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Parkinson's disease (PD) is a complex neurodegenerative disorder that affects dopamine neurons of the substantia nigra pars compacta (SNpc), resulting in motor dysfunction. Among the pathways examined, mitochondria and α-synuclein were found to play a major role in the disease progression. Hence, several attempts are being made to restore mitochondrial bioenergetics or protein aggregation pathways as disease-modifying strategies. Our earlier studies reported the protective effect of 2,4-dihydroxy-azaflavanone (azaflavanone) in a transgenic Drosophila fly model of PD. In the present study, we found that azaflavanone acts as an allosteric activator of SIRT1 in both cell-free and cell-based systems and the effects were more pronounced as compared to resveratrol. Also, azaflavanone appears to interact selectively with SIRT1 as other SIRTs such as SIRT3 and SIRT6 did not exhibit any gross changes in cellular thermal shift assay (CETSA). Molecular docking studies depicted a higher docking score with azaflavanone than with resveratrol. Further, N27 cells treated with azaflavanone exhibited a dose-dependent increase in the mitotracker staining, mtDNA/nuclear DNA ratio, and also mitochondrial bioenergetics. The observed effects appear to be due to the activation of SIRT1, as evidenced by an increase in the expression of PGC-1α and TFAM, which are the downstream targets of SIRT1. Lastly, the Parkinsonian mimic MPP + -induced disturbance in the mitochondrial membrane potential, mitochondrial bioenergetics, and biogenesis were ameliorated by azaflavanone. Overall, our findings indicate that azaflavanone, being an antioxidant and an allosteric activator of SIRT1, is a promising compound for ameliorating the pathophysiology of PD.

Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34 + and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Arsenic (As) exposure is known to cause several neurological disorders through various molecular mechanisms such as oxidative stress, apoptosis, and autophagy. In the current study, we assessed the effect of melatonin (Mel) on As-induced neurotoxicity. Thirty male Wistar rat were treated daily for 28 consecutive days. As (15 mg/kg, gavage) and Mel (10 and 20 mg/kg, i.p.) were administered to rats. Morris water maze test was done to evaluate learning and memory impairment in training days and probe trial. Oxidative stress markers including MDA and GSH levels, SOD activity, and HO-1 levels were measured. Besides, the levels of apoptosis (caspase 3, Bax/Bcl2 ratio) and autophagy markers (Sirt1, Beclin-1, and LC3 II/I ratio) as well as the expression of miR-144 and miR-34a in cortex tissue were determined. As exposure disturbed learning and memory in animals and Mel alleviated these effects. Also, Mel recovered cortex pathological damages and oxidative stress induced by As. Furthermore, As increased the levels of apoptosis and autophagy proteins in cortex, while Mel (20 mg/kg) decreased apoptosis and autophagy. Also, Mel increased the expression of miR-144 and miR-34a which inhibited by As. In conclusion, Mel administration attenuated As-induced neurotoxicity through anti-oxidative, anti-apoptotic, and anti-autophagy mechanisms, which may be recommended as a therapeutic target for neurological disorders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Increasing evidence suggests that peritoneal fibrosis induced by peritoneal dialysis (PD) is linked to oxidative stress. However, there are currently no effective interventions for peritoneal fibrosis. In the present study, we explored whether adding caffeic acid phenethyl ester (CAPE) to peritoneal dialysis fluid (PDF) improved peritoneal fibrosis caused by PD and explored the molecular mechanism. We established a peritoneal fibrosis model in Sprague-Dawley rats through intraperitoneal injection of PDF and lipopolysaccharide (LPS). Rats in the PD group showed increased peritoneal thickness, submesothelial collagen deposition, and the expression of TGFβ1 and α-SMA. Adding CAPE to PDF significantly inhibited PD-induced submesothelial thickening, reduced TGFβ1 and α-SMA expression, alleviated peritoneal fibrosis, and improved the peritoneal ultrafiltration function. In vitro , peritoneal mesothelial cells (PMCs) treated with PDF showed inhibition of the AMPK/SIRT1 pathway, mitochondrial membrane potential depolarization, overproduction of mitochondrial reactive oxygen species (ROS), decreased ATP synthesis, and induction of mesothelial-mesenchymal transition (MMT). CAPE activated the AMPK/SIRT1 pathway, thereby inhibiting mitochondrial membrane potential depolarization, reducing mitochondrial ROS generation, and maintaining ATP synthesis. However, the beneficial effects of CAPE were counteracted by an AMPK inhibitor and siSIRT1. Our results suggest that CAPE maintains mitochondrial homeostasis by upregulating the AMPK/SIRT1 pathway, which alleviates oxidative stress and MMT, thereby mitigating the damage to the peritoneal structure and function caused by PD. These findings suggest that adding CAPE to PDF may prevent and treat peritoneal fibrosis.

Sepsis, a life-threatening condition characterized by dysregulated immune responses, remains a significant clinical challenge. Myricanol, a natural compound, plays a variety of roles in regulating lipid metabolism, anti-cancer, anti-neurodegeneration, and it could act as an Sirtuin 1 (SIRT1) activator. This study aimed to explore the therapeutic potential and underlying mechanism of myricanol in the lipopolysaccharide (LPS)-induced sepsis model. In vivo studies revealed that myricanol administration significantly improved the survival rate of LPS-treated mice, effectively mitigating LPS-induced inflammatory responses in lung tissue. Furthermore, in vitro studies demonstrated that myricanol treatment inhibited the expression of pro-inflammatory cytokines, attenuated signal pathway activation, and reduced oxidative stress in macrophages. In addition, we demonstrated that myricanol selectively enhances SIRT1 activation in LPS-stimulated macrophages, and all of the protective effect of myricanol were reversed through SIRT1 silencing. Remarkably, the beneficial effects of myricanol against LPS-induced sepsis were abolished in SIRT1 myeloid-specific knockout mice, underpinning the critical role of SIRT1 in mediating myricanol's therapeutic efficacy. In summary, this study provides significant evidence that myricanol acts as a potent SIRT1 activator, targeting inflammatory signal pathways and oxidative stress to suppress excessive inflammatory responses. Our findings highlight the potential of myricanol as a novel therapeutic agent for the treatment of LPS-induced sepsis., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Alzheimer's causes cognitive dysfunction. This study investigated the neuro-promoting effects of cordycepin on amyloid-beta precursor protein (APP) synthesis in human neuroblastoma SH-SY5Y cells. Cordycepin was found to boost SH-SY5Y cell proliferation and decreased AD pathology. APP, PS1, and PS2 were downregulated whereas ADAM10 and SIRT1 were upregulated by cordycepin. Cordycepin also reduced APP secretion in a dose-dependent manner. Cordycepin alleviated oxidative stress by the upregulation of GPX and SOD , as well as autophagy genes ( LC3 , ATG5 , and ATG12 ). Cordycepin activity was also found to be SIRT1-dependent. Therefore, cordycepin may relieve the neuronal degeneration caused by APP overproduction, and oxidative stress.

