MetS Rats Research Articles

Reversion to regular diet with alternate day fasting can cure grade-I non-alcoholic fatty liver disease (NAFLD) in high-fructose-intake-associated metabolic syndrome

BackgroundNon-alcoholic fatty liver disease (NAFLD) is an emerging global health problem that accompanied the obesity epidemic and is considered as the hepatic component of metabolic syndrome (MetS). Modification of lifestyle of MetS patients remains the focus to reverse and prevent progression of hepatic steatosis to NAFLD and its worsening to severe forms. The present study investigates the possible curability of metabolic syndrome -associated grade-1 NAFLD merely by alternate day fasting with or without reversion to regular diet in adult male rats. The present study was performed on 66 local strain male rats aged (6–10 m.) distributed randomly into C group (n = 12), on regular rat diet; and M group (n = 54) on high fructose- intake. On the 8th week, then rats were subjected to measurement of BW, BMI, WC, FBG, IPGTT, HDL-C, TGs, and liver histopathology, to include MetS rats randomly into four experimental groups for 4 weeks as follows: MS (n = 14); MSRD (n = 12); MSF (n = 13); and MSRDF (n = 12). On the 12th week, all rats were subjected to measurements of BW, BMI, WC, LW, LW/BW, VFW, VFW/BW, FBG, IPGTT, Ins., HOMA-IR, HbA1C, TGs, TC, LDL-C, HDL-C, CRP, Alb., bilirubin, ALT, L-MDA, and liver histopathology.ResultsOn the 8th week, M group developed MerS and grade-I NAFLD with score-4 hepatosteatosis (69%). On the 12th week, MS group had grade-1 NAFLD with score-4 hepatosteatosis (82%) with significantly increased Ins., HOMA-IR, HDL-C, LW, LW/BW, L-MDA, ALT, CRP, and significantly decreased Alb. than C rats. Both MSRD and MSF groups had grade-1 NAFLD with score-3 hepatosteatosis (42%) with significantly decreased Ins., HOMA-IR, TC, LDL-C, LW, LW/BW, L-MDA, ALT, CRP, and significantly increased HDL-C and Alb. than MS group. MSRDF rats showed cure of grade-1 NAFLD and significantly decreased LW than other groups and normalized HOMA-IR, HbA1C TC, LDL-C, ALT, and CRP.ConclusionOne month of alternate-day fasting and regular rat diet could cure grade-I NAFLD associated with Mets due to high fructose intake possibly by attenuating metabolic disorders. These two interventions might be recommended in the management of MetS patients with grade 1-NAFLD disease.

Ticagrelor alleviates high-carbohydrate intake induced altered electrical activity of ventricular cardiomyocytes by regulating sarcoplasmic reticulum-mitochondria miscommunication.

Metabolic syndrome (MetS) is associated with additional cardiovascular risk in mammalians while there are relationships between hyperglycemia-associated cardiovascular dysfunction and increased platelet P2Y12 receptor activation. Although P2Y12 receptor antagonist ticagrelor (Tica) plays roles in reduction of cardiovascular events, its beneficial mechanism remains poorly understood. Therefore, we aimed to clarify whether Tica can exert a direct protective effect in ventricular cardiomyocytes from high-carbohydrate diet-induced MetS rats, at least, through affectingsarcoplasmic reticulum (SR)-mitochondria (Mit) miscommunication. Tica treatment of MetS rats (150mg/kg/day for 15 days) significantly reversed the altered parameters of action potentials by reversing sarcolemmal ionic currents carried by voltage-dependent Na+ and K+ channels, and Na+/Ca2+-exchanger in the cells, expressed P2Y12 receptors. The increased basal-cytosolic Ca2+ level and depressed SR Ca2+ load were also reversed in Tica-treated cells, at most, though recoveries in the phosphorylation levels of ryanodine receptors and phospholamban. Moreover, there were marked recoveries in Mit structure and function (including increases in both autophagosomes and fragmentations) together with recoveries in Mit proteins and the factors associated with Ca2+ transfer between SR-Mit. There were further significant recoveries in markers of both ER stress and oxidative stress. Taken into consideration the Tica-induced prevention of ER stress and mitochondrial dysfunction, our data provided an important document on the pleiotropic effects of Tica in the electrical activity of the cardiomyocytes from MetS rats. This protective effect seems through recoveries in SR-Mit miscommunication besides modulation of different sarcolemmal ion-channel activities, independent of P2Y12 receptor antagonism.

