Silent Information Regulator 1 Signaling Research Articles

Attenuation of chromium (VI) and arsenic (III)-induced oxidative stress and hepatic apoptosis by phloretin, biochanin-A, and coenzyme Q10 via activation of SIRT1/Nrf2/HO-1/NQO1 signaling.

Heavy metal contamination is an alarming concern on a global scale, as drinking tainted water significantly increases human susceptibility to heavy metals. In a realistic scenario, humans are often exposed to a combination of harmful chemicals rather than a single toxicant. Phloretin (PHL), biochanin-A (BCA), and coenzyme Q10 (CoQ10) are bioactive compounds owning plentiful pharmacological properties. Henceforth, the current research explored the putative energizing effects of selected nutraceuticals in combined chromium (Cr) and arsenic (As) intoxicated Swiss albino mice. Potassium dichromate (75 ppm) and sodium meta-arsenite (100 ppm) were given in the drinking water to induce hepatotoxicity, conjugated with PHL and BCA (50 mg/kg each), and CoQ10 (10 mg/kg) intraperitoneally for 2 weeks. After the statistical evaluation, it was observed that the hepato-somatic index, metal load, and antioxidant activity (lipid peroxidation and protein carbonyl content) increased along with the concomitant decrease in the antioxidants (catalase, glutathione-S-transferase, superoxide dismutase, reduced glutathione, and total thiol) in the Cr and As intoxicated mice. Additionally, light microscopy observations, DNA breakages, decreased silent information regulator 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) gene expressions, together with stimulated apoptotic cell death manifested by the increased expressions of caspase 8 and caspase 3, thus, proved consistency with the aforementioned outcomes. Importantly, the treatment with nutraceuticals not only restored the antioxidant activity but also favorably altered the expressions of SIRT1, Nrf2, HO-1, and NQO1 signaling and apoptosis markers. These findings highlight the crucial role of the PHL, BCA, and CoQ10 combination in reducing Cr and As-induced hepatotoxicity in mice. By averting the triggered apoptosis in conjunction with oxidative stress, this combination increases the SIRT1, Nrf2, HO-1, and NQO1 signaling, thereby reassuringly maintaining the cellular equilibrium.

Icosapent ethyl alleviates acetic acid-induced ulcerative colitis via modulation of SIRT1 signaling pathway in rats.

Ulcerative colitis (UC) is a global inflammatory bowel disease. This study aimed to assess the effects of icosapent ethyl on acetic acid-induced colitis in rats as well as the underlying mechanisms involved. 36 male Wister rats were equally divided into six groups: control, UC, mesalamine 100mg/kg, icosapent 150mg/kg, icosapent 300 mg/kg, and EX527-icosapent 300mg/kg groups. Except for control group, UC was induced by acetic acid instillation into colon. Drugs were administered once daily for one week then under thiopental anaesthesia, colons were excised. Colitis macroscopic and microscopic scores were assessed. A part of colon was homogenized for detection of malondialdehyde (MDA), inerleukin1 (IL-1β), tumor necrosis factor (TNF-α), superoxide dismutase (SOD), phosphorylated Akt (pAkt) and caspase 3 levels. Silent information regulator 1 (SIRT1), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 (Nrf2) mRNA expressions were detected. Mallory-stained colonic sections were examined for collagen fibres detection. Immunohistochemistry of NF-κB and p53 expressionsin colonic sections were assessed. Acetic acid induced colitis with increments in MDA, IL-1β, TNF-α, and caspase 3 levels while decreased SOD, pAkt, SIRT1, HO-1, and Nrf2 with increased collagen fibres as well as NF-κB and p53. Icosapent decreased macro& microscopic colitis scores, MDA, IL-1β, TNF-α, and caspase 3 levels while increased SOD, pAkt, SIRT1, HO-1, and Nrf2 with decreased collagen fibres as well as NF-κB and p53. The effects of icosapent 300mg/kg were similar to mesalamine. Icosapent effects were antagonized by EX527. Icosapent alleviated acetic acid-induced colitis via its anti-inflammatory, antioxidant, and anti-apoptotic effects mediated in part by SIRT1 pathway activation.

