Silent Mating Type Information Regulation 2 Homolog-1 Research Articles

The role of nonesterified fatty acids in cancer biology: Focus on tryptophan and related metabolism

Plasma nonesterified fatty acids (NEFA) are elevated in cancer, because of decreased albumin levels and of fatty acid oxidation, and increased fatty acid synthesis and lipolysis. Albumin depletion and NEFA elevation maximally release albumin-bound tryptophan (Trp) and increase its flux down the kynurenine pathway, leading to increased production of proinflammatory kynurenine metabolites, which tumors use to undermine T-cell function and achieve immune escape. Activation of the aryl hydrocarbon receptor by kynurenic acid promotes extrahepatic Trp degradation by indoleamine 2,3-dioxygenase and leads to upregulation of poly (ADP-ribose) polymerase, activation of which and also of SIRT1 (silent mating type information regulation 2 homolog 1) could lead to depletion of NAD+ and ATP, resulting in cell death. NEFA also modulate heme synthesis and degradation, changes in which impact homocysteine metabolism and production of reduced glutathione and hydrogen sulphide. The significance of the interactions between heme and homocysteine metabolism in cancer biology has received little attention. Targeting Trp disposition in cancer to prevent the NEFA effects is suggested.

Exosomes derived from diabetic serum accelerate the progression of osteoarthritis

Diabetes mellitus (DM) has been demonstrated to accelerate the progression of osteoarthritis (OA) by largely unknown mechanisms. Studies have shown that DM dysfunctional adipocyte-derived exosomes play a crucial role in the pathogenesis of remote organ functions. The present study aimed to clarify whether and how diabetic adipocyte-derived exosomes mediate the pathological regulation of OA. We found that intraarticular injection of DM serum exosomes in the non-diabetic mice significantly exacerbated OA injury as evidenced by a rough and fractured cartilage surface as well as increased chondrocyte apoptosis, decreased mitochondrial membrane potential (△Ψ) and increased expression of cleaved caspase-3. Mechanistic investigation identified that miR-130b-3p was significantly increased in circulating exosomes derived from DM mice and exosomes derived from HG-treated normal adipocytes, and we demonstrated that transfection of miR-130b-3p mimics significantly exacerbated the mitochondrial function of chondrocytes. Our data also indicated that miR-130b-3p impaired the △Ψ, increased cleaved caspase-3 levels, and decreased the expression of 5′-adenosine monophosphate-activated protein kinase α1 (AMPKα1), Silent mating-type information regulation 2 homolog 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in chondrocytes. Pharmacologic activation of AMPKα1 using AICAR reversed the △Ψ and catabolic responses in chondrocytes transfected with miR-130b-3p mimics. Moreover, AICAR decreased the effects of miR-130b-3p mimics on chondrocytes transfected with SIRT1-siRNA or PGC-1α-siRNA. The current study demonstrated that adipocyte-derived exosomal miR-130b-3p under DM conditions suppresses mitochondrial function in chondrocytes through targeting the AMPKα1/SIRT1/PGC1-α pathway, thus exacerbating OA injury.

Serum ANGPTL4 and SIRT1 factor levels and the Carotid Atherosclerotic plaque stability relationship analysis.

