Sodium butyrate improves renal injury in diabetic nephropathy through AMPK/SIRT1/PGC-1α signaling pathway.

Diabetic nephropathy (DN) is a prototypical chronic energy metabolism imbalance disease. The AMPK/Sirt1/PGC-1α signaling pathway plays a pivotal role in regulating energy metabolism throughout the body. Gut microbiota ferment indigestible carbohydrates to produce a variety of metabolites, particularly short-chain fatty acids (SCFAs), which exert positive effects on energy metabolism. However, the potential for SCFAs to ameliorate DN-associated renal injury via the AMPK/Sirt1/PGC-1α pathway remains a matter of debate. In this study, we investigated the effects of sodium butyrate (NaB), a SCFA, on energy metabolism in mice with spontaneous DN at two different doses. Body weight, blood glucose and lipid levels, urinary protein excretion, liver and kidney function, interleukin-6 (IL-6) levels, and the expressions of AMPK, phosphorylated AMPK (p-AMPK), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), and glucagon-like peptide-1 receptor (GLP-1R) were monitored in mice. Additionally, butyrate levels, gut microbiota composition, and diversity in colonic stool were also assessed. Our findings demonstrate that exogenous NaB supplementation can improve hyperglycemia and albuminuria, reduce renal tissue inflammation, inhibit extracellular matrix accumulation and glomerular hypertrophy, and could alter the gut microbiota composition in DN. Furthermore, NaB was found to upregulate the expressions of MFN2, OPA1, p-AMPK, and GLP-1R in DN renal tissue. These results suggest that NaB could improve the composition of gut microbiota in DN, activate the AMPK/Sirt1/PGC-1α signaling pathway, and enhance mitochondrial function to regulate energy metabolism throughout the body. Collectively, our findings indicate that NaB may be a novel therapeutic agent for the treatment of DN.

Canagliflozin Mitigated Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer's Disease in Mice: Role of AMPK/SIRT-1 Signaling Pathway in Modulating Neuroinflammation.

Sporadic Alzheimer's disease (SAD) represents a major health concern especially among elderly. Noteworthy, neuroinflammation and oxidative stress are highly implicated in AD pathogenesis resulting in enhanced disease progression. Moreover, most of the available anti-Alzheimer drugs have several adverse effects with variable efficacy, therefore new strategies, including agents with anti-inflammatory and antioxidant effects, are encouraged. Along these lines, canagliflozin (CAN), with its anti-inflammatory and anti-apoptotic activities, presents a promising candidate for AD treatment. Therefore, this study aimed to evaluate the therapeutic potential of CAN via regulation of AMPK/SIRT-1/BDNF/GSK-3ß signaling pathway in SAD. SAD model was induced by intracerebroventricular streptozotocin injection (ICV-STZ;3 mg/kg, once), while CAN was administered (10 mg/kg/day, orally) to STZ-treated mice for 21 days. Behavioral tests, novel object recognition (NOR), Y-Maze, and Morris Water Maze (MWM) tests, histopathological examination, total adenosine monophosphate-activated protein kinase (T-AMPK) expression, p-AMPK, and silent information regulator-1 (SIRT-1) were evaluated. Furthermore, brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3ß (GSK-3ß), acetylcholinesterase (AChE), Tau protein, insulin-degrading enzyme (IDE), nuclear factor erythroid-2 (Nrf-2), interleukin-6 (IL-6), nuclear factor kappa-B-p65 (NFκB-p65), beta-site APP cleaving enzyme 1 (BACE-1), and amyloid beta (Aß) plaque were assessed. CAN restored STZ-induced cognitive deficits, confirmed by improved behavioral tests and histopathological examination. Besides, CAN halted STZ-induced neurotoxicity through activation of p-AMPK/SIRT-1/BDNF pathway, subsequently reduction of GSK-3ß, Tau protein, AChE, NFκB-p65, IL-6, BACE-1, and Aß plaque associated with increased IDE and Nrf-2. Consequentially, our findings assumed that CAN, via targeting p-AMPK/SIRT-1 pathway, combated neuroinflammation and oxidative stress in STZ-induced AD. Thus, this study highlighted the promising effect of CAN for treating AD.