Cardiac Fibrosis Attenuation by Chlorogenic Acid and Epigallocatechin-Gallate Mediated by Suppression of Galectin-3 Gene Expression and Collagen Deposition in Rat Metabolic Syndrome Model

Objective: Metabolic syndrome (MetS) is a set cluster of risk factors for metabolic abnormalities thatcan develop cardiovascular disease (CVD), one of that is remodeling or cardiac fibrosis. Cardiac fibrosisidentified from the high levels of the profibrotic molecule; one of them is galectin-3. Aim: This studyintended to determine the effect of combination therapy of green coffee (CGA) and green tea (EGCG) oncardiac fibrosis by raise of the galectin-3 gene expression and collagen deposition in rat cardiac tissue inthe rat metabolic syndrome model. Methods: Twenty-four male MetS rats (Sprague-Dawley) divided intotwo control groups and three groups therapy (n=5) administration of the CGA 200mg/kgbw (body weightin kilograms) and EGCG 300mg/kgbw orally. After eight weeks of treatment, rats euthanized, then mRNAexpression of galectin-3 was measured. Furthermore, collagen deposition of cardiac tissue carried out inhistology slides. Results: Research reveals that the expression of galectin-3 decreased in the metabolicsyndrome model group, which given combination therapy compared with metabolic syndrome model micethat did not receive any therapy (P=0.000). Collagen deposition in cardiac tissue also found less than inthe therapy group compared with the group not treated with both compounds (P=0.000). The correlationbetween the two parameters shows a positive association with low strength. Conclusion: This study showsthat the combination therapy of CGA and EGCG is an engaging therapeutic candidate. It expected to reducethe progression of cardiac fibrosis in metabolic syndrome

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome.

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.

Efficacy of Huanglian root decoction on kidney injury in rat's model of metabolic syndrome.

To evaluate the efficacy of Huanglian root decoction (, HLD) on kidney injury in rat's model of metabolic syndrome (MetS), and investigate the possible mechanism. A fructose-induced MetS rat model and human renal tubular epithelial cell-line model were used to compare the efficacy of HLD with that of berberine and tauroursodeoxycholic acid (TUDCA). Blood pressure, biochemical parameters, histopathological changes and the expression levels of oxidative stress markers were evaluated in the animal model at the end of an 8-week treatment regimen. Oxidative stress markers and molecules of the signal pathway of endoplasmic reticulum (ER) stress were evaluated in the human cell-line model. Levels of fasting insulin, systolic blood pressure and diastolic blood pressure were significantly decreased in rats in the Huanglian group compared to those in the MetS group (P < 0.05). Rats treated with HLD and TUDCA exhibited a significant reduction in blood levels of malondialdehyde compared to those in rats in the MetS group (P < 0.05). Significant increases in glutathione peroxidase in human tubular epithelial cells was found in the Huanglian group compared to that in the MetS group (14.02 vs 18.31, P < 0.05). The mRNA expression of protein kinase RNA-like endoplasmic reticulum kinase and eukaryotic translation initiation factor 2 α decreased significantly in Huanglian groups compared with that in the MetS group. HLD has therapeutic efficacy on kidney injury in the MetS rat's model, and is non-inferior to berberine and TUDCA.

Ileal interposition improves metabolic syndrome parameters in a rat model of metabolic syndrome induced by monosodium glutamate

