Sirtuin 1 Levels Research Articles

Hippocampal SIRT1 signaling mediates the ameliorative effect of treadmill exercise on anxiety- and depression-like behavior in APP/PS1 mice

ObjectiveAnxiety and depression-like symptoms occur in the early stages of Alzheimer’s disease. Hippocampal Sirtuin 1 (SIRT1) signaling mediates anxiety- and depression-like behavior. Exercise training improves anxiety and depression-like behavior in various disease models, such as the rat chronic restraint stress model, rat model of posttraumatic stress disorder, and rat model of fetal alcohol spectrum disorders. Here, we aimed to investigate whether exercise ameliorates anxiety- and depression like behaviors in APP/PS1 mice and explore the potential mechanisms.MethodsAfter eight weeks of exercise intervention, we assessed anxiety- and depression-like behaviors in Alzheimer’s disease (AD) model mice. We then measured the levels of SIRT1, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and mitochondrial biogenesis (CO2, ATP6, and mitochondrial content) using immunofluorescence, reverse transcription-quantitative real-time PCR, and transmission electron microscopy. Finally, we investigated the effects of pharmacological activation of SIRT1 on anxiety- and depression-like behaviors, the SIRT1/PGC-1α/NRF1/TFAM signaling axis, and mitochondrial biogenesis.ResultsWe first observed that treadmill exercise improved anxiety- and depression-like behaviors in six-month-old APP/PS1 mice and increased SIRT1 levels in the hippocampus. Pharmacological activation of hippocampal SIRT1 function also reduced anxiety and depression-like behaviors in APP/PS1 mice. Meanwhile, both treadmill exercise and pharmacological activation of hippocampal SIRT1 increased the levels of PGC1α, NRF1, TFAM, and enhanced mitochondrial biogenesis (CO2, ATP6, or mitochondrial content) in the hippocampus of APP/PS1 mice.ConclusionThese findings reveal that treadmill exercise reduces anxiety- and depression-like behaviors in six-month-old APP/PS1 mice by enhancing the SIRT1-dependent PGC-1α/NRF1/TFAM axis, promoting mitochondrial biogenesis in the hippocampus.

The Influence of Nordic Walking Training on the Serum Levels of Sirtuins, FOXO3a, and Vitamin D Metabolites in Patients with Multiple Myeloma

Background: Multiple myeloma, a malignancy of plasma cells, often involves the disruption of vitamin D metabolism. Vitamin D, acting through its receptor (VDR), affects transcription factors like FOXO and sirtuins, which regulate cellular processes. The impact of physical activity on these markers in multiple myeloma patients is unclear. Therefore, the objective of this study was to evaluate the effects of a 6-week training program on these parameters. Material and methods: The study was completed by 30 patients, including 16 in the Nordic walking training group (TG) and 14 in the control group (non-exercising, CG). All participants underwent a thorough medical interview before starting the project. Venous blood samples were collected from all participants four times—at baseline, after 3 weeks, after 6 weeks, and after 9 weeks (follow-up). The serum concentrations of sirtuin 1, sirtuin 3, Foxo3a, vitamin D receptor (VDR), 25(OH)D3, and 1,25(OH)2D were determined. Body composition, physical fitness, and physical activity level were assessed at baseline and after 6 weeks. Results: No statistically significant changes were observed in the serum levels of sirtuins, the FOXO3a protein, and 1,25(OH)2D. A statistically significant difference was observed in the levels of VDR for both time and group factors, but this was not confirmed in the post hoc test. Vitamin 25(OH)D3 level increased significantly in the study group with time. Conclusions: The applied 6-week Nordic walking training cycle positively affected the level of vitamin 25(OH)D3 but did not influence the rest of the biochemical parameters studied. The obtained results also indicate that the applied intervention is safe for patients and does not interfere with body composition.

Characterization of tea polysaccharides from Tieguanyin oolong tea and their hepatoprotective effects via AMP-activated protein kinase-mediated signaling pathways.

