 IF from the nucleus to the cytoplasm of keratinocytes was observed in the upper epidermis of the UG, whereas SIRT2 IF was localized in the cytoplasm of keratinocytes in the epidermis in both the CG and the UG. The translocation of SIRT1 and SIRT6 IF from the nucleus to the cytoplasm of keratinocytes may account for the physiologically protective action of keratinocytes against UVB irradiation. However, the exact role of SIRT1 and SIRT6 translocation in keratinocytes, where SIRT1 and SIRT6 shuttle from the nucleus to the cytoplasm, is not well known. Therefore, further studies are needed to understand the molecular mechanisms of SIRT1 and SIRT6 translocation in keratinocytes upon UVB irradiation.

La piel, situada en la parte más externa del cuerpo, está siempre expuesta a estímulos externos como la luz solar. Se sabe que la exposición de la piel a la radiación ultravioleta B (UVB) de la luz solar es un factor ambiental importante en la inducción del fotoenvejecimiento. Después de la exposición a los rayos UVB, un aumento en las especies reactivas de oxígeno puede afectar la expresión y la actividad de muchas proteínas críticas según la duración y la dosis de la radiación UVB. Las sirtuinas de mamíferos (SIRT), que son proteínas desacetilasas dependientes de dinucleótidos de nicotinamida, son bien conocidas por desempeñar un papel en la longevidad celular. Sin embargo, se sabe poco sobre las alteraciones de la proteína SIRT en los queratinocitos tras la irradiación UVB según los subtipos de SIRT. Por lo tanto, en este estudio, se investigó la distribución de las proteínas SIRT1, SIRT2 y SIRT6 no mitocondriales mediante tinción de inmunofluorescencia (IF) de la piel de ratones SKH-1 (n = 12), después de la irradiación con UVB durante 10 semanas. Posterior a la irradiación, el IF de SIRT1 y SIRT6 aumentaron significativamente en el grupo de ratones irradiados con UVB (UG), pero la diferencia en SIRT2 IF no fue estadísticamente significativa entre el grupo control (CG) y el UG. La translocación de SIRT1 y SIRT6 IF desde el núcleo al citoplasma de los queratinocitos se observó en la epidermis superior de la UG, mientras que SIRT2 IF se localizó en el citoplasma de los queratinocitos en la epidermis, tanto en el GC, como en la UG. La translocación de SIRT1 y SIRT6 IF del núcleo al citoplasma de los queratinocitos puede explicar la acción protectora fisiológica de estos contra la radiación UVB. Sin embargo, el papel exacto de la translocación de SIRT1 y SIRT6 en los queratinocitos, donde SIRT1 y SIRT6 se trasladan desde el núcleo al citoplasma, no se conoce bien. Por lo tanto, se necesitan más estudios para comprender los mecanismos moleculares de la translocación SIRT1 y SIRT6 en los queratinocitos tras la irradiación UVB.

miR-92a-3p promotes ox-LDL induced-apoptosis in HUVECs via targeting SIRT6 and activating MAPK signaling pathway

Atherosclerosis could be induced by multiple factors, including hypertension, hyperlipidemia, and smoking, and its pathogenesis has not been fully elucidated. MicroRNAs have been shown to possess great anti-atherosclerotic potential, but the precise function of miR-92a-3p in atherosclerosis and its potential molecular mechanism have not been well clarified. Flow cytometry assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay were performed to evaluate effects of oxidized low-density lipoprotein (ox-LDL) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs), respectively. Malondialdehyde and superoxide dismutase levels in cell lysate were assessed with biochemical kits. The expression levels of miR-92a-3p and Sirtuin6 (SIRT6) in HUVECs exposed to ox-LDL were estimated by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the protein levels of SIRT6, c-Jun N-terminal kinase (JNK), phosphorylation JNK (p-JNK), p38 mitogen activated protein kinase (p38 MAPK), and phosphorylation p38 MAPK (p-p38 MAPK) were measured by western blot assays. The relationship between miR-92a-3p and SIRT6 was confirmed by dual-luciferase reporter assay. Ox-LDL induced apoptosis and oxidative stress in HUVECs in concentration- and time-dependent manners. Conversely, miR-92a-3p silencing inhibited apoptosis and SIRT6 expression in HUVECs. The overexpression of miR-92a-3p enhanced apoptosis and phosphorylation levels of JNK and p38 MAPK as well as inhibited proliferation in ox-LDL-induced HUVECs. In addition, SIRT6 was a target of miR-92a-3p. miR-92a-3p negatively regulated SIRT6 expression in ox-LDL-induced HUVECs to activate MAPK signaling pathway in vitro. In summary, miR-92a-3p promoted HUVECs apoptosis and suppressed proliferation in ox-LDL-induced HUVECs by targeting SIRT6 expression and activating MAPK signaling pathway.