Andrographolide improves the dysfunction of endothelial progenitor cells from angiotensin II-induced hypertensive mice through SIRT1 signaling

Endothelial progenitor cells (EPCs) are crucial for the maintenance of vascular homeostasis. The dysfunction of EPCs contributes to the endothelial damage in hypertension. Andrographolide (AGP) is a traditional Chinese patent medicine that has been reported to have protective effects on cardiovascular system. However, the effect of AGP on the function of EPCs in hypertension remains unknown. In this study, we aimed to elucidate the effect of AGP on EPCs and the underlying mechanisms. In vivo, the blood pressure and endothelial function (indicated by endothelial dependent vasodilation) of AGP-fed angiotensin II (Ang II)-infused hypertensive mice were examined. In vitro, the function of EPCs isolated from bone marrow were evaluated by tube formation, migration, and adhesion assay. Additionally, a silent information regulator 1 (SIRT1) inhibitor/agonist and a small interfering RNA (si-RNA) targeting SIRT1 were used to determine the pathway involved. The results showed that AGP not only reduced blood pressure, improved endothelial function in hypertensive mice but also restored the dysfunction of EPCs of hypertension in vitro. Mechanistically, AGP up-regulated SIRT1 expression, decreased the Bax/Bcl-2 ratio and the expression level of Cleaved caspase-3, thus inhibiting the apoptosis of Ang II induced EPCs. However, the beneficial effects of AGP on EPCs disappeared after the inhibition or the knockdown of SIRT1. To summarize, this study demonstrates for the first time that AGP improves the dysfunction of EPCs through SIRT1-mediated anti-apoptotic effects. Our findings might provide a novel therapeutic strategy for treating vascular damage in hypertension.

Regulation of radiation-induced liver damage by modulation of SIRT-1 activity: In vivo rat model.

Silent information regulator 1 (SIRT-1), a nicotinamide adenine dinucleotide-dependent deacetylase, was found to regulate cell apoptosis, inflammation, and oxidative stress response in living organisms. Therefore, the role of SIRT-1 in regulating forkhead box O/poly ADP-ribose polymerase-1 (FOXO-1/PARP-1) signaling could provide the necessary validation for developing new pharmacological targets for the promotion or inhibition of SIRT-1 activity toward radiation sensitivity. In the present study, the SIRT-1 signaling pathway is being investigated to study the possible modulatory effect of resveratrol (RSV, SIRT-1 activator) versus nicotinamide (NAM, SIRT-1 inhibitor) in case of liver damage induced by whole-body gamma irradiation. Rats were exposed to 6 Gy gamma radiation after being pretreated with either RSV (10 mg/kg/day) or NAM (100 mg/kg/day) for 5 days, and subsequent examining hepatic morphological changes and apoptotic markers were assessed. The expression of SIRT-1, FOXO-1, and cleaved PARP-1 in the liver was analyzed. RSV improved radiation-induced apoptosis, mitochondrial dysfunction, and inflammation signified by low expression of caspase-3, lactate dehydrogenase, complex-I activity, myeloperoxidase, and total nitric oxide content. RSV increased the expression of SIRT-1, whereas cleaved PARP-1 and FOXO-1 were suppressed. These protective effects were suppressed by inhibition of SIRT-1 activity using NAM. These findings suggest that RSV can attenuate radiation-induced hepatic injury by reducing apoptosis and inflammation via SIRT-1 activity modulation.

Effects and mechanisms of CTRP3 overexpression in secondary brain injury following intracerebral hemorrhage in rats.

C1q/TNF-related protein-3 (CTRP3) is a novel adipokine that serves an important role in oxidative stress, anti-apoptosis, anti-inflammation and immune regulation. The aim of the present study was to investigate the protective role of CTRP3 against intracerebral hemorrhage (ICH)-induced brain injury. A model of autologous arterial blood-induced ICH was constructed in rats. Intracerebral infusion of a lentivirus carrying the CTRP3 gene was used to induce CTRP3 overexpression in the brain. The effects and mechanisms of CTRP3 overexpression on brain injury were investigated by detecting brain edema, blood-brain barrier (BBB) integrity, neurological function and inflammatory-associated factors 3 days after ICH. The present results demonstrated that CTRP3 overexpression ameliorated ICH-induced neurological dysfunction, decreased brain edema, maintained BBB integrity and attenuated inflammation. The protective effect of CTRP3 overexpression was associated with increased activation of silent information regulator 1 (SIRT1). In conclusion, the present study demonstrated that CTRP3 overexpression protected against ICH-induced brain injury in rats, potentially via activating the SIRT1 signaling pathway.