In the present study, we succeeded in extracting tea polysaccharide (TPS) from Tieguanyin oolong tea, and the TPS was characterized. TPS is an acidic heteropolysaccharide containing rhamnose, arabinose, galactose, glucose (Glc), xylose, mannose, galacturonic acid, and guluronic acid. We found that TPS supplementation partially reversed the elevated levels of serum alanine aminotransferase, total cholesterol, and low-density lipoprotein cholesterol in high-fat diet (HD)-induced nonalcoholic fatty liver disease (NAFLD) mice (p<0.05), and hepatic steatosis and impaired Glc tolerance were also ameliorated. After HD intervention, the activity of Adenosine 5'-monophosphate-activated protein kinase (AMPK) and its downstream genes, including Sirtuin 1 (SIRT1), sterol regulatory element-binding protein-1c (SREBP1c), acetyl-coenzyme A carboxylase 1 (ACC1), and adipose triglyceride lipase (ATGL), was significantly inhibited (p<0.05). TPS can increase the expression of these genes. The hepatoprotective effects of TPS in AMPK-/- mice almost completely disappeared. Moreover, the expression levels of SIRT1, SREBP1c, ACC1, and ATGL did not significantly change after TPS supplementation (p>0.05). Therefore, our findings suggest that TPS protects the liver from hepatic glucolipid metabolism disorders in HD-induced NAFLD mice by activating AMPK-mediated signaling pathways.

Circ-TTC17 Promotes Esophagus Squamous Cell Carcinoma Cell Growth, Metastasis, and Inhibits Autophagy-Mediated Radiosensitivity Through miR-145-5p/SIRT1 Axis.

Circular RNA (circRNA) plays a significant role in esophagus squamous cell carcinoma (ESCC) progression. Nevertheless, circ-TTC17 roles in ESCC have not fully understood. The levels of circ-TTC17, miR-145-5p and sirtuin 1 (SIRT1) were determined using qRT-PCR. ESCC cell functions were examined by CCK8 assay, flow cytometry, transwell assay and colony formation assay. The relative protein levels of autophagy marker and SIRT1 were determined by western blot (WB). The interactions among circ-TTC17, miR-145-5p, and SIRT1 were verified by dual-luciferase reporter assay and RIP assay. circ-TTC17 was overexpressed and miR-145-5p was underexpressed in ESCC. circ-TTC17 knockdown restrained ESCC cell proliferation and metastasis, while enhance apoptosis and autophagy-mediated radiosensitivity. Circ-TTC17 could sponge miR-145-5p, and its inhibitor reversed the inhibitory effect of circ-TTC17 knockdown on ESCC cell progression. Additionally, SIRT1 was targeted by miR-145-5p, and SIRT1 overexpression abolished miR-145-5p-mediated the suppressive effect on ESCC cell progression. Also, circ-TTC17 interference reduced ESCC tumor growth via miR-145-5p/SIRT1 axis. circ-TTC17 promoted ESCC cell growth, metastasis and inhibited autophagy-mediated radiosensitivity by miR-145-5p/SIRT1 axis.

2-hydroxy-3-methyl anthraquinone promotes apoptosis and inhibits invasion of human hepatocellular carcinoma cells by targeting nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-1/cellular tumor antigen p53 signaling pathway.

To investigate the anti-liver cancer effect of 2-hydroxy-3-methyl anthraquinone (HMA) and the specific mechanism based on nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-1 (SIRT1)/cellular tumor antigen p53 (p53) pathway. Cell counting kit-8 method was used to observe the effect of HMA on the activity of human hepatocellular carcinoma cells (HepG2) cells. At 72 h and 80 μL HMA, the apoptosis rate of HepG2 cells in each group was measured by flow cytometry. Transwell was used to assay for cell invasion. The protein expression levels of SIRT1, p53, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), caspase-9 (CASP9) and caspase-3 (CASP3) were detected by Western Blot. HMA significantly inhibited the proliferation of HepG2 cells, The half inhibiting concentration (IC50) of the HMA at 24, 48 and 72 h were examined and it were 126.3, 98.6, and 80.55 μM, respectively. Compared with the control group, the apoptosis rate of HMA, Selisistat (EX527), and HMA+ EX527 groups enhanced, while the apoptosis rate of SRT1720 diminished, demonstrating that inhibition of SIRT1 can lead to apoptosis of HepG2 cells. HMA+ EX527 group had the highest apoptosis rate, the lowest expression of SIRT1 and Bcl-2, and the highest expression of p53, Bax, CASP9 and CASP3. The number of invasions of HepG2 was significantly reduced after HMA and EX527 intervened. Western blot shows HMA could inhibit SIRT1, promote the expression of p53, and decrease the ratio of Bcl-2/Bax. HMA induced apoptosis in HepG2 cells, while inhibiting proliferation and invasion. The mechanism of HMA against HCC may be related to the SIRT1/p53 pathway.

