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Objective:To evaluate the effect of sleep deprivation on the expression of sirtuin 6 (SIRT6) in the cerebellum of immature mice.Methods:Fifty SPF healthy male C57BL/6 mice, aged 4 weeks, weighing 14-16 g, were divided into 2 groups ( n=25 each) using a random number table method: control group (Con group) and sleep deprivation group (SD group). The chronic sleep deprivation model was prepared by using the multi-platform water environment method, with 20 h of sleep deprivation per day for 10 consecutive days. After sleep deprivation, a balance beam experiment was performed to test the balance and coordination ability of mice. The mice were sacrificed after anesthesia and cerebellar lobular IV-VI (4-6 cb) tissues were taken for microscopic examination of the ultrastructure (with a transmission electron microscope) and for determination of the dendritic spine density of cerebellar 4-6cb Purkinje neurons (by Golgi staining), co-expression of SIRT6 and Calbindin D-28k (CbD-28k) and expression of glucose transporter Glut3 of cerebellar 4-6cb (by immunofluorescence staining). Results:Compared with group Con, the duration of passage through the balance beam was significantly prolonged, and the number of posterior foot slips was increased, the synaptic gap of cerebellar 4-6cb neurons was increased, the thickness of postsynaptic density was increased, the density of dendritic spines of Purkinje cells and the number of positive cells co-expressing SIRT6 and CbD-28k were decreased, and the expression of Glut3 was down-regulated in group SD ( P<0.05). Conclusions:The mechanism by which sleep deprivation decreases the abilities of balance and coordination is related to down-regulating SIRT6 expression in cerebellar Purkinje cells and decreasing neuronal glucose metabolism, thus damaging the synaptic plasticity of cerebellum in immature mice.

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Objective:To study the effect of senescence gene silent information regulator 6 (Sirt6) knockout on the brain of aged mice.Methods:Sirt6-flox transgenic mice were constructed, and the mouse brain tissue was specifically knocked out by Emx1-Cre tool mice.According to genotyping, 11 wild-type mice were selected as control group(WT group) and 10 Sirt6 gene konckout mice were selected as conditional knockout group(cKO group). Body size and body weight of the aged mice were measured and cerebral cortex thickness was measured by HE staining.Brain neurogenesis was analyzed with EdU markers.The expression of RNA-binding protein HuR and apoptosis-related protein Caspase-3 were detected by Western blot.Meanwhile, histone acetylation levels in the cortex were detected.Results:Sirt6 brain tissue-specific knocked out mice were successfully constructed.Compared with the brain tissue area((2.07±0.22) cm 2)and cortical thickness ((970.56±80.91) μm) of WT mice in the 12-month-old group, the brain tissue area ((1.61±0.14)cm 2) and cortical thickness ((822.88±53.94) μm) in Sirt6 cKO group were smaller, and the differences were statistically significant (both P<0.05). EdU incorporation into nerve cells showed that the number of EdU incorporation into periventricular nerve cells in cKO group was lower ((4.75±1.48)) than that in WT group ((10.29±1.93)). The difference was statistically significant ( P<0.001). In the experiment of 17 months age group, mice in cKO group were smaller in body size, lower in body weight ((29.00±1.08) g) and smaller in brain area ((1.54±0.55)cm 2)compared with WT group in body size, body weight ((35.25±4.17) g) and brain tissue area ((1.98±0.18) cm 2)(both P<0.05). The expression of Caspase-3 and HuR in cortical proteins of these two age groups decreased( t=2.95, 5.38, both P<0.05), and the expression of H3K9ac and H3K56ac increased( t=3.53, 2.78, both P<0.05), but the expression of Sirt1 homologous gene remained unchanged( t=1.26, P>0.05). Conclusion:The specific deletion of Sirt6 in brain tissue can lead to the decrease of brain neurogenesis in aged mice, and the aggravation of aging and the increase of apoptosis, which may be the reason for the thinning of cerebral cortex and brain tissue atrophy.The molecular mechanism is speculated to be related to the increase of acetylation level after Sirt6 knockout

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Objective: To investigate the protective mechanism of Liuwei Dihuangwan on diabetes mellitus with liver injury in terms of inflammation. Method: The 18 db/db mice were selected from animal model of spontaneous type 2 diabetes, mice were randomly divided into model group, Liuwei Dihuangwan group(9.75 g·kg-1·d-1,once a day), resveratrol group(42.6 mg·kg-1·d-1,once a day)based on fasting blood-glucose (FBG). The 12 litter wild db/m mice were randomly divided into normal group, Liuwei Dihuangwan group(9.75 g·kg-1·d-1,once a day). The normal group and the model group were given the same amount of distilled water by gavage. The mice in each group were treated for 16 weeks. FBG, triglyceride (TG) and alanine aminotransferase (ALT) were examined. Histopathological changes were observed by liver biopsy hematoxylin-eosin (HE) staining. Silent information regulator 6 (SIRT6),nuclear factor-kappaB p65 (NF-κB p65),monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in the liver tissue were detected by Western blot. Result: Compared with normal group, FBG, TG and ALT in model group increased significantly(PκB p65,MCP-1,VCAM-1 and ICAM-1 in model group were significantly up-regulated(PPPPκB p65, MCP-1 and VCAM-1 were significantly decreased (PPConclusion: Liuwei Dihuangwan can protect the diabetes mice from liver injury, and its mechanism is related to the improvement of lipid metabolism and the inhibition of inflammatory response.

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Silent information regulator 6 (SIRT6) is broadly considered as a tumor suppressor due to its function in the suppression of oncogene expression. However, the role of SIRT6 in colorectal cancer stem cells (CSCs) remains uncharacterized. In the present study, it was demonstrated that SIRT6 expression was reduced in colorectal CSCs. Overexpression of SIRT6 in colorectal CSCs did not induce cell apoptosis. However, SIRT6 significantly inhibited cell proliferation, colony formation and induced G0/G1 phase arrest in colorectal CSCs. In addition, SIRT6 repressed the expression of cell division cycle 25A (CDC25A), an oncogenic phosphatase. Chromatin immunoprecipitation experiments indicated that SIRT6 directly bound to the CDC25A promoter and decreased the acetylation level of histone H3 lysine 9. Altogether, these data indicated that SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A.

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Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury.

Asunto(s)

Hígado/metabolismo , Daño por Reperfusión/metabolismo , Sirtuinas/metabolismo , Animales , Apoptosis , Autofagia , Muerte Celular , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Hígado/patología , Masculino , Ratones , Ratones Noqueados , Transducción de Señal , Sirtuinas/genética , Transcriptoma

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Objective To analyze mRNA expression of silent information regulator 6 (SIRT6) gene in the blood of population with family history of longevity in Bama county of Guangxi and to explore its association with SIRT6 gene polymorphism and its protein Methods One hundred and thirty-seven people (aged 30 ~ 106, 70 males, 67 females, 6.57% Han nationality, 93.43% Zhuang and Yao nationalities) with family history of longevity (long-lived family history group), and 91 people (aged 22~89, 51 males, 40 females, all Zhuang and Yao nationalities) without family history of longevity were recruited in the study (non-long-lived family history group). Real-time fluorescence quantitative RT-PCR was used to detect mRNA expression of SIRT6 gene in two groups. Results SIRT6 mRNA expression of total and femals in long-lived family history group were higher than those in non-long-lived family history group (P0.05). Conclusion The expression of mRNA in SIRT6 gene may be associated with familial aggregation of longevity in Bama County of Guangxi and high expression of mRNA of SIRT6 in G allele carriers contributes to longevity.