Epigallocatechin-3-gallate ameliorates lipopolysaccharide-induced acute thymus involution in mice via AMPK/Sirt1 pathway.

The thymus, a site to culture the naïve T lymphocytes, is susceptible to atrophy or involution due to aging, inflammation, and oxidation. Epigallocatechin-3-gallate (EGCG) has been proven to possess anti-inflammatory, antioxidant, and antitumor activity. Here, we investigate the effects of EGCG on thymic involution induced by lipopolysaccharide (LPS), an endotoxin derived from Gram-negative bacteria. The methodology included an in vivo experiment on female Kunming mice exposed to LPS and EGCG. Morphological assessment of thymic involution, immunohistochemical detection, and thymocyte subsets analysis by flow cytometry were further carried out to evaluate the potential role of EGCG on the thymus. As a result, we found that EGCG alleviated LPS-induced thymic atrophy, increased mitochondrial membrane potential and superoxide dismutase levels, and decreased malondialdehyde and reactive oxygen species levels. In addition, EGCG pre-supplement restored the ratio of thymocyte subsets, the expression of autoimmune regulator, sex-determining region Y-box 2, and Nanog homebox, and reduced the number of senescent cells and collagen fiber deposition. Western blotting results indicated that EGCG treatment elevated LPS-induced decrease in pAMPK, Sirt1 protein expression. Collectively, EGCG relieved thymus architecture and function damaged by LPS via regulation of AMPK/Sirt1 signaling pathway. Our findings may provide a new strategy on protection of thymus from involution caused by LPS by using EGCG. And EGCG might be considered as a potential agent for the prevention and treatment of thymic involution.

Combined physical exercise re-synchronizes expression of Bmal1 and REV-ERBα and up-regulates apoptosis and metabolism in the prostate during aging.

BACKGROUND: Aging increases the prevalence of prostate cancer. The circadian clock coordinates metabolism, cell cycle, and tumor suppressor p53. Although physical exercise has several effects on preventing prostate diseases, its effect on regulating genes and proteins of the circadian rhythm of the prostate needs to be better evaluated. The present study verified expression of REV-ERBα (Nr1d1), Bmal1, apoptosis, tumor suppressors, energetic metabolism markers, and androgen receptors in the prostatic microenvironment in 18-month-old mice submitted to combined physical training. METHODS: C57BL/6 J mice were divided into 2 groups: 6 months-old (n = 10) and 18 months-old, (n = 20). The 18-month-old animals were divided into 2 subgroups: sedentary (n = 10, 18 m Sed) and submitted to combined physical training (n = 10, 18 m TR). Combined physical training protocol was performed by running on the treadmill (40-60 % of incremental load test) and climbing strength training (40-50 % of maximum repetition test), consisting of 5×/week (3 days aerobic and 2 days strength) for 3 weeks. The prostate was prepared for Western blot and RT-qPCR analysis, and the plasm was prepared for the biochemistry analysis. RESULTS: Combined physical exercise during aging led to increased levels of Bmal1 and decreased levels of REV-ERBα in the prostate. These results were accompanied by a reduction in the AMPK/SIRT1/PGC-1α proteins and an increase in the PI3K/AKT and p53/PTEN/caspase 3 pathways, promoting apoptotic potential. CONCLUSION: These findings suggest that strength and aerobic physical exercise may be preventive in the development of preneoplastic molecular alterations and age-related features by re-synchronizes Bmal1 and REV-ERBα in prostatic tissues.

Nicorandil mitigates arsenic trioxide-induced lung injury via modulating vital signalling pathways SIRT1/PGC-1α/TFAM, JAK1/STAT3, and miRNA-132 expression.