Progress on mitochondrial silence information regulator family in epilepsy / 浙江大学学报·医学版

SIRT3, SIRT4 and SIRT5 are located in mitochondria and also known as mitochondrial sirtuins. They play important roles in regulating many cellular functions including cell survival, cell cycle or apoptosis, DNA repair and metabolism. Mitochondrial sirtuins are involved in the protection of mitochondrial integrity and energy metabolism under stress regulating the expression of neurotransmitter receptors, neurotrophins, extracellular matrix proteins and various transcription factors, thus involved in epileptogenesis triggered by both genetic or acquired factors. Here we review research progress on the actions of mitochondrial sirtuin in epilepsy; and discuss the challenges and perspectives of mitochondrial sirtuin as a potential therapeutic target for epilepsy.

Acute cerebral ischemia-induced down-regulation of Sirt3 protein expression contributes to neuronal injury via damaging mitochondrial function / 生理学报

This study was aimed to determine the effect of acute cerebral ischemia on the protein expression level of silent mating type information regulator 2 homolog 3 (Sirt3) in the neurons and clarify the pathological role of Sirt3 in acute cerebral ischemia. The mice with middle cerebral artery occlusion (MCAO) and primary cultured rat hippocampal neurons with oxygen glucose deprivation (OGD) were used as acute cerebral ischemia models in vivo and in vitro, respectively. Sirt3 overexpression was induced in rat hippocampal neurons by lentivirus transfection. Western blot was utilized to measure the changes in Sirt3 protein expression level. CCK8 assay was used to detect cell viability. Immunofluorescent staining was used to detect mitochondrial function. Transmission electron microscope was used to detect mitochondrial autophagy. The results showed that, compared with the normoxia group, hippocampal neurons from OGD1 h/reoxygenation 2 h (R2 h) and OGD1 h/R12 h groups exhibited down-regulated Sirt3 protein expression levels. Compared with contralateral normal brain tissue, the ipsilateral penumbra region from MCAO1 h/reperfusion 24 h (R24 h) and MCAO1 h/R72 h groups exhibited down-regulated Sirt3 protein expression levels, while there was no significant difference between the Sirt3 protein levels on both sides of sham group. OGD1 h/R12 h treatment damaged mitochondrial function, activated mitochondrial autophagy and reduced cell viability in hippocampal neurons, whereas Sirt3 over-expression attenuated the above damage effects of OGD1 h/R12 h treatment. These results suggest that acute cerebral ischemia results in a decrease in Sirt3 protein level. Sirt3 overexpression can alleviate acute cerebral ischemia-induced neural injuries by improving the mitochondrial function. The current study sheds light on a novel strategy against neural injuries caused by acute cerebral ischemia.

The role of SIRT6 in nonalcoholic steatohepatitis / 生理学报

SIRT6, a member of the silencing information regulatory protein family, is a nicotinamide adenine dinucleotide-dependent histone deacetylase and an ADP-ribose transferase enzyme. It plays an important role in fundamental physiological and pathological processes, including lipid metabolism, inflammation, oxidative stress and fibrosis, and is considered as a potential therapeutic target for metabolic syndrome. SIRT6 knockout mice displayed severe fatty liver, and the expression of SIRT6 in the liver of nonalcoholic steatohepatitis (NASH) mice was significantly lower than that of normal mice. Overexpression of SIRT6 significantly ameliorated NASH-induced liver damage. It is suggested that SIRT6 may play a key role in protecting against NASH. In this paper, we review the important regulatory functions of SIRT6 in the occurrence and development of NASH.

Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats

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.

Mitochondrial Mechanisms in Diabetic Cardiomyopathy

Mitochondrial medicine is increasingly discussed as a promising therapeutic approach, given that mitochondrial defects are thought to contribute to many prevalent diseases and their complications. In individuals with diabetes mellitus (DM), defects in mitochondrial structure and function occur in many organs throughout the body, contributing both to the pathogenesis of DM and complications of DM. Diabetic cardiomyopathy (DbCM) is increasingly recognized as an underlying cause of increased heart failure in DM, and several mitochondrial mechanisms have been proposed to contribute to the development of DbCM. Well established mechanisms include myocardial energy depletion due to impaired adenosine triphosphate (ATP) synthesis and mitochondrial uncoupling, and increased mitochondrial oxidative stress. A variety of upstream mechanisms of impaired ATP regeneration and increased mitochondrial reactive oxygen species have been proposed, and recent studies now also suggest alterations in mitochondrial dynamics and autophagy, impaired mitochondrial Ca²⁺ uptake, decreased cardiac adiponectin action, increased O-GlcNAcylation, and impaired activity of sirtuins to contribute to mitochondrial defects in DbCM, among others. In the current review, we present and discuss the evidence that underlies both established and recently proposed mechanisms that are thought to contribute to mitochondrial dysfunction in DbCM.

Serum Sirtuin 1, 3 and 6 Levels in Acute Myocardial Infarction Patients / Níveis de Sirtuína 1, 3 e 6 em Pacientes com Infarto Agudo do Miocárdio

Abstract Background: Sirtuins may act in many cellular processes like apoptosis, DNA repair and lipid/glucose metabolism. Experimental studies suggested some sirtuin types may have protective effects against endothelial dysfunction, atherosclerosis, cardiac hypertrophy and reperfusion injury. Data about sirtuins in acute myocardial infarction (AMI) patients are scarce. Objectives: To investigate temporal changes of serum sirtuin 1,3 and 6 levels in AMI patients; to compare the serum sirtuin 1,3 and 6 levels between AMI patients and control subjects; and to investigate the association of serum sirtuin 1,3 and 6 levels with prognostic markers of AMI. Methods: Forty patients with AMI and 40 patients with normal coronary arteries were included. Left ventricular ejection fraction (LVEF), serum proBNP, CRP, sirtuin1, sirtuin 3 and sirtuin 6 levels were processed. Peak troponin T levels, GRACE score, first day / second day sirtuin levels were recorded of AMI patients. A p value < 0.05 was considered statistically significant. Results: Serum sirtuin 1,3 and 6 levels in AMI patients were similar to those in normal coronary patients. No temporal change in serum sirtuin 1,3 and 6 levels were found in AMI course. No correlation was evident between the sirtuin levels and the following parameters: proBNP, CRP, peak troponin and LVEF. Baseline sirtuin 1 and 6 levels were positively correlated with reperfusion duration. Baseline sirtuin 3 levels were negatively correlated with GRACE score. Conclusion: Serum sirtuin 1,3 and 6 levels in AMI patients were similar to those in normal coronary patients. This study does not represent evidence of the possible protective effects of sirtuin1, 3 and 6 in AMI patients.