Nicotinamide Riboside Ameliorates Fructose-Induced Lipid Metabolism Disorders in Mice by Activating Browning of WAT, and May Be Also Related to the Regulation of Gut Microbiota.

This study aims to observe the preventive effect of nicotinamide riboside (NR) on fructose-induced lipid metabolism disorders and explore its mechanism. Male C57BL/6J mice were fed a 20% fructose solution and given 400 mg/kg NR daily by gavage for 10 weeks. The results indicated that NR supplementation significantly reduced the body weight, liver weight, white adipose tissue (WAT) weight, serum, and hepatic lipid levels. NR upregulated the protein expression levels of sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), PR domain containing 16 (PRDM16), uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactiva-tor-1-alpha (PGC-1α), nuclear respiratory factor 1-encoding gene (NRF1), mitochondrial transcription factor A (TFAM), cluster of differentiation 137 (CD137), transmembrane protein 26 (TMEM26), and T-box 1 (TBX1). Moreover, NR enhanced the Actinobacteria and Enterorhabdus abundance. Spearman's correlation analysis revealed that significant correlations exist between Firmicutes, Bacteroidetes, and Erysipelotrichaceae with browning-related indicators. In conclusion, NR could alleviate lipid metabolic abnormalities induced by fructose through activating SIRT1/AMPK-mediated browning of WAT. The mechanism by which NR improves fructose-induced lipid metabolism disorders may also be associated with the modulation of intestinal flora.

Antioxidant Effect of a Plant-Derived Extracellular Vesicles' Mix on Human Skin Fibroblasts: Induction of a Reparative Process.

Plant-Derived Extracellular Vesicles extracellular vesicles (PDEVs) from organic agriculture (without the use of pesticides and microbicides) contain high levels of antioxidants. Organic PDEVs have shown an increased antioxidant power compared to PDEVs from single plants, suggesting a synergistic effect of the bioactives constitutively expressed in the PDEVs from single fruits. With this study, we wanted to investigate the beneficial effects of a mix of PDEVs on human skin cells. We found detectable levels of citric acid, ascorbic acid, glutathione, catalase, and SOD in a mix of PDEVs deriving from five different fruits (grape, red orange, papaya, pomegranate, and tangerine). We then treated H2O2-conditioned fibroblasts with the mix of PDEVs. The results showed that the PDEVs' mixture reverted the H2O2-induced redox imbalance, restoring mitochondrial homeostasis, with a strong reduction of mitochondrial anion superoxide and an increase in sirtuin levels. The antioxidant action was consistent with wound repair on a lesion produced in a fibroblast's monolayer. This result was consistent with an increased level of vimentin and matrix metalloproteinase-9, whose expression is directly related to the efficiency of the reparative processes. These data support a beneficial role of PDEVs in both preventing and treating skin injuries through their potent antioxidant and reparative activities.

Evaluation of sirtuin 1 as a predictor of cardiovascular outcomes in diabetic patients with limb-threatening ischemia.

