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1.
Acta Pharmaceutica Sinica B ; (6): 33-49, 2022.
Article in English | WPRIM | ID: wpr-929280

ABSTRACT

Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.

2.
Arch. endocrinol. metab. (Online) ; 65(5): 549-561, 2021. tab, graf
Article in English | LILACS | ID: biblio-1345196

ABSTRACT

ABSTRACT Objective: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes ( Clock, Bmal1 ) and genes involved in lipid metabolism ( Pgc1a, Pparg, Ucp2 ) through nutrient-sensing pathways ( Sirt1, Ampk, Nampt ) in peripheral tissues. Materials and methods: Rats were grouped according to food access: Control group (CG, food ad libitum ), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. Results: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a , Pparg , and Ucp2 but not Ampk and Nampt . Conclusion: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.


Subject(s)
Animals , Rats , Hypothalamus , Liver/metabolism , Nutrients , Circadian Rhythm , Lipid Metabolism
3.
Chinese Journal of Anesthesiology ; (12): 1133-1137, 2021.
Article in Chinese | WPRIM | ID: wpr-911333

ABSTRACT

Objective:To evaluate the role of nicotinamide adenine dinucleotide (NAD + )-mediated deacetylation activity of silent information regulator 1 (SIRT1) in endotoxin-induced acute lung injury (ALI) in mice. Methods:Twenty-five SPF clean-grade healthy male C57BL/6 mice including 10 wild-type (WT) and 15 NMNAT1 conditional-knockout (KO) mice, aged 6-8 weeks, weighing 20-25 g, were selected.The WT mice were divided into 2 groups ( n=5 each) using a random number table method: control group (group WT+ C) and ALI group (group WT+ ALI). The KO mice were divided into 3 groups ( n=5 each) using a random number table method: control group (group KO+ C), ALI group (group KO+ ALI) and ALI plus NAD + precursor substances nicotinamide mononucleotide (NMN) group (KO+ LPS+ NMN group). ALI was produced with lipopolysaccharide (LPS) 15 mg/kg injected intravenously.NMN 500 mg/kg was intraperitoneally injected at 1 h before injection of LPS in KO+ ALI+ NMN group, while the equal volume of normal saline was given instead in control group.Blood samples were collected from the abdominal aorta at 12 h after LPS or normal saline injection for blood gas analysis, and the animals were then sacrificed and the lung tissues were removed for microscopic examination of pathologic changes which were scored and for determination of wet/dry weight ratio (W/D ratio), and interleukin-6 (IL-6), IL-1β and tumor necrosis factor-alpha (TNF-α) contents (by enzyme-linked immunosorbent assay)and content of NAD + (using a spectrophotometer) and levels of SIRT1, acetylated nuclear factor kappaB (Ac-NF-κB), acetylated p53 (Ac-p53), acetylated FoxO1 (Ac-FoxO1) and acetylated PGC1α (Ac-PGC1α) (by Western blot). Results:Compared with group C, pH value and PaO 2 were significantly decreased, the PaCO 2, W/D ratio, lung injury score, contents of IL-6, IL-1β, TNF-α and NAD + were increased, expression of SIRT1 was up-regulated, and expression of Ac-NF-κB, Ac-p53, Ac-FoxO1 and Ac-PGC1α was down-regulated in group ALI ( P<0.05). Compared with group WT+ ALI, pH value and PaO 2 were significantly decreased, the PaCO 2, W/D ratio, lung injury score, contents of IL-6, IL-1β and TNF-α were increased, NAD + content was decreased, expression of SIRT1 was down-regulated, and expression of Ac-NF-κB, Ac-p53, Ac-FoxO1 and Ac-PGC1α was up-regulated in group KO+ ALI ( P<0.05). Compared with group KO+ ALI, pH value and PaO 2 were significantly increased, the PaCO 2, W/D ratio, lung injury score, contents of IL-6, IL-1β and TNF-α were decreased, NAD + content was increased, expression of SIRT1 was up-regulated, and expression of Ac-NF-κB, Ac-p53, Ac-FoxO1 and Ac-PGC1α was down-regulated in group KO+ ALI+ NMN ( P<0.05). Conclusion:The enhanced NAD + -mediated deacetylation activity of SIRT1 is involved in the endogenous protective mechanism in mice with endotoxin-induced ALI.