AimsMetabolic syndrome (MetS) is a cluster of metabolic abnormalities. Anatomically restructuring of the gastrointestinal system has recently been an important subject of research in the treatment of MetS and closely related diseases. The aim of this study is to ensure the remission of parameters that define MetS by ileal interposition (IT) and to examine the effect of IT on plasma total GLP-1 and pancreatic GLP-1R expression. Main methodsTo induce MetS, newborn male Wistar albino rats were given MSG (4 g/mg) on days 0, 2, 4, 6, 8, and 10. The control group was injected with saline. In the 5th month, IT or sham surgery was performed on the MetS rats. The lipid levels, abdominal obesity, insulin level, OGTT, Lee index, HOMA-IR, plasma GLP-1 and pancreas GLP-1R expression were evaluated 2 months after surgery. Key findingsThe results showed that IT significantly improved hyperinsulinemia (p = 0.013) and lipid profile (TG p = 0.0001; TCHOL p = 0.018; HDL p = 0.001). Furthermore, it normalized the Lee index (p = 0.006) and insulin resistance. The IT did not affect the secretion of the GLP-1, but the expression levels of pancreas GLP-1R were increased (p = 0.006). SignificanceIT surgery corrected the MetS parameters in this rat model. The healing effects of IT surgery could be caused by mechanisms in the target tissues of insulin. The decrease in pancreatic GLP-1R levels in the MetS groups might be a compensatory response to the harmful effects of hyperinsulinemia in these groups. These results show that IT can be useful in the treatment of MetS.

Garlic Derived Diallyl Trisulfide in Experimental Metabolic Syndrome: Metabolic Effects and Cardioprotective Role.

This study aimed to examine the effects of diallyl trisulfide (DATS), the most potent polysulfide derived from garlic, on metabolic syndrome and myocardial function in rats with metabolic syndrome (MetS). For that purpose, we used 36 male Wistar albino rats divided into control rats, rats with MetS and MetS rats treated with 40 mg/kg of DATS every second day for 3 weeks. In the first part, we studied the impact of DATS on MetS control and found that DATS significantly raised H2S, decreased homocysteine and glucose levels and enhanced lipid and antioxidative, while reducing prooxidative parameters. Additionally, this polysulfide improved cardiac function. In the second part, we investigated the impact of DATS on ex vivo induced ischemia/reperfusion (I/R) heart injury and found that DATS consumption significantly improved cardiodynamic parameters and prevented oxidative and histo-architectural variation in the heart. In addition, DATS significantly increased relative gene expression of eNOS, SOD-1 and -2, Bcl-2 and decreased relative gene expression of NF-κB, IL-17A, Bax, and caspases-3 and -9. Taken together, the data show that DATS can effectively mitigate MetS and have protective effects against ex vivo induced myocardial I/R injury in MetS rat.

Nonclassical Axis of the Renin-Angiotensin System and Neprilysin: Key Mediators That Underlie the Cardioprotective Effect of PPAR-Alpha Activation during Myocardial Ischemia in a Metabolic Syndrome Model.

The activation of the renin-angiotensin system (RAS) participates in the development of metabolic syndrome (MetS) and in heart failure. PPAR-alpha activation by fenofibrate reverts some of the effects caused by these pathologies. Recently, nonclassical RAS components have been implicated in the pathogenesis of hypertension and myocardial dysfunction; however, their cardiac functions are still controversial. We evaluated if the nonclassical RAS signaling pathways, directed by angiotensin III and angiotensin-(1-7), are involved in the cardioprotective effect of fenofibrate during ischemia in MetS rats. Control (CT) and MetS rats were divided into the following groups: (a) sham, (b) vehicle-treated myocardial infarction (MI-V), and (c) fenofibrate-treated myocardial infarction (MI-F). Angiotensin III and angiotensin IV levels and insulin increased the aminopeptidase (IRAP) expression and decreased the angiotensin-converting enzyme 2 (ACE2) expression in the hearts from MetS rats. Ischemia activated the angiotensin-converting enzyme (ACE)/angiotensin II/angiotensin receptor 1 (AT1R) and angiotensin III/angiotensin IV/angiotensin receptor 4 (AT4R)-IRAP axes. Fenofibrate treatment prevented the damage due to ischemia in MetS rats by favoring the angiotensin-(1-7)/angiotensin receptor 2 (AT2R) axis and inhibiting the angiotensin III/angiotensin IV/AT4R-IRAP signaling pathway. Additionally, fenofibrate downregulated neprilysin expression and increased bradykinin production. These effects of PPAR-alpha activation were accompanied by a reduction in the size of the myocardial infarct and in the activity of serum creatine kinase. Thus, the regulation of the nonclassical axis of RAS forms part of a novel protective effect of fenofibrate in myocardial ischemia.

Vitamin D3 potentiates the nephroprotective effects of metformin in a rat model of metabolic syndrome: role of AMPK/SIRT1 activation and DPP-4 inhibition.

