Impaired mitochondrial biogenesis causes skeletal muscle damage in diabetes. However, whether and how mitochondrial biogenesis is impaired in the diabetic heart remains largely unknown. Whether adiponectin (APN), a potent cardioprotective molecule, regulates cardiac mitochondrial function has also not been previously investigated. In this study, electron microscopy revealed significant mitochondrial disorders in ob/ob cardiomyocytes, including mitochondrial swelling and cristae disorientation and breakage. Moreover, mitochondrial biogenesis of ob/ob cardiomyocytes is significantly impaired, as evidenced by reduced Ppargc-1a/Nrf-1/Tfam mRNA levels, mitochondrial DNA content, ATP content, citrate synthase activity, complexes I/III/V activity, AMPK phosphorylation, and increased PGC-1α acetylation. Since APN is an upstream activator of AMPK and APN plasma levels are significantly reduced in ob/ob mice, we further tested the hypothesis that reduced APN in ob/ob mice is causatively related to mitochondrial biogenesis impairment. One week of APN treatment of ob/ob mice activated AMPK, reduced PGC-1α acetylation, increased mitochondrial biogenesis, and attenuated mitochondrial disorders. In contrast, knocking out APN inhibited AMPK-PGC-1α signaling and impaired both mitochondrial biogenesis and function. The ob/ob mice exhibited lower survival rates and exacerbated myocardial injury after MI, when compared to controls. APN supplementation improved mitochondrial biogenesis and attenuated MI injury, an effect that was almost completely abrogated by the AMPK inhibitor compound C. In high glucose/high fat treated neonatal rat ventricular myocytes, siRNA-mediated knockdown of PGC-1α blocked gAd-enhanced mitochondrial biogenesis and function and attenuated protection against hypoxia/reoxygenation injury. In conclusion, hypoadiponectinemia impaired AMPK-PGC-1α signaling, resulting in dysfunctional mitochondrial biogenesis that constitutes a novel mechanism for rendering diabetic hearts more vulnerable to enhanced MI injury.
The branched-chain amino acids (BCAA) accumulated in type 2 diabetes are independent contributors to insulin resistance. The activity of branched-chain a-keto acid dehydrogenase (BCKD) complex, rate-limiting enzyme in BCAA catabolism, is reduced in diabetic states, which contributes to elevated BCAA concentrations. However, the mechanisms underlying decreased BCKD activity remain poorly understood. Here, we demonstrate that mitochondrial phosphatase 2C (PP2Cm), a newly identified BCKD phosphatase that increases BCKD activity, was significantly downregulated in ob/ob and type 2 diabetic mice. Interestingly, in adiponectin (APN) knockout (APN 2/2 ) mice fed with a high-fat diet (HD), PP2Cm expression and BCKD activity were significantly decreased, whereas BCKD kinase (BDK), which inhibits BCKD activity, was markedly increased. Concurrently, plasma BCAA and branched-chain a-keto acids (BCKA) were significantly elevated. APN treatment markedly reverted PP2Cm, BDK, BCKD activity, and BCAA and BCKA levels in HD-fed APN 2/2 and diabetic animals.Additionally, increased BCKD activity caused by APN administration was partially but significantly inhibited in PP2Cm knockout mice. Finally, APN-mediated upregulation of PP2Cm expression and BCKD activity were abolished when AMPK was inhibited. Collectively, we have provided the first direct evidence that APN is a novel regulator of PP2Cm and systematic BCAA levels, suggesting that targeting APN may be a pharmacological approach to ameliorating BCAA catabolism in the diabetic state.The branched-chain amino acids (BCAA) are essential amino acids such as leucine, isoleucine, and valine; their homeostasis is determined largely by catabolic activities in a number of organs including liver, muscle and adipose tissue (1-3). The first step of BCAA catabolism generates a set of corresponding branched-chain a-keto acids (BCKA), which are irreversibly decarboxylated by the branched-chain a-keto acid dehydrogenase (BCKD) complex (4). As with most nutrients, maintaining of the physiological level of BCAA is critical for cell metabolism and survival. However, many researchers have described increased BCAA and BCKA levels in diabetes and obesity (3,(5)(6)(7)(8). Furthermore, BCAA and their catabolites are strongly associated with insulin resistance (9-11), and elevated BCAA contributes to the development of insulin resistance (10,12). Mechanistically, elevated BCAA levels activate mTOR/p70S6 kinase, resulting in an increased I insulin receptor substrate-1 phosphorylation, thereby inhibiting phosphatidylinositol 3-kinase. This inhibition of phosphatidylinositol 3-kinase in turn leads to impaired insulin signaling (13,14). It is also reported that BCAA are independent predictors of insulin resistance, diabetes, and cardiovascular events (15-17). Therefore, it is necessary to determine the mechanisms of abnormal BCAA catabolism in order to better understand their association with metabolic-related pathogenesis. The BCKD complex is the rate-limiting enzyme in BCAA catabolism (4,12); regulation o...