4.
Article in Chinese | WPRIM | ID: wpr-911186

ABSTRACT

Objective:To evaluate the relationship between silence information regulator 1 (SIRT1) and signal transducers and activators of transcription 3 (STAT3) acetylation during high glucose-induced cardiac microvascular endothelial cell injury.Methods:Cardiac microvascular endothelial cells of Sprague-Dawley rats were cultured.The cells at the logarithmic growth phase were selected and divided into 3 groups ( n=24 each) using a random number table method: control group (C group), high glucose group (HG group) and high glucose+ SIRT1 agonist SRT1720 group (HG+ SRT group). The cardiac microvascular endothelial cells were seeded in a 6- or 96-well cell culture plate at a density of 2×10 5 cells/ml.When the cell density reached 50%, the culture medium was then replaced with high-glucose (glucose 33 mmol/L) DMEM culture medium containing with 10% fetal bovine serum and 1% double antibody in HG and HG+ SRT groups.In group HG+ SRT, 20 μmol/L SRT1720 was added simultaneously, and the cells were cultured at 37 ℃ in an incubator with 5% CO 2 for 24 h. The cell viability was determined by CCK-8 assay, the activity of superoxide dismutase (SOD) was detected using a spectrophotometer, the levels of lactic dehydrogenase (LDH), interleukin-6 (IL-6) and tumor necrosis factor-β (TNF-β) in the supernatant were detected by enzyme-linked immunosorbent assay, and the expression of SIRT1, acetylated STAT3 (ac-STAT3) and phosphorylated STAT3 (p-STAT3) was determined by Western blot. Results:Compared with C group, the cell viability and SOD activity were significantly decreased, levels of LDH, IL-6 and TNF-β in the supernatant were increased, expression of SIRT1 was down-regulated, and expression of ac-STAT3 and p-STAT3 was up-regulated in group HG and group HG+ SRT ( P<0.05). Compared with group HG, the cell viability and SOD activity were significantly increased, levels of LDH, IL-6 and TNF-β in the supernatant were decreased, expression of SIRT1 was up-regulated, and expression of ac-STAT3 and p-STAT3 was down-regulated in group HG+ SRT ( P<0.05). Conclusion:SIRT1 can alleviate high glucose-induced cardiac microvascular endothelial cell injury by promoting STAT3 deacetylation.

5.
Article in Chinese | WPRIM | ID: wpr-883368

ABSTRACT

Objective:To investigate the potential anti-aging mechanism of 9-hydroxy-6,7-dimethoxydalbergiquinol (HDDQ) on hydrogen peroxide (H2O2)-induced oxidative stress in human dermal fibroblasts (HDFs). Methods:The effect of HDDQ on cell viability was assessed by MTT assay, and the effects of HDDQ on senescence-like phenotypes were determined by senescence-associated β-galactosidase (SA-β-gal) staining, Western blotting analysis, and a cell proliferation assay. The expression level and activity of sirtuin-1 (SIRT1) induced by HDDQ were also measured. Results:HDDQ reversed senescence-like phenotypes in the oxidant-challenged model, through reducing SA-β-gal activity and promoting cell growth. Meanwhile, decreases in ac-p53, p21Cip1/WAF1, and p16Ink4a and an increase in pRb were observed. HDDQ induced the expression of SIRT1 in a concentration- and time-dependent manner. Moreover, HDDQ inhibited H2O2-induced phosphorylation of Akt by SIRT1 up-regulation and reduced SA-β-gal staining. Conclusions:HDDQ inhibits H2O2-induced premature senescence and upregulation of SIRT1 expression plays a vital role in the inhibition of the senescence phenotype in HDFs.

6.
Braz. j. med. biol. res ; 54(2): e10271, 2021. tab, graf
Article in English | LILACS, ColecionaSUS | ID: biblio-1142584

ABSTRACT

This study aimed to investigate the value of sirtuin 1 (SIRT1) in differentiating sepsis patients from healthy controls (HCs), and its correlation with inflammation, disease severity, as well as prognosis in sepsis patients. Serum samples were collected from 180 sepsis patients and 180 age- and gender-matched HCs. The SIRT1 level in the serum samples was detected by enzyme-linked immunoassay. The clinical data of the sepsis patients were documented, and their disease severity scores and 28-day mortality rate were assessed. SIRT1 was decreased in sepsis patients compared with HCs, and the receiver operating characteristic curve (ROC) showed that SIRT1 distinguished sepsis patients from HCs (area under the curve (AUC): 0.901; 95% confidence interval (CI): 0.868-0.934). In sepsis patients, SIRT1 negatively correlated with serum creatinine (Scr), white blood cells (WBC), C-reactive protein (CRP), acute physiology, and chronic health evaluation II (APACHE II) score, and sequential organ failure assessment (SOFA) score, while it positively correlated with albumin. No correlation of SIRT1 with primary infection site or primary organism was observed. Furthermore, SIRT1 was reduced in 28-day non-survivors compared with 28-day survivors, and subsequent ROC showed that SIRT1 predicted 28-day mortality of sepsis patients (AUC: 0.725; 95% CI: 0.651-0.800), and its prognostic value was not inferior to Scr, albumin, WBC, and CRP, but was less than SOFA score and APACHE II score. In conclusion, measurement of serum SIRT1 might assist with the optimization of disease assessment, management strategies, and survival surveillance in sepsis patients.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Sepsis/diagnosis , Sirtuin 1/blood , Retrospective Studies , ROC Curve , APACHE , Organ Dysfunction Scores
7.
Article in Chinese | WPRIM | ID: wpr-907413