This study was to investigate the relationship between the levels of Angiopoietin-Like Protein 4 (ANGPTL4) and Silent Mating-type Information Regulation 2 Homolog 1 (SIRT1) and the stability of carotid atherosclerotic plaque. For this purpose, 108 patients with coronary heart disease in our hospital from Jan 2021 to May 2022 were selected as the coronary heart disease (CHD) group and 80 patients with the healthy examination as the control group. Patients' serum levels of ANGPTL4 and SIRT1 were collected, and their stability of carotid atherosclerotic plaque was determined by carotid ultrasound. According to their stability results, patients were divided into three subgroups: No plaque, Stable plaque, and Unstable plaque. The serum ANGPTL4 and SIRT1 levels were analyzed in different groups, and the correlation between their serum levels and the stability of carotid atherosclerotic plaque was analyzed by rank correlation. Results showed that the CHD group's serum ANGPTL4 and SIRT1 levels were lower, with statistical significance (P<0.05); A statistically significant difference in serum ANGPTL4 and SIRT1 levels were observed among patients with No plaques, Stable plaques, and Unstable plaques (P<0.05); A negative correlation was observed between serum levels of ANGPTL4 and SIRT1 and the stability of carotid atherosclerotic plaque (r=-0.438, -0.717, P<0.001); Serum ANGPTL4 and SIRT1 can be used as the evaluation method of carotid atherosclerotic plaque stability. When ANGPTL4 ≤ 30.17mg/L and SIRT1 ≤ 6.91μg/L, patients were more likely to develop unstable plaques; When ANGPTL4 ≤ 30.40mg/L and SIRT1 ≤ 6.87μg/L, patients were more likely to develop plaques (instability and/or stability). In conclusion, the serum levels of ANGPTL4 and SIRT1 in patients with CHD decreased. ANGPTL4 and SIRT1 will participate in the formation and development of carotid plaque, which can be used as a serological evaluation index to evaluate the occurrence and carotid atherosclerotic plaque's stability.

Scalp bacterial species influence SIRT1 and TERT expression in keratinocytes.

Scalp bacteria on the human scalp and scalp hair comprise distinct community structures for sites and individuals. To evaluate their effect on human keratinocyte cellular activity, including that of the hair follicular keratinocytes, the expression of several longevity genes was examined using HaCaT cells. A screening system that uses enhanced green fluorescent protein (EGFP) fluorescence was established to identify scalp bacteria that enhance silent mating type information regulation 2 homolog-1 (SIRT1) promoter activity in transformed HaCaT cells (SIRT1p-EGFP). The results of quantitative polymerase chain reaction (qPCR) revealed that several predominant scalp bacteria enhanced (Cutibacterium acnes and Pseudomonas lini) and repressed (Staphylococcus epidermidis) the expressions of SIRT1 and telomerase reverse transcriptase (TERT) genes in HaCaT cells. These results suggest that the predominant scalp bacteria are related to the health of the scalp and hair, including repair of the damaged scalp and hair growth, by regulating gene expression in keratinocytes.

Resveratrol Attenuates the Disruption of Lipid Metabolism Observed in Amyloid Precursor Protein/Presenilin 1 Mouse Brains and Cultured Primary Neurons Exposed to Aβ

To examine whether resveratrol (RSV), an activator of silent mating-type information regulation 2 homolog 1 (SIRT1), can reverse the disruption of lipid metabolism caused by β-amyloid peptide (Aβ), APP/PS1 mice or cultured primary rat neurons were treated with RSV, suramin (inhibitor of SIRT1), ZLN005, a stimulator of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), or PGC-1α silencing RNA. In the brains of the APP/PS1 mice, expressions of SIRT1, PGC-1α, low-density lipoprotein receptor (LDLR) and very LDLR (VLDLR) were reduced at the protein and, in some cases, mRNA levels; while the levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein E (ApoE), total cholesterol and LDL were all elevated. Interestingly, these changes were reversed by administration of RSV, while being aggravated by suramin. Furthermore, activation of PGC-1α, but inhibition of SIRT1, decreased the levels of PCSK9 and ApoE, while increased those of LDLR and VLDLR in the neurons exposed to Aβ, and silencing PGC-1α, but activation of SIRT1, did not influence the levels of any of these proteins. These findings indicate that RSV can attenuate the disruption of lipid metabolism observed in the brains of APP mice and in primary neurons exposed to Aβ by activating SIRT1, in which the mechanism may involve subsequently affecting PGC-1α.

Ginsenoside Rg1 Attenuates Premature Ovarian Failure of D-gal Induced POF Mice Through Downregulating p16INK4a and Upregulating SIRT1 Expression.

