Silent Information Regulator 2 Homolog 1 Research Articles

Melatonin Mitigates Doxorubicin Induced Chemo Brain in a Rat Model in a NRF2/p53–SIRT1 Dependent Pathway

Cancer is a critical health problem, and chemotherapy administration is mandatory for its eradication. However, chemotherapy like doxorubicin (Dox) has serious side-effects including cognitive impairment or chemo brain. Melatonin is a neuroprotective agent that has antioxidant, and anti-inflammatory effects. We aimed to explore melatonin’s effect on Dox-induced chemo brain to discover new mechanisms associated with Dox-induced neurotoxicity and try to prevent its occurrence. Thirty-two male albino rats had been equally divided into four groups; control, melatonin-administrated, Dox-induced chemo brain, and melatonin + Dox treated. On the 9th day, brain had been excised after scarification and had been assessed for reactive oxygen species measurement, histopathological analysis, immunohistochemical, gene and protein expressions for the nuclear factor erythroid 2-related factor 2 (Nrf2), p53 and Silent information regulator 2 homolog 1 (SIRT1). Our results show that melatonin coadministration diminished Dox induced hippocampal and prefrontal cortex (PFC) cellular degeneration. It alleviated Nitric Oxide (NO) level and reversed the decline of antioxidant enzyme activities. It also upregulated Nrf2, SIRT1 and downregulated p53 gene expression in rats receiving Dox. Moreover, melatonin elevated the protein expression level of Nrf2, SIRT1 and reduced p53 corresponding to immunohistochemical results. The data suggested that melatonin can mitigate Dox-induced neurotoxicity by aggravating the endogenous antioxidants and inducing neurogenesis through activation of Nrf2/p53–SIRT1signaling pathway in adult rats’ PFC. These effects were associated with Nrf2, SIRT1 activation and p53 inhibition. This could be guidance to add melatonin as an adjuvant supplement to Dox regimens to limit its adverse effect on the brain function.

Caloric and time restriction diets improve acute kidney injury in experimental menopausal rats: role of silent information regulator 2 homolog 1 and transforming growth factor beta 1.

Estrogen has a protective impact on acute kidney injury (AKI); moreover, reducing the daily intake of calories impedes developing diseases. The present study aimed to determine the effects of calorie restriction (CR) and time restriction (TR) diets on the expression of silent information regulator 2 homolog 1 (SIRT1), transforming growth factor beta 1 (TGF-β1), and other indicators in the presence and absence of ovaries in AKI female rats. The female rats were divided into two groups, ovariectomized (OVX) and sham, and were placed on CR and TR diets for eight weeks; afterward, AKI was induced by injecting glycerol, and kidney injury indicators and biochemical parameters were measured before and after AKI. After AKI, the levels of urine albumin excretion rate, urea, and creatinine in serum, and TGF-β1 increased, while creatinine clearance and SIRT1 decreased in kidney tissue. CR improved kidney indicators and caused a reduction in TGF-β1 and an increase in SIRT1 in ovary-intact rats. Moreover, CR prevented total antioxidant capacity (TAC) decrease and malondialdehyde (MDA) increase resulting from AKI. Before AKI, an increase in body weight, fasting blood sugar (FBS), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC), and a decrease in high-density lipoprotein (HDL) were observed in OVX rats compared to sham rats, but CR prevented these changes. The effects of TR were similar to those of CR in all indicators except for TGF-β1, SIRT1, urea, creatinine, and albumin. The present study indicated that CR is more effective than TR in preventing AKI, probably by increasing SIRT1 and decreasing TGF-β1 in ovary-intact animals.

α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice

BackgroundIn heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD+ levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes.MethodsIn vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD+ levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis.ResultsAKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD+ levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed.ConclusionSupplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD+, the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.