ABSTRACT

Objective:To investigate the effect of oleanolic acid (OA) on Sirtuin1 (SIRT1)-mediated high-mobility group box 1(HMGB1) deacetylation in the early brain injury after subarachnoid hemorrhage (SAH).Methods:A total of 176 male Sprague-Dawley rats were randomly divided into Sham operation (Sham group) ( n=48), SAH group ( n=48), OA group ( n=48) and Sirtinol group ( n=32). Rats in the SAH group, OA group and the Sirtinol group all adopted internal carotid artery puncture to construct SAH model, while rats in the sham group did not adopt puncture. One hour after modeling, the rats in the OA group were given intraperitoneal injection of OA (20 mg/kg), and the rats in the Sirtinol group were given intracerebroventricular injection of Sirtinol (2 mmol/L, 30 μL/kg). The rats in the sham group and SAH group were injected with equal volumes of sodium chloride injection. The SAH score and neurological score were performed 24 h after SAH, and the water content in the brain tissue and Evans blue exudation rate were measured. The expressions of HMGB1, SIRT1 and acetylated HMGB1 proteins in the brain tissue of rats were detected by Western Blot. The expression of HMGB1 mRNA in the brain of the rats was detected by quantitative real-time PCR. The distribution of HMGB1 protein in the brain of the rats was observed by immunofluorescence staining. TUNEL staining was used to observe the neuronal apoptosis in the brain tissue of the rats. Results:Compared with the SAH group, the SAH score of the OA group was significantly reduced ( P<0.001), the Garcia score was increased ( P<0.01), and the brain water content and Evans blue exudation rate were both reduced (all P<0.01). Compared with the OA group, the SAH score of the Sirtinol group was increased ( P<0.01), the Garcia score was significantly decreased ( P<0.001), and the brain water content and Evans blue exudation rate were both increased (all P<0.01). The results of Western Blot and real-time fluorescent quantitative PCR showed that, compared with the SAH group, the protein level ( P<0.01) and mRNA level ( P<0.05) of HMGB1 in the OA group were decreased, the expression of SIRT1 protein was significantly increased ( P<0.001), and the expression of acetylated HMGB1 protein was decreased ( P<0.01). Immunofluorescence staining showed that OA inhibited the migration of HMGB1 protein from the nucleus to the cytoplasm. TUNEL staining showed that OA could effectively reduce the number of TUNEL-positive cells. Compared with the OA group, Sirtinol significantly increased the number of TUNEL-positive cells. Conclusions:OA can reduce the release of HMGB1 through the SIRT1/HMGB1 pathway, thereby protecting the early brain injury after SAH.

8.
Arq. neuropsiquiatr ; 78(8): 501-511, Aug. 2020. tab, graf
Article in English | LILACS | ID: biblio-1131741

ABSTRACT

ABSTRACT Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible loss of cognitive function. The presence of senile plaques is one of the pathological markers of the disease and is associated with the onset of neuroinflammatory mechanisms. The exact pathophysiology of AD has not been completely understood, and there are no curative therapies yet. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol that is noted for its antioxidant and anti-inflammatory properties. Objective: To review the role of resveratrol in the pathophysiological aspects of AD. Methods: This study carried out a literature review using PubMed/Medline, Virtual Health Library (VHL), Web of Sciences, SCOPUS and the Cochrane Library databases. Original research articles, describing both in vitro and in vivo experiments, published between 2008 and 2018, were included. Results: We identified 667 articles, of which 619 were excluded because they were repeated or did not follow the inclusion criteria. The present study includes the remaining 48 articles. Discussion: Resveratrol demonstrates beneficial and protective effects in AD models and seems to provide a promising therapeutic alternative. Conclusion: Although resveratrol appears to mitigate some pathophysiological aspects of AD, further studies are needed to prove the safety and efficacy of this compound in humans.


RESUMO Introdução: A doença de Alzheimer (DA) é neurodegenerativa e caracterizada por perda progressiva e irreversível da função cognitiva. A presença de placas senis é um dos marcadores patológicos da doença e está associada ao aparecimento de mecanismos neuroinflamatórios. A fisiopatologia exata da DA ainda não é completamente compreendida, e ainda não existem terapias curativas. O resveratrol (3,5,4'-trihidroxi-trans-estilbeno) é um polifenol conhecido por suas propriedades antioxidantes e anti-inflamatórias. Objetivo: Revisar o papel do resveratrol nos aspectos fisiopatológicos da DA. Métodos: Este estudo realizou uma revisão narrativa da literatura a partir das bases de dados PubMed/Medline, Biblioteca Virtual em Saúde (BVS), Web of Science, SCOPUS e Cochrane Library. Foram incluídos artigos originais, realizados in vitro e in vivo, publicados entre 2008 e 2018. Resultados: Foram identificados 667 artigos, dos quais 619 foram excluídos por estarem repetidos ou não se enquadrarem nos critérios de inclusão. O presente estudo inclui os 48 artigos restantes. Discussão: O resveratrol demonstra efeitos benéficos e protetores em modelos de DA, bem como parece fornecer uma alternativa terapêutica promissora. Conclusão: Embora o resveratrol pareça atenuar alguns aspectos fisiopatológicos da DA, são necessários mais estudos para comprovar a segurança e a eficácia deste composto em seres humanos.