Chronic limb-threatening ischemia (CLTI) significantly increases the risk of major adverse limb events (MALE) and major adverse cardiac events (MACE) after lower extremity revascularization (LER). This study aims to identify novel biomarkers that help to further reduce the risk of postoperative cardiovascular complications. In this prospective, nonrandomized, observational study, baseline serum levels of sirtuin 1 (SIRT1) were assessed in 147 diabetic patients scheduled for LER due to CLTI, and participants were followed for the occurrence of MALE and MACE over 12 months. Fifty-three patients experienced MALE, and 33 experienced MACE within the follow-up period. Lower baseline SIRT1 levels were significantly associated with an increased risk of MALE and MACE, independent of other risk factors. The ROC curve analysis identified a SIRT1 cutoff of 3.79 ng/mL for predicting the risk of MALE. Moreover, incorporating SIRT1 into predictive models significantly enhanced the accuracy of predicting adverse outcomes. Results suggest serum SIRT1 is a potential independent marker for predicting MALE and MACE in diabetic patients with CLTI undergoing LER. Further research is needed to clarify the mechanistic pathways in which SIRT1 may influence cardiovascular outcomes, and the role of this novel biomarker in the management of PAD and CLTI among patients with diabetes.

Pathophysiology of vascular ageing and the effect of novel cardio-renal protective medications in preventing progression of chronic kidney disease in people living with diabetes.

Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio-renal complications and guide treatment interventions in people with diabetes. We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon-like peptide-1 (GLP-1) receptor agonists. Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney-derived anti-ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT-2 inhibitors and GLP-1 receptor agonists all influence pathways involved in vascular ageing. A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio-renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes.

Correlation Between Serum and Tissue SIRT1 Levels in Patients With Esophageal Squamous Cell Carcinoma.

Identifying prognostic and molecular markers as therapeutic targets for esophageal squamous cell carcinoma (ESCC) could enhance the efficacy of multidisciplinary treatments. While tissue expression of sirtuin 1 (SIRT1) has been linked to tumor progression in ESCC, prognostic significance of serum SIRT1 levels and their correlation with tissue SIRT1 remains unexplored. This study aimed to investigate the correlation between serum and tissue SIRT1 levels in patients with ESCC. A total of 38 patients diagnosed with ESCC who were untreated preoperatively were recruited for this study. SIRT1 expression in the surgical specimens was assessed through immunostaining, while serum SIRT1 levels were measured using an enzyme-linked immunosorbent assay. We analyzed the association between tissue and serum SIRT1 levels, clinicopathological features, and patient prognosis. Positive SIRT1 expression in tissue was significantly associated with deeper tumor depth (p=0.020). It was also significantly associated with poorer overall survival (OS) and relapse-free survival (RFS) (p=0.041 and p=0.012, respectively). Elevated serum SIRT1 levels were significantly correlated with increased tumor depth and weight loss (p=0.012 and p=0.030). While higher serum SIRT1 levels tended to be associated with poorer OS (p=0.069), no significant correlation was found between SIRT1 expression in tissue and its concentration in serum. SIRT1 tissue expression may be a valuable prognostic marker in ESCC. However, the clinical significance of serum SIRT1 levels appears to differ from that of its tissue expression. Future research is required to clarify the role of serum SIRT1 in ESCC.

M7G-modified mt-tRF3b-LeuTAA regulates mitophagy and metabolic reprogramming via SUMOylation of SIRT3 in chondrocytes

N7-methylguanosine (m7G) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the m7G methyltransferase complex. METTL1-catalyzed m7G as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that m7G modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of m7G modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and m7G levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated m7G modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/m7G/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment.

Luteolin Protects against Vascular Calcification by Modulating SIRT1/CXCR4 Signaling Pathway and Promoting Autophagy.