Constructing surface topography with a certain roughness is a widely used, non-toxic, cost-effective and effective method for improving the microenvironment of cells, promoting the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs), and promoting the osseointegration of grafts and further improving their biocompatibility under clinical environmental conditions. SIRT1 plays an important regulatory role in the osteogenic differentiation of bone marrow-derived MSCs (BM-MSCs). However, it remains unknown whether SIRT1 plays an important regulatory role in the osteogenic differentiation of BM-MSCs with regard to surface morphology. Polydimethylsiloxane (PDMS) with different surface morphologies were prepared using different grits of sandpaper. The value for BMSCs added on different surfaces was detected by cell proliferation assays. RT-qPCR and Western blotting were performed to detect SIRT1 activation and osteogenic differentiation of MSCs. Osteogenesis of MSCs was detected by alkaline phosphatase (ALP) and alizarin red S staining. SIRT1 inhibition experiments were performed to investigate the role of SIRT1 in the osteogenic differentiation of MSCs induced by surface morphology. We found that BM-MSCs have better value and osteogenic differentiation ability on a surface with roughness of PDMS-1000M. SIRT1 showed higher gene and protein expression on a PDMS-1000M surface with a roughness of 13.741 ± 1.388 µm. The promotion of the osteogenic differentiation of MSCs on the PDMS-1000M surface was significantly decreased after inhibiting SIRT1 expression. Our study demonstrated that a surface morphology with certain roughness can activate the SIRT1 pathway of MSCs and promote the osteogenic differentiation of BMSCs via the SIRT1 pathway., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: This study aimed to clarify the intervention effect of salidroside (SAL) on lung injury caused by PM 2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis., Methods: Specific pathogen-free (SPF) grade male C57BL/6 mice were randomly assigned to the following groups: control group, SAL group, PM 2.5 group, SAL+PM 2.5 group. On the first day, SAL was given by gavage, and on the second day, PM 2.5 suspension was given by intratracheal instillation. The whole experiment consist of a total of 10 cycles, lasting 20 days. At the end of treatment, blood samples and lung tissues were collected and analyzed. Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy. The expression of inflammatory, antioxidants, apoptosis, and SIRT1-PGC-1ɑ proteins were detected by Western blotting., Results: Exposure to PM 2.5 leads to obvious morphological and pathologica changes in the lung of mice. PM 2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1, Nrf2, SOD2, SIRT1 and PGC-1ɑ, and an increase in the protein expressions of IL-6, IL-1β, Bax, caspase-9 and cleaved caspase-3. However, SAL reversed the aforementioned changes caused by PM 2.5 by activating the SIRT1-PGC-1α pathway., Conclusion: SAL can activate SIRT1-PGC-1ɑ to ameliorate PM 2.5 -induced lung injury., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Though Isoimperatorin from Angelicae dahuricae is known to have antiviral, antidiabetic, anti-inflammatory and antitumor effects, its underlying antitumor mechanism remains elusive so far. Hence, the apoptotic mechanism of Isoimperatorin was explored in hepatocellular carcinomas (HCCs). In this study, Isoimperatorin inhibited the viability of Huh7 and Hep3B HCCs and increased the subG1 apoptotic portion and also abrogated the expression of pro-poly-ADP ribose polymerase (pro-PARP) and pro-caspase 3 in Huh7 and Hep3B cells. Also, Isoimperatorin abrogated the expression of cyclin D1, cyclin E1, CDK2, CDK4, CDK6 and increased p21 as G1 phase arrest-related proteins in Huh7 and Hep3B cells. Interestingly, Isoimperatorin reduced the expression and binding of c-Myc and Sirtuin 1 (SIRT1) by Immunoprecipitation (IP), with a binding score of 0.884 in Huh7 cells. Furthermore, Isoimperatorin suppressed the overexpression of c-Myc by the proteasome inhibitor MG132 and also disturbed cycloheximide-treated c-Myc stability in Huh7 cells. Overall, these findings support the novel evidence that the pivotal role of c-Myc and SIRT1 is critically involved in Isoimperatorin-induced apoptosis in HCCs as potent molecular targets in liver cancer therapy.

Mitochondrial dysfunction is an early event in Alzheimer's disease (AD) pathogenesis. To assess the impact of vitamin D3 (Vit.D) on neurogenesis, we investigated its role in mitigating cognitive impairment and mitochondrial dysfunction through calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-mediated phosphorylation of Sirtuin1 (SIRT1) in an aluminum-chloride-D-galactose (AlCl3-D-gal)-induced AD rat model. Rats were distributed into four groups: control, AlCl 3  + D-gal (10 + 60 mg/kg, ip), Vit.D (500 IU/kg, po), and AlCl 3  + D-gal+Vit.D. Novel object recognition (NOR), Morris Water Maze, and passive avoidance (PA) tests were used to measure memory abilities. The hippocampal tissue was used to assess vitamin D3 receptor (VDR) and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α) expression by quantitative real-time polymerase chain reaction (qRT-PCR), CAMKK2, p-SIRT1, phosphorylated-AMP-activated protein kinase (p-AMPK), dynamin-related-protein-1 (Drp1), and mitofusin-1 (Mnf1) proteins by western blot and Ca 2+ levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (Aβ), and phospho tau (p-Tau) via enzyme-linked immunosorbent assay(ELISA) in addition to histological and ultrastructural examination of rat's brain tissue. Vit.D-attenuated hippocampal injury reversed the cognitive decline and Aβ aggregation, and elevated p-Tau levels in the AlCl 3  + D-gal-induced AD rat model. In AlCl 3  + D-gal-exposed rats, Vit.D induced VDR expression, normalized Ca 2+ levels, elevated CAMKK2, p-AMPK, p-SIRT1, and PGC-1α expression. Vit.D reduced Drp1, induced Mnf1, increased mitochondrial membrane potential, preserved mitochondrial structure, restored normal mitochondrial function, and retained normal eNOS level and SOD activity in AlCl 3  + D-gal rats. In conclusion, our findings proved that Vit.D may ameliorate cognitive deficits in AlCl3 + D-gal-induced AD by restoring normal mitochondrial function and reducing inflammatory and oxidative stress via CAMKK2-AMPK/SIRT1 pathway upregulation., (© 2023 International Union of Biochemistry and Molecular Biology.)

Granulosa cells are somatic cells located inside follicles that play a crucial role in the growth and development of follicles. Quercetin and tanshinone are two key monomers in traditional Chinese medicine that have antioxidant and anti-aging properties. The KGN cell apoptosis model caused by triptolide (TP) was employed in this work to investigate granulosa cell death and medication rescue. Quercetin and tanshinone therapy suppressed KGN cell death and oxidation while also regulating the expression of critical apoptosis and oxidation-related markers such as B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Further research revealed that the effects of Quercetin and Tanshinone were accomplished via deacetylation of FOXO3A in the cytoplasm and mitochondria via the SIRT1/SIRT3-FOXO3a axis. In summary, Quercetin and tanshinone protect KGN cells from apoptosis by reducing mitochondrial apoptosis and oxidation via the SIRT1/SIRT3-FOXO3a axis.

Objective : Previous studies have shown that the cleavage of Sirt1 contributes to the development of osteoarthritis (OA). In fact, OA was effectively abrogated by the intra-articular (IA) administration of two compounds, one blocking Sirt1 cleavage (CA074me) and the other activating Sirt1 (SRT1720), using a post-traumatically induced model (PTOA) in young female mice. In this study, we attempted to understand if this local treatment is effective in preventing age-associated OA (AOA) progression and symptoms. Design : A group of 17-month-old female C57BL/6J mice were IA administered with CA074me and/or SRT1720 or their combination. Joint histopathological analysis and bone histomorphometry were carried out, with an assessment of knee mechanical hyperalgesia. A serum analysis for NT/CT Sirt1 was carried out along with immunohistochemistry for articular cartilage to detect p16 INK4A or γH2A.X. Similarly, meniscal cartilage was monitored for Lef1 and Col1a1 deposition. The data were compared for young female mice subjected to post-traumatic OA (PTOA). Results : Similar to PTOA, combination-treated AOA exhibited improved knee hyperalgesia, yet structural improvements were undetected, corresponding to unchanged NT/CT Sirt1 serum levels. Both AOA and PTOA exhibited unchanged staining for nuclear p16 INK4A or γH2A.X and lacked a correlation with OA severity. Contrarily to PTOA, the combination treatment with AOA did not exhibit a local reduction in the Lef1 and Col1 targets. Conclusions : When targeting Sirt1 cleavage, the PTOA and AOA models exhibited a similar pain response to the combination treatment; however, they displayed diverse structural outcomes for joint-related damage, related to Lef1-dependent signaling. Interestingly, nuclear p16 INK4A was unaffected in both models, regardless of the treatment's effectiveness. Finally, these findings highlight the variations in the responses between two highly researched OA preclinical models, reflecting OA pathophysiology heterogeneity and variations in gender-related drug-response mechanisms.