Subject(s)
Humans , Alzheimer Disease/drug therapy , Cognition , Resveratrol/therapeutic use , Antioxidants
9.
Braz. j. med. biol. res ; 53(2): e8616, 2020. graf
Article in English | LILACS | ID: biblio-1055497

ABSTRACT

Previous research has shown that suppression of miR-383 can prevent inflammation of the endothelium, as well as postpone the development of atherosclerosis. However, the role of miR-383 in endothelial cell apoptosis in diabetes remains unclear. The aim of this study was to investigate the function of miR-383 in high glucose-induced apoptosis and oxidative stress in endothelial cells. A series of experiments involving qualitative polymerase chain reaction, cell transfection, luciferase assay, assessment of cell death, detection of catalase and superoxide dismutase concentrations, detection of intracellular reactive oxygen species (ROS), and western blot analysis were performed in this study. We found that miR-383 expression was promoted, while NAD+-dependent deacetylase and sirtuin 1 (SIRT1) expressions were suppressed in the endothelium of the aorta in db/db mice as well as in human umbilical vein endothelial cells, which were treated with high glucose (HG). Increased expression of miR-383 decreased expression of SIRT1, while suppression of miR-383 promoted expression of SIRT1 in human umbilical vein endothelial cells (HUVECs). Furthermore, suppression of miR-383 following transfection with miR-383 suppressor repressed cell death and generation of ROS in HUVECs. SIRT1 knockdown by siRNA-SIRT1 reversed the suppressive effect of miR-383 inhibition on ROS production and cell apoptosis induced by HG treatment. Overall, the findings of our research suggested that suppression of miR-383 repressed oxidative stress and reinforced the activity of endothelial cells by upregulation of SIRT1 in db/db mice, and targeting miR-383 might be promising for effective treatment of diabetes.


Subject(s)
Animals , Male , Rabbits , Endothelium, Vascular/drug effects , Apoptosis/drug effects , Oxidative Stress/drug effects , MicroRNAs/antagonists & inhibitors , Sirtuin 1/metabolism , Glucose/pharmacology , Endothelium, Vascular/cytology , Endothelium, Vascular/physiology , Signal Transduction , Cells, Cultured , Mice, Inbred C57BL
10.
Braz. j. med. biol. res ; 53(10): e9849, 2020. tab, graf
Article in English | LILACS, ColecionaSUS | ID: biblio-1132481

ABSTRACT

Testosterone has been demonstrated to antagonize doxorubicin-induced cardiomyocyte senescence. However, whether testosterone prevents the paraquat-induced cardiomyocyte senescence is largely unknown. The detection of SA-β-gal activity was performed using senescence β-gal staining kit and the reactive oxygen species levels were determined by reactive oxygen species assay kit. The plasmids for insulin-like growth factor 1 shRNA (sh-mIGF-1), sirtuin-1 shRNA (sh-SIRT1), scramble shRNA (sh-NC), overexpressing mIGF-1 (mIGF-1), overexpressing SIRT1 (SIRT1), and negative controls (NC) were obtained for this study. The expression of target genes was detected using quantitative real-time PCR, immunolabeling, and western blot. We found that testosterone significantly delayed the paraquat-induced HL-1 cardiomyocyte senescence as evidenced by decreasing senescence-associated β-galactosidase activity and reactive oxygen species generation, which were accompanied by the up-regulated expression of mIGF-1 and SIRT1. RNA interference to reduce mIGF-1 and SIRT1 expression showed that testosterone prevented paraquat-induced HL-1 senescence via the mIGF-1/SIRT1 signaling pathway. Furthermore, myocardial contraction was evaluated by expression of genes of the contractile proteins/enzymes, such as α-myosin heavy chain 6 (MHC6), α-myosin heavy chain 7 (MHC7), α-skeletal actin (ACTA-1), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA2). Testosterone adjusted the above four gene expressions and the adjustment was blocked by mIGF-1 or SIRT1 inhibition. Our findings suggested that the mIGF-1/SIRT1 signaling pathway mediated the protective function of testosterone against the HL-1 cardiomyocyte senescence by paraquat, which provided new clues for the mechanisms underlying the anti-aging role of testosterone in cardiomyocytes.


