The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle ...Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway.
It remains unclear whether the necessity of calcified mellitus induced by high inorganic phosphate (Pi) is required and the roles of autophagy plays in aldosterone (Aldo)‐enhanced vascular ...calcification (VC) and vascular smooth muscle cell (VSMC) osteogenic differentiation. In the present study, we found that Aldo enhanced VC both in vivo and in vitro only in the presence of high Pi, alongside with increased expression of VSMC osteogenic proteins (BMP2, Runx2 and OCN) and decreased expression of VSMC contractile proteins (α‐SMA, SM22α and smoothelin). However, these effects were blocked by mineralocorticoid receptor inhibitor, spironolactone. In addition, the stimulatory effects of Aldo on VSMC calcification were further accelerated by the autophagy inhibitor, 3‐MA, and were counteracted by the autophagy inducer, rapamycin. Moreover, inhibiting adenosine monophosphate‐activated protein kinase (AMPK) by Compound C attenuated Aldo/MR‐enhanced VC. These results suggested that Aldo facilitates high Pi‐induced VSMC osteogenic phenotypic switch and calcification through MR‐mediated signalling pathways that involve AMPK‐dependent autophagy, which provided new insights into Aldo excess‐associated VC in various settings.
Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin‐33 ...(IL‐33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL‐33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL‐33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)‐treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL‐33. Gene expression analysis was used to identify IL‐33‐dependent regulators of ER stress and autophagy. Both db/db mice and PA‐treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL‐33. Treatment with IL‐33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3‐methyladenine (3‐MA) or wortmannin, abolished the protective effects of IL‐33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin‐like growth factor‐binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL‐33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL‐33. IL‐33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL‐33‐induced ER stress resolution and autophagic enhancement during DCM.
Interleukin‐33 (IL‐33) abates diabetic cardiomyopathy (DCM) by alleviating endoplasmic reticulum (ER) stress and promoting autophagy. Insulin‐like growth factor‐binding protein 3 is essential for IL‐33‐induced ER stress resolution and autophagic enhancement during DCM.
Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA ...H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep
mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.
It remains unclear whether triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, is prospectively associated with incident peripheral arterial disease (PAD).
We included 12,320 ...Atherosclerosis Risk in Communities Study participants (aged 54.3 ± 5.7 years) free of a history of PAD at baseline (visit 1: 1987-1989). The TyG index was determined using ln (fasting triglycerides mg/dL × fasting glucose mg/dL/2), and measured at 5 visits between 1987 and 2013. Incident PAD was defined as the first hospitalization with PAD diagnosis or a new onset of measured ABI < 0.90 during follow-up visits. We quantified the association of both baseline and trajectories of TyG index with incident PAD using Cox regression and logistic regression analysis, respectively.
Over a median follow-up of 23 years, 1300 participants developed PAD. After adjustment for traditional PAD risk factors, each 1-SD (0.58) increase in TyG index was associated with an 11.9% higher risk of incident PAD hazard ratio, 1.119 (95% CI, 1.049-1.195). Results were similar when individuals were categorized by TyG index quartiles hazard ratio, 1.239 (95% CI, 1.028-1.492); comparing extreme quartiles. Four distinct trajectories of stable TyG indexes at various levels along the follow-up duration were identified low (22.2%), moderate (43.2%), high (27.5%), and very high (7.1%) trajectory groups. Compared with those with a TyG index trajectory at a low level, those participants with TyG index trajectories at high and very high levels had an even greater risk of future incident PAD odds ratio (95%CI): 1.404 (1.132-1.740) and 1.742 (1.294-2.344), respectively after multivariate adjustments for traditional PAD risk factors.
Higher TyG index is independently associated with an increased risk of incident PAD. Long-term trajectories of TyG index help identify individuals at a higher risk of PAD who deserve specific preventive and therapeutic approaches.
Clinical trial registration number: The ARIC trial was registered at clinicaltrials.gov as NCT00005131.