Resumo Fundamento: As sirtuínas podem atuar em muitos processos celulares, como a apoptose, reparo de DNA e metabolismo de lipídios e de glicose. Estudos experimentais sugeriram que alguns tipos de sirtuínas possam ter efeitos protetores contra disfunção endotelial, aterosclerose, hipertrofia cardíaca e lesão decorrente de reperfusão. Dados sobre as sirtuínas em pacientes com infarto agudo do miocárdio (IAM) são escassos. Objetivos: Avaliar as mudanças temporais dos níveis de sirtuína 1, 3 e 6 entre pacientes com IAM e indivíduos controles; investigar a associação entre os níveis de sirtuína 1, 3 e 6 e marcadores prognósticos de IAM. Métodos: Quarenta pacientes com IAM e 40 pacientes com artérias coronárias normais foram incluídos. Foram avaliados fração de ejeção do ventrículo esquerdo (FEVE), concentrações séricas de pró-BNP, proteína C-reativa, sirtuína 1, sirtuína 3 e de sirtuína 6. Pico de troponina T, escore GRACE, concentrações de sirtuínas no primeiro e no segundo dia foram registrados dos pacientes com IAM. Um valor de p<0,05 foi considerado estatisticamente significativo. Resultados: Os níveis de sirtuína 1, 3 e 6 em pacientes com IAM foram similares aos de pacientes com coronária normal. Não foram observadas mudanças temporais nos níveis de sirtuína 1, 3 e 6 no curso do IAM. Nenhuma correlação evidente foi observada dos níveis de sirtuína com os seguintes parâmetros: pró-BNP, proteína C-reativa, pico de troponina e FEVE. Níveis basais de sirtuína 1 e 6 apresentaram correlação positiva com a duração da reperfusão. Os níveis basais de sirtuína 3 correlacionaram-se negativamente com o escore GRACE. Conclusão: Os níveis de sirtuína 1, 3 e 6 em pacientes com IAM foram similares aos de pacientes com artérias coronárias normais. Este estudo não apresenta evidência de possíveis efeitos protetores da sirtuína 1, 3 e 6 em pacientes com IAM.

Emodin exerts protective effect against palmitic acid-induced endoplasmic reticulum stress in HepG2 cells / 한국영양학회지

PURPOSE: Protein overloading in the endoplasmic reticulum (ER) leads to endoplasmic reticulum stress, which exacerbates various disease conditions. Emodin, an anthraquinone compound, is known to have several health benefits. The effect of emodin against palmitic acid (PA) - induced ER stress in HepG2 cells was investigated. METHODS: HepG2 cells were treated with varying concentrations of palmitic acid to determine the working concentration that induced ER stress. ER stress associated genes such as ATF4, XBP1s, CHOP and GRP78 were checked using RT- PCR. In addition, the expression levels of unfolded protein response (UPR) associated proteins such as IRE1α, eIF2α and CHOP were checked using immunoblotting to confirm the induction of ER stress. The effect of emodin on ER stress was analyzed by treating HepG2 cells with 750 µM palmitic acid and varying concentrations of emodin, then analyzing the expression of UPR associated genes. RESULTS: It was evident from the mRNA and protein expression results that palmitic acid significantly increased the expression of UPR associated genes and thereby induced ER stress. Subsequent treatment with emodin reduced the mRNA expression of ATF4, GRP78, and XBP1s. Furthermore, the protein levels of p-IRE1α, p-elF2α and CHOP were also reduced by the treatment of emodin. Analysis of sirtuin mRNA expression showed that emodin increased the levels of SIRT4 and SIRT7, indicating a possible role in decreasing the expression of UPR-related genes. CONCLUSION: Altogether, the results suggest that emodin could exert a protective effect against fatty acid-induced ER stress and could be an agent for the management of various ER stress related diseases.

Effects of saikosaponin b_2 on inflammation and energy metabolism in mice with acute liver injury induced by LPS/GalN / 中国中药杂志

