Aerobic interval training protects against myocardial infarction‐induced oxidative injury by enhancing antioxidase system and mitochondrial biosynthesis

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Advanced glycation end‐products impair Na+/K+‐ATPase activity in diabetic cardiomyopathy: Role of the adenosine monophosphate‐activated protein kinase/sirtuin 1 pathway

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Growth receptor binding protein 10 inhibits glucose‐stimulated insulin release from pancreatic β‐cells associated with suppression of the insulin/insulin‐like growth factor‐1 signalling pathway

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Dexmedetomidine preconditioning for myocardial protection in ischaemia‐reperfusion injury in rats by downregulation of the high mobility group box 1‐toll‐like receptor 4‐nuclear factor κB signalling pathway

Pharmacological preconditioning reduces myocardial infarct size in ischaemia‐reperfusion (I‐R) injury. Dexmedetomidine, a selective α₂‐adrenoceptor agonist, has a proven cardioprotective effect when administered prior to I‐R, although the underlying mechanisms for this effect are not fully understood. We evaluated whether dexmedetomidine preconditioning could induce a myocardio‐protective effect against I‐R injury by inhibiting associated inflammatory processes through downregulation of the high mobility group box 1 (HMGB1)‐toll‐like receptor 4 (TLR4)‐nuclear factor κB (NF‐κB) signalling pathway. Seventy rats were randomly assigned to seven groups: a control and six test groups, involving I‐R for 30 and 120 minutes, respectively, in isolated rat hearts and different pretreatment protocols with dexmedetomidine (10 nmol/L) as well as yohimbine (1 μmol/L) and recombinant HMGB1 peptide (rHMGB1; 20 μg/L), alone or in combination with dexmedetomidine. Cardiac function was recorded; myocardial HMGB1, TLR4, and NF‐κB activities and levels of tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured as were lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary outflow. Dexmedetomidine preconditioning significantly improved cardiac function (P<.05), downregulated the expression of HMGB1‐TLR4‐NF‐κB, reduced levels of TNF‐α and IL‐6 in isolated ventricles during I‐R injury, and significantly reduced CK and LDH levels in coronary outflow (P<.05). All of these effects were partially reversed by yohimbine (P<.05) or rHMGB1 (P<.05). Dexmedetomidine preconditioning alleviated myocardial I‐R injury in rats through inhibition of inflammatory processes associated with downregulation of the HMGB1‐TLR4‐NF‐κB signalling pathway via activation at α₂‐adrenergic receptors.     

Preventative Effect of Zingiber officinale on Insulin Resistance in a High‐Fat High‐Carbohydrate Diet‐Fed Rat Model and its Mechanism of Action

Insulin resistance is a core component of metabolic syndrome and usually precedes the development of type 2 diabetes mellitus. We have examined the preventative effect of an ethanol extract of ginger (Zingiber officinale, Zingiberaceae) on insulin resistance in a high‐fat high‐carbohydrate (HFHC) diet‐fed rat model of metabolic syndrome. The HFHC control rats displayed severe insulin resistance, whilst rats treated with ginger extract (200 mg/kg) during HFHC diet feeding showed a significant improvement of insulin sensitivity using the homeostatic model assessment of insulin resistance (HOMA‐IR) after 10 weeks (p < 0.01). An in vitro mechanistic study showed that (S)‐[6]‐gingerol, the major pungent phenolic principle in ginger, dose‐dependently (from 50 to 150 μM) increased AMPK α‐subunit phosphorylation in L6 skeletal muscle cells. This was accompanied by a time‐dependent marked increment of PGC‐1α mRNA expression and mitochondrial content in L6 skeletal muscle cells. These results suggest that the protection from HFHC diet‐induced insulin resistance by ginger is likely associated with the increased capacity of energy metabolism by its major active component (S)‐[6]‐gingerol.     