The granulosa cells (GCs) of birds are essential for the reproduction and maintenance of populations in nature. Atrazine (ATR) is a potent endocrine disruptor that can interfere with reproductive function in females and Diaminochlorotriazine (DACT) is the primary metabolite of ATR in the organism. Melatonin (MT) is an endogenous hormone with antioxidant properties that plays a crucial role in development of animal germ cells. However, how ATR causes mitochondrial dysfunction, abnormal secretion of steroid hormones, and whether MT prevents ATR-induced female reproductive toxicity remains unclear. Thus, the purpose of this study is to investigate the protective effect of MT against ATR-induced female reproduction. In the present study, the GCs of quail were divided into 6 groups, as follows: C (Serum-free medium), MT (10 µM MT), A250 (250 µM ATR), MA250 (10 µM MT+250 µM ATR), D200 (200 µM DACT) and MD200 (10 µM MT+200 µM DACT), and were cultured for 24 h. The results revealed that ATR prevented GCs proliferation and decreased cell differentiation. ATR caused oxidative damage and mitochondrial dysfunction, leading to disruption of steroid synthesis, which posed a severe risk to GC's function. However, MT supplements reversed these changes. Mechanistically, our study exhibited that the ROS/SIRT1/STAR axis as a target for MT to ameliorate ATR-induced mitochondrial dysfunction and steroid disorders in GCs, which provides new insights into the role of MT in ATR-induced reproductive capacity and species conservation in birds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Development and progression of sepsis-induced acute lung injury (ALI) involve apoptosis and oxidative stress in lung epithelial cells. Ligustilide (LIG) is one of the main bioactive constituents derived from the Angelica sinensis. As a novel SIRT1 agonist, LIG owns powerful anti-inflammatory and antioxidative properties, exerting remarkable therapeutic effects on cancers, neurological disorders, and diabetes mellitus. However, whether LIG could protect against lipopolysaccharide (LPS)-induced ALI by activating SIRT1 remains unclear. Mice underwent intratracheal LPS injection to mimic sepsis-induced ALI while MLE-12 cells were treated with LPS for 6 h to establish an in vitro ALI model. At the same time, mice or MLE-12 cells were treated with different doses of LIG to access its pharmacological effect. The results demonstrated that LIG pretreatment could improve LPS-induced pulmonary dysfunction and pathological injury, apart from increasing 7-day survival rate. In addition, LIG pretreatment also decreased inflammation, oxidative stress and apoptosis during LPS-induced ALI. Mechanically, LPS stimulation decreased the expression and activity of SIRT1 but increased the expression of Notch1 and NICD. And LIG could also enhance the interaction between SIRT1 and NICD, thus deacetylating NICD. In vitro experiments also unveiled that EX-527, a selective SIRT1 inhibitor, could abolish LIG-elicited protection in LPS-treated MLE-12 cells. And in SIRT1 knockout mice with ALI, LIG pretreatment also lost its effects on inflammation, apoptosis, and oxidative stress during ALI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: P53 represents a key player in apoptosis-induction in cancers including colorectal cancer (CRC) that ranks third worldwide in cancer prevalence as well as mortality statistics. Although a pro-apoptotic effect of resveratrol has been repeatedly proven in CRC cells, its pathway mechanisms are not completely understood, as there are controversial statements in the literature regarding its activation or inhibition of the counteracting proteins Sirt-1 and p53., Methods: CRC cells as wild-type (HCT-116 WT) or p53-deficient (HCT-116 p53 -/- ) were cultured using multicellular tumor microenvironment (TME) cultures containing T-lymphocytes and fibroblasts to elucidate the role of p53/Sirt-1 modulation in resveratrol's concentration-dependent, pro-apoptotic, and thus anti-cancer effects., Results: Resveratrol dose-dependently inhibited viability, proliferation, plasticity as well as migration, and induced apoptosis in HCT-116 WT more effectively than in HCT-116 p53 -/- cells. Moreover, resveratrol stimulated Sirt-1 expression when administered at low concentrations (<5µM) but suppressed it when added at high concentrations (>10µM) to CRC-TME. In parallel, similar to the knockdown of Sirt-1 at the mRNA level, treatment with high-concentration resveratrol boosted the acetylation of p53, the expression of p21, Bax, cytochrome C, caspase-3, and ultimately induced apoptosis in CRC WT but not in CRC p53 -/- cells. Notably, increasing concentrations of resveratrol were found to promote hyperacetylation of p53 and FOXO3a as post-translational substrates of Sirt-1, indicating a negative regulatory loop between Sirt-1 and p53., Discussion: These results demonstrate for the first time, a negative reciprocal crosstalk between the regulatory circuits of p53 and Sirt-1, consequently, apoptosis induction by higher resveratrol concentrations in CRC-TME., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brockmueller, Buhrmann, Shayan and Shakibaei.)

Clinical application of doxorubicin is limited because of its potential side effects. The present study examined whether naringin had protective actions on doxorubicin-induced liver injury. Male BALB/c mice and alpha mouse liver 12 (AML-12) cells were used in this paper. The results showed that AML-12 cells treated with naringin significantly reduced cell injury, reactive oxygen species release and apoptosis level; Moreover, naringin notably alleviated liver injury by decreasing aspartate transaminase, alanine transaminase and malondialdehyde, and increasing superoxide dismutase, glutathione and catalase levels. Mechanism researches indicated that naringin increased the expression levels of sirtuin 1 (SIRT1), and inhibited the downstream inflammatory, apoptotic and oxidative stress signaling pathways. Further validation was obtained by knocking down SIRT1 in vitro, which proved the effects of naringin on doxorubicin-induced liver injury. Therefore, naringin is a valuable lead compound for preventing doxorubicin-induced liver damage by reducing oxidative stress, inflammation, and apoptosis via up-regulation of SIRT1., (© 2023 Wiley Periodicals LLC.)

Chlorpyrifos (CPF) is a widely used broad-spectrum pesticide with multi-organ toxic effects. Oxidative stress was found to play a role in the deleterious effects of CPF, including nephrotoxicity. This study investigated the protective effect of the antioxidant polyphenol rosmarinic acid (RA) against CPF-induced kidney injury, with an emphasis on oxidative injury, inflammation, SIRT1, and Nrf2/HO-1 signaling. Rats received 10 mg/kg CPF and 25, 50, and 100 mg/kg RA orally for 28 days, and the samples were collected for analysis. CPF increased serum urea and creatinine and kidney Kim-1 and caused several histopathological alterations. ROS, MDA, NO, NF-κB p65, TNF-α, and IL-1β were elevated in the kidney of CPF-intoxicated rats. RA ameliorated kidney function markers, prevented tissue injury, suppressed ROS, MDA, and NO, and downregulated NF-κB p65, TNF-α, and IL-1β in CPF-intoxicated rats in a dose-dependent manner. RA decreased Bax, caspase-3, oxidative DNA damage, and Keap1, boosted antioxidant enzymes and Bcl-2, and upregulated Nrf2, HO-1, and SIRT1 in CPF-administered rats. Molecular docking simulation revealed the binding affinity of RA toward NF-κB, Keap1, HO-1, and SIRT1. In conclusion, RA prevented CPF nephrotoxicity by attenuating oxidative stress, inflammation, and apoptosis and upregulating SIRT1 and Nrf2/HO-1 signaling., Competing Interests: Declaration of competing interest All authors declare no conflict of interests in relation to the manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Bergenin (BGN) is a C-glycoside of 4-O-methylgallic acid with anti-inflammatory, antioxidant, and tissue-repairing abilities. Here, we probed the roles and mechanisms of BGN in ischemic stroke-mediated cerebral injury., Methods: The middle cerebral artery occlusion (MCAO) model was established in mice, which were injected intraperitoneally with varying concentrations of BGN (10, 20, and 40 mg/kg). The modified neurological severity score (mNSS) and the water maze experiment were adopted to evaluate mice's neural functions (movement and memory). The brain edema was assessed by the dry and wet method. TdT-mediated dUTP nick end labeling (TUNEL)-labeled apoptotic neurons and Iba1-labeled microglia in the cortex were measured by immunohistochemistry (IHC). Quantitative reverse transcription-PCR and ELISA were implemented to determine the expression of inflammatory cytokines (TNFα, IL-1β, and IL-6), neurotrophic factors (BDNF and VEGF), and oxidative stress factors (SOD and MDA) in brain tissues. The profiles of Sirt1, FOXO3a, Nrf2, NF-κB, and STAT6 in brain tissues were checked by western blot., Results: BGN significantly improved MCAO mice's cognitive, learning, and motor functions, reduced brain edema, hampered the production of inflammatory factors and oxidative stress mediators, and suppressed neuronal apoptosis. Additionally, BGN dampened the expression of proinflammatory cytokines and upregulated neurotrophic factors and oxidative stress factors in ischemic brain tissues of MCAO mice. Meanwhile, BGN reduced the expression of inflammatory cytokines and oxidative stressors in oxygen-glucose deprivation/reoxygenation-induced BV2 microglia. Further mechanistic studies revealed that BGN concentration dependently elevated the profiles of Sirt1, FOXO3a, STAT6, and Nrf2, and abated the NF-κB phosphorylation., Conclusion: BGN protects against ischemic stroke in mice by boosting the Sirt1/FOXO3a pathway, suggesting its potential as a therapeutic agent for ischemic stroke., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Ethnopharmacological Relevance: Polyalthia longifolia var. angustifolia Thw. (Annonaceae) is commonly used in traditional medicine as a tonic for rejuvenation and exhibiting good antioxidant activities., Aim of the Study: To evaluate P. longifolia methanolic leaf extract (PLME) antiaging activity at 1 mg/mL in Saccharomyces cerevisiae BY611 yeast., Materials and Methods: The antiaging effect of PLME was studied via replicative lifespan assay, antioxidative stress assays, reactive oxygen species (ROS) determination, reduced glutathione (GSH) determination, superoxide dismutase (SOD) and Sirtuin 1 (SIRT1) genes regulation studies and SOD and SIRT1 proteins activities., Results: The PLME treatment increased the growth and prolonged the lifespan of the yeast significantly (p < 0.05) compared to the untreated yeast group. Besides, the PLME also protected the yeast from oxidative stress induced by 4-mM-H 2 O 2 via decreasing (p < 0.05) the ROS from 143.207 to 127.223. The antioxidative action of PLME was proved by spot assay. Phloxine B staining was further confirmed the PLME antioxidative action of PLME, where more whitish-pink live yeast cells were observed. In addition, the PLME also enhanced GSH content significantly (p < 0.05) in yeast treated with PLME from 16.81 to 25.31 μmol. Furthermore, PLME increased the SOD and SIRT1 genes expression significantly (p < 0.05) with ΔCt values of 1.11 and 1.15, respectively. The significantly (p < 0.05) elevated SOD and SIRT1 protein activities were recorded as 51.54 U/mg Prot and 1716 ng/mL, respectively., Conclusions: PLME exhibited good antiaging activities in S. cerevisiae, by modulating oxidative stress, enhancing GSH content, and increasing SOD and SIRT1 genes expression., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Ovatodiolide (OVA), a bioactive substance extracted from the bioactive component of Anisomeles indica, is reported to be endowed with anti-inflammatory properties. Nonetheless, its function in ischemia-reperfusion (I/R)-induced neurological deficits and microglial inflammation remains unclear., Method: A middle cerebral artery occlusion (MCAO) model was set up in SD rats, which were then dealt with varying doses of OVA. The rats' neurological functions were estimated at diverse periods postoperatively. The dry and wet method, triphenyl tetrazolium chloride (TTC) staining, and Nissl's staining were conducted to measure brain edema, cerebral infarction area and neuronal damage, respectively. Immunohistochemistry (IHC) was performed to detect neuronal apoptosis and microglial activation, and the profiles of inflammatory factors in the cerebral tissues were estimated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In-vitro assays were implemented on HT22 neuronal cells and BV2 microglia to elaborate the effect of OVA against oxygen-glucose deprivation (OGD)-mediated effects., Results: OVA relieved HT22 cell apoptosis and eased inflammation in BV2 microglia, which were induced by OGD. OVA mitigated NF-κB phosphorylation in BV2 cells, whereas boosted SIRT1 expression. However, inhibiting SIRT1 abolished the anti-inflammatory effects of OVA in BV2 microglia under OGD stimulation. The condition medium (CM) of OGD-treated BV2 cells enhanced HT22 cell apoptosis and damage. OVA treatment in BV2 cells relieved BV2-mediated injury on HT22 cells, which was reversed by SIRT1 inhibitor. In-vivo results revealed that OVA dose-dependently attenuated I/R rats' neurological deficits, reduced brain edema, cerebral infarction area, neuronal apoptosis and microglial overactivation. Additionally, OVA inactivated the NF-κB pathway and up-regulated SIRT1 in the I/R rat model., Conclusion: OVA prevented rats from brain I/R damage by hampering neuronal apoptosis and microglial inflammation via the SIRT1-NF-κB pathway., Data Availability: The data sets used and analyzed during the current study are available from the corresponding author on reasonable request., (Copyright © 2022. Published by Elsevier Inc.)