Activation of SIRT1 by Resveratrol Alleviates Pressure Overload-Induced Cardiac Hypertrophy via Suppression of TGF-β1 Signaling

Introduction: Silent information regulator 1 (SIRT1) has been extensively investigated in the cardiovascular system and has been shown to play a pivotal role in mediating cell death/survival, energy production, and oxidative stress. However, the functional role of SIRT1 in pressure overload-induced cardiac hypertrophy and dysfunction remains unclear. Resveratrol (Rsv), a widely used activator of SIRT1, has been reported to protect against cardiovascular disease. We here examine whether activation of SIRT1 by Rsv attenuate pressure overload-induced cardiac hypertrophy and to identify the underlying molecular mechanisms. Methods: In vivo, rat model of pressure overload-induced myocardial hypertrophy was established by abdominal aorta constriction (AAC) procedure. In vitro, Angiotensin II (Ang II) was applied to induce hypertrophy in cultured neonatal rat cardiomyocytes (NCMs). Hemodynamics and histological analyses of the heart were evaluated. The expression of SIRT1, transforming growth factor-β1 (TGF-β1)/phosphorylated (p)-small mother against decapentaplegic (Smad)3 and hypertrophic markers were determined by immunofluorescence, real-time PCR, and Western blotting techniques. Results: In the current study, Rsv treatment improved left ventricular function and reduced left ventricular hypertrophy and cardiac fibrosis significantly in the pressure overload rats. The expression of SIRT1 was significantly reduced, while the expression of TGF-β1/p-Smad3 was significantly enhanced in AAC afflicted rat heart. Strikingly, treatment with Rsv restored the expressions of SIRT1 and TGF-β1/p-Smad3 under AAC influence. However, SIRT1 inhibitor Sirtinol (Snl) markedly prevented the effects of Rsv, which suggest that SIRT1 signaling pathway was involved in the cardiac protective effect of Rsv. In vitro studies performed in Ang II-induced hypertrophy in NCMs confirmed the cardiac protective effect of Rsv. Furthermore, the study presented that SIRT1 negatively correlated with the cardiac hypertrophy, cardiac fibrosis, and the TGF-β1/p-Smad3 expression. Conclusions: Taken together, these results indicated that activation of SIRT1 by Rsv attenuates cardiac hypertrophy, cardiac fibrosis, and improves cardiac function possibly via regulation of the TGF-β1/p-Smad3 signaling pathway. Our study may provide a potential therapeutic strategy for cardiac hypertrophy.

Tropisetron protects against brain aging via attenuating oxidative stress, apoptosis and inflammation: The role of SIRT1 signaling

AimsThe aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 (SIRT1). Materials and methodsAging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene (SIRT1) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed. Key findingsTropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate SIRT1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. SignificanceTropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via SIRT1 signaling activation.

Propofol relieves oxidative stress response of cerebral ischemiareperfusion injury through SIRT1 signaling pathway.

This study explored the effects of propofol on the cognitive function and expressions of superoxide dismutase (SOD) and malondialdehyde (MDA) through the silent information regulator 1 (SIRT1) signaling pathway during cerebral ischemia-reperfusion (I/R) injury. C57BL/6J mice were used and divided into Sham group, I/R group (I/R model established via ligation of artery) and Treated group (peritoneal injection of propofol) according to different treatments. The memory ability of mice was evaluated using Morris water maze test, and the motor coordination was assessed using Rota rod test and oblique beam walking test. The brain tissues were prepared into embedded sections, and then the pathological changes in brain neurons were detected via hematoxylin-eosin (HE) staining, and the changes in apoptosis of brain tissues were detected via flow cytometry. Moreover, after the mice were anesthetized and sacrificed, the brain tissues were isolated and whole blood was collected. Then the changes in SIRT1 protein were determined using Western blotting, and the changes in MDA and SOD activity were determined through biochemical assays. The results of Morris water maze test and elevated plus-maze test revealed that transfer latency time (TLT) was significantly prolonged, and escape latency time (ELT) was significantly shortened in the I/R group compared with those in Sham group (*P<0.05), indicating memory impairment after cerebral I/R injury. TLT was shortened, and ELT was significantly prolonged in the Treated group compared with those in I/R group (#P<0.05). In Rota rod test, the falling down time was obviously shorter in the I/R group than in the Sham group (*P<0.05), while it was obviously longer in the Treated group than that in the I/R group (#P<0.05). Compared with the Sham group, the I/R group had neurological impairment, manifested as the evident increase in motor performance score (*P<0.05), and the motor performance score in the Treated group was evidently lower than that in the I/R group (#P<0.05). The apoptosis was markedly enhanced in the I/R group (*P<0.05), while it was markedly weakened in the Treated group (#P<0.05) compared with that in the Sham group. In addition, the results of Western blotting showed that the expression of SIRT1 was evidently higher in I the /R group than that in the Sham group, while it evidently declined after treatment with propofol (#P<0.05).

Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity

Silent Information Regulator 1 (SIRT1), an NAD+-dependent deacetylase, contributes to the neuroprotective effect. However, intracellular signaling pathways that affect SIRT1 function remain unknown. It is well known that N-methyl-D-aspartate (NMDA) receptor activation induces calcium influx which then activates PKC, and SIRT1 is a mRNA target for HuR protein. We hypothesize that Ca2+-PKC-HuR-SIRT1 pathway modulates SIRT1 function. The present study is to investigate the potential pathway of SIRT1 in the SH-SY5Y cell line as an in vitro model of NMDA-induced neurotoxicity. The results showed that: (1) SIRT1 levels were downregulated in NMDA model; (2) NMDA induced an increase in serine phosphorylation of HuR, while inhibition of serine phosphorylation of HuR increased SIRT1 levels, promoting cell survival; (3) PKC inhibitor (Gö 6976) reversed NMDA insults and also suppressed serine phosphorylation of HuR; (4) 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, fully reversed NMDA insults and also inhibited PKC activity evoked by NMDA. These results indicate that intracellular elevated Ca2+ activates PKC, which phosphorylates HuR and then promotes SIRT1 mRNA decay and subsequent neuronal death in NMDA model. Therefore, the study suggests that inhibition of Ca2+-PKC-HuR-SIRT1 pathway could be an effective strategy for preventing certain neurological diseases related to NMDA excitotoxicity.

SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride.

Rationale: Potential adverse effects of fluoride on neurodevelopment has been extensively explored and mitochondria have been recognized as critical targets. Mitochondrial biogenesis serves a crucial role in maintaining mitochondrial homeostasis and salubrious properties of resveratrol (RSV) has been well-defined. However, the molecular mechanisms governing mitochondrial biogenesis in developmental fluoride neurotoxicity remain unclear and the related therapeutic dietary agent is lacking.Methods: In vitro neuroblastoma SH-SY5Y cells and in vivo Sprague-Dawley rat model of developmental fluoride exposure were adopted. A total population of 60 children under long-term stable fluoride exposure were also recruited. This work used a combination of biochemical and behavioral techniques. Biochemical methods included analysis of mitochondrial function and mitochondrial biogenesis, as well as mRNA and protein expression of mitochondrial biogenesis signaling molecules, including silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Behavioral studies investigated spatial learning and memory ability of rats.Results: Both in vivo and in vitro experiments showed that sodium fluoride (NaF) caused mitochondrial dysfunction and impaired mitochondrial biogenesis. Also, NaF elevated SIRT1 levels and suppressed SIRT1 deacetylase activity along with decreased levels of PGC-1α, NRF1 and TFAM, suggestive of dysregulation of mitochondrial biogenesis signaling molecules. Moreover, enhancement of mitochondrial biogenesis by TFAM overexpression alleviated NaF-induced neuronal death through improving mitochondrial function in vitro. Further in vivo and in vitro studies identified RSV, the strongest specific SIRT1 activator, improved mitochondrial biogenesis and subsequent mitochondrial function to protect against developmental fluoride neurotoxicity via activating SIRT1-dependent PGC-1α/NRF1/TFAM signaling pathway. Noteworthy, epidemiological data indicated intimate correlations between disturbed circulating levels of mitochondrial biogenesis signaling molecules and fluoride-caused intellectual loss in children.Conclusions: Our data suggest the pivotal role of impaired mitochondrial biogenesis in developmental fluoride neurotoxicity and the underlying SIRT1 signaling dysfunction in such neurotoxic process, which emphasizes RSV as a potential therapeutic dietary agent for relieving developmental fluoride neurotoxicity.

Melatonin Inhibits Apoptosis and Oxidative Stress of Mouse Leydig Cells via a SIRT1-Dependent Mechanism.