NO-1886 ameliorates glycogen metabolism in insulin-resistant HepG2 cells by GSK-3β signalling

Objectives The aim of the study was to elucidate the possible role and mechanism of NO‐1886 (ibrolipim, a lipoprotein lipase activator) in ameliorating insulin resistance induced by high palmitate. Methods HepG2 cells were cultured in RPMI 1640 medium and were treated with palmitate to induce insulin resistance. Free fatty acids (FFAs), glucose, glycogen, cell viability and mRNA and protein levels were analysed separately. Key findings We found that HepG2 cells treated with 0.5 mm palmitate for 48 h led to a significant decrease of insulin‐induced glucose consumption (from 2.89 ± 0.85 mm in the control to 0.57 ± 0.44 mm in palmitate). Insulin resistance (IR) of HepG2 cells was induced by 0.5 mm palmitate for 48 h. NO‐1886 stimulated glucose consumption, glycogen synthesis and FFA absorption in insulin‐resistant HepG2 cells. Maximum stimulation effects were observed with 10 µm NO‐1886 for 24 h. Compared with the dimethyl sulfoxide‐treated group, 2.5 µm NO‐1886 or higher could induce the mRNA expression of lipoprotein lipase. Meanwhile, NO‐1886 increased the protein content of P‐GSK‐3βser⁹ and decreased the protein level of GSK‐3β in insulin‐resistant HepG2 cells, but NO‐1886 didn't change the protein levels of PI3‐Kp85 and Akt2. Conclusion Lipoprotein lipase activator NO‐1886 could increase glycogen synthesis in HepG2 cells and could ameliorate the insulin resistance, which was associated with GSK‐3 signalling.     

Maternal fructose intake during pregnancy modulates hepatic and hypothalamic AMP‐activated protein kinase signalling in a sex‐specific manner in offspring

Dietary fructose ingestion during gestation affects carbohydrate metabolism in the offspring. In the present study, we investigated the effects of excess fructose intake during pregnancy on hepatic and hypothalamic AMP‐activated kinase (AMPK) expression and phosphorylation, as well as hepatic glucose‐6‐phosphatase (G6Pase) activity in offspring. Pregnant Wistar rats received normal chow and 100 g/L fructose solution or normal water during gestation ad libitum. On gestational Day 21, some dams were killed and plasma samples and fetuses were collected. The remaining dams received normal water after spontaneous delivery during lactation. Pups were killed on postnatal Day 22 and the plasma, liver and hypothalamus were collected and analysed. Plasma glucose and insulin levels increased in female but not male offspring in the fructose group. Although the mRNA and total protein levels of AMPKα were unchanged, levels of phosphorylated AMPKα protein in the fructose group of female offspring were significantly lower in the liver and 4.6‐fold higher in the hypothalamus. The hepatic protein level of sirtuin 1, which is involved in AMPK phosphorylation and activation, was significantly reduced in the fructose group of female offspring. The activity of G6Pase, which plays a role in gluconeogenesis, was significantly enhanced in the liver of female offspring from fructose‐fed dams. These changes were not observed in male offspring. In conclusion, we found that excessively high fructose intake during pregnancy may modulate the hepatic and hypothalamic AMPK signalling pathways in female offspring after birth.     

Curcumin Attenuates Diet‐Induced Hepatic Steatosis by Activating AMP‐Activated Protein Kinase

Curcumin is a well‐known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high‐fat/cholesterol diet (HFD)‐induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body‐weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p < 0.05). The levels of total cholesterol, fasting glucose and insulin in serum were decreased, and HFD‐induced impairment of insulin sensitivity was improved by curcumin supplementation (p < 0.05). Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation. Moreover, curcumin activated AMP‐activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator‐activated receptor alpha. By contrast, curcumin suppressed the HFD‐mediated increases in sterol regulatory element‐binding protein‐1, acetyl‐CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression. Taken together, these findings indicate that curcumin attenuates HFD‐induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis.     

Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

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[Sar1, Ile4, Ile8]‐angiotensin II Potentiates Insulin Receptor Signalling and Glycogen Synthesis in Hepatocytes

The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]‐angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long‐term pre‐treatment of hepatocytes with SII Ang II increased insulin‐stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin‐stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt‐mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin‐stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin‐stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.     

Calycosin induces apoptosis in adenocarcinoma HT29 cells by inducing cytotoxic autophagy mediated by SIRT1/AMPK‐induced inhibition of Akt/mTOR

Autophagy promotes cell survival or induces apoptosis in cancer cells. While SIRT1 and AMPK induce autophagy in both normal and cancer cells, Akt and mTOR can inhibit it. Calycosin, a methoxyisoflavone, protects against several types of solid tumours including colorectal cancer. However, the mechanisms behind the antitumour effect of Calycosin remain largely unknown. This study investigates if autophagy mediates the anti‐tumourigenesis effect afforded by Calycosin and examines if this effect involves activation of SIRT1 and/or AMPK. Human colorectal (HT29) carcinoma cells were cultured under normal conditions with Calycosin (50 μmol/L) in the presence or absence of chloroquine (10 μmol/L), EX‐527 (100 nmol/L, SIRT1 inhibitor), or IGF‐1 (100 ng/mL, Akt/mTOR activator) for 48 hours. Calycosin inhibited cell growth, proliferation and invasion and increased protein levels of Beclin‐1 and LC3II, markers of autophagy. It significantly increased protein levels of cleaved caspase‐3, Bax, and SIRT1, and activity of AMPK and reduced those of Bcl‐2. These effects were parallel with concomitant reduction in protein levels p‐src, integrin‐β1 and Cyclin‐D1 and activities of Akt and mTOR. Inhibition of autophagy by CQ reversed all these effects except cell invasion. Interestingly, co‐incubating the cells with either EX‐527 or IGF‐1 completely prevented Calycosin‐induced autophagy and all other associated effects and increased cell invasion. Also, blockade of SIRT‐1 prevented the activation of AMPK, Akt, and mTOR, suggesting it to be an upstream regulator of these markers. In conclusion, Calycosin stimulates CRC cell apoptosis and inhibits their invasion by acting as SIRT1 activator which induces activation of AMPK‐induced inhibition of Akt/mTOR axis.     

Puerarin Inhibits C‐Reactive Protein Expression via Suppression of Nuclear Factor κB Activation in Lipopolysaccharide‐Induced Peripheral Blood Mononuclear Cells of Patients with Stable Angina Pectoris

Abstract: Puerarin (4′‐7‐dihydroxy‐8‐β‐d ‐glucosylisoflavone), the most abundant isoflavone‐C‐glucoside extracted from the root of the plant Pueraria lobata, has demonstrated anti‐inflammatory activity in cellular models of inflammation. In this report, we examined the ability of puerarin to modulate C‐reactive protein (CRP) expression and key molecules in the nuclear factor kappa B (NF‐κB) pathway to determine its molecular target. The protein and mRNA levels of CRP were determined in lipopolysaccharide (LPS)‐induced peripheral blood mononuclear cells of patients with unstable angina pectoris. Also, we detected the I‐κBα phosphorylation and the p65NF‐κB expression in peripheral blood mononuclear cells under our experimental condition. The results indicated that puerarin inhibited the expression of the protein and mRNA levels of CRP in LPS‐induced peripheral blood mononuclear cells. Subsequently, we determined that the inhibition of CRP expression was because of a dose‐dependent inhibition of phosphorylation and degradation of inhibitor kappaB(I‐κB), which resulted in a reduction of p65NF‐κB nuclear translocation. We conclude that puerarin acts as an anti‐inflammatory agent by blocking NF‐κB signalling, and may possibly be developed as a useful agent for the chemoprevention of atherosclerosis.     