Background: Diabetes mellitus (DM)-related corneal epithelial dysfunction is a severe ocular disorder; however, the effects of nicotinamide mononucleotide (NMN) on high-glucose (HG)-treated human corneal epithelial cells (HCECs) remain unclear., Methods: We conducted an in-vitro study to examine the effects of NMN treatment on HG-treated HCECs. Cell viability was measured using trypan blue stain, mitochondrial membrane potential was measured using JC-1 stain, and intracellular reactive oxygen species and apoptosis assays were conducted using flow cytometry. Transepithelial electrical resistance (TEER) and zonula occludens-1 (ZO-1) immunofluorescence for tight junction examinations were conducted. Immunoblot analyses were conducted to analyze the expression of silent information regulator-1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) of the SIRT1/Nrf2/HO-1 pathway., Results: NMN increased cell viability by reducing cell damage, reducing apoptosis, increasing cell migration, and restoring tight junctions in HG-treated HCECs. By analyzing the expressions of SIRT1, Nrf2, HO-1, NMN demonstrated protective effects via the SIRT1/Nrf2/HO-1 pathway., Conclusions: NMN increases cell viability by reversing cell damage, reducing apoptosis, increasing cell migration, and restoring tight junctions in HG-treated HCECs, and these effects may be mediated by the SIRT1/Nrf2/HO-1 pathway., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The aim of this study was to investigate the efficacy and underlying mechanism of high concentration of hydrogen on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We have established a corresponding mouse model and examined the function of hydrogen inhalation on lung pathology and pulmonary edema induced by LPS, as well as contents of IL-1β, TNF-α and IL-8. The pulmonary microvascular permeability and 66.7 % hydrogen on the expression of sirt1 and its downstream signaling molecules were tested. Results showed that 66.7 % hydrogen alleviated lung pathological changes and pulmonary edema caused by LPS, and reduced the degree of ALI by inhibiting pro-inflammatory cytokine release and oxidative stress response, thereby decreasing the expression of molecules related to intercellular adhesion. sirt1 contributed to the repair of LPS-induced ALI by hydrogen through the regulation of NF-κB and catalase expression. In conclusion, 66.7 % hydrogen protected against LPS-induced ALI by suppressing inflammatory response and oxidative stress mediated by NF-κB and catalase in a sirt1-dependent manner., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study evaluated if the hepatic protective effect of Isoliquiritigenin (ISL) against doxorubicin (DOX)-treated rats involves upregulating sirtuin-1 (SIRT1) signaling. Adult male was divides into 5 groups (n = 6 rats/each) as control (vehicle), ISL (25 mg/kg), DOX (15 mg/kg), DOX + ISL, and DOX + ISL + EX-527 (a SIRT1 inhibitor, 5 mg/kg). ISL and EX-527 were administered 10 days before and after the single treatment of DOX. Also, cultured AML-12 hepatocytes (5 ×10 4 ) were treated with 10 µM of ISL for 24 h with or without DOX-treatments (10 µM) and in the presence or absence of EX-527 (5 µM). ISL prevented hepatocyte damage and decreased serum levels of hepatic transaminases, hepatic levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and hepatic mRNA levels of Bax and caspases-3,8, and 9. In the liver of the control and DOX-treated rats, ISL reduced levels of malondialdehyde (MDA) but increased hepatic levels of glutathione (GSH), superoxide dismutase (SOD), and catalase, as well as mRNA levels of Bcl2. In vitro, ISL stimulated cell survival and lowered levels of ROS but increased GSH levels. In vivo and in vitro, in the livers of control and DOX-treated animals, ISL significantly increased the nuclear activity and mRNA levels of SIRT1, enhanced the nuclear levels of Nrf2, and reduced nuclear levels of NF-κB p65. In conclusion, ISL alleviates DOX-induced hepatocyte toxicity by stimulating the Nrf2/antioxidants axis and concomitant suppression of NF-κB, mainly by upregulating/activating SIRT1., (Copyright © 2021. Published by Elsevier Masson SAS.)

The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group ( p < 0.01). However, Stevia Rebaudiana Bertoni ( Stevia R. ) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region ( p < 0.01). In conclusion, Stevia R . exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