To study the effects of saikosaponin b2( SS-b2) on inflammatory factors and energy metabolism against lipopolysaccharide/galactosamine( LPS/Gal N) induced acute liver injury in mice. Mice were randomly divided into normal group( equal amount of normal saline),model group( 100 g·kg~(-1) LPS and 400 mg·kg~(-1) Gal N),low,medium,high dose group of SS-b2( SS-b25,10,20 mg·kg~(-1)·d-1) and positive control group( dexamethasone,10 mg·kg~(-1)). All of the groups except for the normal group were treated with LPS/Gal N though intraperitoneally injection to establish the acute liver injury model. The organ indexes were calculated. The levels of serum transaminases( ALT and AST) and the activities of ATPase( Na+-K+-ATPase,Ca2+-Mg2+-ATPase) in liver were detected. The activity of tumor necrosis factor-α( TNF-α),interleukin-1β( IL-1β) and interleukin-6( IL-6) were determined by the enzyme-linked immunosorbent assay( ELISA). The contents of lactate dehydrogenase( LDH) in liver were determined by micro-enzyme method. HE staining was used to observe the histopathological changes of the liver. Histochemical method was used to investigate the protein expression of liver lactate dehydrogenase-A( LDH-A). The protein expressions of Sirt-6 and NF-κB in the liver were detected by Western blot. According to the results,compared with the model group,there were significant changes in organ indexes in the high-dose group of SS-b2( P<0. 05). The level of ALT,AST,TNF-α,IL-1β,IL-6 and the activities of LDH in serum of mice with liver injury were significantly reduced in the medium and high dose groups of SS-b2( P<0. 01). With the increase of the concentration of SS-b2,the range of hepatic lesions and the damage in mice decreased. The activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in liver of mice were significantly enhanced in each dose group( P<0. 01). The expression of NF-κB in liver tissues was significantly down-regulated in the medium and high dose group( P<0. 01). Meanwhile,the expression of Sirt-6 protein in the liver of mice with acute liver injury was significantly increased in each dose group( P<0. 01).In summary,SS-b2 has a significant protective effect on LPS/Gal N-induced acute liver injury in mice,which may be related to the down-regulation of NF-κB protein expression and up-regulation of Sirt-6 protein expression to improve inflammatory injury and energy metabolism.

Supplementation with psyllium seed husk reduces myocardial damage in a rat model of ischemia/reperfusion

BACKGROUND/OBJECTIVES: Myocardial infarction (MI) is caused by extensive myocardial damage attributed to the occlusion of coronary arteries. Our previous study in a rat model of ischemia/reperfusion (I/R) demonstrated that administration of arabinoxylan (AX), comprising arabinose and xylose, protects against myocardial injury. In this study, we undertook to investigate whether psyllium seed husk (PSH), a safe dietary fiber containing a high level of AX (> 50%), also imparts protection against myocardial injury in the same rat model. MATERIALS/METHODS: Rats were fed diets supplemented with PSH (1, 10, or 100 mg/kg/d) for 3 d. The rats were then subjected to 30 min ischemia through ligation of the left anterior descending coronary artery, followed by 3 h reperfusion through release of the ligation. The hearts were harvested and cut into four slices. To assess infarct size (IS), an index representing heart damage, the slices were stained with 2,3,5-triphenyltetrazolium chloride (TTC). To elucidate underlying mechanisms, Western blotting was performed for the slices. RESULTS: Supplementation with 10 or 100 mg/kg/d of PSH significantly reduces the IS. PSH supplementation (100 mg/kg/d) tends to reduce caspase-3 generation and increase BCL-2/BAX ratio. PSH supplementation also upregulates the expression of nuclear factor erythroid 2-related factor 2 (NRF2), and its target genes including antioxidant enzymes such as glutathione S-transferase mu 2 (GSTM2) and superoxide dismutase 2 (SOD2). PSH supplementation upregulates some sirtuins (NAD+-dependent deacetylases) including SIRT5 (a mitochondrial sirtuin) and SIRT6 and SIRT7 (nuclear sirtuins). Finally, PSH supplementation upregulates the expression of protein kinase A (PKA), and increases phosphorylated cAMP response element-binding protein (CREB) (pCREB), a target protein of PKA. CONCLUSIONS: The results from this study indicate that PSH consumption reduces myocardial I/R injury in rats by inhibiting the apoptotic cascades through modulation of gene expression of several genes located upstream of apoptosis. Therefore, we believe that PSH can be developed as a functional food that would be beneficial in the prevention of MI.

