SIRT1

Coronary heart disease patients with type 2 diabetes were subject to higher vulnerability for cardiac ischemia-reperfusion (I/R) injury. This study was designed to evaluate the impact of ZP2495 (a glucagon-GLP-1 dual-agonist) on cardiac function and energy metabolism after myocardial I/R injury in db/db mice with a focus on mitochondrial function. C57BLKS/J-lepr/lepr(BKS) and db/db mice received 4-week treatment of glucagon, ZP131 (GLP-1 receptor agonist), or ZP2495, followed by cardiac I/R injury. The results showed that cardiac function, cardiac glucose metabolism, cardiomyocyte apoptosis, cardiac mitochondrial morphology, and energetic transition were improved or ameliorated by ZP2495 to a greater extent than that of glucagon and ZP131.study showed that ZP2495, rather than glucagon, alleviated mitochondrial depolarization, cytochrome C release, and mitochondria ROS generation in neonatal rat ventricular myocytes subjected to high-glucose and simulated I/R injury conditions, the e...

This study aimed to investigate the impact of Borreria hispida extract on gene expression in NRK-52E cells under conditions of glucotoxicity. Gene expression analysis was conducted using RT-PCR following the exposure of cultured NRK-52E cells to glucotoxic conditions and varying concentrations of Borreria hispida extract. The results demonstrated a dose-dependent increase in SIRT1 gene expression and a concomitant decrease in HIF-1λ, ET-1, and VEGFR-2 gene expressions upon treatment with Borreria hispida extract. Additionally, molecular docking studies suggested the potential inhibition of Rho-kinase as a mechanistic explanation for these effects. Borreria hispida extract may confer renoprotective benefits against glucotoxicity-induced cellular damage. The potential therapeutic utility of Borreria hispida extracts in managing renal complications associated with conditions such as diabetes. Furthermore, our docking studies shed light on the potential molecular mechanisms underlying the observed effects, suggesting interactions between phytochemicals present in Borreria hispida extract and the JNK-1 protein. These interactions may contribute to the augmentation of SIRT1 activity, further bolstering the extract's therapeutic utility in DKD.

Telomerase and SIRT1 (member of the sirtuin protein family) along with the lifestyle and diet are the major determinants of aging and its associated diseases such as cancer and cardiovascular disorders. The study objective was to investigate the effect of Consciousness Energy Healing based novel test formulation in pre-adipocytes (3T3-L1) and human peripheral blood mononuclear cells (PBMCs) for anti-aging activity using SIRT1 and telomerase assay. The test formulation was divided into two parts. One portion was denoted as the untreated test item without any Biofield Energy Treatment, while the other portion was defined as the Biofield Energy Healing Treatment, which received the Biofield Energy Healing Treatment by a renowned Biofield Energy Healer, Mahendra Kumar Trivedi. The cell viability using MTT assay showed that the cell viability of 3T3-L1 and PBMCs cells was more than 70% indicating a safe and nontoxic profile. The experimental data in PBMCs cells showed that the Biofield Energy Treated Test formulation showed a significant improved telomerase activity by 39.25%, 20.86%, and 17.95% at concentrations 0.01, 5, and 100 μg/mL, respectively as compared with the untreated test formulation group. These results indicate that the Biofield Energy Healing Treatment would be the significant approach to prevent aging-related disorders such as decline cardiovascular diseases, osteoporosis, dementia, osteoarthritis, Alzheimer’s, hypertension, cancer, Parkinson's Disease, Chronic Obstructive Pulmonary Disease (COPD), Stress, Asthma, cataract, age-related macular degeneration (AMD), hearing loss and metabolic disorders.

Context: N-(4-t-butylbenzoyl)-N’-phenylthiourea, a derivative compound of N-benzoyl-N’-phenylthiourea, has relatively high lipophilicity with the epidermal growth factor receptor and silent mating type information regulation-1 enzyme as its molecular targets.

Aims: To determine the anticancer activity of N-(4-t-butylbenzoyl)-N’-phenylthiourea as an in silico and in vitro anticancer candidate for the breast and cervical cancer.