A1BG-AS1 promotes the biological functions of osteosarcoma cells via regulating the microRNA-148a-3p/USP22 axis and stabilizing the expression of SIRT1 through deubiquitinase function

ABSTRACT Background The study aims to explore the role of A1BG antisense RNA 1 (A1BG-AS1), microRNA (miR)-148a-3p and ubiquitin-specific protease 22 (USP22) on osteosarcoma (OS) cell growth. Research design & methods A1BG-AS1, miR-148a-3p, USP22, and silent information regulator 2 homolog 1 (SIRT1) levels in OS tissues and cells were determined. The effects of A1BG-AS1, miR-148a-3p, and USP22 on the biological functions of OS cells were examined by functional assays. In vivo assay was conducted to observe the effect of A1BG-AS1 on OS growth in vitro. The relationship of A1BG-AS1, miR-148a-3p, and USP22 was analyzed by bioinformatics analysis, RNA-fluorescence in situ hybridization, luciferase activity, and RNA binding protein immunoprecipitation assays. The relation between USP22 and SIRT1 was evaluated by immunoprecipitation. Results A1BG-AS1 and USP22 were highly expressed, and miR-148a-3p was lowly expressed in OS tissues and cells. Down-regulation of A1BG-AS1 and USP22 or up-regulation of miR-148a-3p impaired the malignant behaviors of OS cells. A1BG-AS1 sponged miR-148a-3p, and miR-148a-3p targeted USP22, thereby inhibiting USP22 expression. Up-regulating USP22 reversed the A1BG-AS1 suppression-induced phenotypic inhibition of OS cells. USP22 affected the biological functions of OS cells by deubiquitinating SIRT1. Conclusion A1BG-AS1 facilitates the biological functions of OS cells via mediating the miR-148a-3p/USP22 axis.

Role of SIRT1 in Chemoresistant Leukemia.

Leukemias of the AML, CML, and CLL types are the most common blood cancers worldwide, making them a major global public health problem. Furthermore, less than 24% of patients treated with conventional chemotherapy (low-risk patients) and 10-15% of patients ineligible for conventional chemotherapy (high-risk patients) survive five years. The low levels of survival are mainly due to toxicity and resistance to chemotherapy or other medication, the latter leading to relapse of the disease, which is the main obstacle to the treatment of leukemia. Drug resistance may include different molecular mechanisms, among which epigenetic regulators are involved. Silent information regulator 2 homolog 1 (SIRT1) is an epigenetic factor belonging to the sirtuin (SIRT) family known to regulate aspects of chromatin biology, genome stability, and metabolism, both in homeostasis processes and in different diseases, including cancer. The regulatory functions of SIRT1 in different biological processes and molecular pathways are dependent on the type and stage of the neoplasia; thus, it may act as both an oncogenic and tumor suppressor factor and may also participate in drug resistance. In this review, we explore the role of SIRT1 in drug-resistant leukemia and its potential as a therapeutic target.

N-acetylcysteine protects human periodontal ligament fibroblasts from pyroptosis and osteogenic differentiation dysfunction through the SIRT1/NF-κB/Caspase-1 signaling pathway

ObjectiveThis study was aimed to determine whether N-acetylcysteine (NAC) could inhibit lipopolysaccharides / adenosine triphosphate (ATP)-induced pyroptosis and alleviate the damage of osteogenic differentiation in human periodontal ligament fibroblasts (hPDLFs). Furthermore, this study detected whether NAC acted effectively by modulating the silent information regulator 2 homolog 1 (SIRT1)/ the nuclear factor-κB (NF-κB)/Caspase-1 signaling pathway in hPDLFs. DesignCell Counting Kit-8 assay was employed to determine the appropriate concentration of NAC for the follow-up experiments. To explore the effect and the underlying mechanisms of NAC on pyroptosis and osteogenic differentiation in hPDLFs, intracellular reactive oxygen species levels were detected using 2′,7′-Dichlorodihydrofluorescein Diacetate kits. Moreover, SIRT1 inhibitor, SIRT1 activator, NF-κB inhibitor and Caspase-1 inhibitor were applied, the incidence of pyroptosis was detected by flow cytometry, the osteogenic differentiation of hPDLFs was observed using alkaline phosphatase and alizarin red staining, Real-time quantitative polymerase chain reaction and Western Blot were used to detect the expression of relevant factors, the release of interleukin-1β, interleukin-18 and lactate dehydrogenase were detected by Enzyme-linked immunosorbent assay. ResultsThe results demonstrated that NAC protected hPDLFs from lipopolysaccharides/ATP-induced damage, alleviating pyroptosis and osteogenic differentiation dysfunction. Moreover, NAC abrogated the inhibition of SIRT1 activity by scavenging reactive oxygen species, thereby reduced pyroptosis and osteogenic differentiation dysfunction by inhibiting the NF-κB/Caspase-1signaling pathway. ConclusionNAC could inhibit pyroptosis and osteogenic differentiation dysfunction of hPDLFs by scavenging reactive oxygen species to regulate the SIRT1/NF-κB/Caspase-1 signaling axis.