Premature ovarian failure (POF) refers to pathological amenorrhea before 40 years. To explore the regulatory effect of Rg1 on POF and clarify associated mechanisms. POF mice were induced by injecting with D-galactose (D-gal, 200 mg/kg/- day). Mice were divided into phosphate buffered saline (PBS), D-gal (POF mice), D-gal/Rg1 group (POF mice administrating D-gal/Rg1). Weight growth rate and ovarian weight coefficient were measured. Serum estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), superoxide dismutase (SOD), catalase (CAT) levels were examined using ELISA. The status of follicle and corpus luteum was determined using hematoxylin-eosin (HE) staining. P16INK4a and silent- mating type information regulation-2 homolog-1 (SIRT1) were determined using western blotting and RT-PCR. Weight growth rate and ovarian weight coefficient of mice in D-gal group were significantly decreased than PBS group (p<0.05). Serum E2, LH, SOD, CAT levels were significantly decreased, FSH levels were remarkably increased in D-gal group than PBS group (p<0.05). Rg1 (D-- gal/Rg1 group) significantly increased weight growth rate and ovarian weight coefficient, enhanced E2, LH, SOD, CAT levels and decreased FSH levels than D-gal group (p<0.05). HE staining demonstrated normal follicle morphology/structure of mice in PBS group and decreased the number of follicles, obvious vacuolation of corpus luteum and increased atretic follicles of mice in D-gal group. Compared with D-gal group, the number of follicles was increased, luteal follicles were decreased in mice in D-gal/Rg1 group (p<0.05). Rg1 significantly (D-gal/Rg1) downregulated p16INK4a and upregulated SIRT1 expression in ovarian tissues of mice compared to the D-gal group (p<0.05). Rg1 could delay premature ovarian failure in D-gal induced POF mouse model through downregulating p16INK4a and upregulating SIRT1 expression.

Local treatment with Sema3a could promote the osseointegration of hydroxyapatite coated titanium rod in diabetic rats.

Recently, semaphorin 3A (Sema3A) has been identified as a critical gene for osteogenic differentiation of mesenchymal stem cells and increases osteoblastic bone formation. However, in current research studies, there is a lack of focus on whether Sema3a can affect the osseointegration of titanium rods in diabetes and through what biological mechanisms. Therefore, the present work was aimed to evaluate the effect of local administration with Sema3A on hydroxyapatite coated titanium rod osseointegration in diabetic rat model and preliminary exploration of possible mechanisms. The MC3T3-E1 cells were co-cultured with Sema3A and high glucose and induced to osteogenesis, and the cell viability, osteogenic activity was observed by Cell Counting Kit-8(CCK-8), Alkaline Phosphatase staining, Alizarin Red Staining, and Western Blot. In vitro experiments, CCK-8, ALP, and ARS staining results show that the mineralization and osteogenic activity of MC3T3-E1increased significantly after intervention by Sema3A, as well as a higher levels of protein expressions including Runt-Related Transcription Factor 2, silent mating type information regulation 2 homolog-1(SIRT1), catalase (CAT), superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2). In vivo experiment, a better stability and osseointegration of the titanium rod were observed after treatment with Sema3A, as well as a higher SOD1, SOD2, CAT, and SIRT1 gene expression. The present study indicates that local treatment with Sema3A was associated with increased osseointegration of titanium rod by reducing the oxidative stress of osteoblasts and enhancing the function of osteoblasts in a diabetic rat.

Activation of SIRT-1 Signalling in the Prevention of Bipolar Disorder and Related Neurocomplications: Target Activators and Influences on Neurological Dysfunctions.