Subject(s)
Paraquat/toxicity , Testosterone/physiology , Myocytes, Cardiac , Sirtuin 1 , Signal Transduction , Cells, Cultured
11.
Acta Pharmaceutica Sinica B ; (6): 383-398, 2020.
Article in English | WPRIM | ID: wpr-793001

ABSTRACT

Herpes simplex virus type 1 (HSV-1), a neurotropic herpes virus, is able to establish a lifelong latent infection in the human host. Following primary replication in mucosal epithelial cells, the virus can enter sensory neurons innervating peripheral tissues nerve termini. The viral genome is then transported to the nucleus where it can be maintained without producing infectious progeny, and thus latency is established in the cell. Yin-Yang balance is an essential concept in traditional Chinese medicine (TCM) theory. Yin represents stable and inhibitory factors, and Yang represents the active and aggressive factors. When the organism is exposed to stress, especially psychological stress caused by emotional stimulation, the Yin-Yang balance is disturbed and the virus can re-engage in productive replication, resulting in recurrent diseases. Therefore, a better understanding of the stress-induced susceptibility to HSV-1 primary infection and reactivation is needed and will provide helpful insights into the effective control and treatment of HSV-1. Here we reviewed the recent advances in the studies of HSV-1 susceptibility, latency and reactivation. We included mechanisms involved in primary infection and the regulation of latency and described how stress-induced changes increase the susceptibility to primary and recurrent infections.

12.
Article in Chinese | WPRIM | ID: wpr-755602

ABSTRACT

Objective To evaluate the effect of tyrosol on myocardial ischemia-reperfusion (I/R) injury in diabetic rats and the role of silent mating-type information regulation 1 (SIRT1)/adenosine monophosphate-activated protein kinase (AMPK)/endothelial nitric oxide synthase (eNOS) signaling pathway.Methods SPF healthy adult male Sprague-Dawley rats,weighing 200-220 g,were intraperitoneally injected with streptozotocin 60 mg/kg to establish the model of diabetes mellitus.Fifty-six diabetic rats were divided into 4 groups (n =14 each) using a random number table method:sham operation group (S group),myocardial I/R group (I/R group),myocardial I/R plus tyrosol group (I/R+T group),and myocardial I/R plus tyrosol plus SIRT1 inhibitor EX527 group (I/R+T+E group).In I/R+T and I/R+T+E groups,tyrosol 20 mg · kg-1 · d-1 was given by gavage for 45 consecutive days,and the equal volume of normal saline was given in the other two groups.In I/R+T+E group,EX527 5 mg · kg-1 · d-1 was intraperitoneally injected for 3 consecutive days before ischemia,and EX527 5 mg/kg was intraperitoneally injected at 20 min before repeffusion.Myocardial I/R was induced by ligation of the left anterior descending branch of coronary artery for 30 min followed by 2-h reperfusion.The myocardial infarct volume was measured by TTC staining.The levels of creatine kinase-MB (CK-MB),lactic dehydrogenase (LDH) and 5-F2t-isoprostane in serum and superoxide dismutase (SOD) in myocardial tissues were detected by enzyme-linked immunosorbent assay.The expression of SIRT1,AMPK,phosphorylated AMPK (p-AMPK),eNOS and p-eNOS was detected by Western blot.Results Compared with S group,the levels of serum CK-MB,LDH and 15-F2t-Isoprostane and myocardial infarction volume were significantly increased,the SOD activity was decreased,and the SIRT1 expression was down-regulated in I/R group,and the levels of serum CKMB,LDH and 15-F2t-Isoprostane and myocardial infarction volume were significantly increased,the SOD activity was decreased,the SIRT1 expression was down-regulated,and the expression of p-AMPK and peNOS was up-regulated in I/R+T and I/R+T+E groups (P<0.05).Compared with I/R group,the levels of serum CK-MB,LDH and 15-F2t-Isoprostane and myocardial infarction volume were significantly decreased,the SOD activity was increased,and the expression of SIRT1,p-AMPK and p-eNOS was up-regulated in I/R+T group (P<0.05),and no significant change was found in the parameters mentioned above in I/R+ T+E group (P>0.05).Compared with I/R+T group,the levels of CK-MB,LDH and 15-F2t-isoprostane in serum and myocardial infarct volume were significantly increased,the SOD activity was increased,and the expression of SIRT1,p-AMPK and p-eNOS was down-regulated in I/R+T+E group (P<0.05).Conclusion Tyrosol can mitigate myocardial I/R injury,and the mechanism may be related to activating SIRT1/AMPK/eNOS signaling pathway and inhibiting oxidative stress response in diabetic rats.