BACKGROUND AND PURPOSE: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug-induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)-induced lung injury and to elucidate the underlying mechanistic pathways. EXPERIMENTAL APPROACH: We assessed the effects of nicorandil (15 mg·kg-1, p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg-1, i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin-1, sirtuin-3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted. KEY RESULTS: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti-inflammatory actions. On a molecular level, treatment with nicorandil down-regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro-RNA 132 while up-regulating Sirt1, 3, TFAM, AMPK, and ERR-α in lung tissue. CONCLUSIONS AND IMPLICATIONS: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings.

Structural characterization and improves cognitive disorder in ageing mice of a glucomannan from Dendrobium huoshanense.

In the present work, a neutral polysaccharide (DHP-2W) with attenuating cognitive disorder was identified from Dendrobium huoshanense and its structure was clarified. The polysaccharide was successfully purified from D. huoshanense by column chromatography and its activity was evaluated. With a molecular weight of 508.934kDa, this polysaccharide is composed of mannose and glucose at a molar ratio of 75.81: 24.19. Structural characterization revealed that DHP-2W has a backbone consisting of 4)-ß-D-Manp-(1 and 4)-ß-D-Glcp-(1. In vivo experiments revealed that DHP-2W improved cognitive disorder in D-galactose treated mice and relieved oxidative stress and inflammation. DHP-2W attenuates D-galactose-induced cognitive disorder by inhibiting the BCL2/BAX/CASP3 pathway and activating the AMPK/SIRT pathway, thereby inhibiting apoptosis. Furthermore, DHP-2W had a significant effect on regulating the serum levels of Flavin adenine dinucleotide, Shikimic acid, and Kynurenic acid in aged mice. These, in turn, had a positive impact on AMPK/SIRT1 and BCL2/BAX/CASP3, resulting in protective effects against cognitive disorder.

gCTRP3 inhibits oophorectomy­induced osteoporosis by activating the AMPK/SIRT1/Nrf2 signaling pathway in mice.

C1q/tumor necrosis factor­related protein 3 (CTRP3) expression is markedly reduced in the serum of patients with osteoporosis. The present study aimed to investigate whether CTRP3 reduces bone loss in oophorectomy (OVX)­induced mice via the AMP­activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/nuclear factor E2­related factor 2 (Nrf2) signaling pathway. Female C57BL/6J mice and MC3T3­E1 cells were used to construct in vivo and in vitro models of osteoporosis, respectively. The left femurs of mice were examined using micro­computed tomography scans and bone­related quantitative morphological evaluation was performed. Pathological changes and the number of osteoclasts in the left femurs of mice were detected using hematoxylin and eosin, and tartrate­resistant acid phosphatase (TRAP) staining. Runt­related transcription factor­2 (RUNX2) expression in the left femurs was detected using immunofluorescence analysis, and the serum levels of bone resorption markers (C­telopeptide of type I collagen and TRAP) and bone formation markers [osteocalcin (OCN) and procollagen type 1 N­terminal propeptide] were detected. In addition, osteoblast differentiation and calcium deposits were examined in MC3T3­E1 cells using alkaline phosphatase (ALP) and Alizarin red staining, respectively. Moreover, RUNX2, ALP and OCN expression levels were detected using reverse transcription­quantitative PCR, and the expression levels of proteins associated with the AMPK/SIRT1/Nrf2 signaling pathway were detected using western blot analysis. The results revealed that globular CTRP3 (gCTRP3) alleviated bone loss and promoted bone formation in OVX­induced mice. gCTRP3 also facilitated the osteogenic differentiation of MC3T3­E1 cells through the AMPK/SIRT1/Nrf2 signaling pathway. The addition of an AMPK inhibitor (Compound C), SIRT1 inhibitor (EX527) or Nrf2 inhibitor (ML385) reduced the osteogenic differentiation of MC3T3­E1 cells via inhibition of gCTRP3. In conclusion, gCTRP3 inhibits OVX­induced osteoporosis by activating the AMPK/SIRT1/Nrf2 signaling pathway.

Cathelicidin-BF regulates the AMPK/SIRT1/NF-κB pathway to ameliorate murine osteoarthritis: In vitro and in vivo studie.