Methods: In silico test was performed to predict the cytotoxic activity using AutoDock Vina. This activity was also measured in vitro using the Microculture Tetrazolium Technique assays of three cancer cells (MCF-7, T47D, and HeLa) and normal cells (Vero cells).

Results: In silico test predicted that N-(4-t-butylbenzoyl)-N’-phenylthiourea was more cytotoxic at epidermal growth factor receptor than silent mating type information regulation-1 receptor. In vitro tests showed it exhibited cytotoxic activities against MCF-7, T47D, and HeLa without harming Vero cells.

Conclusions: N-(4-t-butylbenzoyl)-N’-phenylthiourea has the potential as an anticancer candidate for breast and cervical cancers.

Aging is usually accompanied by a cognitive decline in quantitative reasoning and perceptual speed, which is associated with decreased white matter volume and integrity in certain brain areas such as the prefrontal cortex. The decline in the antioxidant enzymes has been shown to be associated with the changes in structure and volume of white matter. This chapter focuses on the antioxidant biomarkers and their clinical significance in brain aging in relation to brain white matter.

Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5′AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol s...

BACKGROUND AND OBJECTIVE: SIRT1 and PGC-1α are two factors that increase the body's antioxidant capacity, which can improve inflammation and free radicals in obesity. The present study was conducted to determine the effect of eight weeks of water training on SIRT1, PGC-1α and body fat percentage in obese men. METHODS: In this quasi-experimental study, obese men (BMI = 30, waist-to-height ratio (WHtR) > 0.5) were selected voluntarily and were randomly divided into two groups of water training (n = 11) and control (n = 11). The training program included three sessions per week for eight weeks with training intensity of 60 to 80% of maximal heart rate. BMI, body fat percentage and weight of subjects were examined before and after the intervention. Arterial blood samples were used to measure SIRT1 and PGC-1α during the pre-test and post-test stages. FINDINGS: The assessments showed that PGC-1α levels increased from 7.7 to 8.7 and SIRT1 levels increased from 11.3 to 12.6, and this increase was significant in the training group compared to the control group (p < 0.001). The results showed that body fat percentage decreased from 30.2 to 27.83 and weight decreased from 94.7 to 92.2, which was significant compared to the control group (p<0.001). CONCLUSION: Based on the results of this study, water training can increase the levels of SIRT1 and PGC-1α and decrease weight and body fat percentage.

The health benefits of regular exercise are well established. Nonetheless, the molecular mechanism(s) responsible for exercise-induced health benefits remain a topic of debate. One of the key cell-signaling candidates proposed to provide exercise-induced benefits is sirtuin 3 (SIRT3). SIRT3, an NAD+ dependent mitochondrial deacetylase, positively modulates many cellular processes, including energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. Although the exercise-induced change in SIRT3 signaling is a potential mechanism contributing to the health advantages of exercise on aging, studies investigating the impact of exercise on SIRT3 abundance in cells provide conflicting results. To resolve this conundrum, this narrative review provides a detailed analysis of the role that exercise-induced changes in SIRT3 play in providing the health and aging benefits associated with regular physical activity. We begin with an overview of SIRT3 function in cells f...

C/EBP homologous protein (CHOP) is an endoplasmic reticulum stress-inducible protein that plays a critical role in the regulation of programmed cell death; however, the regulation of its function has not been well characterized. We have previously demonstrated that CHOP is regulated by the ubiquitin-proteasome system. In this study, during the process of clarifying the mechanism of the degradation of CHOP, we identified a novel regulation domain of CHOP in its N-terminal portion that is involved in various regulations and functions. The CHOP N-terminal domain is necessary not only for protein degradation but also for its transactivity and interaction with p300. In addition, trichostatin A, a histone deacetylase inhibitor, repressed the degradation of CHOP protein via the N-terminal domain. TRB3, a mammalian tribbles homolog that functions as a repressor of CHOP, also interacted with CHOP via the N-terminal portion and significantly blocked the association of p300 with CHOP. These results suggest that the N-terminal portion of CHOP plays a crucial role in its functional regulation and enable us to identify a novel function of TRB3 as an intracellular antagonist of the p300-binding domain of CHOP. CCAAT/enhancer-binding proteins (C/EBPs) 2 are a family of leucine zipper transcription factors that are critical for the regulation of various aspects of cellular differentiation and function in multiple tissues. This family consists of six members: C/EBP␣, ␤ (NF-IL6), ␥ (Ig/EBP), ␦, ⑀, and C/EBP homologous protein (CHOP, C/EBP)/growth arrest-DNA damage-inducible 153 (GADD153) (1). The prototypic C/EBP contains a transcriptional activation domain and a bZIP region for DNA binding and dimerization. All family members share strong homology in the C-terminal domain, which carries a basic DNA-binding domain and a leucine zipper motif.