Vascular calcification (VC) is a common pathological manifestation of atherosclerosis, hypertension, diabetes vascular disease, vascular injury, chronic kidney disease and aging, which is mainly manifested as increased stiffness of the vascular wall. Oxidative stress and autophagy dysfunction are key factors in the pathogenesis of vascular calcification, but the specific mechanisms and the therapeutic strategy of vascular calcification have not been clarified. In the present study, Sirtuin 1 (SIRT1) was screened as the therapeutic targets for vascular calcification by the bioinformatics. SIRT1 is a nicotinamide adenine dinucleotide, which plays an important role in inhibiting oxidative stress and promoting autophagy. Luteolin(LUT), a kind of natural tetrahydroxyl flavonoid, exists in many plants and has many pharmacological effects such as anti-oxidation and anti-apoptosis. We have reported that luteolin has certain anti-osteoporosis effects in the previous study, and it is accepted that the development of vascular calcification is similar to bone formation, indicating that luteolin may also resist vascular calcification. And luteolin is known to activate SIRT1 to some extent. Moreover, the molecular docking analysis predicted that SIRT1 could bind directly to luteolin. Therefore, the purpose of this study was to investigate the potential role of luteolin in inhibiting oxidative stress and promoting autophagy during vascular calcification via modulating SIRT1 expression. The results showed that luteolin significantly improved vascular calcification induced by a high-fat diet (HFD) and vitamin D3 in rats in vivo. In addition, luteolin significantly repressed the formation of mineralized nodules and ALP activity in H2O2-treated A7r5 cells. Luteolin reduced the level of MDA, LDH and ROS generation, inhibited the protein expression of cleaved caspase-3, cleaved caspase-9, β-catenin and BMP-2 in the aortic tissue of the rat and rat smooth muscle cells (A7r5) treated with hydrogen peroxide. At the same time, luteolin could promote the expression of autophagy related proteins. Moreover, luteolin also produced effects to increase the protein expression levels of SIRT1 more than 2 times both in vivo and in vitro. In terms of mechanism, luteolin attenuated vascular calcification by inhibiting oxidative stress and improving autophagy level, via modulating SIRT1 / CXCR4 signaling pathway. In conclusion, this experiment for the first time revealed that LUT protected against VC via modulating SIRT1 / CXCR4 signaling pathway to promote autophagy and inhibit vascular calcification and may be developed as a new therapeutic agent for vascular calcification and atherosclerosis.

USP26 Combats Age-Related Declines in Self-Renewal and Multipotent Differentiation of BMSC by Maintaining Mitochondrial Homeostasis.

Age-related declines in self-renewal and multipotency of bone marrow mesenchymal stem cells (BMSCs) limit their applications in tissue engineering and clinical therapy. Thus, understanding the mechanisms behind BMSC senescence is crucial for maintaining the rejuvenation and multipotent differentiation capabilities of BMSCs. This study reveals that impaired USP26 expression in BMSCs leads to mitochondrial dysfunction, ultimately resulting in aging and age-related declines in the self-renewal and multipotency of BMSCs. Specifically, decreased USP26 expression results in decreased protein levels of Sirtuin 2 due to its ubiquitination degradation, which leads to mitochondrial dysfunction in BMSCs and ultimately resulting in aging and age-related declines in self-renewal and multilineage differentiation potentials. Additionally, decreased USP26 expression in aging BMSCs is a result of dampened hypoxia-inducible factor 1α (HIF-1α) expression. HIF-1α facilitates USP26 transcriptional expression by increasing USP26 promoter activity through binding to the -191 - -198 bp and -262 - -269 bp regions on the USP26 promoter. Therefore, the identification of USP26 as being correlated with aging and age-related declines in self-renewal and multipotency of BMSCs, along with understanding its expression and action mechanisms, suggests that USP26 represents a novel therapeutic target for combating aging and age-related declines in the self-renewal and multipotent differentiation of BMSCs.

Shenmai injection improves lipid metabolism in post-myocardial infarction heart failure based on network pharmacology and experimental validation