Osteoarthritis (OA) is a chronic degenerative disease with a significant prevalence that causes cartilage damage and can lead to disability. The main factors contributing to the onset and progression of OA include inflammation and degeneration of the extracellular matrix. Cathelicidin-BF (BF-30), a natural peptide derived from Bungarus fasciatus venom, has shown multiple important pharmacological effects. However, the action mechanism of BF-30 in OA treatment remains to be elucidated. In this research, X-ray and Safranin O staining were employed to evaluate the imageology and histomorphology differences in the knee joints of mice in vivo. Techniques such as Western blot analysis, RT-qPCR, ELISA, and immunofluorescence staining were applied to examine gene and protein level changes in in vitro experiments. It was found that BF-30 significantly decreased inflammation and enhanced extracellular matrix metabolism. For the first time, it was demonstrated that the positive effects of BF-30 are mediated through the activation of the AMPK/SIRT1/NF-κB pathway. Moreover, when BF-30 was co-administered with Compound C, an AMPK inhibitor, the therapeutic benefits of BF-30 were reversed in both in vivo and in vitro settings. In conclusion, the findings suggest that BF-30 could be a novel therapeutic agent for OA improvement.

[Exercise promotes irisin expression to ameliorate renal injury in type 2 diabetic rats].

OBJECTIVE: To investigate the role of irisin in exercise-induced improvement of renal function in type 2 diabetic rats. METHODS: Forty male SD rats aged 4-6 weeks were randomized into normal control group, type 2 diabetes mellitus model group, diabetic exercise (DE) group and diabetic irisin (DI) group (n=8). The rats in DE group were trained with treadmill running for 8 weeks, and those in DI group were given scheduled irisin injections for 8 weeks. After the treatments, blood biochemical parameters of the rats were examined, and renal histopathology was observed with HE, Masson and PAS staining. Western blotting was used to detect the protein expression levels in the rats'kidneys. RESULTS: The diabetic rats showed significantly increased levels of fasting insulin, total cholesterol, triglyceride, serum creatinine and blood urea nitrogen with lowered serum irisin level (all P < 0.05). Compared with those in DM group, total cholesterol, triglyceride, serum creatinine and blood urea nitrogen levels were decreased and serum irisin levels were increased in both DE and DI groups (all P < 0.05). The rats in DM group showed obvious structural disorders and collagen fiber deposition in the kidneys, which were significantly improved in DE group and DI group. Both regular exercises and irisin injections significantly ameliorated the reduction of FNDC5, LC3-II/I, Atg7, Beclin-1, p-AMPK, AMPK and SIRT1 protein expressions and lowered of p62 protein expression in the kidneys of the diabetic rats (all P < 0.05). CONCLUSION: Both exercise and exogenous irisin treatment improve nephropathy in type 2 diabetic rats possibly due to irisin-mediated activation of the AMPK/SIRT1 pathway in the kidneys to promote renal autophagy.

EGCG alleviates heat-stress-induced fat deposition by targeting HSP70 through activation of AMPK-SIRT1-PGC-1α in porcine subcutaneous preadipocytes.

Obesity has emerged as a prominent global health concern, with heat stress posing a significant challenge to both human health and animal well-being. Despite a growing interest in environmental determinants of obesity, very few studies have examined the associations between heat stress-related environmental factors and adiposity. Consequently, there exists a clear need to understand the molecular mechanisms underlying the obesogenic effects of heat stress and to formulate preventive strategies. This study focused on culturing porcine subcutaneous preadipocytes at 41.5 ℃ to induce heat stress, revealing that this stressor triggered apoptosis and fat deposition. Analysis demonstrated an upregulation in the expression of HSP70, BAX, adipogenesis-related genes (PPARγ, AP2, CEBPα and FAS), the p-AMPK/AMPK ratio and SIRT1, PGC-1α in the heat stress group compared to the control group (P < 0.05). Conversely, the expression of lipid lysis-related genes (ATGL, HSL and LPL) and Bcl-2 decreased in the heat stress group compared to the control group (P < 0.05). Furthermore, subsequent activator and/or inhibitor experiments validated that heat stress modulated HSP70 and AMPK signalling pathways to enhance lipogenesis and inhibit lipolysis in porcine subcutaneous preadipocytes. Importantly, this study reveals, for the first time, that EGCG mitigates heat-stress-induced fat deposition by targeting HSP70 through the activation of AMPK-SIRT1-PGC-1α in porcine subcutaneous preadipocytes. These findings elucidate the molecular mechanisms contributing to heat stress-induced obesity and provide a foundation for the potential clinical utilisation of EGCG as a preventive measure against both heat stress and obesity.