Introduction: Exercise through BDNF induces its beneficial effects on the brain. However, its cellular mechanisms are not fully understood. Thus, the purpose of this study was to investigate the effect of 8 weeks interval aerobic training on mRNA expression of SIRT1, CREB and BDNF genes in the hippocampus of male Westar rats.
Methods: Twelve 8 week old rats were the subjects of this study rats were randomly divided into two groups: exercise group and control group animals in the exercise group experienced interval aerobic exercise for 8 weeks (5 sessions per week at a speed of 10 to 15 m/min). Forty-eight hours after the last training session, animals were sacrificed and hippocampal tissue was extracted. mRNA expression of SIRT1, CREB and BDNF genes was determined by the real-time PCR method. An independent t-test was used to compare groups and significant differences were considered at the P≤0.05 level.
Results: The results showed that the expression of SIRT1, CREB and BDNF mRNA levels in hippocampal tissue of the exercised group were significantly increased (P ≤0.001).
Conclusion: Overall, it appears that interval aerobic exercise is able to upregulate brain BDNF levels through the SIRT1/CREB/BDNF signaling pathway hence, this type of exercise training can be used to induce the beneficial effects of exercise on brain health.

Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response ...

Sirtuin 1 (SIRT1) is a sensor of cell energy availability, and with leptin and adiponectin, it regulates metabolic homeostasis. Widely studied in tissues, SIRT1 is under evaluation as a plasmatic marker. We aimed at assessing whether circulating SIRT1 behaves consistently with leptin and adiponectin in conditions of deficiency, excess or normal fat content. Eighty subjects were evaluated: 27 with anorexia nervosa (AN), 26 normal-weight and 27 with obesity. Bloodstream SIRT1, leptin and adiponectin (ELISA), total and trunk fat mass (FM) %, abdominal visceral adipose tissue, liver steatosis and epicardial fat thickness (EFT) were assessed. For each fat store, the coefficient of determination (R2) was used to evaluate the prediction capability of SIRT1, leptin and adiponectin. Plasma SIRT1 and adiponectin coherently decreased with the increase of FM, while the opposite occurred with leptin. Mean levels of each analyte were different between groups (p &lt; 0.005). A significant associat...

The collateral effects of obesity/metabolic syndrome include inflammation and renal function decline. As renal disease in obesity can occur independently of hypertension and diabetes, other yet undefined causal pathological pathways must be present. Our study elucidate novel pathological pathways of metabolic renal injury through LDL-induced lipotoxicity and metainflammation. Our in vitro and in vivo analysis revealed a direct lipotoxic effect of metabolic overloading on tubular renal cells through a multifaceted mechanism that includes intralysosomal lipid amassing, lysosomal dysfunction, oxidative stress, and tubular dysfunction. The combination of these endogenous metabolic injuries culminated in the activation of the innate immune NLRP3 inflammasome complex. By inhibiting the sirtuin-1/LKB1/AMPK pathway, NLRP3 inflammasome dampened lipid breakdown, thereby worsening the LDL-induced intratubular phospholipid accumulation. Consequently, the presence of NLRP3 exacerbated tubular ox...