Atg2 is a key gene in autophagy formation and plays an important role in regulating aging progress. Exercise is an important tool to resist oxidative stress in cells and delay muscle aging. However, ...the relationship between exercise and the muscle Atg2 gene in regulating skeletal muscle aging remains unclear. Here, overexpression or knockdown of muscle Atg2 gene was achieved by constructing the AtgUAS/MhcGal4 system in Drosophila, and these flies were also subjected to an exercise intervention for 2 weeks. The results showed that both overexpression of Atg2 and exercise significantly increased the climbing speed, climbing endurance, cardiac function, and lifespan of aging flies. They also significantly up‐regulated the expression of muscle Atg2, AMPK, Sirt1, and PGC‐1α genes, and they significantly reduced muscle malondialdehyde and triglyceride. These positive benefits were even more pronounced when the two were combined. However, the effects of Atg2 knockdown on skeletal muscle, heart, and lifespan were reversed compared to its overexpression. Importantly, exercise ameliorated age‐related changes induced by Atg2 knockdown. Therefore, current results confirmed that both overexpression of muscle Atg2 and exercise delayed age‐related deteriorations of skeletal muscle, the heart function, and lifespan, and exercise could also reverse age‐related changes induced by Atg2 knockdown. The molecular mechanism is related to the overexpression of the Atg2 gene and exercise, which increase the activity of the AMPK/Sirt1/PGC‐1α pathway, oxidation and antioxidant balance, and lipid metabolism in aging muscle.
Muscle Atg2 gene, endurance exercise activates the AMPK/Sirt1/PGC‐1α pathway and regulates age‐related decline in skeletal muscle and cardiac function.
Polysaccharide chromium (III) derivatives are gaining increasing attention in improving type 2 diabetes. In this study, the sulfated polysaccharide from
(SPE) with 4.8 kDa was prepared by specific ...enzymatic hydrolysis. The obtained SPE was used to prepare a rhamnan-type sulfated polysaccharide derivative (SPED). Results indicated that O-H, C=O, and S=O were effectively involved in the chelation of SPED (chromium content 20.26%). Acute (half lethal dose > 2.38 g/kg) and sub-acute toxicity showed that SPED had no damaging effects on mice. Anti-diabetic experiment demonstrated that SPED improved glucose metabolism. Moreover, SPED promoted the PI3K/PKB/GSK-3β signaling pathway by regulating mRNA expression of insulin receptors (IR), insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB), and glycogen synthase kinase 3β (GSK-3β). In conclusion, the SPED might represent a novel marine-derived candidate against hyperglycemia, which may undergo further pharmaceutical development as a hypoglycemic agent.
Aim
To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D).
Materials ...and Methods
This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non‐high‐density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications.
Results
During a median follow‐up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10‐point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47‐0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53‐0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups.
Conclusion
Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.
•First elaborating the protective effect of EPA-enriched PL on oxidative damage.•The mechanism was related to EPA-enriched PL antioxidant and anti-apoptosis effects.•First testified EPA-enriched PL ...had improvement effect on learning and memory.•The behavior improvement effect was related to EPA-enriched PL antioxidant activity.•Offering a novel and efficient strategy to explore novel drugs or functional food.
Alzheimer’s disease (AD) is a common neurodegenerative disorders, in which oxidative stress plays an important role. The present study investigated the effect of eicosapentaenoic acid-enriched phospholipids (EPA-enriched PL) from the sea cucumber Cucumaria frondosa on oxidative injury in PC12 cells induced by hydrogen peroxide (H2O2) and tert-butylhydroperoxide (t-BHP). We also studied the effect of EPA-enriched PL on learning and memory functions in senescence-accelerated prone mouse strain 8 (SAMP8) in vivo. Pretreatment with EPA-enriched PL resulted in an enhancement of survival in a dose-dependent manner in H2O2 or t-BHP damaged PC12 cells. EPA-enriched PL pretreatment could also reduce the leakage of lactate dehydrogenase (LDH), and increase the intracellular total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activity compared with the H2O2 or t-BHP group. The down-regulated Bcl-2 mRNA level and up-regulated Bax, Caspase-9, and Caspase-3 mRNA expression induced by H2O2 or t-BHP could be restored by EPA-enriched PL pretreatment. These results demonstrated that EPA-enriched PL exhibited its neuroprotective effects by virtue of its antioxidant activity, which might be achieved by inhibiting the mitochondria-dependent apoptotic pathway. The neuroprotective effect of EPA-enriched PL was also verified in vivo test: the EPA-enriched PL administration prevented the development of learning and memory impairments in SAMP8 mice. Our results indicated that EPA-enriched PL could offer an efficient and novel strategy to explore novel drugs or functional food for neuronprotection and cognitive improvement.
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