The cumulative effects of cell damage result in aging, which gradually decreases human function in various aspects and leads to multiple age-related chronic diseases. To overcome the adverse effects of aging, silent mating type information regulation 2 homologue (SIRT1) activators are promising bioactive compounds that mimic calorie restriction to improve quality of life and prevent aging. In this study, 11 new flavonostilbenes ( 1 - 11 ) and three known compounds ( 12 - 14 ) were purified from stems of Rhamnoneuron balansae . The structures of the new compounds were determined using extensive data from spectroscopic methods, including NMR and HRESIMS. Their absolute configurations were deduced by ECD calculations with coupling constant analysis. All of the isolated new compounds ( 1 - 11 ) were evaluated for their effects on SIRT1 deacetylase activity, the NAD + /NADH ratio, and the AMP-activated protein kinase activation level in cell-based assays. The results showed that rhamnoneuronal D ( 1 ) exhibits promising biological activity in several in vitro models related to SIRT1 and suggest it is a potential natural-product-based antiaging agent.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Although mounting studies have been conducted, no effective therapy is available to halt its progression. Indole-3-carbinol (I3C) is a naturally occurring compound obtained by β-thioglucosidase-mediated autolysis of glucobrassicin in cruciferous vegetables. Besides its powerful antioxidant activity, I3C has shown neuroprotection against depression and chemically induced neurotoxicity via its anti-inflammatory and antiapoptotic effects. This study aimed to investigate the neuroprotective effects of I3C against rotenone (ROT)-induced PD in male albino rats. The possible protective mechanisms were also explored. PD was induced by subcutaneous administration of ROT (2 mg/kg) for 28 days. The effects of I3C (25, 50, and 100 mg/kg/day) were assessed by catalepsy test (bar test), spontaneous locomotor activity, rotarod test, weight change, tyrosine hydroxylase (TH) expression, α-synuclein (α-Syn) expression, striatal dopamine (DA) content, and histological examination. The highest dose of I3C (100 mg/kg) was the most effective to prevent ROT-mediated motor dysfunctions and amend striatal DA decrease, weight loss, neurodegeneration, TH expression reduction, and α-Syn expression increase in both the midbrain and striatum. Further mechanistic investigations revealed that the neuroprotective effects of I3C are partially attributed to its anti-inflammatory and antiapoptotic effects and the activation of the sirtuin 1/AMP-activated protein kinase pathway. Altogether, these results suggested that I3C could attenuate biochemical, molecular, and functional changes in a rat PD model with following repeated rotenone exposures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diabetic nephropathy (DN) is a common complication of diabetes. Yishen capsule, composed of Chinese herbs, improves the clinical outcome in DN patients. However, its therapeutic potential and underlying mechanisms require further elucidation. Hence, our study aimed to investigate the underlying mechanisms and therapeutic potential of Yishen capsule in DN. Streptozotocin-induced DN rats were treated with Yishen capsules (1.25 g/kg/day) for 8 weeks. Then, blood glucose and urine protein levels were measured. Hematoxylin and eosin staining and western blot assays were used to examine the histologic changes and gene expression, respectively, in kidney samples. Mouse podocytes were treated with rat serum containing Yishen capsule and transmission electron microscopy was used to examine autophagosome formation. Cell counting kit-8 assay was performed to examine cell proliferation. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were conducted to detect changes in gene expression. The localization of SIRT1 was examined in the podocytes using immunocytofluorescence assay. We found that Yishen capsule relieved pathological changes, decreased urine protein, increased SIRT1, LC3-II, and Beclin-1 expression, and reduced acetylated NF-κB p65 expression in vivo . In addition, rat serum containing Yishen capsule showed improved podocyte proliferation, promoted the mRNA and protein levels of LC3-II and Beclin-1, and induced nuclear translocation of SIRT1. Furthermore, it increased SIRT1 expression and decreased mRNA level of NF-κB in the serum. SIRT1 inhibitor increased the mRNA level of NF-κB. Our data suggests that Yishen capsule improves DN by promoting podocyte autophagy via the SIRT1/NF-κB pathway.

Mitochondrial injury in granulosa cells (GCs) is associated with the pathophysiological mechanism of polycystic ovary syndrome (PCOS). Melatonin reduces the mitochondrial injury by enhancing SIRT1 (NAD-dependent deacetylase sirtuin-1), while the mechanism remains unclear. Mitochondrial membrane potential is a universal selective indicator of mitochondrial function. In this study, mitochondrial swelling and membrane defect mitochondria in granulosa cells were observed from PCOS patients and DHT-induced PCOS-like mice, and the cytochrome C level in the cytoplasm and the expression of BAX (BCL2-associated X protein) in mitochondria were significantly increased in GCs, with p-Akt decreased, showing mitochondrial membrane was damaged in GCs of PCOS. Melatonin treatment decreased mitochondrial permeability transition pore (mPTP) opening and increased the JC-1 (5,5',6,6'-tetrachloro1,1',3,3'-tetramethylbenzimidazolylcarbocyanine iodide) aggregate/monomer ratio in the live KGN cells treated with DHT, indicating melatonin mediates mPTP to increase mitochondrial membrane potential. Furthermore, we found melatonin decreased the levels of cytochrome C and BAX in DHT-induced PCOS mice. PDK1/Akt played an essential role in improving the mitochondrial membrane function, and melatonin treatment increased p-PDK 1 and p-Akt in vivo and in vitro. The SIRT1 was also increased with melatonin treatment, while knocking down SIRT1 mRNA inhibiting the protective effect of melatonin to activate PDK1/Akt. In conclusion, melatonin enhances SIRT1 to ameliorate mitochondrial membrane damage by activating PDK1/Akt in granulosa cells of PCOS., (© 2021. The Author(s).)

Recent studies reported that miR-128 was differentially expressed in cardiomyocytes in response to pathologic stress. However, its function and mechanism remain to be fully elucidated. The aim of the present study was to investigate the role of miR-128 in chronic angiotensin II (Ang II) infusion-induced cardiac remodeling and its underlying mechanism. The cardiac remodeling and heart failure in vivo were established in C57BL/6 mice by chronic subcutaneous Ang II delivery. Knocking down miR-128 was conducted in the hearts of the mice by intravenous injection of HBAAV2/9-miR-128-GFP sponge (miR-128 inhibitor). In vitro experiments of cardiac hypertrophy, apoptosis, and aberrant autophagy were performed in cultured cells after Ang II treatment or transfection of miR-128 antagomir. Our results showed that chronic Ang II delivery for 28 days induced cardiac dysfunction, hypertrophy, fibrosis, apoptosis, and oxidative stress in the mice, while the miR-128 expression was notably enhanced in the left ventricle. Silencing miR-128 in the hearts of mice ameliorated Ang II-induced cardiac dysfunction, hypertrophy, fibrosis apoptosis, and oxidative stress injury. Moreover, Ang II induced excessive autophagy in the mouse hearts, which was suppressed by miR-128 knockdown. In cultured cells, Ang II treatment induced a marked elevation in the miR-128 expression. Downregulation of miR-128 in the cells by transfection with miR-128 antagomir attenuated Ang II-induced apoptosis and oxidative injury probably via directly targeting on the SIRT1/p53 pathway. Intriguingly, we found that miR-128 inhibition activated PIK3R1/Akt/mTOR pathway and thereby significantly damped Ang II-stimulated pathological autophagy in cardiomyocytes, which consequently mitigated cell oxidative stress and apoptosis. In conclusion, downregulation of miR-128 ameliorates Ang II-provoked cardiac oxidative stress, hypertrophy, fibrosis, apoptosis, and dysfunction in mice, likely through targeting on PIK3R1/Akt/mTORC1 and/or SIRT1/p53 pathways. These results indicate that miR-128 inhibition might be a potent therapeutic strategy for maladaptive cardiac remodeling and heart failure., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Heqin Zhan et al.)

Mitochondrial dysfunction has been implicated as a one of the major factors linked to the development of painful diabetic neuropathy (DN). Several studies have demonstrated that sirtuin (SIRT1) activation recuperates nerve function by activating mitochondrial biogenesis. Polydatin, a resveratrol glycoside, has been explored to improve mitochondrial function via SIRT1 activation. However, the neuroprotective effects of polydatin in DN remain elusive. In this study, polydatin (25 and 50 mg/kg, oral) was administered for last 2 weeks of 8-week study to diabetic Sprague-Dawley rats weighing 250-300 g (post 6-weeks of streptozotocin 55 mg/kg, intraperitoneal). Treatment with polydatin significantly attenuated mechanical and thermal hyperalgesia in diabetic rats. Treated diabetic rats also showed improvement in motor/sensory nerve conduction velocities and nerve blood flow. For in vitro studies, Neuro2a cells were exposed to high-glucose (30 mM) condition to simulate short-term hyperglycemia. Polydatin was evaluated for its role in SIRT1 and Nrf2 activation at a dose of 5, 10, and 20 µM concentrations. Polydatin exposure normalized the mitochondrial superoxides, membrane potentials and improved neurite outgrowth in high-glucose-exposed Neuro2a cells. Increased SIRT1 activation by polydatin resulted in peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis. SIRT1 activation also facilitated Nrf2-directed antioxidant signaling. Study results inferred that decline in mitochondrial biogenesis and oxidative function in diabetic rats and high-glucose-exposed Neuro2a cells, could be counteracted by polydatin administration, postulated via enhancing SIRT1 and Nrf2 axis., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Four new C-11 monosaccharide attached dammarane triterpenoid glycosides cypaliurusides SV (1-4), along with nine known dammarane triterpenoid glycosides (5-13) were isolated from a CHCl 3 -soluble extract of the leaves of Cyclocarya paliurus. All characterized compounds were assayed for their cytotoxicities against HepG2 cells and 10 compounds were evaluated for the agonistic effects on sirtuin1 (SIRT1). The results showed that compounds 1, 5 and 6 were strongly cytotoxic in HepG2 cell line. Two dammarane triterpenoid glycosides 3 and 10 exhibited agonistic activities on SIRT1 with IC 50 of 10 μM and 20 μM, respectively., (Copyright © 2021. Published by Elsevier B.V.)