The current study aimed to investigate the molecular mechanisms of metformin and vitamin D3-induced nephroprotection in a metabolic syndrome (MetS) rat model, evaluating the capacity of vitamin D3 to potentiate metformin action. MetS was induced by 10% fructose in drinking water and 3% salt in the diet. After 6 weeks, serum lipid profile and uric acid were measured, an oral glucose tolerance test (OGTT) was performed, and kidney function was investigated. In conjunction with the same concentrations of fructose and salt feeding, MetS rats with significant weight gain, dyslipidemia, hyperuricemia, and dysglycemia were treated orally with metformin (200mg/kg), vitamin D3 (10µg/kg), or both daily for 6 weeks. At the end of the study period, anthropometrical parameters were recorded, OGTT was reperformed, urine and blood samples were collected, and tissue samples were harvested at sacrifice. MetS rats showed dramatically declined renal function, enhanced intrarenal oxidative stress and inflammation, and extravagant renal histopathological damage with interstitial fibrosis. Metformin and vitamin D3 significantly reversed all the aforementioned deleterious effects in MetS rats. The study has verified the nephroprotective effects of metformin and vitamin D3 in MetS, accentuating the critical role of AMP-activated protein kinase/sirtuin-1 activation and dipeptidyl peptidase-4 inhibition. Given the synergistic effects of the combination, vitamin D3 is worth being investigated as an additional therapeutic agent for preventing MetS-induced nephropathy.

Spermatogenesis and steroidogenesis disruption in a model of metabolic syndrome rats

Context Metabolic syndrome (MetS) is a clustering of several physiological alterations. Objective This study was designed to evaluate the effects of MetS on rats spermatogenesis and steroidogenesis. Materials and methods We developed a MetS rodent model using high-sugar and high-fat diet. Results MetS rats showed severe disorders in sperm parameters. Interestingly, a significant increase in malondialdehyde level and a decrease in the antioxidant activities were observed. Moreover, qRT-PCR analysis showed Bax down-regulation and Bcl-2 up-regulation. A decrease in testosterone level was identified, correlated with the CYP11A1, CYP17A1 and 17β HSD testicular marker down-regulation. Finally, MetS rats showed an up-regulation of pro-inflammatory cytokines receptors IL-1R and IL-6R. Conclusion MetS induced severe testis toxicity in male rats. Mets markedly distorted sperm parameters, inhibited the transcription of steroidogenic enzymes and led to oxidative stress, inflammation, and alteration of Bax/Bcl-2 ratioin testicular tissues.

The Novel Angiotensin-(1-7) Analog, A-1317, Improves Insulin Resistance by Restoring Pancreatic β-Cell Functionality in Rats With Metabolic Syndrome.

In previous studies we have shown that oral Ang-(1–7) has a beneficial therapeutic effect on cardiometabolic disturbances present in metabolic syndrome (MetS). Based on the fact that Ang-(1–7) acts through release of nitric oxide (NO), a new peptide, A-1317 was engineered adding the amino acid L-Arginine, the NO precursor, to the N-terminal portion of the Ang-(1–7). Therefore, in a single molecule the substrate and the activator of NO are combined. In the present study, we evaluated the effect of A-1317 oral treatment on liver-glucose metabolism in MetS induced by high fat (HF) diet in rats. Rats were subjected to control (AIN-93M, CT) or HF diets for 15 weeks to induce MetS and treated with A-1317, Ang-(1–7) included into hydroxypropyl-β-cyclodextrin (HPβCD) or empty HPβCD (E), in the last 7 weeks. At the end of 15 weeks, hemodynamic, biometric, and biochemical parameters, redox process, and qRT-PCR gene expression of NO synthase and RAS components were evaluated in the liver. HF/E rats increased body mass gain, adiposity index, despite the reduction in food intake, increased plasma leptin, total cholesterol, triglycerides, ALT, fasting blood glucose, OGTT and insulin, HOMA-IR and MAP and HR. Furthermore, the MetS rats presented increased in liver angiotensinogen, AT1R, ACE mRNA gene expression and concentration of MDA and carbonylated protein. Both Ang-(1–7) and A-1317 oral treatment in MetS rats reverted most of these alterations. However, A-1317 was more efficient in reducing body mass gain, ALT, AST, total cholesterol, insulin, fasting blood glucose, ameliorating β cell capacity by increasing HOMA-β and QUICKI, whereas Ang-(1–7) reduced HOMA-β and QUICKI. In addition, Ang-(1–7) increased Mas and AKT liver mRNA gene expression, while A-1317 increased both Mas and MRGD and AMPK liver mRNA gene expression, suggesting a distinct pathway of action of Ang-(1–7) and A-1317 in MetS rats. Taken together, our data showed that treatment with A-1317 was able to ameliorate MetS disorders and suggested that this effect was mainly via MRGD via activation of AMPK and increasing β cell function.