SIRT-1 (silent mating-type information regulation 2 homolog-1) is a protein found in neuronal nuclei, microglia, and astrocyte cells of the brain. It is sometimes referred to as NAD + -dependent deacetylase (nicotinamide adenine dinucleotide). The activation of sirtuins (SIRT-1-7) has been shown to protect against a wide range of disorders, including neurodegenerative and neuropsychiatric disorders. SIRT-1 has gained considerable interest from these families because of its early link to long-life expansion and calorie restriction involvement. SIRT-1 is necessary for gene silencing, cell cycle regulation, fat and glucose metabolism, oxidative stress, ageing, and memory formation. In this review, we investigate the role of SIRT-1 downregulation in the progression of bipolar disorder (BD) and neurological abnormalities, as well as related neurological alterations such as genetic dysfunction, neurotransmitter imbalance, oxidative stress-induced apoptosis, and mitochondrial dysfunction. BD is a psychiatric disease distinguished by extreme mood fluctuations that range from depressive lows to manic highs. BD is a complicated disorder with numerous clinical signs and neurocomplications that produce significant behavioural problems. SIRT-1 deficiency in the brain has been demonstrated to affect the activity of its transcription factors and molecular changes, including genetic defects. SIRT-1 is now being studied as a potential therapeutic target for a range of brain disorders. A recent study also found that activating SIRT-1 signalling performs a protective effect in avoiding depression and mania-like behaviours. Furthermore, this review investigates the potential mechanisms by which SIRT-1 regulates neuronal transmission and neurogenesis. As a result of our review, we revealed that SIRT-1 activators have neuroprotective potential in BD and related neurological dysfunctions.

Post-translational Modification in Control of SIRT1 Stability during DNA Damage Response.

SIRT1 (silent mating type information regulation 2 homolog 1), a class III histone deacetylase, is known to participate in multiple steps of the DNA damage response (DDR) by deacetylating several key DDR proteins. At present, the mechanisms regulating SIRT1 protein stability upon DNA damage have yet to be fully elucidated. In this study, we reveal that, under severe DNA damage, SIRT1 undergoes two forms of post-translational modifications (PTMs): (i) increased polyubiquitination and proteasomal degradation mediated by TRIM28 (tripartite motif-containing protein 28), a RING-domain E3 ligase; and (ii) cleavage at C-terminal mediated by caspases. Importantly, there is reciprocal effects between these forms of PTMs: while suppression of proteasome reduces caspases-mediated cleavage, the cleaved SIRT1 has enhanced interaction with TRIM28, thus facilitating the ubiquitination and proteasomal degradation of SIRT1. Functionally, SIRT1 works as an anti-apoptotic protein in DDR, and the above-mentioned PTMs of SIRT1 subsequently enhances cell death induced by DNA damage agents. Thus, our study has uncovered a pivotal role of SIRT1 post-translational regulation in determining cell fate in DDR.

Hyperoside Attenuate Inflammation in HT22 Cells via Upregulating SIRT1 to Activities Wnt/β-Catenin and Sonic Hedgehog Pathways.

Neuroinflammation plays important roles in the pathogenesis and progression of altered neurodevelopment, sensorineural hearing loss, and certain neurodegenerative diseases. Hyperoside (quercetin-3-O-β-D-galactoside) is an active compound isolated from Hypericum plants. In this study, we investigate the protective effect of hyperoside on neuroinflammation and its possible molecular mechanism. Lipopolysaccharide (LPS) and hyperoside were used to treat HT22 cells. The cell viability was measured by MTT assay. The cell apoptosis rate was measured by flow cytometry assay. The mRNA expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) were determined by quantitative reverse transcription polymerase chain reaction. The levels of oxidative stress indices superoxide dismutase (SOD), reactive oxygen species (ROS), catalase (CAT), glutathione (GSH), and malondialdehyde (MDA) were measured by the kits. The expression of neurotrophic factor and the relationship among hyperoside, silent mating type information regulation 2 homolog-1 (SIRT1) and Wnt/β-catenin, and sonic hedgehog was examined by western blotting. In the LPS-induced HT22 cells, hyperoside promotes cell survival; alleviates the level of IL-1β, IL-6, IL-8, TNF-α, ROS, MDA, Bax, and caspase-3; and increases the expression of CAT, SOD, GSH, Bcl-2, BDNF, TrkB, and NGF. In addition, hyperoside upregulated the expression of SIRT1. Further mechanistic investigation showed that hyperoside alleviated LPS-induced inflammation, oxidative stress, and apoptosis by upregulating SIRT1 to activate Wnt/β-catenin and sonic hedgehog pathways. Taken together, our data suggested that hyperoside acts as a protector in neuroinflammation.