The purpose of the present study is to examine the effects of melatonin on apoptosis and oxidative stress in mouse Leydig cells and to elucidate the mechanisms responsible for these effects. Our results indicated that 10 ng/mL of melatonin significantly promoted cell viability, the ratio of EdU-positive (5-Ethynyl-2′-deoxyuridine) cells, and increased the mRNA expression of proliferating cell nuclear antigen (PCNA), cyclin D1(CCND1), and cell division control protein 42 (CDC42) (p < 0.05). We also observed that melatonin inhibited apoptosis of mouse Leydig cells, accompanied with increased B-cell lymphoma-2 (BCL-2) and decreased BCL2 associated X (BAX) mRNA and protein expression. Moreover, addition of melatonin significantly decreased the reactive oxygen species (ROS) production and malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels, while it increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels (p < 0.05). In addition, we also found that melatonin increased the expression of SIRT1 (Silent information regulator 1) (p < 0.05). To explore the role of SIRT1 signaling in melatonin-induced cells, mouse Leydig cells were pretreated with EX527, an inhibitor of SIRT1. The protective effects of melatonin on mouse Leydig cells were reversed by EX527, as shown by decreased cell proliferation and increased cell apoptosis and oxidative stress. In summary, our results demonstrated that melatonin inhibited apoptosis and oxidative stress of mouse Leydig cells through a SIRT1-dependent mechanism.

Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis.

Background/Aims: Diabetic non-healing skin ulcers represent a serious challenge in clinical practice, in which the hyperglycemia-induced disturbance of angiogenesis, and endothelial dysfunction play a crucial role. Resveratrol (RES), a silent information regulator 1 (SIRT1) agonist, can improve endothelial function and has strong pro-angiogenic properties, and has thus become a research focus for the treatment of diabetic non-healing skin ulcers; however, the underlying mechanism by which RES regulates these processes remains unclear. Therefore, the present study was intended to determine if RES exerts its observed protective role in diabetic wound healing by alleviating hyperglycemia-induced endothelial dysfunction and the disturbance of angiogenesis.Methods: We investigated the effects of RES on cell migration, cell proliferation, apoptosis, tube formation, and the underlying molecular mechanisms in 33 mM high glucose-stimulated human umbilical vein endothelial cells (HUVECs) by semi-quantitative RT-PCR, western blot analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and immunofluorescence in vitro. We further explored the role of RES on endothelial dysfunction and wound healing disturbance in db/db mice by TUNEL staining, immunofluorescence, and photography in vivo.Results: We observed an obvious inhibition of hyperglycemia-triggered endothelial dysfunction and a disturbance of angiogenesis, followed by the promotion of diabetic wound healing via RES, along with restoration of the activity of the hyperglycemia-impaired SIRT1 signaling pathway. Pretreatment with EX-527, a SIRT1 inhibitor, abolished the RES-mediated endothelial protection and pro-angiogenesis action, and then delayed diabetic wound healing. Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner. Pretreatment with 10058-F4, a c-Myc inhibitor, repressed RES-mediated endothelial protection, angiogenesis, and diabetic wound healing.Conclusion: Our findings indicate that the positive role of RES in diabetic wound healing via its SIRT1-dependent endothelial protection and pro-angiogenic effects involves the inhibition of FOXO1 and the de-repression of c-Myc expression.

Melatonin protective effect against amyloid β-induced neurotoxicity mediated by mitochondrial biogenesis; involvement of hippocampal Sirtuin-1 signaling pathway

Melatonin has a potential therapeutic value in Alzheimer's disease (AD), a disease that is associated with a dramatic decline in memory and cognitive abilities. The aggregation of the amyloid β (Aβ) peptide, a hallmark of AD, deactivates mitochondrial biogenesis and antioxidant defenses. Melatonin as an endogenous antioxidant, decreases in plasma and cerebrospinal fluid of AD patients. Even though several experimental studies have demonstrated the melatonin neuroprotection in AD, clinical trials of melatonin therapy have not yet confirmed outstanding results in AD patients. Better understanding of the molecular mechanisms involved in melatonin neuroprotective effects may pave the way for an efficient therapy. Hence, we investigated the involvement of silent information regulator 1 (SIRT1) signaling and mitochondrial biogenesis in melatonin neuroprotection in a rat model of cognitive impairment induced by intra-hippocampal Aβ injection. Animals assigned to melatonin treatment in the presence or absence of SIRT1 inhibitor (EX527), for 14 consecutive days. Spatial working memory and anxiety level were examined with Y-maze and elevated plus maze tests respectively. Hippocampal SIRT1, transcription factor-A mitochondrial (TFAM) and mitochondrial DNA (mtDNA) copy number were measured. We observed a decrease in hippocampal SIRT1, which accompanied with reduction in TFAM and mtDNA copy number in the Aβ-injected rats. Melatonin treatment increased hippocampal SIRT1 and TFAM expression and enhanced mtDNA copy number in the hippocampus. It also improved memory, ameliorated the anxiety, and attenuated hippocampal cell damage in the Aβ-injected animals. These effects were blocked by EX527 administration, suggesting SIRT1 signaling involvement in melatonin neuroprotective effect. This mechanism may introduce a new promising strategy in battle against AD.