SIRT1 exerts anti-hypertensive effect via FOXO1 activation in the rostral ventrolateral medulla

The rostral ventrolateral medulla (RVLM) is a pivotal region in the central regulation of blood pressure (BP). It has been documented that silent information regulator 2 homolog 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent multifunctional transcription regulatory factor, has many cardiovascular protective effects. However, the role and significance of SIRT1 in the central regulation of cardiovascular activity, especially in RVLM, remains unknown. Therefore, the aim of this study was to explore the role and underlying mechanism of SIRT1 in the central regulation of cardiovascular activity in hypertension. Spontaneously hypertensive rats (SHRs) were given resveratrol (RSV) via intracerebroventricular (ICV) infusion or injected with SIRT1-overexpressing lentiviral vectors into the RVLM. In vitro experiments, angiotensin II (Ang II)-induced rat pheochromocytoma cell line (PC12 cells) were transfected with forkhead box protein O1 (FOXO1) small interfering RNA (siRNA) before treatment with RSV. Our results showed that SIRT1 activation with RSV or overexpression in the RVLM significantly decreased BP and sympathetic outflow of SHRs. Furthermore, SIRT1 overexpression in the RVLM significantly decreased reactive oxygen species (ROS) production and facilitated the forkhead box protein O1 (FOXO1) activation, accompanied by upregulation of the ROS-detoxifying enzyme superoxide dismutases 1 (SOD1) in the RVLM of SHRs. In PC12 cells, it was found that Ang II could induce oxidative stress and downregulate the SIRT1-FOXO1-SOD1 signaling pathway, which indicated that the suppressed expression of SIRT1 in the RVLM of SHRs might relate to the elevated central Ang II level. Furthermore, the enhanced oxidative stress and decreased SIRT1-FOXO1-SOD1 axis induced by Ang II were restored by treatment with RSV. However, these favorable effects mediated by SIRT1 activation were blocked by FOXO1 knockdown. Based on these findings, we concluded that SIRT1 activation or overexpression in the RVLM exerts anti-hypertensive effect through reducing oxidative stress via SIRT1-FOXO1-SOD1 signaling pathway, which providing a new target for the prevention and intervention of hypertension.

Effect of Sodium Fluoride on Reproductive Function Through Regulating Reproductive Hormone Level and Circulating SIRT1 in Female Rats.

Fluorosis causes female reproductive dysfunction with reduced fertility without established pathogenesis. To clarify the mechanism, Sprague-Dawley female rats were selected with drinking water containing 0, 50 (low), 100 (moderate), and 150mg/L (high) sodium fluoride (NaF) for a short (2months), medium (4months), and long term (6months). The water consumption and body weight of female rats were recorded daily. The effect of NaF on the estrous cycle was examined by vaginal smears and recorded in different term treatments. Female and male rats were mated in a 2:1 ratio for 1week at 2-, 4-, and 6-month treatment time for mating performance and fertility rate. Selected female rats were executed for tissue and blood collection at different treatment terms. Twenty-four-hour urine sample from each female rat was collected using the metabolic cage. The levels of steroid hormones and silent information regulator 2 homolog 1 (SIRT1) in serum were measured by appropriate ELISA kits. Body weight of the high NaF group was significantly less during short-term treatment than that of other treatment groups or control group. Urinary fluoride concentration was increased linearly with treatment time. Treatment of NaF significantly decreased steroid hormone level while increased SIRT1 level in the serum. In addition, NaF treatment significantly decreased pregnancy rate. It is concluded that NaF inhibits the secretion of hormone and estradiol (E2) release from the ovary, thereby reducing the rate of pregnant. SIRT1 may be involved in this NaF-induced reproductive dysfunction in female rats through regulating reproductive hormone, FSH, and LH secretion.