Spinal cord injury (SCI) can cause severe trauma to the central nervous system. Resveratrol has been widely studied for several of its medicinal properties, including anti-inflammatory, anti-aging and anti-oxidative effects. The regulation of SIRT-1 is thought to be related to the effects of resveratrol. As a downstream component of SIRT-1, NF-κB is one of the important signaling pathways that regulate the inflammatory response. Herein, we explored how treatment with resveratrol promoted recovery of motor function after SCI by activating the SIRT-1/NF-κB signaling pathway and inhibiting inflammation in rat models. Recovery of hind limb function was observed using the Basso, Beattie, and Bresnahan locomotor rating scale at different time points after SCI. Western blot analysis, immunofluorescence, Nissl staining and HE staining were utilized to observe the morphological characteristics of spinal cord tissue, as well as the expression of SIRT-1, NF-κB, TNF-α, IL-1β, IL-6 and brain-derived neurotrophic factor. Resveratrol treatment promoted motor function recovery, increased the expression of brain-derived neurotrophic factor, and reduced loss of motor neurons and lesion size among rats after SCI. Meanwhile, inflammatory response was inhibited as the SIRT-1/NF-κB signaling pathway was modulated. These results suggest that resveratrol can help achieve neuroprotective effect by inhibiting inflammation, regulated by the SIRT-1/NF-κB signaling pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The peroxisome proliferator-activated receptor (PPAR) α / γ -adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum , Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPAR α / γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPAR α / γ and AMPK α 1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPAR α / γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPAR α / γ -AMPK pathway and fatty acid metabolism., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Yufei Bei et al.)

Endoplasmic reticulum (ER) stress plays a key role in cadmium chloride (CdCl2)-induced nephrotoxicity. Sirtuin-1 (SIRT1) is a potent inhibitor of ER stress. In this study, we examined whether the protective effect of quercetin (QUR) against CdCl 2 -induced nephrotoxicity in rats involved modulation of SIRT1 and/or ER stress. Adult male rats were divided into five groups (n = 8, each) and treated for eight weeks as follows: control, control + QUR, CdCl 2 , CdCl 2 + QUR, and CdCl 2 + QUR + EX-527 (a SIRT1 inhibitor). Treatment of rats with QUR preserved the glomerulus and tubule structure, attenuated interstitial fibrosis, increased creatinine excretion, and reduced urinary levels of albumin, N-acetyl-β-D-glucosaminidase, and β2-microglobulin in CdCl 2 -treated rats. Concomitantly, QUR increased renal levels of Bcl-2, reduced mRNA levels of CHOP, and protein levels of Bax, caspase-3, and cleaved caspase-3, but failed to reduce the mRNA levels of GRP78, PERK, eIf2α, ATF-6, and xbp-1. QUR also reduced the renal levels of reactive oxygen species, tumour necrosis factor, and interleukin-6 and the nuclear activity of NF-κB in the control and CdCl 2 -treated rats but increased the nuclear activity of Nrf2 and levels of glutathione and manganese superoxide dismutase. Additionally, QUR increased the total levels and nuclear activity of SIRT1 and reduced the acetylation of eIf2α and xbp-1. The nephroprotective effects of QUR were abrogated by treatment with EX-527. Thus, QUR ameliorated CdCl 2 -induced nephrotoxicity through antioxidant and anti-inflammatory effects and suppressed ER stress mediated by the upregulation or activation of SIRT1-induced deacetylation of Nrf2, NF-κB p65, eIF2α, and xbp-1., (Copyright © 2021. Published by Elsevier Masson SAS.)

Obesity remains a continuing global health concern, as it is associated with an increased risk of many chronic diseases. Atractylodes chinensis Koidz. (Ac) is traditionally used in the treatment of inflammatory diseases, such as arthritis, hepatitis, and gastric ulcers. Despite the diverse pharmacological activities of Ac, scientific evidence for the use of Ac in obesity is still limited. Therefore, the present study aimed to determine the anti-obesity effects of Ac. C57BL/6N mice were divided into five groups as follows: chow diet group (CON), 45% HFD group, HFD + oral administration of orlistat group, and HFD + oral administration of Ac groups. RT-PCR and western blotting were used to examine the expression of molecules relating to obesity progression. Ac-administered mice showed dramatically decreased body weight and weight gain compared to the high-fat diet (HFD)-fed mice. In addition, Ac administration attenuated the protein expression levels of adipogenic transcription factors in the white adipose tissue (WAT) and livers of HFD-fed mice. Furthermore, Ac administration declined the expression levels of lipogenic genes, while enhancing those of the fatty acid oxidation genes in the WAT of HFD-fed mice. Importantly, Ac administration highly upregulated the AMP-activated kinase (AMPK) and sirtuin 1 (SIRT1) expression levels in WAT of the HFD-induced obese mouse model. Our results provide evidence that Ac can effectively ameliorate weight gain and adipose tissue expansion.

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null ( Ephx2 -/- ) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide [NAM, sirtuin-1 (SIRT1) inhibitor] simultaneously for 4 wk. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2 knockout mice ( Ephx2 -/- mice) without NAM treatment. However, the arterial protective effects were gone in Ephx2 -/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced matrix metalloproteinase 2 (MMP2) upregulation via SIRT1-mediated yes-associated protein (YAP) deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation. NEW & NOTEWORTHY We presently show that sEH knockout repressed nicotine-induced arterial stiffness and extracellular matrix remodeling via SIRT1-induced YAP deacetylation, which highlights that sEH is a potential therapeutic target in smoking-induced arterial stiffness and vascular remodeling.

The SIRT family of proteins constitutes highly conserved deacetylases with diverse and extensive functions. These proteins have specific biological functions, including regulation of transcription, cell cycle, cell differentiation, apoptosis, stress, metabolism, and genomic stability. Polydatin is a monocrystalline compound isolated from a Chinese herb, Polygonum cuspidatum. The pharmacological mechanisms of polydatin are mostly unclear but involve members of the SIRT protein family, among which SIRT1 plays a vital role. Polydatin is usually considered a potential SIRT1 activator. This review summarizes the signaling mechanism of polydatin involving SIRT1 and discusses the roles of related signal molecules such as PGC-1α, Nrf2, p38-MAPK, NLPR3 inflammasome, and p53. Further, we describe the metabolic regulation of related biological macromolecules and demonstrate that SIRT1, as a metabolic sensor, may act as a new pharmacological target for polydatin., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Hesperetin (HSP) is a natural flavonoid that offers useful curative effects for cardiovascular diseases, but its effect on myocardial ischemia and its precise mechanism remains unclear. The aim of this study is to explore the potential cardioprotective mechanism of HSP on myocardial ischemia caused by isoproterenol (ISO). Adult male Kunming mice were randomly divided into five groups: control, ISO, low-dose HSP (L-HSP, 25 mg/kg/d), high-dose HSP (H-HSP, 50 mg/kg/d), and verapamil (VER) group. Treatment groups of mice received HSP or VER for seven days, and the groups other than the control group were injected with ISO (100 mg/kg/d) subcutaneously for two consecutive days to establish a model of myocardial ischemia. Electrocardiogram and heart-histology changes were used to assess changes in myocardial architecture. The activities and the content of oxidative stress markers and inflammatory cytokines were determined and assayed using kits respectively. The expressions of proteins associated with apoptosis and the Sirt1/Nrf2 pathway were evaluated by Western blotting. The results demonstrate that VER, L-HSP and H-HSP significantly reduced the J-point displacement, heart rate, cardiac pathomorphological changes, and the levels of creatine kinase, lactated dehydrogenase, malonaldehyde, interleukin-6, and tumor necrosis factor-α in serum while promoting the activation of superoxide dismutase, catalase, glutathione in serum in the ISO-treated animals. Furthermore, L-HSP and H-HSP also reversed the ISO-induced apoptosis and the changes in the Sirt1/Nrf2 signaling pathway, as evident from the levels of proteins Bax, Bcl-2, caspase-3, Sirt1, Nrf2, NQO-1, and HO-1. In conclusion, HSP plays a protective role in ISO-induced myocardial ischemia by modulating oxidative stress, inflammation, and apoptosis via Sirt1/Nrf2 pathway activation., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aims/hypothesis: Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant high energy-density food availability in present-day society contributes to the pathogenesis of chronic diseases, including diabetes and its complications, with intermittent fasting (IF) and energy restriction shown to improve metabolic health. We have previously demonstrated that IF prevents the development of diabetic retinopathy in a mouse model of type 2 diabetes (db/db); however the mechanisms of fasting-induced health benefits and fasting-induced risks for individuals with diabetes remain largely unknown. Sirtuin 1 (SIRT1), a nutrient-sensing deacetylase, is downregulated in diabetes. In this study, the effect of SIRT1 stimulation by IF, fasting-mimicking cell culture conditions (FMC) or pharmacological treatment using SRT1720 was evaluated on systemic and retinal metabolism, systemic and retinal inflammation and vascular and bone marrow damage., Methods: The effects of IF were modelled in vivo using db/db mice and in vitro using bovine retinal endothelial cells or rat retinal neuroglial/precursor R28 cell line serum starved for 24 h. mRNA expression was analysed by quantitative PCR (qPCR). SIRT1 activity was measured via histone deacetylase activity assay. NR1H3 (also known as liver X receptor alpha [LXRα]) acetylation was measured via western blot analysis., Results: IF increased Sirt1 mRNA expression in mouse liver and retina when compared with non-fasted animals. IF also increased SIRT1 activity eightfold in mouse retina while FMC increased SIRT1 activity and expression in retinal endothelial cells when compared with control. Sirt1 expression was also increased twofold in neuronal retina progenitor cells (R28) after FMC treatment. Moreover, FMC led to SIRT1-mediated LXRα deacetylation and subsequent 2.4-fold increase in activity, as measured by increased mRNA expression of the genes encoding ATP-binding cassette transporter (Abca1 and Abcg1). These changes were reduced when retinal endothelial cells expressing a constitutively acetylated LXRα mutant were tested. Increased SIRT1/LXR/ABC-mediated cholesterol export resulted in decreased retinal endothelial cell cholesterol levels. Direct activation of SIRT1 by SRT1720 in db/db mice led to a twofold reduction of diabetes-induced inflammation in the retina and improved diabetes-induced visual function impairment, as measured by electroretinogram and optokinetic response. In the bone marrow, there was prevention of diabetes-induced myeloidosis and decreased inflammatory cytokine expression., Conclusions/interpretation: Taken together, activation of SIRT1 signalling by IF or through pharmacological activation represents an effective therapeutic strategy that provides a mechanistic link between the advantageous effects associated with fasting regimens and prevention of microvascular and bone marrow dysfunction in diabetes.