Maresin 1 attenuates the inflammatory response and mitochondrial damage in mice with cerebral ischemia/reperfusion in a SIRT1-dependent manner

Maresin 1 (MaR1) confers brain-protective effects against cerebral ischemia/reperfusion (I/R) injury. Activation of silent information regulator 1 (SIRT1) signaling has also been demonstrated to inhibit cerebral I/R injury. We hypothesize that MaR1 may protect against cerebral I/R injury by activating SIRT1 signaling. The present study investigated the protective effect of MaR1 treatment on cerebral I/R injury and elucidated the potential mechanisms. Mice were exposed to the treatment in the presence or absence of MaR1 or the SIRT1 inhibitor EX527 and then subjected to the middle cerebral artery occlusion (MCAO) operation. MaR1 conferred a brain-protective effect by up-regulating SIRT1 and Bcl2 expression, down-regulating acetylated neuclear factor kappaB (AC-NF-κB) and Bax expression, reducing pro-inflammatory factor levels (IL-1, IL-6 and TNF-α), increasing the mitochondrial membrane potential, and diminishing neuronal degeneration, the infarct size and the neurological defects of cerebral I/R. These protective effects were partially blocked by the SIRT1 inhibitor EX527, indicating that SIRT1 signaling might be specifically involved in the protection provided by MaR1 against cerebral I/R injury. In summary, our results demonstrate that MaR1 treatment attenuates cerebral I/R injury by reducing inflammatory responses and mitochondrial damage via activation of SIRT1 signaling.

SIRT1 activation by butein attenuates sepsis-induced brain injury in mice subjected to cecal ligation and puncture via alleviating inflammatory and oxidative stress

Sepsis-induced brain injury is frequently encountered in critically ill patients with severe systemic infection. Butein (3,4,2′,4′-tetrahydroxychalcone) has been demonstrated as the neuro-protective agent via reducing inflammation and oxidative stress on neurons. Moreover, activation of silent information regulator 1 (SIRT1) inhibits apoptosis, oxidation and inflammation thus alleviating sepsis-induced multiorgan injuries. In present study, we show that butein administrated intraperitoneally (10 mg/kg) saved mice from sepsis-induced lethality by increasing 7-day survival rate after cecal ligation and puncture (CLP) surgery. Additionally, butein treatment enhanced SIRT1 signaling thus decreasing the Ac-NF-κB, Ac-FOXO1 and Ac-p53 levels, thus attenuating the brain injury of mice after CLP surgery by decreasing cerebral edema, maintaining the blood-brain barrier integrity, inhibiting neuronal apoptosis, and decreasing pro-inflammatory cytokines production (IL-6, TNF-α and IL-1β) and oxidative stress (downregulation of MDA, and upregulation of SOD and CAT) in both serum and cerebral cortex tissues. Moreover, butein treatment attenuated LPS induced neurological function loss. However, all above mentioned neuro-protective actions of butein were partially inhibited by EX527 co-treatment, one standard SIRT1 inhibitor. Collectively, butein attenuates sepsis-induced brain injury through alleviation of cerebral inflammation, oxidative stress and apoptosis by SIRT1 signaling activation.