13.
Article in Chinese | WPRIM | ID: wpr-755531

ABSTRACT

Objective To evaluate the role of silent information regulator 1 (SIRT1) signaling pathway in endotoxin-induced acute lung injury (ALI) in rats.Methods Ninety-six clean-grade healthy male Sprague-Dawley rats,aged 4 weeks,weighing 160-180 g,were divided into 4 groups (n=24 each) using a random number table method:control group (group C),ALI group,ALI + SIRT1 agonist SRT1720 group (group SRT),and ALI + SIRT1 inhibitor EX527 group (group EX).ALI was induced by injecting lipopolysaccharide (LPS) 5 mg/kg (diluted to 0.5 ml with 0.9% normal saline) in ALI,SRT and EX groups.SRT1720 10 mg/kg was injected via the tail vein,and 30 min later ALI model was established in group SRT.EX527 1 μg/kg was injected via the tail vein,and 30 min later ALI model was established in group EX.Blood samples were collected from the abdominal aorta at 6,24 and 48 h after LPS injection for blood gas analysis,rats were then sacrificed and lungs were removed for determination of wet to dry weight ratio (W/D ratio) and expression of SIRT1,nuclear factor kappa B p65 (NF-κB p65),interleukin-6 (IL-6) and IL-1β protein and mRNA (by Western blot or real-time polymerase chain reaction) and for examination of pathological changes of lung tissues (with a light microscope).Results Compared with groups C,PaO2 was significantly decreased,and PaCO2 and W/D ratio were increased at each time point after LPS injection in ALI,SRT and EX groups,the expression of SIRT1 protein and mRNA was significantly down-regulated,and the expression of NF-κB p65,IL-6 and IL-1β protein and mRNA was upregulated at each time point after LPS injection in ALI and EX groups,and the expression of SIRT1,NFκB p65,IL-6 and IL-1β was significantly up-regulated at each time point after LPS injection in group SRT (P<0.05).Compared with group ALI,PaO2 was significantly increased,PaCO2 and W/D ratio were decreased,the expression of SIRT1 protein and mRNA was up-regulated,the expression of NF-κB p65,IL-6 and IL-1β protein and mRNA was down-regulated at each time point after LPS injection (P<0.05),and the pathological changes were significantly attenuated in group SRT,and no significant change was found in the parameters mentioned above at each time point after LPS injection in group EX (P>0.05).Conclusion Inhibited SIRT1/NF-κB signaling pathway is involved in endotoxin-induced ALI in rats.

14.
Article in Chinese | WPRIM | ID: wpr-777494

ABSTRACT

To investigate the effects of geniposidic acid( GPA) on hepato-enteric circulation in cholestasis rats,and to explore the mechanism based on the sirtuin 1( Sirt1)-farnesol X receptor( FXR) pathway,sixty SD rats were randomly divided into 6 groups:blank control group,ANIT model group,ursodeoxycholic acid group( 100 mg·kg~(-1)·d-1 UDCA),and GPA high,medium and low( 100,50 and 25 mg·kg~(-1)·d-1) dosage groups,10 rats in each group. Corresponding drugs were intragastrically( ig) administered for10 days. After administration on day 8,all rats except blank rats were administered with 65 mg·kg~(-1)α-naphthalene isothiocyanate( ANIT) once. After the last administration,the serum levels of alanine aminotransferase( ALT),glutamine oxalacetate aminotransferase( AST),gamma-glutamyltransferase( γ-GGT),alkaline phosphatase( ALP),total bilirubin( TB) and total bile acid( TBA)were measured,and the mRNA transcription levels of Sirt1,FXR,multidrug resistant associated protein 2( MRP2),bile salt export pump( BSEP),sodium taurocholate contractible polypeptide( NTCP) in liver and apical sodium bile acid transporter( ASBT),ileum bile acid binding protein( IBABP) in ileum were detected by reverse transcription-polymerase chain reaction( RT-PCR). The protein expression levels of Sirt1,FXR and NTCP were detected by Western blot; the expression of MRP2,BSEP in liver and ASBT,IBABP in ileum were determined by immunofluorescence three staining. Primary rat hepatocytes were cultured in vitro to investigate the inhibitory effect of GPA on a potent and selective Sirt1 inhibitor( EX 527),and the mRNA and protein expression levels of Sirt1 and FXR were detected by RT-PCR and Western blot. GPA significantly decreased the levels of ALT,AST,γ-GGT,ALP,TB,TBA in serum( P<0.01) and improved the pathological damage of liver tissues in ANIT-induced cholestasis rats; significantly increased the mRNA and protein expression levels of Sirt1,FXR,MRP2,BSEP,NTCP in liver and ASBT,IBABP in ileum( P< 0.01). In vitro primary hepatocytes experiment indicated that the gene and protein expression levels of FXR and Sirt1 were noticeably improved by GPA in primary hepatocytes inhibited by EX-527( P<0.01). It was found that the improvement of GPA was in a dose-dependent manner. GPA could improve bile acid hepatointestinal circulation and play a liver protection and cholagogu role in cholestasis rats induced by ANIT.The mechanism may be that GPA activated FXR by regulating Sirt1,a key regulator of oxidative stress injury,and then the activated FXR could regulate protein of bile acid hepato-enteric circulation.