Autonomous activation of CaMKII exacerbates diastolic calcium leak during beta-adrenergic stimulation in cardiomyocytes of metabolic syndrome rats

Autonomous Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation induces abnormal diastolic Ca2+ leak, which leads to triggered arrhythmias in a wide range of cardiovascular diseases, including diabetic cardiomyopathy. In hyperglycemia, Ca2+ handling alterations can be aggravated under stress conditions via the β-adrenergic signaling pathway, which also involves CaMKII activation. However, little is known about intracellular Ca2+ handling disturbances under β-adrenergic stimulation in cardiomyocytes of the prediabetic metabolic syndrome (MetS) model with obesity, and the participation of CaMKII in these alterations.MetS was induced in male Wistar rats by administering 30 % sucrose in drinking water for 16 weeks. Fluo 3-loaded MetS cardiomyocytes exhibited augmented diastolic Ca2+ leak (in the form of spontaneous Ca2+ waves) under basal conditions and that Ca2+ leakage was exacerbated by isoproterenol (ISO, 100 nM). At the molecular level, [3H]-ryanodine binding and basal phosphorylation of cardiac ryanodine receptor (RyR2) at Ser2814, a CaMKII site, were increased in heart homogenates of MetS rats with no changes in RyR2 expression. These alterations were not further augmented by Isoproterenol. SERCA pump activity was augmented 48 % in MetS hearts before β-adrenergic stimuli, which is associated to augmented PLN phosphorylation at T17, a target of CaMKII. In MetS hearts. CaMKII auto-phosphorylation (T287) was increased by 80 %. The augmented diastolic Ca2+ leak was prevented by CaMKII inhibition with AIP. In conclusion, CaMKII autonomous activation in cardiomyocytes of MetS rats with central obesity significantly contributes to abnormal diastolic Ca2+ leak, increasing the propensity for β-adrenergic receptor-driven lethal arrhythmias.

Memory-Enhancing Effect of a Phytosome Containing the Combined Extract of Mulberry Fruit and Ginger in an Animal Model of Ischemic Stroke with Metabolic Syndrome.

The prevalence of dementia following cerebral ischemia in metabolic syndrome (MetS) condition is increasing, and most of the cases are often severe. Unfortunately, no effective strategy for treating this condition is available. Based on the positive modulation effect of a polyphenol-rich substance on dementia and the improvement in bioavailability and stability of polyphenols induced by the phytosome technique together with the use of the synergistic concept, we hypothesized that a phytosome containing the combined extract of mulberry fruit and ginger (PMG) should mitigate dementia and memory impairment following ischemic stroke in MetS. MetS was induced in male Wistar rats weighing 180-200 g by exposure to a 16-week feeding period of high-carbohydrate high-fat (HCHF) diet. MetS rats were orally given PMG at doses of 50, 100, and 200 mg·kg−1 BW 21 days before and 21 days after the occlusion of the right middle cerebral artery (Rt. MCAO). Then, their spatial memory was determined and the possible underlying mechanisms explored via the alterations of acetylcholinesterase (AChE), neuron density, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), interleukin-6 (IL-6), and signal transduction via extracellular signal-regulated kinase (ERK) pathway in both the cerebral cortex and the hippocampus. It was found that PMG significantly enhanced memory. It also decreased AChE, IL-6, and MDA but increased SOD, CAT, GSH-Px, neuron density, and phosphorylation of ERK. These data suggested the cognitive enhancing effect of PMG. The possible underlying mechanisms might occur partly via the improvement of cholinergic function via the ERK pathway together with the decrease in neurodegeneration induced by the reduction of oxidative stress and inflammation. However, a subchronic toxicity study is also required to assure the safety of PMG consumption before moving forward to a clinical trial study.