Dietary kaempferol exerts anti-obesity effects by inducing the browing of white adipocytes via the AMPK/SIRT1/PGC-1α signaling pathway.

Browning of white adipose tissue is a novel approach for the management of obesity and obesity-related metabolic disorders. Kaempferol (KPF) is a common dietary nutrient found abundantly in many fruits and vegetables and has been shown to have the potential to regulate lipid metabolism. However, the detailed mechanism by which it affects the browning of white adipose tissue remains unclear. In the present study, we sought to determine how KPF induces adipocytes to undergo a browning transformation by establishing a primary adipocyte model and an obese mouse model. Our results showed that KPF-treated mice were rescued from diet-induced obesity, glucose tolerance and insulin resistance, associated with increased expression of adaptive thermogenesis-related proteins. KPF-promoted white adipose browning correlated with the AMPK/SIRT1/PGC-1α pathway, as the use of an AMPK inhibitor in preadipocytes partially reversed the observed browning phenotype of KPF-treated cells. Taken together, these data suggest that KPF promotes browning of white adipose tissue through activation of the AMPK/SIRT1/PGC-1α pathway. This study demonstrates that KPF is a promising natural product for the treatment of obesity by promoting white fat browning.

Resveratrol attenuates cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in the rat mesenteric artery.

Cyclosporin A, an immunosuppressive agent, is extensively utilized for the prevention of transplant rejection and treat autoimmune disease in the clinic, despite its association with a high risk of hypertension development among patients. Resveratrol is a kind of non-flavonoid phenolic compound that widely exists in many plants. The aim of the present study was to investigate the mechanism by which resveratrol ameliorates cyclosporin A-induced hypertension. The arterial rings of the mesentery were incubated with cyclosporin A and resveratrol in vitro. Rats were administered cyclosporin A and/or resveratrol for 3 weeks in vivo. Blood pressure was measured via the tail arteries. Vasoconstriction curves were recorded using a sensitive myograph. The protein expression was evaluated through Western blotting. This study demonstrated that resveratrol mitigated the cyclosporin A-induced increase in blood pressure in rats. Furthermore, resveratrol markedly inhibited the cyclosporin A-induced upregulation of thromboxane A2 receptor-mediated vasoconstriction in the rat mesenteric artery both in vitro and in vivo. Moreover, resveratrol activated AMPK/SIRT1 and inhibited the MAPK/NF-κB signaling pathway. In conclusion, resveratrol restored the cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in rats.

Abscisic acid ameliorates d-galactose -induced aging in mice by modulating AMPK-SIRT1-p53 pathway and intestinal flora.

Abscisic acid (ABA) is a plant hormone with various biological activities. Aging is a natural process accompanied by cognitive and physiological decline, and aging and its associated diseases pose a serious threat to public health, but its mechanisms remain insufficient. Therefore, the purpose of this study was to investigate the ameliorative effects of ABA on d-galactose (D-Gal)-induced aging in mice and to delve into its molecular mechanisms. Aging model was es-tablished by theintraperitoneal injection of D-Gal. We evaluated the oxidative stress by measuring superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) levels in serum. Proteins content in brain were determined by Western blot. D-Gal-induced brain damage was monitored by measuring the levels of acetylcholinesterase (AChE) content and hematoxylin-eosin staining (H&E). To evaluate the effects of ABA on aging, we measured the gut microbiota. The results demonstrated that ABA increased SOD, CAT and AChE, decreased MDA level. H&E staining showed that ABA could improve D-Gal-induced damage. In addition, ABA regulated the B-cell-lymphoma-2 (BCL-2) family and Phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling pathway, while further regulating the acetylation of p53 protein by modulating the AMPK pathway and activating SIRT1 protein, thereby inhibiting the apoptosis of brain neurons and thus regulating the aging process. Interestingly, ABA improved the ratio of intestinal bacteria involved in regulating multiple metabolic pathways in the aging process, such as Bacteroides, Firmicutes, Lactobacillus and Ak-kermansia. In conclusion, the present study suggests that ABA may be responsible for improving and delaying the aging process by enhancing antioxidant activity, anti-apoptosis and regulating intestinal flora.