Sirtuin 1 (SIRT1) is a sensor of cell energy availability, and with leptin and adiponectin, it regulates metabolic homeostasis. Widely studied in tissues, SIRT1 is under evaluation as a plasmatic marker. We aimed at assessing whether circulating SIRT1 behaves consistently with leptin and adiponectin in conditions of deficiency, excess or normal fat content. Eighty subjects were evaluated: 27 with anorexia nervosa (AN), 26 normal-weight and 27 with obesity. Bloodstream SIRT1, leptin and adiponectin (ELISA), total and trunk fat mass (FM) %, abdominal visceral adipose tissue, liver steatosis and epicardial fat thickness (EFT) were assessed. For each fat store, the coefficient of determination (R2) was used to evaluate the prediction capability of SIRT1, leptin and adiponectin. Plasma SIRT1 and adiponectin coherently decreased with the increase of FM, while the opposite occurred with leptin. Mean levels of each analyte were different between groups (p &lt; 0.005). A significant associat...

Background and Objectives: Cardiac rehabilitation improves functional capacity of post-coronary artery bypass grafting (CABG) patients. Therefore, the aim of this study was to evaluate effects of eight weeks of cardiac rehabilitation on serum levels of sirutin1 (SIRT1) and functional capacity of post-CABG patients. Methods: Forty-five non-active men (mean age: 47.4 ± 3.3 years, duration of disease: 150 ± 69.12 months) were randomly divided into three equal groups: aerobic exercise, combined (resistance and aerobic) exercise and control. The subjects performed trainings at 60-75% of maximum heart rate, three sessions a week for eight weeks. Blood samples were collected 24 hours before the first exercise session and 48 hours after the last exercise session. Data were analyzed with SPSS 16.0 using one-way ANOVA and the Tukey post hoc test. P-values less than 0.05 were considered statistically significant. Results: Aerobic and combined exercise increased serum SIRT1 levels and functional capacity. There was no significant decrease in body mass index (P=0.06). The SIRT1 level did not differ significantly between the two exercise groups after the intervention (P=0.91). There were significant difference between the study groups in terms of the travelled distance (P<0.034). Conclusion: Both combined and aerobic exercise can increase serum levels of SIRT1, reduce body mass index and improve functional capacity in CABG patients.

Background and objectives: Sirtuin-1 (SIRT1) is a conserved a NAD +-dependent protein deacetylase essential for cellular metabolism and defence against oxidative stress and endothelial dysfunction. This study aimed to compare effects of 8 weeks of aerobic and combined training on serum level of SIRT1 and PGC1-α in coronary artery bypass graft patients. Methods: In this semi-experimental study, 45 non-active men (mean age 47.4 ± 3.3 years) who had undergone coronary artery bypass graft surgery were randomly divided into three groups: aerobic training, combined resistance and aerobic training and control. Trainings were performed at 80% of maximum heart rate, three sessions a week for 8 weeks. Blood samples were collected 24 hours before the first exercise session and 48 hours after the last training session. T-test and one-way analysis of variance were used for assessment of within-group and between-group differences, respectively. P-values less than 0.05 were considered as statistically significant. Results: The 8-week aerobic and combined training increased serum levels of SIRT1 and PGC-1α compared with the control group, and significantly decreased the weight of subjects (p=0.001). There was no significant difference in serum levels of SIRT1 and PGC-1α between the two training groups (P≥0.05). Conclusion: Both combined and aerobic training significantly improve the SIRT1 and PGC-1α levels in coronary artery bypass graft patients.