Dexmedetomidine alleviates postoperative cognitive dysfunction in aged rats probably via silent information regulator 1 pathway

To explore the role of silent information regulator 1 (SIRT1) signaling pathway in mediating the effect of dexmedetomidine (DEX) to alleviate postoperative cognitive dysfunction (POCD) in aged rats. Seventy-two healthy male Sprague-Dawley rats aged 18-20 months (weighing 500-700 g) were randomized equally into normal control group, POCD model group, DEX pretreatment group, and DEX and SIRT1 inhibitor (EX527) pretreatment group. In the latter 2 groups, DEX (25 μg/kg) was injected intraperitoneally in the rats 30 min before the operation, and normal saline was injected instead in the other 2 groups; in EX527 group, EX527 (1 μg/kg) was injected intravenously 5 min before the operation. In all but the control group, the rats were subjected to laparotomy lasting 30 min, and on days 1, 3, and 5 following the operation, 6 rats were randomly selected from each group for Morris water maze test to evaluate their cognitive functions. Immediately after the test, the rats were sacrificed and the hippocampus was collected for determination of the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) using ELISA; Western blotting was used to detect the expression of SIRT1 and nuclear factor- κB (NF-κB) in the hippocampal neurons. Compared with the control rats, the rats in POCD group and EX527 group showed significantly prolonged escape latency, decreased frequency of crossing the original platform, increased TNF-α and IL-6 levels, lowered SIRT1 expression in the hippocampal neurons, and increased NF-κB expression (P &lt; 0.05), and these parameters were comparable between POCD group and EX527 group (P &gt; 0.05). DEX pretreatment significantly alleviated cognitive dysfunction and attenuated the changes in TNF-α, IL-6, SIRT1, and NF-κB expressions induced by the operation (P &lt; 0.05), and EX527 pretreatment of the rats obviously blocked the effects of DEX (P &lt; 0.05). DEX alleviates POCD in aged rats probably via SIRT1 signaling pathway.

Protective effects of selenium-glutathione-enriched probiotics on CCl4-induced liver fibrosis

Hepatic fibrosis is a common pathological basis of liver cirrhosis and hepatocellular carcinomas. So, prevention and treatment of liver fibrosis is one of the crucial therapeutic goals in hepatology. Organic selenium, glutathione or probiotics supplementation could ameliorate hepatic fibrosis, respectively. The purpose of this study is to develop a novel selenium-glutathione-enriched probiotics (SGP) and to investigate its protective effect on CCl4-induced liver fibrosis in rats. Yeast strains with the high-yield glutathione were isolated and identified by analysis of 26S ribosomal DNA sequences. The fermentation parameters of SGP were optimized through single-factor, Plackett–Burman (PB) design and response surface methodology (RSM). The final SGP contained 38.4 μg/g of organic selenium, 34.1 mg/g of intracellular glutathione, approximately 1×1010 CFU/g live Saccharomyces cerevisiae and 1×1012 CFU/g live Lactobacillus acidophilus. SGP had better protective effects on liver fibrosis than selenium, glutathione or probiotics, respectively. The hepatic silent information regulator 1 (SIRT1) level was down-regulated and oxidative stress, endoplasmic reticulum (ER) stress, inflammation and phosphorylated MAPK was increased in CCl4-treated rats. However, SGP can significantly reverse these changes caused by CCl4. Our findings suggest that SGP was effective in attenuating liver fibrosis by the activation of SIRT1 signaling and attenuating hepatic oxidative stress, ER stress, inflammation and MAPK signaling.

Reduced silent information regulator 1 signaling exacerbates sepsis-induced myocardial injury and mitigates the protective effect of a liver X receptor agonist

Myocardial injury and dysfunction are critical manifestations of sepsis. Previous studies have reported that liver X receptor (LXR) activation is protective during sepsis. However, whether LXR activation protects against septic heart injury and its underlying mechanisms remain elusive. This study was designed to determine the role of LXR activation in the septic heart with a focus on SIRT1 (silent information regulator 1) signaling. Male cardiac-specific SIRT1 knockout mice (SIRT1-/-) and their wild-type littermates were subjected to sepsis by cecal ligation and puncture (CLP) in the presence or absence of LXR agonist T0901317. The survival rate of mice was recorded during the 7-day period post CLP. Our results demonstrated that SIRT1-/- mice suffered from exacerbated mortality and myocardial injury in comparison with their wild-type littermates. Meanwhile, T0901317 treatment improved mice survival, accompanied by significant ameliorations of myocardial injury and dysfunction in wild-type mice but not in SIRT1-/- mice. Furthermore, the levels of myocardial inflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1, MPO and HMGB1), oxidative stress (ROS generation, MDA), endoplasmic-reticulum (ER) stress (protein levels of CHOP, GRP78, GRP94, IRE1α, and ATF6), and cardiac apoptosis following CLP were inhibited by T0901317 treatment in wild-type mice but not in SIRT1-/- mice. Mechanistically, T0901317 enhanced SIRT1 signaling and the subsequent deacetylation and activation of antioxidative FoxO1 and anti-ER stress HSF1, as well as the deacetylation and inhibition of pro-inflammatory NF-ΚB and pro-apoptotic P53, thereby alleviating sepsis-induced myocardial injury and dysfunction. Our data support the promise of LXR activation as an effective strategy for relieving heart septic injury.