Alcohol can induce adipogenesis by bone marrow stromal cells and may cause osteonecrosis of the femoral head. Currently, there are no medications available to prevent alcohol-induced osteonecrosis. We hypothesized puerarin, a Chinese herbal medicine with antioxidative and antithrombotic effects, can prevent alcohol-induced adipogenesis and osteonecrosis. Both bone marrow stromal cells (in vitro) and mice (in vivo) were treated either with ethanol or with ethanol and puerarin, with an untreated group serving as a control. In the in vitro study, the number of adipocytes, contents of triglycerides, and levels of PPARc mRNA expression were decreased and alkaline phosphatase activity, contents of osteocalcin, and levels of osteocalcin mRNA expression were increased in cells treated with both alcohol and puerarin, compared with cells treated with alcohol only. In the in vivo study, marrow necrosis, fat cell hypertrophy and proliferation, thinner and sparse trabeculae, diminished hematopoiesis, and increased empty osteocyte lacunae in the subchondral region of the femoral head were observed in mice treated with alcohol. However, no such changes were seen in femoral heads of mice treated with alcohol and puerarin. The data suggest puerarin can inhibit adipogenic differentiation by bone marrow stromal cells both in vitro and in vivo and prevents alcohol-induced osteonecrosis in this model.
Clinical trials have reported the effects of Tripterygium wilfordii Hook F (TwHF) extracts (TEs) in the treatment of rheumatoid arthritis (RA); however, the results have been inconsistent. This meta-analysis is aimed to assess the safety of TEs and their effects on the treatment of RA. Randomised controlled trials (RCTs) comparing the effects of TEs and placebo (PBO) or disease-modifying antirheumatic drugs (DMARDs) in patients with RA were included. Weighted mean differences (MDs) were calculated for net changes by employing fixed-effect or random-effects models. After filtering, ten RCTs (involving 733 participants) were included in this study. The methodological quality of these studies was generally low. Compared with DMARDs, TEs alone produced a mild increase in grip strength (GS) (P = 0.02; standard mean difference (SMD) = 0.81; 95% confidence interval (CI): 0.14 to 1.48). The most common adverse effects (AEs) of TEs were gastrointestinal discomfort, menstruation disorders, and amenorrhea. In conclusion, TEs, as a sort of “herbal DMARD,” could be as effective as synthetic DMARDs in the treatment of RA. However, the efficacy of TEs in treating RA should be further estimated with better designed, fully powered, confirmatory RCTs that apply the American College of Rheumatology (ACR) improvement criteria to evaluate their outcomes.