Background and Objectives: Sirtuin (SIRT), Fibroblast Growth Factor21 (FGF21) and Fetuin A are proteins that cause a wide range of metabolic disorders such as type 2 diabetes mellitus (T2DM). On the other hand, regular physical activity is known to play a key role in prevention and management of T2DM. Thus, this study investigated the effect of vigorous aerobic exercise on serum levels of metabolic parameters including SIRT1, FGF21 and Fetuin A in women with T2DM. Methods: The study was performed on 28 randomly selected women with T2DM who were divided into an exercise group and a control group. The training intervention consisted eight weeks of vigorous aerobic exercise (three times a week at 70-80% of maximum heart rate). The serum levels of SIRT1, FGF21 and Fetuin A were evaluated before the first session and 48 hours after the last session. Paired sample t-test and independent t-test were used to analyze within and between group differences, respectively. All statistical analyses were performed in SPSS (version 19) at significance of 0.05. Results: The eight-week aerobic training caused a significant reduction in body weight, body mass index, insulin resistance, low-density lipoprotein, fasting blood sugar, triglycerides and Fetuin A of women with T2DM. In addition, it caused a significant increase in SIRT1 and FGF21 levels. There was no significant difference in the level of high-density lipoprotein and cholesterol between the two groups. Conclusion: As a non-pharmacological therapy, regular aerobic exercise might improve the metabolic parameters, SIRT1, FGF21, and Fetuin A in women with T2DM.

Background: Hepatic steatosis is among the most common causes of chronic liver diseases, although established effective treatments are not evident.  Previous studies reported that Kurozu improved hypercholesterolemia and carbohydrate metabolism. However, the effect of Kurozu on the incidence of hepatic steatosis is not clear.
Objective: The effect of Kurozu on the onset of hepatic steatosis by administering a high-fat diet (HFD) for 110 weeks was evaluated in C57BL/6J mice.
Methods: HFD treatment for 110 weeks accelerated the onset of hepatic steatosis more than a standard diet, whereas concentrated Kurozu (CK) supplementation ameliorated the effect of an HFD feeding. The effect of supplementation with resveratrol in an HFD on the onset of hepatic steatosis was also evaluated. To elucidate the mechanism of the effect of Kurozu on the expression of lipid metabolism genes, acute treatment for 10 days with Kurozu was also examined.
Results: Supplementation with resveratrol in HFD-fed mice did not ameliorate hepatic steatosis. Body weights were significantly lower in the CK + HFD and Resveratrol + HFD groups than in the control HFD group in middle age. No significant differences in all-cause mortality were observed following supplementation with CK or resveratrol. CK and resveratrol supplements significantly inhibited decreases in dehydroepiandrosterone sulphate serum levels at postnatal week 120. CK and resveratrol supplements did not affect the survival of mice. The ingestion of Kurozu for 10 days significantly elevated the expression levels of Sirt1, Pgc-1α, Lpin1, and Igfbp1 in the liver.
Conclusion: These results suggest that ingesting CK may delay the onset of hepatic steatosis HFD feeding causes.

Sirt1/AMPK and Akt/mTOR axes regulate cellular energy homeostasis and metabolism. Sodium butyrate (NaB) is a product of healthy gut microbiota and a histone deacetylase inhibitor. Recent studies have shown that NaB activates the intracellular pathways involving key metabolic regulator molecules. However, the effect of NaB on Sirt1/AMPK and Akt/mTOR axes is not reported. We compared genetic expression of Sirt1, AMPK, Akt, and mTOR in adipose tissue from mice treated with NaB versus placebo. Four groups of mice (n=27) mice were administered oral NaB, intraperitoneal (i.p) NaB, oral placebo or i.p placebo for 16 days. RNA was isolated from the epididymal fat pads and relative genetic expression of AMPK, Sirt1, mTOR and Akt was measured using real time PCR. Oral NaB group showed decreased genetic expression of AMPK (0.04 fold, p<0.001), mTOR (0.30 fold, p=0.04), Akt (0.29 fold, p=0.67) and Sirt1 (0.83 fold, p=0.18). In the I/P group AMPK (2.26 fold, p=0.33), Akt (1.3 fold, p=0.59) and Sirt1 (1.69, p=0.45) were increased while mTOR was unchanged (0.99 fold, p=0.81). Our study for the first time reports on change in genetic expression of Sirt1/AMPK and Akt/mTOR axes in adipose tissue of mice given oral and intraperitoneal NaB treatment.