Polycystic ovary syndrome is a common endocrine disorder worldwide. Recently, quercetin has been extensively investigated as a therapeutic option in patients with PCOS. Therefore, this study aimed to investigate the mechanisms underlying quercetin's positive effects by modulating key components of energy homeostasis and adipose tissue hormones in rats with letrozole-induced PCOS. Eighteen female Wistar rats were divided into three groups including control group (received carboxy methylcellulose (CMC 0.5%)), letrozole-induced PCOS ± quercetin group (received 1 mg/kg letrozole in CMC 0.5%), and letrozole-induced PCOS +/+ quercetin group (received same dose of letrozole + 100 mg/kg quercetin in CMC 0.5%). The estrous cycle, biochemical and hormonal parameters, as well as insulin resistance (IR) were evaluated in all groups. Western blotting was used to assess the expression levels of sirtuin-1 (SIRT-1), 5' AMP-activated protein kinase (AMPK), and adiponectin in target tissues of rats. The expression levels of visfatin and resistin were also evaluated through Real-time polymerase chain reaction (PCR). Treatment with quercetin improved the PCOS related disturbances in estrous cycle, lipid profile, serum levels of testosterone, estradiol and progesterone, and IR. Besides, the expression levels of AMPK and SIRT-1 in ovarian tissue were upregulated in the rats which received quercetin. Quercetin also reversed the PCOS-induced alteration in adipose tissue levels of adiponectin, visfatin, and resistin. Modulation of energy homeostasis through key components involved in this axis, as well as regulation of hormones releasing from adipose tissue may be the main underlying mechanisms for positive effects of quercetin in PCOS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cardiac microvascular endothelial cell (CMEC) dysfunction is considered as a major contributor to the cardiovascular complications in diabetes mellitus, with oxidative stress caused by hyperglycemia playing a critical role in the progression of CMEC dysfunction. Melatonin is a kind of hormone well known for its antioxidant properties, which has potential protective effects against diabetes mellitus and its complications. However, the role of melatonin on CMEC dysfunction caused by hyperglycemia and its molecular mechanisms underlying these effects has not been clarified. Herein, we investigate the protective effects of melatonin on high glucose- (HG-) evoked oxidative stress and apoptosis in CMECs and underlying mechanisms. Our results revealed that melatonin ameliorated the injury caused by HG in primary cultured rat CMECs. Injury can be accompanied by reduced reactive oxygen species (ROS) and malondialdehyde (MDA) production, and enhanced superoxide dismutase (SOD) activity. Meanwhile, melatonin treatment significantly inhibited HG-induced CMEC apoptosis. Moreover, melatonin increased the activity of the AMPK/SIRT1 signaling axis in CMECs under HG condition, whereas administration of the AMPK inhibitor compound C or SIRT1 silencing partially abrogated the beneficial effects of melatonin. In streptozotocin- (STZ-) evoked diabetic mice, melatonin notably ameliorated cardiac dysfunction and activated the AMPK/SIRT1 signaling. In conclusion, our findings revealed that melatonin attenuates HG-induced CMEC oxidant stress, apoptosis injury, and STZ-induced cardiac dysfunction through regulating the AMPK/SIRT1 signaling pathway., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this article., (Copyright © 2021 Bin Wang et al.)

Neuroinflammation is associated with the development of depression. Deacetylases SIRT1 and SIRT2 are reported to exert neuroprotective effects in aging, neurogenesis, neurodegeneration and neuroinflammation. Therefore, this study aimed to investigate the effects of SIRT1 and SIRT2 modulators on LPS-induced neuroinflammation and neurodegeneration in vitro. To achieve this, HAPI rat microglial cells were pre-treated with the SIRT1 activator resveratrol (0.1-20 µM), the selective SIRT1 inhibitor EX527 (0.1; 1 µM), the dual SIRT1/SIRT2 inhibitor sirtinol (0.1-20 µM) and the SIRT2 inhibitor AGK2 (0.1; 1 µM), prior to exposure with LPS (5 ng/mL) for 20 h. The reference antidepressant drug fluoxetine and the nonsteroidal anti-inflammatory drug ibuprofen were also evaluated in the same paradigm, both at 1 μM. Resveratrol and sirtinol inhibited TNF-α production to a greater degree than either fluoxetine or ibuprofen. Resveratrol, sirtinol, EX527 and AGK2 significantly reduced PGE 2 production by up to 100% in microglia. Then, the supernatant was transferred to treat SH-SY5Y cells for 24 h. In all cases, SIRT modulator pretreatment significantly protected undifferentiated SH-SY5Y human neuroblastoma cells from the insult of LPS-stimulated HAPI supernatant by up to 40%. Moreover, resveratrol and sirtinol also showed significantly better neuroprotection than fluoxetine or ibuprofen by up to 83 and 69%, respectively. In differentiated SH-SY5Y cells, only sirtinol (20, 10 µM) and AGK2 (0.1 µM) pretreatment protected the cells from LPS-stimulated HAPI supernatant. This study suggests that SIRT1 and SIRT2 modulators are effective in inhibiting LPS-stimulated production of TNF-α and PGE 2 in HAPI microglial cells and protecting SH-SY5Y cells from inflammation. Thus, we provide proof of concept for further investigation of the therapeutic effect of SIRT1 and SIRT2 modulators and combination with current antidepressant medication as a treatment option.

Nuclear factor (NF)-κB-mediated neuroinflammation is an important mechanism of intracerebral hemorrhage (ICH)-induced neurotoxicity. Silent information regulator 1 (SIRT1) plays a multi-protective effect in a variety of diseases by deacetylating and inhibiting NF-κB/p65. However, the role of SIRT1 in brain damage following ICH remains unclear. We hypothesized that SIRT1 can protect against ICH-induced brain damage by inhibiting neuroinflammation through deacetylating NF-κB/p65. The ICH model was induced in vivo (with collagenase) and in vitro (with hemoglobin). Resveratrol and Ex527 were administered to activate or inhibit SIRT1, respectively. Western blot, immunohistochemistry, and immunofluorescence assays were performed to detect the expression of SIRT1 and p65. Enzyme-linked immunosorbent assays (ELISAs) were used to explore tumor necrosis factor (TNF)-α and interleukin (IL)-1β release. The neurological score, brain water content, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and brain hemoglobin content were determined to evaluate the neuroprotective effect of SIRT1. SIRT1 expression was decreased, whereas the level of acetylated p65 (Ac-p65) was elevated after ICH in vivo. Moreover, hemoglobin treatment decreased the expression of SIRT1 in vitro. Activation of SIRT1 by resveratrol had a neuroprotective effect, along with decreased levels of Ac-p65, IL-1β, TNF-α, and apoptosis after ICH. The effect of resveratrol was abolished by the SIRT1 inhibitor Ex527. Our results are consistent with the hypothesis that SIRT1 exerts a neuroprotective effect after ICH by deacetylating p65 to inhibit the NF-κB-dependent inflammatory response., (© 2020 International Society for Neurochemistry.)