Cannabidiol Induces Autophagy to Protects Neural Cells From Mitochondrial Dysfunction by Upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways.

The protective effect of Cannabidiol on Parkinson’s disease (PD) has been found in recent study. However, the specific mechanism of the protective effect of Cannabidiol on PD nerve damage require further exploration. This study aims to investigate effect of Cannabidiol on MMP-induced Neural Cells (SH-SY5Y) mitochondrial dysfunction. MMP+ and Cannabidiol were used to treat SH-SY5Y cells, the cells viability was measured by MTT assay. The expression of Tyrosine hydroxylase (TH) in cells was measured by western blotting and Immunofluorescence staining. The relationship among Cannabidiol, Silent mating type information regulation 2 homolog-1 (SIRT1) and NOTCH signaling, NF-κB signaling was examined by western blotting. The effect of Cannabidiol on MMP+-induced mitochondrial dysfunction of SH-SY5Y cells was measured by western blotting. Cannabidiol alleviated loss of TH expression and cytotoxicity in the MPP+-induced SH-SY5Y cells. Further mechanistic investigation showed that Cannabidiol induced SH-SY5Y cells autophagy to protects cells from mitochondrial dysfunction by upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways. Taken together, Cannabidiol acts as a protector in PD.

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.

Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood. We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model. LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart. LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.

Long non‑coding RNA H19 inhibition ameliorates oxygen‑glucose deprivation‑induced cell apoptosis and inflammatory cytokine expression by regulating the microRNA‑29b/SIRT1/PGC‑1α axis.

As one of the earliest discovered long non‑coding (lnc)RNAs, lncRNA H19 imprinted maternally expressed transcript (H19) participates in regulating ischemic stroke. The present study aimed to investigate the combined roles of lncRNA H19, microRNA (miR)‑29b, silent mating‑type information regulation 2 homolog 1 (SIRT1) and peroxisome proliferator‑activated receptor‑g co‑activator‑1α(PGC‑1α) following ischemic stroke. lncRNA H19 expression levels in the middle cerebral artery occlusion(MCAO) mouse model and HT22 cells subjected to oxygen‑glucose deprivation(OGD) were detected via reverse transcription‑quantitative PCR (RT‑qPCR). H19 small interfering RNA was used to knockdown H19 expression. Following OGD treatment, MTT, flow cytometry, ELISA, RT‑qPCR and western blotting assays were performed to assess cell proliferation, cell apoptosis, inflammatory cytokine concentrations, and lncRNA H19, miR‑29b, SIRT1, PGC‑1α expression levels, respectively. In the present study, MCAO model mice and OGD‑treated cells displayed significantly increased lncRNA H19 expression levels compared with sham mice and control cells, respectively. lncRNA H19 knockdown ameliorated OGD‑induced cell apoptosis and increases in inflammatory cytokine concentrations. Furthermore, lncRNA H19 knockdown also attenuated OGD‑mediated downregulation of miR‑29b, SIRT1 and PGC‑1α expression levels. Collectively, the results of the present study demonstrated that lncRNA H19 knockdown ameliorated OGD‑induced cell apoptosis and increases in inflammatory cytokine concentrations by regulating miR‑29b, SIRT1 and PGC‑1α expression levels, which suggested the potential role of lncRNA H19 in ischemic stroke.