The sirtuin family comprises seven NAD+-dependent deacetylases which control the overall health of organisms through the regulation of pleiotropic metabolic pathways. Sirtuins are important modulators of adipose tissue metabolism and their expression is higher in lean than obese subjects. At present, the role of sirtuins in adipose-derived stem cells has not been investigated yet. Therefore, in this study, we evaluated the expression of the complete panel of sirtuins in adipose-derived stem cells isolated from both subcutaneous and visceral fat of non-obese and obese subjects. We aimed at investigating the influence of obesity on sirtuins’ levels, their role in obesity-associated inflammation, and the relationship with the peroxisome proliferator-activated receptor delta, which also plays functions in adipose tissue metabolism. The mRNA levels in the four types of adipose-derived stem cells were evaluated by quantitative polymerase chain reaction, in untreated cells and also after 8 h of hypoxia exposure. Correlations among sirtuins’ expression and clinical and molecular parameters were also analyzed. We found that sirtuin1–6 exhibited significant higher mRNA expression in visceral adipose-derived stem cells compared to subcutaneous adipose-derived stem cells of non-obese subjects. Sirtuin1–6 levels were markedly reduced in visceral adipose-derived stem cells of obese patients. Sirtuins’ expression in visceral adipose-derived stem cells correlated negatively with body mass index and C-reactive protein and positively with peroxisome proliferator-activated receptor delta. Finally, only in the visceral adipose-derived stem cells of obese patients hypoxia-induced mRNA expression of all of the sirtuins. Our results highlight that sirtuins’ levels in adipose-derived stem cells are consistent with protective effects against visceral obesity and inflammation, and suggest a transcriptional mechanism through which acute hypoxia up-regulates sirtuins in the visceral adipose-derived stem cells of obese patients.

SIRT1 (silent information regulator two protein) is a type III protein deacetylase that regulates a variety of important metabolic and physiologic processes including stress resistance, metabolism, apoptosis and energy balance. It reverses cholesterol transport and reduces risk for development of atherosclerosis and cardiovascular disease. The following review highlights the potential role of SIRT1 on cardiovascular biology and function.

Aims: To determine the effects and underlying molecular mechanisms of caloric restriction (CR) in C57BL/6 mice. Methods: Thirty-six 6-week-old male C57BL/6 mice were assigned to a normal control group (NC, n = 12), a high energy group (HE, n = 12), and a CR group (n = 12), and received a normal diet, a high-calorie diet, or a calorie-restricted diet, respectively, for 44 weeks. Body weight and serum glucose concentration were regularly recorded, and animals were sacrificed and hippocampus tissues were collected for immunohis-tochemistry (n = 6 per group), western blotting (n = 3 per group) and real-time polymerase chain reaction (n = 3 per group) analysis at the end of the 44-week experimental period. Immunohistochemistry, western blotting and real-time polymerase chain reaction were used to detect changes in hippocampal proteins may be involved in the SIRT1/mTOR pathways. Results: Body weight and serum glucose over the 44 weeks in animals from the CR group were lower than those of HE group. The number of SIRT1-immunoreactive cells in the CR group was significantly higher than in the NC and HE groups, and SIRT1 mRNA expression in the CR group was significantly higher than that in the HE group, but there was no difference in SIRT1 protein expression among the three groups. mTOR and S6K1 protein activation and mTOR and S6K1 mRNA were significantly lower in the CR group than in the NC group. Conclusions: Our findings suggest that a CR diet could lead to activation of SIRT1 and suppression of mTOR and S6K1 activation in C57BL/6 mice. We have shown that the SIRT1/mTOR signaling pathways may be involved in the neuroprotective effect of CR.

Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and
progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression
and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis.