Ginsenoside CK Inhibits TGF-β-Induced Epithelial-Mesenchymal Transition in A549 Cell via SIRT1

Ginsenoside CK is the main metabolite of protopanaxadiol saponins in intestinal bacteria. Previous studies have shown that ginsenoside CK can affect many aspects of tumor development through a variety of mechanisms. However, few studies have reported the antimetastatic effects of ginsenoside CK in non-small-cell lung cancer (NSCLC). In this study, we explored the effect of ginsenoside CK on epithelial-mesenchymal transition (EMT) induced by TGF-β in A549 cells and the potential molecular mechanisms. Our data showed that ginsenoside CK effectively prevented TGF-β-induced EMT, as indicated by the upregulation of E-cadherin and downregulation of vimentin. Furthermore, ginsenoside CK inhibited the metastatic ability of A549 cells in the tail vein lung metastasis model of nude mice. Additionally, ginsenoside CK decreased the expression of silent information regulator 2 homolog 1 (SIRT1) in the inhibition of EMT induced by TGF-β. Moreover, the antimetastatic effect of ginsenoside CK was reversed by SIRT1 overexpression. Generally, our results indicated the antimetastatic effect and underlying mechanism of ginsenoside CK on TGF-β-induced EMT in A549 cells, suggesting that ginsenoside CK can be used as an effective antineoplastic agent.

NF-κB inducible miR-30b-5p aggravates joint pain and loss of articular cartilage via targeting SIRT1-FoxO3a-mediated NLRP3 inflammasome.

MicroRNAs (miRNAs) contribute to osteoarthritis (OA) development. Nevertheless, the function and mechanism of miR-30b-5p in OA are unclear. In the present article, we gauged the miR-30b-5p level in OA patients and analyzed its correlation with OA stages. Then, we conducted in-vivo and in-vitro gain-of-function assays to determine the function of miR-30b-5p, silent information regulator 2 homolog 1 (SIRT1) and Fox. Cell counting Kit-8 (CCK-8) assay, BrdU assay and flow cytometry were utilized to gauge cell viability and apoptosis of human chondrocyte (HC-A). The targeting association between miR-30b-5p and SIRT1 was validated through the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment. The results signified that miR-30b-5p was up-regulated in OA patients, OA rats and interleukin-1β (IL-1β)-induced chondrocytes. The higher miR-30b-5p expression brought about progressive stages of OA patients and enhanced levels of pro-inflammatory mediators in the synovial fluid. Functionally, overexpressing miR-30b-5p hampered cell viability, aggravated chondrocyte apoptosis and NLRP3 inflammasome activation induced by IL-1β, while down-regulating miR-30b-5p exerted the reverse effects. The in-vivo experiment exhibited that down-regulating miR-30b-5p improved joint pain and loss of articular cartilage in the rats with restrained inflammation and NLRP3 inflammasome activation. Mechanistically, miR-30b-5p targeted the 3’-non-translated region (3’UTR) of SIRT1, and miR-30b-5p was inducible with NF-κB phosphorylation enhancement. Overexpressing SIRT1 or inhibiting NF-κB relieved miR-30b-5p-induced apoptosis and NLRP3 inflammasome activation by promoting FoxO3a, while down-regulating SIRT1 or FoxO3a reversed miR-30b-5p-in-induced anti-inflammatory and apoptosis-suppressive effects. Collectively, NF-κB-induced miR-30b-5p modulates chondrocyte apoptosis and OA progression by regulating the SIRT1-FoxO3a-mediated NLRP3 inflammasome.

MiR-425 regulates lipophagy via SIRT1 to promote sorafenib resistance in liver cancer.