Postprandial triglyceride-rich lipoproteins-induced premature senescence of adipose-derived mesenchymal stem cells via the SIRT1/p53/Ac-p53/p21 axis through oxidative mechanism

The accumulation of senescent adipose-derived mesenchymal stem cells (AMSCs) in subcutaneous white adipose tissue (WAT) is the main cause for the deterioration of WAT and the subsequent age-related disorders in obesity. The number of AMSCs staining positively for senescence-associated-β-galactosidase (SA-β-Gal) increased significantly after incubation with postprandial triglyceride-rich lipoproteins (TRL), accompanied by an impaired cell proliferation capacity and increased expression of inflammatory factors. Besides, the expression of anti-aging protein, silent mating-type information regulation 2 homolog 1 (SIRT1), was downregulated significantly, while those of acetylated p53 (Ac-p53), total p53, and p21 proteins were upregulated significantly during postprandial TRL-induced premature senescence of AMSCs. Furthermore, the production of intracellular reactive oxygen species (ROS) in the TRL group increased significantly, while pretreatment with the ROS scavenger N-acetyl-L-cysteine effectively attenuated the premature senescence of AMSCs by decreasing ROS production and upregulating SIRT1 level. Thus, postprandial TRL induced premature senescence of AMSCs through the SIRT1/p53/Ac-p53/p21 axis, partly through increased oxidative stress.

Effects of electroacupuncture on miR-34a-5p/SIRT1 signaling in the trigeminal ganglion of rats with migraine

To investigate the effect of electroacupuncture(EA) on miR-34a-5p, silent mating type information regulation 2 homolog-1 (SIRT1) and nuclear factor-κB subunit p65 (NF-κB p65) in the trigeminal ganglion of rats with migraine, so as to explore the mechanisms of EA underlying prevention of migraine. Male SD rats were randomly divi-ded into normal, sham operation, model, EA, and EA plus EX527(a SIRT1 inhibitor) groups, with 10 rats in each group. The rat model of migraine was established by electrical stimulation of the trigeminal ganglion. Before modeling, EA was applied at "Waiguan"(TE5) and "Fengchi"(GB20) for 20 min each time, once a day for 5 consecutive days, and intraperitoneal injection of EX527 (5 mg/kg) every day simultaneously. Serum prostaglandin E2 (PGE2) and calcitonin gene-related peptide (CGRP) concentrations were measured by enzyme-linked immunosorbent assay. The levels of miR-34a-5p, SIRT1 and interleukin-1β (IL-1β) mRNA，and protein expression of SIRT1, IL-1β, NF-κB p65, NF-κB Ac-p65 and cyclooxygenase-2 （COX2） in trigeminal ganglia were detected by real-time quantitative PCR and Western blot, separately. The serum concentrations of PGE2 and CGRP， the expression of miR-34a-5p, IL-1β mRNA and protein, NF-κB p65, NF-κB Ac-p65 and COX2 protein expression in the trigeminal ganglion were remarkably increased (P<0.05), while the SIRT1 mRNA and protein decreased (P<0.05) in the model group in contrast to the normal group. Following EA intervention， the serum PGE2 and CGRP concentrations, miR-34a-5p expression, IL-1β mRNA and protein, NF-κB p65, NF-κB Ac-p65 and COX2 protein expression were significantly down-regulated (P<0.05), and SIRT1 mRNA and protein significantly up-regulated (P<0.05). Compared with the EA group, the serum concentrations of PGE2 and CGRP, IL-1β mRNA and protein, NF-κB p65, NF-κB Ac-p65 and COX2 protein expressions increased (P<0.05), and SIRT1 protein decreased (P<0.05) in the EA plus EX527 group. In migraine rats, EA can inhibit miR-34a-5p expression in the trigeminal ganglion, increase SIRT1 expression, down-regulate IL-1β/COX2 inflammation signals, reduce PGE2 synthesis, and thus redue CGRP released from the peripheral terminals, which may be one of the mechanisms of EA in preventing migraine.