BackgroundShenmai injection (SMI), a traditional Chinese medicine formulation derived from the herbal decoction Shenmai Yin, is widely used in treating cardiovascular disorders. This study extensively investigated the effects and mechanisms of action of SMI on lipid metabolism in post-myocardial infarction heart failure (pMIHF). MethodsNetwork pharmacology was employed to predict the key targets and associated pathways involved in lipid metabolism for potential SMI treatments in post-myocardial infarction heart failure (pMIHF). Subsequently, a pMIHF mouse model and an ischemia/reperfusion (I/R) cell model were established to delve deeper into and validate the underlying mechanism of action. ResultsWe performed network pharmacology analysis, which identified 48 active components in SMI and 201 common gene targets. Subsequent screening using the protein–protein interaction network identified 26 core targets, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, peroxisome proliferator-activated receptor alpha (PPARα), and sirtuin 1 (SIRT1). Based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, we predicted that SMI might act on lipid metabolism in pMIHF through the PPARα pathway, a hypothesis supported by the strong binding affinity between this receptor and the active components of SMI, as confirmed via molecular docking. In a left anterior descending artery-ligation mouse model, SMI significantly improved cardiac function, reduced serum free fatty acid levels, decreased inflammatory cell infiltration and myocardial fibrosis, and maintained myocardial mitochondrial morphology. In ischemia-reperfusion (I/R) cells, SMI reduced cell apoptosis, improved mitochondrial membrane potential, and decreased mRNA expression levels of IL-6 and TNF-α, while increasing protein levels of PPARα, SIRT1, and PPARα co-activator-1 alpha (PGC1α). ConclusionCollectively, our findings suggest that SMI enhances myocardial lipid metabolism and ameliorates pMIHF by upregulating the PPARα/SIRT1/PGC1α pathway.

Lygodium microphyllum Inhibits de Novo Lipogenesis Activity in the Hepatocytes of High-Fat High-Fructose-Induced Rats by Increasing the Levels of SIRT1 and AMPK.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is currently of great concern due to its risk of developing T2DM and cardiovascular disease. The development of NAFLD may be initiated by de novo lipogenesis in the hepatocytes. Sirtuin1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK), are responsible for the lipogenesis mechanism. Interestingly, plant sterols, such as beta-sitosterol and stigmasterol, have the potential to lower the LDL-cholesterol in dyslipidemic patients. Beta-sitosterol was present in the ethanol extract of Lygodium microphyllum herbs at a concentration of 283.55µg/g extract. This sterol interacted with the active allosteric-binding site of SIRT1 and AMPK similarly to the proteins' activators. To investigate the anti-lipogenesis activity of the ethanol extract of L. microphyllum (ELM) in the liver tissue of rats through the SIRT1 and AMPK levels. Forty male Wistar rats were used in this study: (1) normal control group; (2) high-fat high-fructose diet (HFHFD) rats; (3) HFHFD rats treated with metformin; (4) HFHFD rats treated with resveratrol; (5) HFHFD rats treated with beta-sitosterol; (6-8) HFHFD rats treated with ELM doses of 200, 400, and 600 mg/kg BW. Rats in the normal control group were fed regular chow, while other groups of rats were given HFHFD for 35 days. All drugs were given orally on D15 till D35. On D35, the rats were sacrificed, and the liver organs were examined for the liver index, morphology, NAFLD activity score (NAS), and levels of SIRT1 and AMPK. ELM improves the morphology, the liver index, the steatosis condition, and the NAS of HFHFD-induced NAFLD rats. ELM increases the levels of SIRT1 and AMPK in the liver tissue of HFHFD-induced NAFLD rats. ELM may have the potential to inhibit de novo lipogenesis by increasing the levels of SIRT1 and AMPK.

Quercetin Prevents Hypertension in Dahl Salt-sensitive Rats F ed a High-salt Diet Through Balancing Endothelial Nitric Oxide Synthase and Sirtuin 1.

A high-salt diet is a leading dietary risk factor for elevated blood pressure and cardiovascular disease. Quercetin reportedly exhibits cardioprotective and antihypertensive therapeutic effects. The objective of this study is to examine the effect of quercetin on high-salt dietinduced elevated blood pressure in Dahl salt-sensitive (SS) rats and determine the underlying molecular mechanism. Rats of the Dahl SS and control SS-13 BN strains were separated into five groups, SS-13 BN rats fed a low-salt diet (BL group), SS-13 BN rats fed a high-salt diet (BH group), Dahl SS rats fed a low-salt diet (SL group), Dahl SS rats fed a high-salt diet (SH group), and SH rats treated with quercetin (SHQ group). Blood pressure was checked three weeks into the course of treatment, and biochemical markers in the urine and serum were examined. Additionally, western blot was done to evaluate the sirtuin 1 (SIRT1) and endothelial nitric oxide synthase (eNOS) expression levels. Immunohistochemical analysis was performed to verify SIRT1 levels. We demonstrated that a high-salt diet elevated blood pressure in both SS-13 BN and Dahl SS rats, and quercetin supplementation alleviated the altered blood pressure. Compared with the SH group, quercetin significantly elevated the protein expression of SIRT1 and eNOS. Immunohistochemistry results further confirmed that quercetin could improve the protein expression of SIRT1. Quercetin reduced blood pressure by enhancing the expression of SIRT1 and eNOS in Dahl SS rats fed a high-salt diet.