Subject(s)
Animals , Cholestasis , Iridoid Glucosides , Liver , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear , Signal Transduction , Sirtuin 1
15.
Article in English | WPRIM | ID: wpr-776723

ABSTRACT

Sirtuin 1 (SIRT1) is a protein deacetylase, which regulates various physiological activities by deacetylating different protein substrates. An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism, proliferation, genomic instability, and chemotherapy resistance. Depending on the protein targets in a certain oncogenic context, SIRT1 may play a unique role in each individual blood cancer subtype. Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) promotes disease maintenance. On the other hand, an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome (MDS) stem cells and holds promise as a potential therapeutic approach. Herein, we present a concise summary of the different functions of SIRT1 in hematologic malignancies.

16.
Neuroscience Bulletin ; (6): 877-888, 2019.
Article in English | WPRIM | ID: wpr-776482

ABSTRACT

Synaptic dysfunction and abnormal processing of amyloid precursor protein (APP) are early pathological features in Alzheimer's disease (AD). Recently, non-coding RNAs such as microRNAs (miRNAs) and circular RNAs (circRNAs) have been reported to contribute to the pathogenesis of AD. We found an age-dependent elevation of miR-138 in APP/PS1 (presenilin-1) mice. MiR-138 inhibited the expression of ADAM10 [a disintegrin and metalloproteinase domain-containing protein 10], promoted amyloid beta (Aβ) production, and induced synaptic and learning/memory deficits in APP/PS1 mice, while its suppression alleviated the AD-like phenotype in these mice. Overexpression of sirtuin 1 (Sirt1), a target of miR-138, ameliorated the miR-138-induced inhibition of ADAM10 and elevation of Aβ in vitro. The circRNA HDAC9 (circHDAC9) was predicted to contain a miR-138 binding site in several databases. Its expression was inversely correlated with miR-138 in both Aβ-oligomer-treated N2a cells and APP/PS1 mice, and it co-localized with miR-138 in the cytoplasm of N2a cells. CircHDAC9 acted as a miR-138 sponge, decreasing miR-138 expression, and reversing the Sirt1 suppression and excessive Aβ production induced by miR-138 in vitro. Moreover, circHDAC9 was decreased in the serum of both AD patients and individuals with mild cognitive impairment. These results suggest that the circHDAC9/miR-138/Sirt1 pathway mediates synaptic function and APP processing in AD, providing a potential therapeutic target for its treatment.

17.
Article in English | WPRIM | ID: wpr-847039

ABSTRACT

Sirtuin 1 (SIRT1) is a protein deacetylase, which regulates various physiological activities by deacetylating different protein substrates. An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism, proliferation, genomic instability, and chemotherapy resistance. Depending on the protein targets in a certain oncogenic context, SIRT1 may play a unique role in each individual blood cancer subtype. Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) promotes disease maintenance. On the other hand, an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome (MDS) stem cells and holds promise as a potential therapeutic approach. Herein, we present a concise summary of the different functions of SIRT1 in hematologic malignancies.

18.
Acupuncture Research ; (6): 270-275, 2019.
Article in Chinese | WPRIM | ID: wpr-844323

ABSTRACT

OBJECTIVE: To observe the effect of electroacupuncture (EA) on expression of hypothalamic sirtuin 1(SIRT1) and proopiomelanocortin (POMC), and body weight, food-intake, blood glucose, and blood lipid levels in obese rats, so as to explore its mechanisms underlying improvement of obesity. METHODS: Forty male Wistar rats were randomly divided into normal, model, EA, and sham EA groups (n=10 rats in each group). The obesity model was established by feeding the rats with high fat diet. EA (2 Hz, 1 mA) was applied to "Zusanli" (ST36), "Zhongwan" (CV12), "Guanyuan" (CV4) and "Fenglong" (ST40) or sham acupoints (about 5 mm beside each acupoint, shallow needling) for 20 min, once every other day for 8 weeks. The rats' body weight and food-intake were recorded. The blood glucose (fasting plasma glucose: FPG, postprandial plasma glucose: PPG) and blood lipids (triglyceride: TG, total cholesterol: TC, non esterified fatty acid: NEFA) were assayed by using an automatic biochemical analyzer. The protein and mRNA expression levels of SIRT1 and POMC in the hypothalamus were detected by Western blot and quantitative real-time PCR, respectively. RESULTS: In comparison with the normal group, the body weight, food-intake, blood lipids, and PPG levels were significantly increased (P<0.05,P<0.01), and the expression levels of SIRT1 protein and mRNA in the hypothalamus were significantly doun-regulated in the model group (P<0.05). Following EA, the body weight, food-intake, blood lipids, and PPG levels were considerably down-regulated (P<0.01,P<0.05), and the expression levels of SIRT1 and POMC protein and mRNA in the hypothalamus were significantly up-regulated in the EA group rather than those in the sham EA and the model groups (P<0.05).. CONCLUSION: EA can reduce the obese rats' body weight, food-intake, blood lipids and blood glucose, which may be associated with its effect in up-regulating the SIRT1 and POMC expression of hypothalamus.