Sirtuins (Sirt) are NAD-dependent
deacetylases that are activated by the antioxidants resveratrol
(RSV) and lipoic acid (LA). The objective of
this study was to determine in bovine liver and muscle
slice cultures the effect of RSV and LA treatment on
the expresssion of Sirt1, Sirt3, peroxisome proliferator-
activated receptor γ coactivator 1α (PPARGC1A),
and the forkhead box O transcription factors FoxO1
and FoxO3 as well as other factors involved in glucose
and lipid metabolism and related to Sirt activity.
Tissue slices from crossbred bulls were treated during
60 min with 40 or 80 μM RSV and 30, 100, 300,
or 1,000 μM LA under restricted conditions (Krebs-
Ringer buffer without nutrients) and fed conditions
(2.5 mM propionate in combination with 1 nM glucagon)
for liver slices or with 0.01 μM epinephrine for
muscle slices. Quantitative real-time PCR was used
to analyze the expression of the mRNA for the genes
studied and western blot analysis for the expression
of the protein for Sirt1. Our results show that the
expression of the mRNA for Sirt1 was enhanced by
RSV in liver under restriction (P ≤ 0.0112) and by
LA in muscle, more under restriction (P ≤ 0.0121)
than after epinephrine administration (P < 0.0001).
Sirt3 is affected in a dose-dependent manner by both
compounds in both tissues and under both metabolic
conditions (P ≤ 0.0452). The expression of the protein
for Sirt1 was increased by LA in both tissues under
restricted conditions (P = 0.0026 and P = 0.0201,
respectively) but in liver also in fed conditions (P =
0.0016). Genes involved in the antioxidant response
were upregulated in both tissues. These results indicate
that bovine Sirt respond differently to RSV and
LA stimulation than monogastric Sirt do and that
gluconeogenesis in ruminants is not related to Sirt to
the same degree as in monogastric species. However,
these results provide information about the possible
role of Sirt in ruminant metabolism.

Sirtuins, the mammalian homologs of the silent information regulator 2 gene of Saccharomyces cerevisiae, are members of the NAD(+)-dependent family of histone deacetylases. In vertebrates, 7 sirtuins have been described, with different cellular localizations and target proteins. Glucose and lipid metabolism are among the processes regulated by these enzymes. In ruminants, gluconeogenesis is the main biochemical pathway by which glucose is obtained. Because sirtuins in bovines have not been studied, the aim of this work was to obtain sequences coding for the 7 sirtuins and determine the expression patterns of sirtuin1 (Sirt1) and sirtuin3 (Sirt3) in the liver, muscle, and adipose tissue of calves and bulls. Using PCR amplification, we obtained sirtuin gene sequences and reported them to the National Center for Biotechnology Information GenBank. Characteristic sequence motifs corresponding to the sirtuin catalytic core domain were found, including the active and zinc-binding sites. Relative expression patterns of Sirt1 and Sirt3 in liver, muscle, and adipose tissue were quantified by real-time PCR, normalizing to the geometric mean of the housekeeping genes cyclophilin A and β-actin. Expression of Sirt1 was less in liver and muscle, whereas it was greater in adipose tissue of adult animals, with statistical differences (P=0.0071) only in the latter. In the case of Sirt3, expression was greater in all 3 adult tissues, but statistical differences were found only in liver (P=0.0141) and muscle (P=0.0017). The greatest expression was observed in liver for Sirt1 and in muscle for Sirt3, whereas the least expression was in muscle for Sirt1 and in adipose tissue for Sirt3. In other species, sirtuin expression (both Sirt1 and Sirt3) in liver is reported to be the greatest among these 3 tissues, a pattern different from what we measured. These differences in expression can be associated with metabolic differences between nonruminant and ruminant species. However, further research on the relationship between bovine sirtuins and ruminant metabolism is required for a better understanding of these fields.

Lin28 is a small RNA-binding protein that plays an important role in regulating developmental timing, stem cell reprogramming, and oncogenesis. However, the significance of the effect of post-translational modifications on Lin28 activity is not fully understood. In this study, we demonstrated that PCAF directly interacted with and acetylated Lin28. We also showed that the acetylation of Lin28 can be specifically reversed by the deacetylase SIRT1. These findings suggest that the PCAF/SIRT1 balance plays an important role in regulating Lin28 activity. Furthermore, we found that the cold shock domain of Lin28 is the major target of PCAF-mediated acetylation, which leads to a severe reduction in the Lin28 protein levels and an increase in the level of mature let-7a. This study provides the first demonstration that post-translational modification regulates Lin28 activity during let-7a biogenesis and sheds light on the regulation of Lin28 in ES cells and carcinogenesis.