Mechanism Research of DHEA Treatment Improving Diminished Ovarian Reserve by Attenuating the AMPK-SIRT1 Signaling and Mitophagy.

This study aims to investigate the effect and mechanism of dehydroepiandrosterone (DHEA) on diminished ovarian reserve (DOR) by modulating the AMPK-SIRT1 signaling and mitophagy in rats. Three-month-old female Sprague-Dawley (SD) rats were randomized and injected intraperitoneally with sesame oil as the control or deoxyvinylcyclohexene (VCD) to induce DOR. The VCD-injected rats were randomized and injected subcutaneously with vehicle as the model group or with DHEA for 21 days as the DHEA group. After being identified in proestrus, rat blood samples were collected to prepare serum samples, and their ovarian tissues were dissected. Compared with the controls, significantly lower serum estradiol (E2), anti-Müllerian hormone (AMH), and inhibin B (IHNB) and higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were detected in the model group (DOR rats). The model group of rats displayed an increase in follicular atresia and a decrease in ovarian volume and the number of growing follicles and corpus luteum, accompanied by increased frequency of oocyte apoptosis and reduced levels of mitochondrial function. Furthermore, significantly higher levels of the AMPK-SIRT1 signaling and mitophagy were observed in the ovaries of rats in the model group. In contrast, treatment with DHEA significantly ameliorated the hormone disorder and morphological changes in the ovaries, reduced the frequency of apoptotic oocytes, and improved mitochondrial function in the ovaries of DOR rats. Mechanistically, DHEA treatment significantly attenuated the AMPK-SIRT1 signaling and mitophagy in the ovaries of DOR rats. DHEA treatment reduced the severity of DOR and enhanced ovarian reserve function by attenuating the AMPK-SIRT1 signaling and mitophagy in the ovaries of rats.

Rap1GAP exacerbates myocardial infarction by regulating the AMPK/SIRT1/NF-κB signaling pathway.

Rap1 GTPase-activating protein (Rap1GAP) is an important tumor suppressor. The purpose of this study was to investigate the role of Rap1GAP in myocardial infarction (MI) and its potential mechanism. Left anterior descending coronary artery ligation was performed on cardiac-specific Rap1GAP conditional knockout (Rap1GAP-CKO) mice and control mice with MI. Seven days after MI, Rap1GAP expression in the hearts of control mice peaked, the expression of proapoptotic markers (Bax and cleaved caspase-3) increased, the expression of antiapoptotic factors (Bcl-2) decreased, and the expression of the inflammatory factors IL-6 and TNF-α increased; thus, apoptosis occurred, inflammation, infarct size, and left ventricular dysfunction increased, while the heart changes caused by MI were alleviated in Rap1GAP-CKO mice. Mouse heart tissue was obtained for transcriptome sequencing, and gene set enrichment analysis (GSEA) was used to analyze Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We found that Rap1GAP was associated with the AMPK and NF-κB signaling pathways and that Rap1GAP inhibited AMPK/SIRT1 and activated the NF-κB signaling pathway in model animals. Similar results were observed in primary rat myocardial cells subjected to oxygen-glucose deprivation (OGD) to induce ischemia and hypoxia. Activating AMPK with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reversed the damage caused by Rap1GAP overexpression in cardiomyocytes. In addition, the coimmunoprecipitation results showed that exogenous Rap1GAP interacted with AMPK. Rap1GAP was verified to regulate the AMPK SIRT1/NF-κB signaling pathway and exacerbate the damage to myocardial cells caused by ischemia and hypoxia. In conclusion, our results suggest that Rap1GAP promotes MI by modulating the AMPK/SIRT1/NF-κB signaling pathway and that Rap1GAP may be a therapeutic target for MI treatment in the future.