Role of fetuin‐A in atherosclerosis associated with diabetic patients

Objectives Fetuin‐A is a circulating glycoprotein, formed in the liver. It regulates bone remodelling and calcium metabolism. Fetuin‐A has adipogenic properties, so fat accumulation in the liver may be associated with higher levels of fetuin‐A. Fetuin‐A is an inhibitor of the phosphorylation of the insulin receptor tyrosine kinase. Key findings High concentrations of fetuin‐A in humans causes insulin resistance. Insulin sensitivity is also found to be increased in fetuin‐A knockout mice. Fetuin‐A has been shown to cause insulin resistivity in type‐2 diabetes mellitus and worsens the pro‐atherogenic milieu. Summary Fetuin‐A should be considered as a hepatic bio‐marker. Vascular diseases like atherosclerosis are major causes of disability in patients with diabetes mellitus.     

Metformin inhibits high glucose‐induced mesangial cell proliferation,inflammation and ECM expression through the SIRT1‐FOXO1‐autophagy axis

The aim of this study was to investigate the role of metformin in high glucose‐induced mesangial cell proliferation, inflammation and extracellular matrix (ECM) accumulation and to elucidate the underlying mechanism of metformin function. An MTT assay was used to examine rat mesangial cell (RMC) proliferation. The levels of TNF‐α, IL‐6 and TGF‐β in RMCs were determined by ELISA. The protein expression of fibronectin, collagen IV and autophagy‐related proteins (Beclin‐1, LC3‐I and LC3‐II) in RMCs was detected using western blot. Fluorescence microscopy analysis was carried out to evaluate RMC autophagy. Our results showed that high glucose‐induced RMC proliferation, inflammation and ECM expression, but these effects were markedly reduced by metformin. We confirmed that metformin suppressed high glucose‐induced RMC proliferation, inflammation and ECM expression via induction of autophagy. Mechanistic investigation demonstrated an axis of SIRT1‐FOXO1 in RMC autophagy. Our data indicated that metformin inhibits high glucose‐induced mesangial cell proliferation, inflammation and ECM expression through a SIRT1‐FOXO1‐autophagy axis.     

Sensitization of Hepatocellular Carcinoma Cells to Apo2L/TRAIL by a Novel Akt/NF‐κB Signalling Inhibitor

Hepatocellular carcinoma (HCC) cells are intrinsically resistant to tumour necrosis factor‐related apoptosis ligand (Apo2L/TRAIL), in part, due to the compensatory activation of nuclear factor‐kappaB (NF‐κB). To broaden the clinical utilization of Apo2L/TRAIL in HCC, OSU‐A9, a potent indole‐3‐carbinol‐derived Akt/NF‐κB signalling inhibitor was used to overcome the intrinsic resistance. The antitumour effects of OSU‐A9, Apo2L/TRAIL and the therapeutic combination were assessed by MTT assay, caspase activation and PARP cleavage, and the synergistic interactions were determined by Calcusyn analysis. NF‐κB reporter gene and RT‐PCR were tested for the activation of NF‐κB and the expression of death receptors (DR)4 and 5. OSU‐A9 could sensitize HCC cells to Apo2L/TRAIL with high potency through down‐regulation of Akt/NF‐κB signalling. OSU‐A9 dose‐dependently reduced Akt phosphorylation and the expression and nuclear localization of RelA/p65, accompanied by parallel decreases in the expression of NF‐κB target products, including Bcl‐xL, Mcl‐1, cIAP1, cIAP2 and survivin. Moreover, OSU‐A9 increased DR5 expression through a reactive oxygen species (ROS)‐dependent mechanism. Concertedly, these mechanisms underlie the synergistic interaction between OSU‐A9 and Apo2L/TRAIL in mediating apoptotic death in HCC cells. The ability of OSU‐A9 to accentuate Apo2L/TRAIL‐induced apoptosis by inactivating Akt/NF‐κB signalling might foster a promising therapeutic strategy for HCC.     

Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway

Mitochondrial energy metabolism and oxidative stress play a crucial role in ameliorating myocardial ischemia/reperfusion injury (MIRI). Tilianin has been reported to have a significant protection for mitochondrion in MIRI. However, the underlying mechanisms remain unknown. This study investigated whether Tilianin regulates mitochondrial energy metabolism and oxidative stress in MIRI via AMPK/SIRT1/PGC-1 alpha signaling pathway. The MIRI model was established by 30 min of coronary occlusion followed by 2 h of reperfusion in rats. The results revealed that Tilianin significantly reduced myocardial infarction, improved the pathological morphology of myocardium, markedly increased the contents of ATP and NAD⁺, decreased ADP and AMP contents and the ratio of AMP/ATP, reduced the level of ROS and MDA, enhanced SOD activity, evidently increased the levels of AMPK, SIRT1 and PGC-1 alpha mRNA, up-regulated the expressions of AMPK, pAMPK, SIRT1, PGC-1alpha, NRF1, TFAM and FOXO1 proteins. However, these effects were respectively abolished by Compound C (a specific AMPK inhibitor) and EX-527 (a specific SIRT1 inhibitor). Taken together, this study found that Tilianin could attenuate MIRI by improving mitochondrial energy metabolism and reducing oxidative stress via AMPK/SIRT1/PGC-1 alpha signaling pathway.     

Calcitriol Attenuates Weight‐Related Systemic Inflammation and Ultrastructural Changes in the Liver in a Rodent Model

The role of vitamin D in maintaining calcium homoeostasis and bone mineralization is well‐established. The aim of the current investigation was to evaluate the effect of calcitriol treatment on inflammation, insulin resistance and liver changes induced by increased body‐weight. Four groups of mice (n = 11 each) were maintained on either low‐fat diet (LFD) or high‐fat diet (HFD) with and without 1α, 25‐dihydroxyvitamin D3 (calcitriol) for 16 weeks. Body‐weight of animals was recorded at the start of the study and every 4 weeks thereafter. At the end of the experiment, blood samples were collected for the determination of biochemical parameters, and liver tissues were harvested for the histopathological evaluation. A significant gradual decrease in weight was observed in HFD‐fed mice treated with calcitriol compared with a steady increase in controls (p < 0.01). Furthermore, calcitriol treatment reduced concentrations of various inflammatory markers including TNF‐α, CRP and IL‐6 (p < 0.05). Treated animals also exhibited lower levels of C‐peptide and insulin (539.4 ng/ml versus 718.9 ng/ml and 0.77 ng/ml versus 1.7 ng/ml, respectively; p < 0.05), which are consistent with improved insulin resistance. Liver histology and ultrastructural studies showed a marked accumulation of fat droplets in approximately 60–70% of hepatocytes of mice fed on HFD, while calcitriol administration rendered the whole structure more normal. Overall, our data signify an important effect of calcitriol on inflammation under HFD conditions and a protective effect on the liver structure.     

Structure‐based discovery of new selective small‐molecule sirtuin 5 inhibitors

Human sirtuin 5 (SIRT5) is a protein deacylase regulating metabolic pathways and stress responses and is implicated in metabolism‐related diseases. Small‐molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein, we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, six compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19 , a series of newly synthesized (E)‐2‐cyano‐N‐phenyl‐3‐(5‐phenylfuran‐2‐yl)acrylamide derivatives/analogues were carried out structure–activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC₅₀ value of 5.59 ± 0.75 μM. The biochemical studies revealed that 37 likely acts via competitive inhibition with the succinyl‐lysine substrate, rather than the NAD⁺ cofactor, and it manifested substantial selectivity for SIRT5 over SIRT2 and SIRT6. This study will aid further efforts to develop new selective SIRT5 inhibitors as tools and therapeutics.