Silent Mating–Type Information Regulation 2 Homolog 1 Attenuates the Neurotoxicity Associated with Alzheimer Disease via a Mechanism Which May Involve Regulation of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α

To investigate the neuroprotective role of silent mating-type information regulation 2 homolog 1 (SIRT1) in Alzheimer disease (AD), brain tissues from patients with AD and APP/PS1 mice as well as primary rat neurons exposed to oligomers of amyloid-β peptide were examined. The animals were treated with resveratrol (RSV) or suramin for 2 months. Cell cultures were treated with RSV, suramin, and the peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) stimulator ZLN005. Cells were transiently transfected with PGC-1α silencing RNA. The level of SIRT1 in brain tissues from patients with AD and APP/PS1 mice, including nuclear and mitochondrial proteins, as well as in primary neurons exposed to oligomers of amyloid-β peptide, was decreased. Overexpression of APP/PS1 impaired learning and memory of mice; produced more senile plaques, disrupted membranes, and resulted in broken or absent cristae of mitochondria in the brain; decreased levels of A disintegrin and metallopeptidase domain 10, beta-secretase 2, 8-oxoguanine DNA glycosylase-1, PGC-1α, and NAD+; and increased levels of beta-secretase 1 and apoptosis. Interestingly, these changes were attenuated significantly by RSV treatment but enhanced by suramin administration. By activating PGC-1α but inhibiting SIRT1, apoptotic cell death was significantly decreased; however, by activating SIRT1 but inhibiting PGC-1α with small interfering PGC-1α, these levels remained unchanged. These findings indicate that SIRT1 may protect against AD-associated neurotoxicity, which might involve PGC-1α regulation.

Acupuncture Targeting SIRT1 in the Hypothalamic Arcuate Nucleus Can Improve Obesity in High-Fat-Diet-Induced Rats with Insulin Resistance via an Anorectic Effect

Objective: To investigate the anorexigenic and anti-obesity effectiveness of electroacupuncture (EA) on high-fat-diet-induced (HFDI) obese rats with insulin resistance (IR) and to reveal the possible mechanisms of EA affecting SIRT1 (silent mating type information regulation 2 homolog 1) in the central nervous system (CNS). Methods: We divided 60 rats into 6 groups. All interventions, including EA and intracerebroventricular administration, were performed after 8 weeks of model establishment. We tested obesity phenotypes like body weight (BW) gain; food intake; and IR levels including glucose infusion rate, intraperitoneal insulin tolerance test (IPITT), and intraperitoneal glucose tolerance test (IPGTT) during treatment. We detected protein expression and microscopic locations in hypothalamic SIRT1, the transcription factor FOXO1 (forkhead box protein O1), acetylated FOXO1 (Ac-FOXO1), pro-opiomelanocortin (POMC), and neuropeptide Y (NPY) via Western blotting and immunofluorescence, and monitored gene expression by real-time polymerase chain reaction. Results: Like the SIRT1 agonist, EA suppressed BW gain and IR levels in obese rats, but this was only partially blocked by the SIRT1 antagonist. EA could upregulate protein expression of hypothalamic SIRT1 and downregulate the acetylation level of FOXO1 in the hypothalamic arcuate nucleus (ARC), which decreased gene expression of NPY and increased that of POMC. The agonist targeted the hypothalamic SIRT1 gene, unlike EA, which targeted posttranscriptional regulation. Conclusion: EA could improve obesity in HFDI rats with IR via its anorectic effect. This effect targeted posttranscriptional regulation of the SIRT1 gene, which induced upregulation of ARC FOXO1 deacetylation and mediated the gene expression of POMC and NPY.