Progress in roles and mechanisms of deacetylase SIRT7 / 生物工程学报

As a member of the Sirtuins family in mammals, SIRT7 locates in nucleus and is a highly specific H3K18Ac (acetylated lysine 18 of histone H3) deacetylase. Recent studies showed that SIRT7 could participate in the ribosomal RNA transcription, cell metabolism, cell stress and DNA damage repair through various signaling pathways. In addition, SIRT7 is also closely related with aging, heart disease and fatty liver. In particular, SIRT7 plays important roles in the regulation of initiation and development of various tumors, such as liver cancer, gastric cancer, breast cancer, bladder cancer, colorectal cancer, and head/neck squamous cell carcinoma. This review describes the cellular and molecular functions of SIRT7, and systematically summarizes recent progress of SIRT7 in human disease.

Nicotinamide riboside regulates inflammation and mitochondrial markers in AML12 hepatocytes

BACKGROUND/OBJECTIVES: The NAD+ precursor nicotinamide riboside (NR) is a type of vitamin B3 found in cow's milk and yeast-containing food products such as beer. Recent studies suggested that NR prevents hearing loss, high-fat diet-induced obesity, Alzheimer's disease, and mitochondrial myopathy. The objective of this study was to investigate the effects of NR on inflammation and mitochondrial biogenesis in AML12 mouse hepatocytes. MATERIALS/METHODS: A subset of hepatocytes was treated with palmitic acid (PA; 250 µM) for 48 h to induce hepatocyte steatosis. The hepatocytes were treated with NR (10 µM and 10 mM) for 24 h with and without PA. The cell viability and the levels of sirtuins, inflammatory markers, and mitochondrial markers were analyzed. RESULTS: Cytotoxicity of NR was examined by PrestoBlue assay. Exposure to NR had no effect on cell viability or morphology. Gene expression of sirtuin 1 (Sirt1) and Sirt3 was significantly upregulated by NR in PA-treated hepatocytes. However, Sirt1 activities were increased in hepatocytes treated with low-dose NR. Hepatic pro-inflammatory markers including tumor necrosis factor-alpha and interleukin-6 were decreased in NR-treated cells. NR upregulated anti-inflammatory molecule adiponectin, and, tended to down-regulate hepatokine fetuin-A in PA-treated hepatocytes, suggesting its inverse regulation on these cytokines. NR increased levels of mitochondrial markers including peroxisome proliferator-activated receptor γ coactivator-1α, carnitine palmitoyltransferase 1, uncoupling protein 2, transcription factor A, mitochondrial and mitochondrial DNA in PA-treated hepatocytes. CONCLUSIONS: These data demonstrated that NR attenuated hepatic inflammation and increased levels of mitochondrial markers in hepatocytes.

Rejuvenating Aged Hematopoietic Stem Cells Through Improvement of Mitochondrial Function

Mitochondria are the powerhouses of the cell as well as the primary site of hematopoiesis, which also occurs in the cytoplasm. Hematopoietic stem cells (HSCs) are characterized by a very high turnover rate, and are thus considered to be relatively free from the age-related insults generated by mitochondria. However, HSCs are also subject to these age-related insults, including the incidence of myeloid proliferative diseases, marrow failure, hematopoietic neoplasms, and deterioration of the adaptive human immune system. Recently, NAD⁺ dietary supplements, known as niacin or vitamin B₃, including tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD⁺ precursor nicotinamide riboside, have been shown to play a role in restoring adult stem cell function through the amelioration of mitochondrial dysfunction. This insight motivated a study that focused on reversing aging-related cellular dysfunction in adult mouse muscle stem cells by supplementing their diet with nicotinamide riboside. The remedial effect of nicotinamide riboside enhanced mitochondrial function in these muscle stem cells in a SIRT1-dependent manner, affecting cellular respiration, membrane potential, and production of ATP. Accordingly, numerous studies have demonstrated that sirtuins, under nuclear/mitochondrial control, have age-specific effects in determining HSC phenotypes. Based on the evidence accumulated thus far, we propose a clinical intervention for the restoration of aged HSC function by improving mitochondrial function through NAD⁺ precursor supplementation.