ED-71 promotes osseointegration of titanium implants in a rat model of GIOP by alleviating the effects of dexamethasone on bone remodeling in a SIRT1-dependent manner

ObjectiveGlucocorticoid-induced osteoporosis (GIOP), a common complication of glucocorticoid usage, plays a critical role in the success of dental implant restoration by affecting osseointegration. Eldecalcitol (ED-71) prevents GIOP; however, its role in the osseointegration of implants under GIOP conditions remains elusive. MethodsDexamethasone was used to establish a rat model of GIOP. Subsequently, mini-implant surgery was performed on the femur. GIOP rats were administered ED-71 via gavage to assess its role in the osseointegration of titanium implants under GIOP conditions. MC3T3-E1 and RAW264.7 cells were utilized to explore the molecular mechanism of ED-71 in ameliorating disorder of bone remodeling caused by dexamethasone. ResultsThe administration of ED-71 promoted the formation of newly formed woven bone and the resolution of inflammation around titanium implants. In vitro experiments indicated that ED-71 ameliorated dexamethasone-induced dysfunction of osteoblasts and osteoclasts by increasing the expression level of sirtuin 1 (SIRT1). Inhibition of SIRT1 by selisistat counteracts the regulatory effects of ED-71 on dexamethasone-induced disorder of bone remodeling. Molecular docking and Western blotting revealed that the neurogenic locus notch homolog protein and nuclear factor kappa B signaling pathways are essential for the effects of ED-71 on dexamethasone-induced disorder of bone remodeling. ConclusionED-71 promoted implant osseointegration in a rat model of GIOP by alleviating the effects of dexamethasone on bone remodeling in a SIRT1-dependent manner.

Neurodegeneration: Effects of calorie restriction on the brain sirtuin protein levels

BackgroundCalorie restriction (CR) is suggested to activate protective mechanisms in neurodegenerative diseases (NDDs). Despite existing literature highlighting the protective role of Sirtuin (SIRT) proteins against age-related neurodegeneration (ND), no study has explored the total levels of SIRT 1, 3, and 6 proteins simultaneously in brain homogenates by ELISA following intermittent calorie restriction. Applying CR protocols in mice to induce stress, we aimed to determine whether ND would be more pronounced with ad libitum (AL) or with CR. MethodsMice were randomly assigned to ad libitum (AL), Chronic CR (CCR), or Intermittent CR (ICR) groups at 10 weeks of baseline age (BL). SIRT 1, 3, and 6 protein levels were measured in the homogenized whole-brain supernatants of 49/50 weeks old mice by the ELISA method. Neuronal morphology was evaluated by the cresyl violet on the hippocampus. Neurodegeneration (ND) was assessed by the fluoro-jade and ImageJ was used for quantifications. ResultsIn the ICR group, SIRT1 levels were elevated compared to both the AL and BL groups. Similarly, the CCR group exhibited higher SIRT1 values compared to the AL and BL groups. While SIRT3 levels were higher in both the ICR and CCR groups compared to the AL and BL groups, this disparity did not reach statistical significance. SIRT6 levels were also higher in the ICR group compared to both the BL and AL groups, with the CCR group showing higher values compared to the BL and AL groups as well. Image quantification demonstrated significant neurodegeneration in the AL group compared to the CCR and ICR group, with no observed alterations in nerve cell morphology and number. ConclusionThis study revealed that the levels of SIRT 1, SIRT 3, and SIRT 6 in brain tissue were notably elevated, and there was less evidence of ND at the 50-week mark in groups undergoing continuous calorie restriction and intermittent calorie restriction compared to baseline and ad libitum groups. Our findings illustrate that CR promotes increased SIRT expression in the mouse brain, thereby potentially mitigating neurodegeneration.