Shensong Yangxin Protects Against Metabolic Syndrome-Induced Ventricular Arrhythmias by Inhibiting Electrical Remodeling.

Shensong Yangxin (SSYX) is a traditional Chinese medicine, which has been proven to improve the clinical symptoms of arrhythmia. However, the role of SSYX in metabolic syndrome (MetS)-induced electrical remodeling remains to be fully elucidated. Here, we sought to clarify whether SSYX can alter the electrophysiological remodeling of cardiac myocytes from MetS rats by regulating transient outward potassium current (I to) and calcium current (I Ca-L). Male Wistar rats were subjected to 16 weeks of high-carbohydrate, high-fat to produce a MetS model group. SSYX (0.4 g/kg) was administrated by daily gavage 8 weeks following high-carbohydrate, high-fat for 8 weeks. In vivo electrophysiological study was performed to evaluated ventricular arrhythmias (VA) vulnerability and electrophysiological properties. The potential electrical mechanisms were estimated by whole-cell patch-clamp and molecular analysis. The H9C2 cells were used to verify the protective role of SSYX in vitro. After 16-week high-carbohydrate, high-fat feeding, MetS model rats showed increased body weight (BW), blood pressure (BP), blood sugar (BS), heart rate (HR) and heart weights to tibia length (HW/TL) ratio. Furthermore, MetS rats depicted increased VA inducibility, shortened effective refractory period (ERP) and prolonged action potential duration (APD). Lower I Ca-L and I to current densities were observed in MetS rats than CTL rats. Additionally, MetS rats exhibited significantly increased cardiac fibrosis, decreased Cx43 expression and protein levels of Cav1.2, Kv4.2, Kv4.3 than CTL group. As expected, these MetS-induced effects above were reversed when SSYX was administrated. Mechanistically, SSYX administrated significantly down-regulated the TLR4/MyD88/CaMKII signaling pathway both in vivo and in vitro. Collectively, our data indicated that the electrical remodeling induced by MetS contributed to the increased VA susceptibility. SSYX protects against MetS-induced VA by inhibiting electrical remodeling through TLR4/MyD88/CaMKII signaling pathway.

Stingless Bee Honey Reduces Anxiety and Improves Memory of the Metabolic Disease-induced Rats.

Scientific studies support the evidence of the involvement of Metabolic Syndrome (MetS) in the progression of neurodegenerative diseases through oxidative stress. Consumption of antioxidant compounds was found to be beneficial for brain-health as it reduced the brain oxidative stress level and improved cognitive performance in animals. Stingless bee honey or locally known as Kelulut Honey (KH) has high phenolic content and is widely used as a food supplement. In this study, we aimed to investigate the effects of KH on the brain of MetS-induced rats. Forty male Wistar rats were divided into 5 groups; 8 weeks (C8) and 16 weeks control groups (C16), groups that received High-Carbohydrate High Fructose (HCHF) diet for 8 weeks (MS8) and 16 weeks (MS16), and a group that received HCHF for 16 weeks with KH supplemented for the last 35 days (KH). Serum fasting blood glucose decreased in the KH group compared to the MS16 group. HDL levels were significantly decreased in MetS groups compared to control groups. Open field experiments showed that KH group exhibits less anxious behavior compared to the MetS group. Probe trial of Morris water maze demonstrated significant memory retention of KH group compared to the MS16 group. Nissl staining showed a significant decrease in the pyramidal hippocampal cells in the MS16 compared to the KH group. KH has the ability to normalise blood glucose and reduce serum triglyceride and LDL levels in MetS rats, while behavior studies complement its effect on anxiety and memory. This shows a promising role of KH in attenuating neurodegenerative diseases through the antioxidant activity of its polyphenolic content.

Titin and CK2α are New Intracellular Targets in Acute Insulin Application-Associated Benefits on Electrophysiological Parameters of Left Ventricular Cardiomyocytes From Insulin-Resistant Metabolic Syndrome Rats.