Liver cancer is one of the most malignant cancer, with poor outcomes and a high incidence rate, and current treatment approaches to prevent tumor progression and development remain unsatisfactory. Therefore, it is urgent to explore novel methods to inhibit tumor growth and metastasis. Autophagy is a highly conserved process associated with metastasis and drug resistance. Lipids are selectively recognized and degraded via autophagy; thus, autophagy is a crucial process to maintain tumor self-protection. MicroRNA (miR)-425 is a tumor-associated gene involved in liver cancer development that can induce cell proliferation and drug resistance. Using Cell Counting Kit-8 assays, western blot analysis and immunofluorescence assays, the present study revealed that inhibition of miR-425 promoted lipophagy by mediating the autophagy process, which in turn helps to promote sorafenib resistance. Using a bioinformatics website, it was revealed that autophagy promoted lipophagy by targeting silent information regulator 2 homolog 1 (SIRT1). The results of luciferase reporter assays supported this finding, and rescue experiments provided additional evidence. Overall, the current results suggested that inhibition of miR-425 expression increased SIRT1 expression to promote lipophagy, leading to the inhibition of liver cancer cell proliferation.

Cynandione A causes a dynamic change in SIRT1 nuclear trafficking via PKA signaling and beige adipocyte differentiation in 3T3-L1 cells

Inducible brown-like adipocytes, also known as beige adipocytes, dissipate energy through thermogenesis. Although recent reports suggest that silent information regulator 2 homolog 1 (SIRT1) promotes beige adipocyte differentiation (beiging), the activation mechanism of SIRT1 remains unknown. Here, we report that cynandione A (CA), a major component of Cynanchum wilfordii, causes dynamic changes in SIRT1 nuclear trafficking via protein kinase cAMP-dependent (PKA) signaling and induces the beiging process in adipocyte lineage cells. SIRT1 is located in both the cytoplasm and the nucleus of 3T3-L1 cells. Using cell fractionation and RNA interference experiments, we found that the translocation of SIRT1 from the cytoplasm to the nucleus was enhanced after CA treatment and was followed by upregulation of beige adipocyte-related gene expression. Moreover, we found that CA-induced SIRT1 nuclear trafficking is dependent on the PKA signaling pathway. These results suggest a novel mechanism of CA by which PKA signaling promotes SIRT1 nuclear trafficking, which permits the docking of SIRT1 to its nuclear substrates, leading to beiging in 3T3-L1 cells.

Renoprotective effects of estrogen on acute kidney injury: the role of SIRT1.

Acute kidney injury (AKI) is a common syndrome associated with high morbidity and mortality, despite progress in medical care. Many studies have shown that there are sex differences and different role of sex hormones particularly estrogens in kidney injury. In this regard, the incidence and rate of progression of kidney diseases are higher in men compared with women. These observations suggest that female sex hormone may be renoprotective. Silent information regulator 2 homolog 1 (SIRT1) is a histone deacetylase, which is implicated in multiple biologic processes in several organisms. In the kidneys, SIRT1 inhibits renal cell apoptosis, inflammation, and fibrosis. Studies have reported a link between SIRT1 and estrogen. In addition, SIRT1 regulates ERα expression and inhibition of SIRT1 activity suppresses ERα expression. This effect leads to inhibition of estrogen-responsive gene expression. In this text, we review the role of SIRT1 in mediating the protective effects of estrogen in the onset and progression of AKI.

Amelioration of Juglanin against LPS-Induced Activation of NLRP3 Inflammasome in Chondrocytes Mediated by SIRT1.

Arthritis is characterized by irreversible joint destruction and presents a global health burden. Natural alternatives to synthetic drugs have been gaining popularity for their safety and effectiveness. Juglanin has demonstrated a range of anti-inflammatory effects in various tissues and cell types. However, the pharmacological function of Juglanin in arthritis and chondrocytes has been little studied. ATDC5 cells were treated with 1μg/mL lipopolysaccharide (LPS) in the presence or absence of juglanin (2.5, 5μM) for 24h. The effects of juglanin on cellular nucleotide-binding domain leucin-rich repeat receptor 3 (NLRP3) inflammasome complex and endproduct interleukin 1β (IL-1β) and interleukin (IL-18) were assessed by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot experiments. The oxidative stress was measured by super oxide dismutase (SOD) activity and NADPH oxidase 4 (NOX4) expression. The dependent effect of juglanin on silent information regulator 2 homolog 1 (SIRT1) was evaluated by siRNA knockdown approach. Juglanin significantly reduced cellular oxidative stress by downregulating NOX4 expression production and rescuing the decreased activity of total SOD induced by LPS. Juglanin inhibited the activation of the TxNIP/NLRP3/ASC/caspase-1 axis, and decreased production of IL-1β and IL-18. Moreover, juglanin rescued the LPS-induced decrease in SIRT1 expression. SIRT1 silencing abolished the anti-NLRP3 inflammasome effect of juglanin, indicating that the effects of juglanin are dependent on its amelioration on SIRT1 expression. Juglanin possesses an anti-inflammatory and anti-ROS capacity in chondrocytes, and this study provides available evidence that juglanin may be of use in the treatment of arthritis.