Astaxanthin attenuates contrast-induced acute kidney injury through silent mating-type information regulation 2 homolog-1/peroxisome proliferator-activated receptor γ co-activator–α/NRF1 signaling pathway

Objectives: In this study, we established a model of contrast-induced acute kidney injury with iohexol. This model was used to investigate whether astaxanthin (AST) attenuates oxidative stress and apoptosis by activating silent mating-type information regulation 2 homolog-1 (SIRT1) signaling pathway in rat renal tubular epithelial cells (NRK-52E). Materials and Methods: NRK-52E cells were randomly divided into six groups: control group (CON group), vehicle (dimethyl sulfoxide group, iohexol group (I group), AST pretreatment group (AST + I group), AST plus nicotinamide (NA) co-pretreatment group (AST + NA + I group), and NA treatment group (NA + I group). The cellular activity was measured by cell counting kit-8. We estimated the levels of malonaldehyde (MDA) by the thiobarbituric acid method, and the level of intracellular reactive oxygen species (ROS) was measured by flow cytometry. Western blot analysis was conducted to detect the protein levels of SIRT1, peroxisome proliferator-activated receptor γ co-activator–α (PGC-1α), and NRF1. Results: Compared with the CON group, the I group showed suppressed cellular activity; increased levels of MDA and ROS; and decreased levels of SIRT1, PGC-1α, and NRF1 protein. Compared with the I group, AST + I pretreated group showed high cellular activity; low levels of MDA and ROS; and increased levels of SIRT1, PGC-1α, and NRF1 protein. SIRT1 inhibitor NA reversed the protective effect of AST. Compared with the AST + NA + I group, NA + I group showed low cellular activity; high levels of MDA and ROS; and low levels of SIRT1, PGC-1α, and NRF1 protein, which further confirmed the protective effect of AST. Conclusion: AST alleviated iohexol-induced NRK-52E cell injury by decreasing the formation of MDA and ROS and upregulating the SIRT1/PGC-1α/NRF1 signaling pathway.

Febuxostat, a novel inhibitor of xanthine oxidase, reduces ER stress through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression.

Endoplasmic reticulum (ER) stress has been implicated in the development of various renal diseases. Thus, inhibition of ER stress using pharmacological agents may serve as a promising therapeutic approach. We postulated that febuxostat, a novel xanthine oxidase inhibitor, could suppress the ER stress through upregulation of SIRT1 (silent mating type information regulation 2 homolog 1)-AMPK (AMP activated protein kinase)-HO-1 (heme oxygenase-1)/thioredoxin expression. We examined the effect of febuxostat on the ER stress induced by a chemical inducer, tunicamycin and non-chemical agents such as angiotensin II, aldosterone, high glucose, and albumin in renal tubular cells. We further examined the in vivo effects of febuxostat using mouse model of kidney disease induced by unilateral ureteral obstruction (UUO). Expression of ER stress was measured by western blot analysis and immunohistochemical stain. Febuxostat suppressed the ER stress induced by tunicamycin and non-chemical agents, as shown by inhibition of increased GRP78 (glucose-related protein78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor 2α) expression. Inhibitory effect of febuxostat was mediated through upregulation of SIRT1-AMPK followed by induction of HO-1 and thioredoxin. In animal model of UUO, febuxostat reduced the UUO-induced ER stress, which was abolished by pretreatment with SIRT1 inhibitor (sirtinol) and AMPK inhibitor (compound C). Febuxostat could suppress the ER stress caused by various ER stress inducers through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression. Targeting these pathways might serve as one of the possible therapeutic approaches in kidney diseases under excessive ER stress.

S51RECALIBRATING THE EPIGENETIC CLOCK: APPLICATIONS FOR ASSESSING BIOLOGICAL AGEING IN THE HUMAN BRAIN

Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed on human social habits and physiology during the past 50 years. This drastic change in life-style is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase silent mating-type information regulation 2 homolog 1 (SIRT1) as a molecular effector of the environment in shaping the circadian epigenetic landscape.