Long-term exposure of sucralose induces neuroinflammation and ferroptosis in human microglia cells via SIRT1/NLRP3/IL-1β/GPx4 signaling pathways.

Microglia serve as the primary defense mechanism in the brain. Artificial sweeteners are widely used as dietary supplements, though their long-term effects remain uncertain. In this study, we investigated the effects of sucralose on microglia during prolonged exposure via the neuroinflammatory and ferroptosis pathways. Initially, human microglial clone 3 (HMC3) cells were exposed to sucralose (0-50 mM) for 24, 48, and 72 h to investigate the short-term effects. Subsequently, HMC3 cells were treated with 1 mM sucralose for 7, 14, and 21 days to examine long-term effects. We measured levels of interleukin-1β (IL-1β), NOD-like receptor protein 3 (NLRP3), 8-hydroxydeoxyguanosine (8-OHdG), Sirtuin-1 (SIRT1), glutathione peroxidase-4 (GPx4), reduced glutathione (GSH), malondialdehyde (MDA), ferrous iron (Fe2+), and caspase 3/7. Additionally, we analyzed the impact of sucralose on cell morphology, migration, and expression levels of IL-1β, NLRP3, SIRT1, and GPx4. Sucralose inhibited cell viability and proliferation in HMC3 cells in a concentration- and time-dependent manner and induced membrane and nuclear abnormalities. Moreover, sucralose significantly reduced the cell migration rate. Long-term sucralose treatment decreased Fe2+, GPx4, GSH, and SIRT1 levels in HMC3 cells while increasing IL-1β, MDA, NLRP3, 8-OHdG, and caspase 3/7 activity. Sucralose treatment also enhanced microglial activation and neuroinflammation by upregulating IL-1β and NLRP3 and downregulating SIRT1 and GPx4, thereby inducing ferroptosis and suppressing cell viability. Consequently, high concentrations or long-term sucralose treatment may induce neuroinflammation and ferroptosis by targeting the SIRT1/NLRP3/IL-1β/GPx4 pathway in HMC3 cells.

Dual Time-Dependent Effects of Interleukin-33 Administration on the Kidney Postmyocardial Infarction.

Kidney damage is a serious prevalent complication that occurs after a myocardial infarction (MI) and is associated with worse outcomes. Interleukin-33 (IL-33), a member of the IL-1 superfamily, functions as an alarmin that is released upon necrosis or tissue damage to alert immune cells expressing the ST2L receptor. IL-33 is increased in kidney disease, and recent studies have shown that the IL-33/ST2 axis is instrumental in both disease progression and repair. In this study, we investigated the effect of IL-33 administration on kidneys in C57BL6/J male mice 4 and 7 days after the induction of MI. The mice received either IL-33 or vehicle (PBS) treatment. Cardiac systolic function and systemic inflammation were assessed, and kidneys were subjected to histological and molecular analysis. The administration of IL-33 for 4 days post-MI improved renal structure consistent with reduced expression of profibrotic markers, reduced apoptosis, and increased expression of the anti-inflammatory cytokine IL-4. In addition, IL-33 administration enhanced the levels of Sirtuin3, nicotinamide phosphoribosyltransferase, and the renal nicotinamide adenine dinucleotide pool which are critical for mitochondrial function and energy production, indicating metabolic benefits. However, this protection seems to be lost with the continued administration of IL-33 for 7 days post-MI coinciding with aggravated cardiac dysfunction and increased systemic inflammation. These findings demonstrate that while IL-33 treatment can help improve kidney damage post-MI in the short term, extended treatment may not be beneficial. This may be due to the direct effects of IL-33 on the kidneys or indirectly mediated by adverse cardiac remodeling influencing the cardiorenal crosstalk.