Previous studies have demonstrated that a high-carbohydrate intake could induce metabolic syndrome (MetS) in male rats with marked cardiac functional abnormalities. In addition, studies mentioned some benefits of insulin application on these complications, but there are considerable disagreements among their findings. Therefore, we aimed to extend our knowledge on the in-vitro influence of insulin on left ventricular dysfunction and also in the isolated cardiomyocytes from MetS rats. At the organ function level, an acute insulin application (100-nM) provided an important beneficial effect on the left ventricular developed pressure in MetS rats. Furthermore, to treat the freshly isolated cardiomyocytes from MetS rats with insulin provided marked recoveries in elevated resting intracellular Ca2+-level, as well as significant prevention of prolonged action potential through an augmentation in depressed K+-channel currents. Insulin also normalized the cellular levels of increased ROS and phosphorylation of PKCα, together with normalizations of apoptotic markers in MetS cardiomyocytes through the insulin-mediated regulation of phospho-Akt. Since not only elevated PKCα-activity but also reductions in phospho-Akt are key modulators of titin-based cardiomyocyte stiffening in hyperglycemia, insulin treatment of the cardiomyocytes prevented the activation of titin via the above pathways. Furthermore, CK2α-activation and NOS-phosphorylation could be prevented with insulin treatment. Mechanistically, we found that impaired insulin signaling and elevated PKCα and CK2α activities, as well as depressed Akt phosphorylation, are key modulators of titin-based cardiomyocyte stiffening in MetS rats. We propose that restoring normal kinase activities and also increases in phospho-Akt by insulin can contribute marked recoveries in MetS heart function, indicating a promising approach to modulate titin-associated factors in heart dysfunction associated with type-2 diabetes mellitus. Graphical Abstract.

Renoprotective effects of vitamin D3 supplementation in a rat model of metabolic syndrome.

The study aimed to investigate the potential nephroprotective effects of vitamin D3 in metabolic syndrome (MetS) and the molecular basis of the underlying mechanisms of its action. MetS was induced in adult male Wistar rat‏s by adding fructose (10%) to every day drinking water and salt (3%) to the diet. Sixweeks after fructose/salt consumption, fasting serum lipid profile and uric acid levels were determined, an oral glucose tolerance test (OGTT) was performed and kidney function was checked. MetS rats were then treated orally with vitamin D3 (10µg/kg/day) for 6weeks. At the end of the study period (12weeks), the OGTT test was reperformed, anthropometrical parameters were measured, urine, blood and tissue samples were collected and the animals were euthanised. The incidence of MetS was confirmed 6weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia,insulin resistance,hyperinsulinemia and impaired glucose tolerance. After 12weeks, MetS rats displayed markedly declined renal function alongside with extravagant renal histopathological damages and interstitial fibrosis. Furthermore, significantly enhanced renal oxidative stress and inflammation were manifested. Vitamin D3 supplementation in MetS rats significantly reversed all the above-mentioned deleterious effects. The study has indeed provided mounting evidence of the promising therapeutic potential of vitamin D3 against development and progression of MetS-induced nephropathy. A new insight has been introduced into the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5'adenosine monophosphate-activated protein kinase activation in the renoprotective effects of vitamin D3.

Insulin Similar to Activator of KCNQ1 Channel Recovers the Prolonged Repolarization of Ventricular Cardiomyocytes from Insulin Resistant Aged Rats