Caveolin-1(Cav-1) is involved in lipid metabolism and energy homeostasis, which is important for the energetically demanding retina. Although retinal function deficits were noted in Cav-1 knockout (Cav-1 -/- ) mice, the underlying causes remain largely unknown. Here, we investigate if the disruption in energy homeostasis presents a potential mechanism for retinal function deficits in Cav-1 -/- retina and if it can be ameliorated by nicotinamide (NAM). In this study, NAM was administrated orally for 2 weeks in Cav-1 -/- mice before experiments. Oxidative lipidomics was conducted to detect the oxylipin changes, the retinal energy flux was measured by seahorse assay, and the retinal function was assessed by electroretinogram (ERG). Cav-1 deficiency induced the dysregulation of oxidative lipidomics and reduction in energy consumption/production in the retina by decreasing Na + /K + -ATPase, oxidative phosphorylation CII, cytochrome c, and oxygen consumption rate (OCR). A decrease in Sirt1 was also detected. Therapeutic administration of NAM significantly increased Sirt1 expression and improved energy deficiency by increasing Na + /K + -ATPase, cytochrome c, and OCR. The dysregulation of oxidative lipidomics was partially recovered, and the retinal function was improved as assessed by ERG compared to Cav-1 -/- mice. Our study demonstrated the dysregulation of oxidative lipidomics in Cav-1 -/- retina and established a link between energy deficiency and retinal function deficits in Cav-1 -/- mice. Administration of NAM ameliorated energy deficiency, increased the expression of Sirt1, and improved retinal function, which presents a potential therapeutic strategy for Cav-1 deficiency-induced retinal function deficits., (© 2020 International Society for Neurochemistry.)

UV radiation is one of the main contributors to skin photoaging by promoting the accumulation of cellular senescence, which in turn induces a proinflammatory and tissue-degrading state that favors skin aging. The members of the sirtuin family of NAD + -dependent enzymes play an anti-senescence role and their activation suggests a promising approach for preventing UV-induced senescence in the treatment of skin aging. A two-step screening designed to identify compounds able to protect cells from UV-induced senescence through sirtuin activation identified shikimic acid (SA), a metabolic intermediate in many organisms, as a bona-fide candidate. The protective effects of SA against senescence were dependent on specific activation of SIRT1 as the effect was abrogated by the SIRT1 inhibitor EX-527. Upon UV irradiation SA induced S-phase accumulation and a decrease in p16 INK4A expression but did not protect against DNA damage or increased polyploidies. In contrast, SA reverted misfolded protein accumulation upon senescence, an effect that was abrogated by EX-527. Consistently, SA induced an increase in the levels of the chaperone BiP, resulting in a downregulation of unfolded protein response (UPR) signaling and UPR-dependent autophagy, avoiding their abnormal hyperactivation during senescence. SA did not directly activate SIRT1 in vitro , suggesting that SIRT1 is a downstream effector of SA signaling specifically in the response to cellular senescence. Our study not only uncovers a shikimic acid/SIRT1 signaling pathway that prevents cellular senescence, but also reinforces the role of sirtuins as key regulators of cell proteostasis.

The benefits of walnut ( Juglans regia ) consumption for metabolic health are known, but the molecular background underlying their putative antioxidant and anti-inflammatory/immunomodulatory effects is underexplored. We assessed that walnut supplementation (6 weeks) reverted unfavorable changes of the SIRT1/FoxO3a/MnSOD/catalase axis in the heart induced by fructose-rich diet (FRD). Intriguingly, Nox4 was increased by both FRD and walnut supplementation. FRD increased the cytosolic fraction and decreased the nuclear fraction of the uniquely elucidated ChREBP in the heart. The ChREBP nuclear fraction was decreased in control rats subjected to walnuts. In addition, walnut consumption was associated with a reduction in systolic BP in FRD and a decrease in fatty acid AA/EPA and AA/DHA ratios in plasma. In summary, the protective effect of walnut supplementation was detected in male rats following the fructose-induced decrease in antioxidative/anti-inflammatory capacity of cardiac tissue and increase in plasma predictors of low-grade inflammation. The current results provide a novel insight into the relationship between nutrients, cellular energy homeostasis, and the modulators of inflammatory/immune response in metabolic syndrome, emphasizing the heart and highlighting a track for translation into nutrition and dietary therapeutic approaches against metabolic disease., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Maja Bošković et al.)

Binge drinking (BD) is the main alcohol consumption pattern among teenagers. Recently, oxidative stress (OS) generated by BD exposure has been related to hepatic metabolic deregulation and cardiovascular dysfunction. This study analyzed if BD by generating oxidative stress modulates the alteration in hepatic energy homeostasis through two important regulators of energy metabolism: the NAD + -dependent sirtuin deacetylase (SIRT1) and AMP-activated protein kinase (AMPK) and if supplementation with the antioxidant selenium (Se) improves these metabolic disorders. Four groups of adolescent rats supplemented or not with Se (0.4 ppm) and exposed to intermittent i.p. BD were used. BD rats showed an increased AST/ALT ratio, total bilirubin in serum and lipid peroxidation in the liver. The BD rats also showed a higher abdominal/thoracic ratio and increased levels of TG, gluc, and chol compared to the control group, provoking an increase in mean blood pressure (MBP). This alcohol consumption pattern decreased hepatic Se deposits, cytoplasmic GPx activity, and GSH levels as well as the expressions of two metabolic sensors and the pAMPK/AMPK ratio. Se supplementation restored antioxidant parameters and decreased lipid oxidation, avoiding OS and improving the hepatic expression of pAMPK and SIRT1, contributing to the improvement of metabolic (better lipid profile and IRS-1 expression) and vascular function (lower MBP), and to the increase of hepatic functionality (lower AST/ALT ratio). All these actions decrease cardiometabolic risk factor development in the short and long term and could disrupt the relationship between BD and MS, two problems which are currently affecting adolescents.

Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1 OSX -/- mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1 OSX -/- mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Cerebral ischemic/reperfusion injury is the most common neurological disorder and the second leading cause of death worldwide. Modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state has been suggested as a potential therapeutic approach in the treatment of this injury. SRT2104, a novel activator of histone deacetylase Sirtuin-1 (Sirt1), has recently been shown to have anti-inflammation properties. However, the effect of SRT2104 on cerebral ischemic/reperfusion injury has not been elucidated. Here, we found that SRT2104 inhibited neuron and microglia death directly and indirectly through microglia condition medium from an oxygen glucose deprivation/reoxygenation (OGD/R) -induced cell injury models. Moreover, SRT2104 treatment modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, we found that SRT2104 could significant inhibit the activation of NF-κB and enhanced Sirt1 expression in microglia. Mechanism studies using the BV2 microglial cell line confirmed that knockdown Sirt1 significantly reduced the effect of SRT2104 on the activation of NF-κB pathway and microglial phenotype shift. Altogether, our result shows SRT2104 protect OGD/R-induced injury through shifting microglia phenotype, which may have potential in further studies as a novel neuroprotective agent for cerebral ischemic/reperfusion injury therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Diabetes-induced oxidative stress is vital in initiating neuronal damage in the diabetic retina, leading to diabetic retinopathy (DR). This study investigates the possible effects of coumestrol (CMS) on streptozotocin (STZ)-induced DR. First, we established a rat model of DR by STZ injection and a cell model involving high-glucose (HG) exposure of human retinal microvascular endothelial cells (hRMECs). We characterized the expression patterns of oxidative stress indicators, pro-inflammatory cytokines, and pro-apoptotic proteins in hRMECs. Polymerase chain reaction showed sirtuin 1 (SIRT1) to be poorly expressed in the retinal tissues of STZ-treated rats and HG-exposed hRMECs, but its expression was upregulated upon treatment with CMS treatment. Furthermore, CMS treatment attenuated the STZ-induced pathologies such as oxidative stress, inflammation, and cell apoptosis. Consistent with the in vivo results, CMS activated the expression of SIRT1, thereby inhibiting oxidative stress, inflammation, and apoptosis of HG-treated hRMECs. From these findings, we concluded that CMS ameliorated DR by inhibiting inflammation, apoptosis and oxidative stress through activation of SIRT1.