Arctigenin attenuates ischemic stroke via SIRT1-dependent inhibition of NLRP3 inflammasome

Arctigenin (ARC), a phenylpropanoid dibenzylbutyrolactone lignan derived from Arctium lappa L, has been reported to protect against cerebral ischemia injury in rats, but the underlying mechanism is unclear. In this study, we investigated whether ARC ameliorated ischemic stroke by inhibiting NLRP3 inflammasome-derived neuroinflammation and whether SIRT1 signaling was involved in this process. ARC (20 mg/kg) or vehicle were intraperitoneally injected to Sprague-Dawley rats for 3 days before middle cerebral artery occlusion (MCAO) surgery performed. The infarct volume, neurological score, brain water content, neuroinflammation, NLRP3 inflammasome activation and SIRT1 protein expression were assessed. Furthermore, we also investigated whether ARC protected against cerebral ischemia via SIRT1-dependent inhibition of NLRP3 inflammasome by administrating EX527, a specific SIRT1 inhibitor, under oxygen–glucose deprivation (OGD) condition. We found that ARC pretreatment decreased infarct volume, neurological score and brain water content. Moreover, ARC treatment effectively inhibited cerebral ischemia induced NLRP3 inflammasome activation and IL-1β, IL-18 secretion both in vivo and in vitro. Futhermore, ARC treatment activated Silent information regulator 1 (SIRT1) singnaling in the brain. Importantly, suppress of SIRT1 reversed the inhibitory effect of ARC on NLRP3 inflammasome activation. Taken together our results demonstrated that ARC may confer protection against ischemic stroke by inhibiting NLRP3 inflammasome activation. The activation of SIRT1 signaling pathway may contribute to the neuroprotection of ARC in MCAO.

Roles of silent information regulator 1-serine/arginine-rich splicing factor 10-lipin 1 axis in the pathogenesis of alcohol fatty liver disease.

Alcohol exposure is a major reason of morbidity and mortality all over the world, with much of detrimental consequences attributing to alcoholic liver disease (ALD). With the continued ethanol consumption, alcoholic fatty liver disease (AFLD, the earliest and reversible form of ALD) can further develop to more serious forms of alcoholic liver damage, including alcoholic steatohepatitis, fibrosis/cirrhosis, and even eventually progress to hepatocellular carcinoma and liver failure. Furthermore, cell trauma, inflammation, oxidative stress, regeneration, and bacterial translocation are crucial promoters of ethanol-mediated liver lesions. AFLD is characterized by excessive fat deposition in liver induced by excessive drinking, which is related closely to the raised synthesis of fatty acids and triglyceride, reduction of mitochondrial fatty acid β-oxidation, and the aggregation of very-low-density lipoprotein (VLDL). Although little is known about the cellular and molecular mechanisms of AFLD, it seems to be correlated to diverse signal channels. Massive studies have suggested that liver steatosis is closely associated with the inhibition of silent information regulator 1 (SIRT1) and the augment of lipin1 β/α ratio mediated by ethanol. Recently, serine/arginine-rich splicing factor 10 (SFRS10), a specific molecule functioning in alternative splicing of lipin 1 (LPIN1) pre-mRNAs, has emerged as the central connection between SIRT1 and lipin1 signaling. It seems a new signaling axis, SIRT1-SFRS10-LPIN1 axis, acting in the pathogenesis of AFLD exists. This article aims to further explore the interactions among the above three molecules and their influences on the development of AFLD. Impact statement ALD is a major health burden in industrialized countries as well as China. AFLD, the earliest and reversible form of ALD, can progress to hepatitis, fibrosis/cirrhosis, even hepatoma. While the mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. SIRT1, SFRS10, and LIPIN1 had been separately reported to participate in lipid metabolism and the pathogenesis of AFLD. Noteworthy, we found the connection among them via searching articles in PubMed and we had elaborated the connection in detail in this minireview. It seems a new signaling axis, SIRT1-SFRS10-LIPIN1 axis, acting in the pathogenesis of AFLD exists. Further study aimed at SIRT1-SFRS10-LIPIN1 signaling system will possibly offer a more effective therapeutic target for AFLD.