Colchicine ameliorates myocardial injury induced by coronary microembolization through suppressing pyroptosis via the AMPK/SIRT1/NLRP3 signaling pathway.

BACKGROUND: Coronary microembolization(CME)is a common complication in acute coronary syndrome and percutaneous coronary intervention, which is closely related to poor prognosis. Pyroptosis, as an inflammatory programmed cell death, has been found to be associated with CME-induced myocardial injury. Colchicine (COL) has potential benefits in coronary artery disease due to its anti-inflammatory effect. However, the role of colchicine in pyroptosis-related CME-induced cardiomyocyte injury is unclear. This study was carried out to explore the effects and mechanisms of colchicine on myocardial pyroptosis induced by CME. METHODS: The CME animal model was constructed by injecting microspheres into the left ventricle with Sprague-Dawley rats, and colchicine (0.3 mg/kg) pretreatment seven days before and on the day of modeling or compound C(CC)co-treatment was given half an hour before modeling. The study was divided into 4 groups: Sham group, CME group, CME + COL group, and CME + COL + CC group (10 rats for each group). Cardiac function, serum myocardial injury markers, myocardial histopathology, and pyroptosis-related indicators were used to evaluate the effects of colchicine. RESULTS: Colchicine pretreatment improved cardiac dysfunction and reduced myocardial injury induced by CME. The main manifestations were the improvement of left ventricular systolic function, the decrease of microinfarction area, and the decrease of mRNA and protein indexes related to pyroptosis. Mechanistically, colchicine increased the phosphorylation level of adenosine monophosphate-activated protein kinase (AMPK), promoted the expression of silent information regulation T1 (SIRT1), and inhibited the expression of NOD-like receptor pyrin containing 3 (NLRP3) to reduce myocardial pyroptosis. However, after CC co-treatment with COL, the effect of colchicine was partially reversed. CONCLUSION: Colchicine improves CME-induced cardiac dysfunction and myocardial injury by inhibiting cardiomyocyte pyroptosis through the AMPK/SIRT1/NLRP3 signaling pathway.

A mechanistic exploration of the metabolome of African mango seeds and its potential to alleviate cognitive impairment induced by high-fat/high-carbohydrate diets: Involvement of PI3K/AKT/GSK-3ß/CREB, PERK/CHOP/Bcl-2, and AMPK/SIRT-1/mTOR Axes.

ETHNOPHARMACOLOGICAL RELEVANCE: Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as "African mango" or "bush mango", belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health. AIM OF THE STUDY: The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction. Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat, metformin, and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways. MATERIALS AND METHODS: Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days. RESULTS: More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 µg Gallic acid equivalent/mg extract and 8.039 ± 0.53 µg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3ß/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways. CONCLUSION: Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3ß/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.

Neuroprotective effects of vitamin D in an Alzheimer's disease rat model: Improvement of mitochondrial dysfunction via calcium/calmodulin-dependent protein kinase kinase 2 activation of Sirtuin1 phosphorylation.

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, AlCl3 + D-gal (10 + 60 mg/kg, ip), Vit.D (500 IU/kg, po), and AlCl3 + 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 Ca2+ levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (Aß), 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 Aß aggregation, and elevated p-Tau levels in the AlCl3 + D-gal-induced AD rat model. In AlCl3 + D-gal-exposed rats, Vit.D induced VDR expression, normalized Ca2+ 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 AlCl3 + 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.

Empagliflozin repurposing in Parkinson's disease; modulation of oxidative stress, neuroinflammation, AMPK/SIRT-1/PGC-1α, and wnt/ß-catenin pathways.