Prognostic Significance of Sirtuins Expression in Papillary Thyroid Carcinoma

BACKGROUND AND OBJECTIVES: Sirtuins (SIRTs) play important roles in cellular and organismal homeostasis. They have distinct gene expression patterns in various cancers; however, the relationship between SIRT expression and the progression of thyroid cancer is unclear. We investigated the expression of SIRTs in patients with papillary thyroid carcinoma (PTC) and their role as biomarkers for predicting the aggressiveness of this disease. MATERIALS AND METHODS: We used immunohistochemical staining to evaluate the expression of SIRT1 and SIRT3 in tumor specimens from 270 patients with PTC. We also evaluated the potential association between SIRT expression and diverse clinicopathological features. RESULTS: High SIRT1 expression was negatively correlated with lymphovascular invasion, central lymph node metastasis, and lateral lymph node metastasis. Multivariate analyses revealed that high SIRT1 expression was a negative independent risk factor for lateral lymph node metastasis. By contrast, high SIRT3 expression was positively correlated with locoregional recurrence. Interestingly, when patients were grouped by tumor SIRT expression patterns, the group with low SIRT1 expression and high SIRT3 expression was correlated with more aggressive cancer phenotypes including central lymph node metastasis and lateral lymph node metastasis. CONCLUSION: Our results suggest that SIRTs play dual roles in tumor progression, and the combination of decreased SIRT1 expression and increased SIRT3 expression is significantly associated with a poor prognosis in patients with PTC.

Luteolin and fisetin suppress oxidative stress by modulating sirtuins and forkhead box O3a expression under in vitro diabetic conditions

BACKGROUND/OBJECTIVE: Chronic hyperglycemia induces oxidative stress via accumulation of reactive oxygen species (ROS) and contributes to diabetic complications. Hyperglycemia induces mitochondrial superoxide anion production through the increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This study aimed to determine whether fisetin and luteolin treatments suppress the oxidative stress by modulating the expression of sirtuins (SIRTs) and forkhead box O3a (FOXO3a) under hyperglycemic conditions in human monocytes. MATERIALS/METHODS: Human monocytic cells (THP-1) were cultured under osmotic control (14.5 mmol/L mannitol), normoglycemic (NG, 5.5 mmol/L glucose), or hyperglycemic (HG, 20 mmol/L glucose) conditions, in the absence or presence of fisetin and luteolin for 48 h. To determine the effect of fisetin and luteolin treatments on high glucose-induced oxidative stress, western blotting and intracellular staining were performed. RESULTS: Hyperglycemic conditions increased the ROS production, as compared to normoglycemic condition. However, fisetin and luteolin treatments inhibited ROS production under hyperglycemia. To obtain further insight into ROS production in hyperglycemic conditions, evaluation of p47phox expression revealed that fisetin and luteolin treatments inhibited p47phox expression under hyperglycemic conditions. Conversely, the expression levels of SIRT1, SIRT3, SIRT6, and FOXO3a were decreased under high glucose conditions compared to normal glucose conditions, but exposure to fisetin and luteolin induced the expression of SIRT1, SIRT3, SIRT6, and FOXO3a. The above findings suggest that fisetin and luteolin inhibited high glucose-induced ROS production in monocytes through the activation of SIRTs and FOXO3a. CONCLUSIONS: The results of our study supports current researches that state fisetin and luteolin as potential agents for the development of novel strategies for diabetes.