19.
Acupuncture Research ; (6): 492-496, 2019.
Article in Chinese | WPRIM | ID: wpr-844288

ABSTRACT

OBJECTIVE: To observe the impact of electroacupuncture (EA) on liver lipid metabolism and expression of hepatic sirtuin 1(Sirt1) and peroxisome proliferator activated receptor γ(PPARγ) of abdominal obese rats induced by high-fat diet. METHODS: Eighteen male SD rats were divided into blank control, model and EA groups (n=6 per group). The abdominal obesity model was established by feeding the rats with high-fat diet for 12 weeks. EA (2 Hz/15 Hz, 1.5 mA) was applied to bilateral "Daimai"(GB26) for 20 min every time, once every other day for 8 weeks. Rats of the model group were also restrained for 20 min. The body mass and abdominal circumference were measured every week, and the contents of serum cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), aspartate aminotransferase (AST) were detected by using an automated biochemical analyzer. Histopathological changes of the liver tissues were observed under microscope after oil red "O" staining. The expression of hepatic Sirt1 and PPARγ mRNAs and proteins were detected using quantitative real time PCR and Western blot, separately. RESULTS: After modeling, the body weight and abdominal circumference, and serum TC, TG, ALT and AST contents, and expression of hepatic PPARγ mRNA and protein were significantly increased (P<0.001, P<0.01, P<0.05), and the expression levels of hepatic Sirt1 mRNA and protein obviously down-regulated (P<0.05, P<0.01) in the model group. Following EA intervention, the increased body weight and abdominal circumference, and serum TC, TG, ALT and AST contents, and hepatic PPARγ mRNA and protein expression were remarkably suppressed (P<0.05, P<0.01), and the decreased hepatic Sirt1 mRNA and protein were remarkably up-regulated (P<0.001,P<0.05). The lipid droplets in hepatocytes were reduced in the EA group relevant to the model group. CONCLUSION: EA intervention can significantly improve the liver lipid metabolism of abdominal obese rats, which is possibly related with its effect in up-regulating the expression of hepatic Sirt1 mRNA and protein, and in down-regulating the expression of hepatic PPARγ mRNA and protein.

20.
Article in Chinese | WPRIM | ID: wpr-817793

ABSTRACT

@#【Objective】ThisstudyaimstoinvestigatewhetherrutecarpinehasaneffectoncalcificationofVSMCand itsunderlyingmechanism.【Methods】InvitromodelofratVSMCcalcificationwasusedinthisstudy.Rutecarpineat differentconcentrationswasusedtotreatculturedratVSMC.Theexpressionof Runx2,BMP2 and Osterix wasanalyzed byqRT-PCRandmineraldepositionwasdetectedbyalizarinredstaining.Inaddition,weexaminedtheeffectofrutecar⁃ pineonSirtuin-1(Sirt1)expressioninVSMCandtheeffectofSirt1inhibitoronVSMCcalcification.【Results】Alizarinred stainingandcalciumcontentassayshowedthatrutecarpineatdifferentconcentrationssignificantlyreducedcalcificationof ratVSMCinducedbyhighphosphorusandhighcalcium(136±10,75±6,52±6,31±5.29,P<0.05).Usageofrutecar⁃ pinedecreasedtheactivityofALP,anosteogenicdifferentiationmolecularmarker,anddown-regulatedtheexpressionof Runx2(2.85±0.25,1.75±0.18,1.62±0.13,1.36±0.16,P <0.05),BMP2(3.2±0.32,1.85±0.17,1.65±0.15,1.43± 0.12,P<0.05)andOsterix(2.60±0.27,1.82±0.16,1.55±0.15,1.36±0.17,P<0.05),suggestingthatrutecarpineinhib⁃ ited osteogenic differentiation of VSMC. In addition,high phosphorus and high calcium down-regulated the expres⁃ sionofSirt1inVSMC.qRT-PCRandwesternblotanalysisconfirmedthatrutecarpineup-regulatedtheexpressionof Sirt1atbothmRNA(0.35±0.06,0.75±0.11;0.22±0.08,0.87±0.13,P <0.05)andproteinlevels(0.38±0.09,0.71±0.13,P<0.05).QuantificationofcalciumcontentanalysisshowedinhibitionofSirt1byEX-527blockedtheinhibitory effectofrutecarpineonVSMCcalcification(138±13,36±7,87±8,P<0.05) .【Conclusion】Wedemonstratethatrutecar⁃ pineattenuatesVSMCcalcificationviaup-regulationofSirt1.

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