Parkinson's disease is a neuroprogressive disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta. Empagliflozin (EMPA), a SGLT-2 inhibitor, is an oral hypoglycemic agent with reported anti-inflammatory and antioxidant effects. The current study aimed to evaluate the neuroprotective effect of EMPA in rotenone-induced Parkinson's disease. Rats were randomly distributed among five groups as follows: control, rotenone (2 mg/kg), rotenone + EMPA (10 mg/kg), rotenone + EMPA (20 mg/kg), and EMPA (20 mg/kg) groups. They were treated for 30 consecutive days. Rotenone reduced locomotor activity and retention time on the rotarod performance test while elongated descent latency time. On the other side, EMPA corrected these behavioral changes. These results were confirmed by histological examination and number of intact neurons. Moreover, rotenone induced alpha-synuclein accumulation, reduced tyrosine hydroxylase expression, dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentrations. On the other side, EMPA reversed such effects induced by rotenone. Depending on previous results, EMPA (20 mg/kg) was selected for further mechanistic studies. Rotenone ameliorated superoxide dismutase and catalase activities and enhanced lipid peroxidation, interleukin-1ß, and tumor necrosis factor-α levels. By contrast, EMPA opposed rotenone-induced effects on oxidative stress and inflammation. Besides, rotenone reduced the expression of pAMP-activated protein kinase (pAMPK), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and Sirtuin-1 (SIRT-1), as well as abrogated NAD+/NADH ratio. However, EMPA activated the AMPK/SIRT-1/PGC-1α pathway. Moreover, rotenone hindered the wnt/ß-catenin pathway by reducing the wnt-3a level and ß-catenin expression. On the other side, EMPA triggered activation of the wnt/ß-catenin pathway. Collectively, EMPA may provide a promising solution for Parkinson's patients worldwide.

Neuroprotective effect of curcumin against experimental autoimmune encephalomyelitis-induced cognitive and physical impairments in mice: an insight into the role of the AMPK/SIRT1 pathway.

Multiple sclerosis (MS) is an incurable chronic neurodegenerative disease where autoimmunity, oxidative stress, and neuroinflammation collaboration predispose myelin sheath destruction. Interestingly, curcumin, a natural polyphenol, showed a neuroprotective effect in numerous neurodegenerative diseases, including MS. Nevertheless, the influence of curcumin against MS-induced cognitive impairment is still vague. Hence, we induced experimental autoimmune encephalomyelitis (EAE) in mice using spinal cord homogenate (SCH) and complete Freund's adjuvant, which eventually mimic MS. This study aimed not only to evaluate curcumin efficacy against EAE-induced cognitive and motor dysfunction, but also to explore a novel mechanism of action, by which curcumin exerts its beneficial effects in MS. Curcumin (200 mg/kg/day) efficacy was evaluated by behavioral tests, histopathological examination, and biochemical tests. Concisely, curcumin amended EAE-induced cognitive and motor impairments, as demonstrated by the behavioral tests and histopathological examination of the hippocampus. Interestingly, curcumin activated the adenosine monophosphate (AMP)-activated protein kinase/silent mating type information regulation 2 homolog 1 (AMPK/SIRT1) axis, which triggered cyclic AMP response element-binding protein/brain-derived neurotrophic factor/myelin basic protein (CREB/BDNF/MBP) pathway, hindering demyelination of the corpus callosum. Furthermore, AMPK/SIRT1 activation augmented nuclear factor erythroid 2-related factor 2 (Nrf2), a powerful antioxidant, amending EAE-induced oxidative stress. Additionally, curcumin abolished EAE-induced neuroinflammation by inhibiting Janus kinase 2 /signal transducers and activators of transcription 3 (JAK2/STAT3) axis, by various pathways, including AMPK/SIRT1 activation. JAK2/STAT3 inhibition halts inflammatory cytokines synthesis. In conclusion, curcumin's neuroprotective effect in EAE is controlled, at least in part, by AMPK/SIRT1 activation, which ultimately minimizes EAE-induced neuronal demyelination, oxidative stress, and neuroinflammation.