Influência da terapêutica hormonal estrogênica e do treinamento de força sobre o tecido muscular esquelético de ratas senis / Influence of hormonal estrogenic therapy and strength training on skeletal muscle of senile rats

A diminuição das concentrações plasmáticas de estrógeno está intimamente relacionada com o aumento do estresse oxidativo e a diminuição da massa muscular em idosos. A terapêutica hormonal estrogênica (THE) e o treinamento de força (TF) apresentam resultados efetivos sobre a manutenção do tecido muscular em idosos. No entanto, os mecanismos responsáveis pelas melhorias induzias por ambas as intervenções são pouco elucidados. Nesse sentido, avaliamos os efeitos da THE, do TF e a associação sobre a manutenção do tecido muscular esquelético de ratas periestropausadas. Ratas Wistar (18 meses) foram distribuídas em: Grupo não treinado (NT-Veh), Grupo NT tratado com a THE (NT-E2), Grupo TF (TF-Veh) e Grupo TF-E2. Os animais receberam a THE (17ß estradiol; 2 x semana; 25 µg/kg/administração) e/ou praticaram TF (3 x semana; 80% sobrecarga) durante 16 semanas. A THE e o TF induzem benefícios ao tecido muscular esquelético de ratas periestropausadas, no entanto, por diferentes maneiras. Enquanto a THE induziu diminuição do estresse oxidativo muscular (Dihidroetidina), o TF resultou em melhoras significativas na função muscular, no sistema antioxidante muscular (Catalase) e na expressão de miRNAs (206, 146b e 133a). Já a interação das intervenções resultou em melhora no estado redox (Sirt1, Sirt3, PGC-1α, COXIV), na responsividade dos receptores estrogênicos (ERα, ERß e GPR30), e atividade de vias de sinalização do tecido muscular (IGF-1/Akt-1/mTOR). Além disso, as intervenções de maneira isolada ou em associação, levaram ao aumento no percentual de fibras glicolíticas e redução das oxidativas. Sugerimos que a aderências das intervenções (associadas ou não) possam minimizar/atenuar a perda da massa muscular observada em fases tardias durante o processo de envelhecimento(AU)

The decrease of estrogen (E2) circulating levels is strongly related to increased oxidative stress and the loss of muscle mass in elderly. The hormone replacement therapy (HRT) and strength training (ST) are the main effective interventions to prevent the loss of muscle mass, however, the mechanisms involved in interventions-induced benefits are not well elucidated. In this sense we evaluate the effect of HRT, ST and association on skeletal muscle maintenance of periestropaused rats. Female Wistar rats (18 months old) were randomly assigned into: non-exercised and non-treated group (NE-Veh), NE treated group (NE-E2), exercised and non-treated group (ST-Veh) and ST-E2 group. The animals received the HRT (17ß estradiol; 2 x week; 50 µg/kg/week) and/or performed ST (3 x week, 80% overload) for 16 weeks. The HRT and ST promoted beneficial effects on skeletal muscle of periestropaused rats, however, by different manners. While HRT treatment leaves the reduction of oxidative stress (Dihidroetidine), the ST resulted in significate improvement on skeletal muscle function, in skeletal muscle antioxidant system (Catalase) and in miRNAs expression (2016, 146b and 133a). Already, the association of interventions resulted in improvement of redox state (Sirt1, Sirt3, PGC-1α, COXIV), in estrogen receptor responsiveness (ERα, ERß and GPR30) and the activity of skeletal muscle signaling pathways (IGF-1/Akt-1/mTOR). In addition, the interventions, isolated or combinated, leaves an increase of the percentage of glycolytic fibers and reduced percentage of oxidative fibers. We suggest that the adherence to interventions (combinated or not) could minimize/attenuate the loss of skeletal muscle mass observed in later phases of aging process(AU)

Function of SIRT6 in tumor initiation and progression / 生物工程学报

As a member of the sirtuins family, also called Class III histone deacetylases (HDACs), SIRT6 has many catalytic enzyme activities and plays a pivotal role in biological processes including anti-aging, chromatin regulation, transcriptional control, glucose and lipid metabolism, and DNA damage repair. Recently, increasing evidences indicated that SIRT6 was related to initiation and development of tumors, such as hepatic cancer, lung cancer, breast cancer and genital system tumors. However, SIRT6 might play a dual role in tumorigenesis and progression. SIRT6 often acted as a tumor suppressor, but might play an oncogenic role. Based on our current study, we depicted the essential roles of SIRT6 in the initiation and progression of various tumors, and summarized its mode of actions, which might provide clues for cancer therapy.