In Vivo Effect of Resveratrol-Loaded Solid Lipid Nanoparticles to Relieve Physical Fatigue for Sports Nutrition Supplements.

Resveratrol (RSV) is a natural flavonoid polyphenol compound extracted from the plants which shows various biological activities. However, the clinical application of RSV is limited by its poor aqueous solubility, rapid metabolism and poor bioavailability. In this study, resveratrol-loaded solid lipid nanoparticles (RSV- SLNs) was design as a nano-antioxidant against the physical fatigue. The resultant RSV-SLNs were characterized by photon correlation spectroscopy (PCS), transmission electron micrographs (TEM), zeta potential, differential scanning calorimetry (DSC) and Raman spectroscopy pattern. Furthermore, the in vivo anti-fatigue effect assays showed that RSV-SLNs prolonged the mice exhausted time and running distance. The biochemical parameters of blood related to fatigue suggested that RSV-SLNs have potential applications to improve the antioxidant defense of the mice after extensive exercise and confer anti-fatigue capability. Furthermore, the molecular mechanisms of antioxidant by RSV-SLNs supplementation was investigated through the analysis of silent information regulator 2 homolog 1 (SIRT1) protein expression, which demonstrated that it could downregulate the expression of SIRT1 and increase autophagy markers, microtubule-associated protein 1 light chain 3-II (LC3-II) and sequestosome-1 (SQSTM1/p62). These results reveal that the RSV-SLNs may have great potential used as a novel anti-fatigue sports nutritional supplement.

Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway.

Inflammation is a crucial component of various stress-induced responses that contributes to the pathogenesis of major depressive disorder (MDD). Depressive-like behavior (DLB) is characterized by decreased mobility and depressive behavior that occurs in systemic infection induced by Lipopolysaccharide (LPS) in experimental animals and is considered as a model of exacerbation of MDD. We assessed the effects of melatonin on behavioral changes and inflammatory cytokine expression in hippocampus of mice in LPS-induced DLB, as well as its effects on NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, oxidative stress and pyroptotic cell death in murine microglia in vitro. Intraperitoneal 5 mg/kg dose of LPS was used to mimic depressive-like behaviors and melatonin was given at a dose of 500 mg/kg for 4 times with 6 h intervals, starting at 2 h before LPS administration. Behavioral assessment was carried out at 24 h post-LPS injection by tail suspension and forced swimming tests. Additionally, hippocampal cytokine and NLRP3 protein levels were estimated. Melatonin increased mobility time of LPS-induced DLB mice and suppressed NLRP3 expression and interleukin-1β (IL-1β) cleavage in the hippocampus. Immunofluorescence staining of hippocampal tissue showed that NLRP3 is mainly expressed in ionized calcium-binding adapter molecule 1 (Iba1) -positive microglia. Our results show that melatonin prevents LPS and Adenosine triphosphate (ATP) induced NLRP3 inflammasome activation in murine microglia in vitro, evidenced by inhibition of NLRP3 expression, Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, caspase-1 cleavage and interleukin-1β (IL-1β) maturation and secretion. Additionally, melatonin inhibits pyroptosis, production of mitochondrial and cytosolic reactive oxygen species (ROS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The beneficial effects of melatonin on NLRP3 inflammasome activation were associated with nuclear factor erythroid 2–related factor 2 (Nrf2) and Silent information regulator 2 homolog 1 (SIRT1) activation, which were reversed by Nrf2 siRNA and SIRT1 inhibitor treatment.