Both cardiac dysfunction and systemic insulin resistance mostly observed together with advancing aging or metabolic syndrome (MetS), while the exact underlying mechanisms of heart‐specific insulin resistance and cardiac dysfunction still remain unclear. There also are relations between delayed ventricular repolarization, increased risk in arrhythmia and QT‐prolongation in ECG with diabetes, aging and MetS. They also showed that the mutations/functional alterations in QT‐prolongation related K+‐channels such as KCNQ1‐channels might be responsible for these changes. In addition, most of recent observations that insulin sensitivity of glucose metabolism are affected by a new molecule KCNQ1, which brings up a thought on possible relation of development of insulin resistance, changes in this channel and QT‐prolongations in senescent mammalian cardiomyocytes. Therefore, we aimed to clarify a possible association between prolonged action potential duration and alterations in KCNQ1‐channel function as well as insulin application in ventricular cardiomyocytes from either insulin resistant aged or MetS rats. Our data showed that there is a significant prolongation in action potential repolarization phase in isolated cardiomyocytes from insulin‐resistant aged or MetS rats, while those animals have a significant prolonged‐QT in ECG and can respond to insulin application. Besides, application of KCNQ1‐channel activator reduced the prolonged action potential repolarizations and this indicates the contribution of KCNQ1‐currents and possible benefits of insulin on action potential prolongation of both aged and MetS cardiomyocytes. Our present study also showed that the protein expression level of KCNQ1 and KCNE1 remained unchanged. Overall, our present results can reveal important information on the contributions of these parameters on the aging‐related or metabolic syndrome‐related cardiac dysfunction and the effect of insulin on these alterations. Therefore, our findings will contribute to the literature and the clinical applications with a new therapeutic approach by revealing the molecular mechanisms of insulin treatment on insulin resistant aged or MetS mammalian cardiac dysfunction.Support or Funding InformationSupported through TUBITAK SBAG‐119S661

Chemical characterisation, hypoglycaemic and renoprotective effects of aqueous leaf extract of Limoniastrum guyonianum on fructose-induced metabolic syndrome in rats

In the present study, we chemically characterised the aqueous leaf extract of Limoniastrum guyonianum by HPLC-TOF/MS and evaluated its effects on fructose-induced metabolic syndrome (MetS) in Wistar rats. MetS groups were given (10% w/v) fructose solution to drink ad libitum for 9 weeks, whereas, normal animals received ordinary water. LG extract was administrated to treated groups by gavage for the last 6 weeks of the experimental period. Fructose feeding as a liquid solution increased body weight, reduced insulin sensitivity, raised blood glucose level and provoked atherogenic dyslipidemia associated with renal oxidative stress and structural damage. Treating MetS rats with LG extract at doses of 100, 200 and 300 mg/kg b.w./day considerably ameliorated the fructose-induced alterations. From this study, it was concluded that aqueous leaf extract of L. guyonianum possesses hypoglycaemic, hypolipidemic, antioxidant and renoprotective abilities against fructose-induced metabolic syndrome in rats.

Aortae of Young Rats with Metabolic Syndrome Exhibit Enhanced Vasoconstrictor Activity Than Older Rats

Abstract Background Metabolic syndrome (MetS) causes pathological remodeling of the heart and adjacent vessels. The functional changes in the big vessels in different age groups had not been fully delineated. Aim of the work The present study was planned to investigate aortic vasodilator and vasoconstrictor reactivity in young, adult and old female rats with MetS. Design: The experimental study was performed on 90 female albino rats randomized into 6 groups: young, adult and old rats with MetS and their respective control groups. Methods MetS was induced by feeding rats 41% fructose -containing diet and giving fructose solution (5 g fructose in 4 ml distilled water/day) by gavage in two sessions (2 ml/session). On the 8th week, all rats were sacrificed and were subjected to determination of body weight (BW), body mass index (BMI), absolute and relative visceral fat weight (VF), fasting blood glucose (FBG), plasma insulin (PI), homeostasis model of insulin resistance (HOMA-IR) and plasma lipid profile. All rats’ aortae were subjected to study of vascular reactivity to Potassium chloride (KCL), phenylephrine (PE) and acetyl choline (A.Ch) as well as estimation of nitrite content. Results On the 8th week of the study, all MetS groups developed criteria of metabolic syndrome as evidenced by the significant increase in final BW, BMI, absolute and relative VF weights, FBG, PI and HOMA-IR compared to their control group values. Also, MetS rat groups exhibited evident dyslipidemia in the form of significant increase in plasma levels of triglycerides, total cholesterol and significant decrease in HDL-cholesterol compared to their control group values. Aortae of young and adult MetS rat groups showed significant increase in their vasoconstrictor response to KCl and PE and decrease in A.Ch/KCL% and A.Ch/PE % compared to their controls, while old MetS rat group showed significantly increased vasoconstrictor response only to KCL compared to their controls. When compared to each other, young age MetS group had significantly higher vasoconstrictor response to PE compared to old MetS group despite comparable nitrite content. Conclusion Met.S causes functional vascular changes in all age groups with unexpectedly enhanced vasoconstrictor response in the young group compared to old.