P rehypertension is very prevalent worldwide (30% of the adult population), and is often associated with other cardiovascular risk factors and independently increases the risk of hypertension and subsequent cardiovascular events. Lifestyle modifications or drug intervention that can delay progression from prehypertension to hypertension would be of value. [1][2][3] Vascular insulin resistance is a common pathophysiological change observed in hypertension as well as many other diabetic cardiovascular diseases. The insulin-signaling pathway via phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial NO synthase (eNOS) induces vasodilation by regulating production of NO from endothelium, 4 whereas insulin also regulates secretion of the vasoconstrictor endothelin-1 (ET-1) through Ras, Raf-1, mitogen-activated protein kinase kinase 1/2 (MEK1/2), and mitogen-activated protein kinase pathway and consequently induces vasoconstriction. Thus, the net hemodynamic action of insulin is dependent on a balance between its vasodilator and vasoconstrictor effects. Vascular insulin resistance, characterized by imbalance between insulin-induced endothelial vasodilator NO and the vasoconstrictor ET-1, contributes to elevated peripheral vascular resistance and subsequent hypertension. 5 Factors that shift the vasoconstrictor action to vasodilator effect of insulin tend to be more effective in preventing hypertension and improving insulin sensitivity. 6 Previous studies have demonstrated that young spontaneously hypertensive rats (ySHRs) without hypertension showed an impaired insulin signaling (PI3K/Akt/eNOS) in the vasculature, suggesting that vascular insulin resistance is possibly a Abstract-Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension.Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN −/− ) mice were used to evaluate the role of hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN −/− mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo...
Acute kidney injury (AKI) is an extremely dangerous clinical syndrome with high morbidity and mortality. Stem cell-based therapies have shown great promise for AKI treatment. Urine-derived stem cells (USCs) are a novel cell source in tissue engineering and cell therapy which provide advantages of simple, noninvasive, and low-cost harvest methods, efficient proliferation, and multi-differentiation potential. Here, we described the therapeutic effects of USCs in a rat model of cisplatin-induced AKI as a novel therapy. In vivo, the intravenous administration of USCs alleviated the renal functional damage in AKI rats, for the levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were significantly decreased. The USCs-treated group also exhibited improved histological and ultrastructural changes, promoted proliferation, and inhibited apoptosis in renal tissues. After the USC therapy, the expression levels of proinflammatory cytokines (TNF-α and IL-6) and apoptosis-related proteins (BAX and cleaved caspase-3) were downregulated. In addition, the presence of a few GFP-labeled USCs was confirmed in rat renal tissues. In vitro, rat tubular epithelial (NRK-52E) cells were incubated with cisplatin to induce cell damage and then cocultured with USCs. After coculture with USCs, the cisplatin-induced NRK-52E cells showed higher cell viability and a lower apoptosis ratio than those of the control group, and cell cycle arrest was improved. In conclusion, our results demonstrated that USC therapy significantly improved the renal function and histological damage, inhibited the inflammation and apoptosis processes in the kidney, and promoted tubular epithelial proliferation. Our study exhibited the potential of USCs in the treatment of AKI, representing a new clinical therapeutic strategy.
A limited number of studies have explored whether the role of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in the pathogenesis of acute myocardial infarction (AMI) is sex specific. The purpose of the present study was to examine sex differences in plasma PCSK9 in Chinese patients with AMI. In this study, a total of 281 records from patients presenting with AMI were analyzed.We compared hospital data and plasma PCSK9 levels by sex difference for inpatients presenting with AMI. After 1 year of follow-up, major adverse cardiac events(MACE) were recorded. A Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. We found that, compared with male groups, PCSK9 levels were higher in female patients not only for overall patients with AMI but also for patients with ST-elevation myocardial infarction (STEMI) (median: 273.6 [215.6–366.8] vs. 325.1 [247.5–445.3] ng/ml, P = 0.0136; 273.4 [215.6–369.7] vs. 317.1 [249.6–450.1], P = 0.0275, respectively). The cumulative incidence of cardiac death and 1-year MACE were significantly higher in the female group compared with male group (10% vs. 2.74%, P = 0.025; 15% vs. 4.11%, P = 0.0054, respectively). On multivariate Cox regression analysis, female sex, total triglyceride, glycosylated hemoglobin A, and homocysteic acid were independent risk factors of 1-year MACE. There was no significant correlation between PCSK9 and 1-year MACE in total AMI patients. In conclusion, PCSK9 levels and 1-year MACE were higher in women with AMI than in men with AMI, however, female sex but not PCSK9 were significant correlated with the 1-year MACE. The clinical implications of this finding are worthy of further investigations and must be confirmed in larger cohorts.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.