Phloretin protects against cardiac damage and remodeling via restoring SIRT1 and anti-inflammatory effects in the streptozotocin-induced diabetic mouse model.

Diabetic cardiomyopathy increases the risk of heart failure independent of coronary artery disease and hypertension. Phloretin (PHL) shows anti-inflammatory effects in macrophages. In this study, we explored the protective effects of PHL on high glucose (HG)-induced injury in diabetic cardiomyopathy in vivo and in vitro. Using streptozotocin-induced diabetic mouse model and incubating cardiac cells line under a HG environment, PHL were evaluated of the activities of anti-inflammation and anti-fibrosis. In the study, PHL treatment ameliorated cardiomyocyte inflammation injury, and reduced fibrosis in vivo and in vitro. PHL also improved cardiac biochemical criterions after 8 weeks of induction of diabetes in C57BL/6 mice. Molecular docking results indicated that silent information regulator 2 homolog 1 (SIRT1) bound to PHL directly and that SIRT1 expression was upregulated in the PHL-treated group in HG-induced H9C2 cells. Protective effect of PHL was been eliminated in silence SIRT1 H9C2 cells. Taken together, these results suggested that PHL suppressed HG-induced cardiomyocyte injury via restoring SIRT1 expression.

MiR-217 Inhibits Proliferation, Migration, and Invasion by Targeting SIRT1 in Osteosarcoma.

Purpose: Many studies have revealed that microRNAs (miRNAs) play crucial roles in cancer development and progression. miRNA-217 (miR-217) has been implicated in various cancers. However, the role of miR-217 in osteosarcoma (OS) remains unclear. In this study, the authors examined the role of miR-217 in development of OS. Materials and Methods: Using quantitative real-time PCR, they assessed expression levels of miR-217 in cultured cells and patient samples and examined the proliferation, migration, and invasion of cultured cells by MTT cell proliferation assays, cell scratch test, and cell transwell test. The proliferation, migration, and invasion were examined for MG63 and U2OS transfected by miR-217. Silent information regulator 2 homolog 1 (SIRT1) overexpression plasmid was designed. Results: Expression of miR-217 was downregulated in samples of OS tissue and cultured cells. Proliferation, migration, and invasion were inhibited by ectopic overexpression of miR-217. SIRT1 was identified as targets of miR-217. Expression levels of SIRT1 were inhibited by miR-217 expression in cultured cells, and the expression levels of miR-217 and SIRT1 were inversely correlated in patients with OS. Conclusion: MiR-217 acts as a tumor suppressor in the development of OS. The tumor-suppressive function of miR-217 in OS suggests inhibition of SIRT1.

The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure.

SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.

Expression of silent information regulator 2 homolog 1 (SIRT1) in periapical granulomas.

Silent information regulator 2 homolog 1 (SIRT1) inhibits oxidative injury and has anti-inflammatory effects. SIRT1 may be involved in healing of periapical periodontitis; however, SIRT1 expression in periapical periodontitis lesions has not been investigated. This study evaluated SIRT1 expression and a marker of oxidative stress-8-hydroxy-2'-deoxyguanosine (8-OHdG)-in periapical granulomas. First, we used real-time polymerase chain reaction to determine whether U-937 monocytes express SIRT1. U-937 cells treated with the SIRT1 activator resveratrol exhibited the highest SIRT1 mRNA level after 6-h incubation. By contrast, treating cells with the SIRT1 inhibitor sirtinol returned SIRT1 expression level to that of the control. In addition, immunocytochemical analysis using cytospin specimens showed that U-937 cells co-expressed SIRT1 and Ki-67. Dual-color immunofluorescence imaging showed that round cells in periapical granulomas co-expressed SIRT1 and 8-OHdG; however, neither was expressed in healthy gingival tissues. The number of 8-OHdG-expressing cells was significantly greater than the number of SIRT1-expressing cells. Our findings suggest that macrophages express SIRT1 and that wound healing in periapical granulomas is enhanced by a SIRT1-mediated reduction in the level of oxidative stress.