Atorvastatin attenuates obese-induced kidney injury and impaired renal organic anion transporter 3 function through inhibition of oxidative stress and inflammation.

An excessive consumption of high-fat diet can lead to the alterations of glucose and lipid metabolism, impaired insulin signaling and increased ectopic lipid accumulation resulting in renal lipotoxicity and subsequent renal dysfunction. Atorvastatin is a lipid-lowering drug in clinical treatment. Several studies have reported that atorvastatin has several significant pleiotropic effects including anti-inflammatory, antioxidant, and anti-apoptotic effects. However, the effects of atorvastatin on metabolic disturbance and renal lipotoxicity in obesity are not fully understood. In this study, obesity in rat was developed by high-fat diet (HFD) feeding for 16 weeks. After that, the HFD-fed rats were received either a vehicle (HF), atorvastatin (HFA) or vildagliptin (HFVIL), by oral gavage for 4 weeks. We found that HF rats showed insulin resistance, visceral fat expansion and renal lipid accumulation. Impaired renal function and renal organic anion transporter 3 (Oat3) function and expression were also observed in HF rats. The marked increases in MDA level, renal injury and NF-κB, TGF-ß, NOX-4, PKC-α expression were demonstrated in HF rats. Atorvastatin or vildagliptin treatment attenuated insulin resistance and renal lipid accumulation-induced lipotoxicity in HFA and HFVIL rats. Moreover, the proteins involved in renal inflammation, fibrosis, oxidative stress and apoptosis were attenuated leading to improved renal Oat3 function and renal function in the treated groups. Interestingly, atorvastatin showed higher efficacy than vildagliptin in improving insulin resistance, renal lipid accumulation and in exerting renoprotective effects in obesity-induced renal injury and impaired renal Oat3 function.

Dapagliflozin attenuates renal gluconeogenic enzyme expression in obese rats.

The kidneys release glucose into the systemic circulation through glucose reabsorption and renal gluconeogenesis. Currently, the significance of renal glucose release in pathological conditions has become a subject of interest. We examined the effect of sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i) on renal gluconeogenic enzyme expression in obese rats. Male Wistar rats (180-200 g) were fed either a normal diet (ND, n = 6) or a high-fat diet. At 16 weeks, after confirming the degree of glucose intolerance, high-fat diet-fed rats were randomly subdivided into three groups (n = 6/group): untreated group (HF), treated with dapagliflozin 1 mg/kg/day (HFSG) and treated with metformin 30 mg/kg/day (HFM). The treatment was continued for 4 weeks. We observed that dapagliflozin or metformin mitigated the enhanced expression of renal gluconeogenic enzymes, PEPCK, G6Pase and FBPase, as well as improved glucose tolerance and renal function in obese rats. Dapagliflozin downregulated the elevated expression of gluconeogenic transcription factors p-GSK3ß, p-CREB and coactivator PGC1α in the renal cortical tissue. Metformin reduced the expression levels of renal cortical FOXO1 and CREB. Furthermore, reduced renal insulin signaling was improved and renal oxidative stress was attenuated by either dapagliflozin or metformin treatment in obese rats. We concluded that glucose tolerance was improved by dapagliflozin in obese prediabetic rats by suppressing renal glucose release from not only glucose reabsorption but also renal gluconeogenesis through improving renal cortical insulin signaling and oxidative stress. The efficacy of dapagliflozin in improving renal insulin signaling, oxidative stress and renal function was greater than that of metformin.

Renal Lipid Metabolism and Lipotoxicity in Diabetes.

The pathogenesis of diabetic kidney disease is a complex process caused by both glucotoxicity and lipotoxicity due to lipid accumulation. In cases of diabetic animals, lipid deposition is found in both tubular and glomerular portions of the kidneys, which are the major sites of diabetic nephropathy lesions. The aim of this review was to provide insights into the mechanisms that lead to the development of renal lipid accumulation and the effects of renal lipotoxicity in the diabetic condition. An increased number of lipogenic genes and a decreased number of lipid oxidation genes are also detected in diabetic kidneys, both of which lead to lipid accumulation. The induction of oxidative stress, inflammation, fibrosis and apoptosis caused by lipid accumulation and lipid metabolites is called lipotoxicity. Renal lipotoxicity due to derangement in lipid metabolism may be a pathogenic mechanism leading to diabetic nephropathy and renal dysfunction.

Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats.

BACKGROUND: With an increasing prevalence of obesity and metabolic syndrome, exploring the effects and delineating the mechanisms of possible therapeutic agents are of critical importance. We examined the effects of SGLT2 inhibitor-dapagliflozin on insulin resistance, hepatic gluconeogenesis, hepatic injury and pancreatic ER stress in high-fat diet-induced obese rats. MATERIALS AND METHODS: Male Wistar rats were fed with normal diet (ND) or high-fat diet for 16 weeks. Then high-fat rats were given vehicle (HF) or dapagliflozin (1 mg/kg/day; HFDapa) or metformin (30 mg/kg/day; HFMet) for another 4 weeks. RESULTS: We found that dapagliflozin ameliorated high-fat diet-induced insulin resistance. The fasting plasma glucose level was comparable among groups, although dapagliflozin treatment led to substantial glycosuria. Hepatic gluconeogenic enzymes, PEPCK, G6Pase and FBPase, expression was not different in HF rats compared with ND rats. Meanwhile, dapagliflozin-treated group exhibited the elevation of these enzymes in parallel with the rise of transcription factor CREB, co-factor PGC1α and upstream regulator SIRT1. Hepatic oxidative stress, inflammation and NAFLD activity score as well as hepatic and pancreatic ER stress and apoptosis in obese rats were attenuated by dapagliflozin. CONCLUSION: We conclude that dapagliflozin improved obesity-related insulin resistance, hepatic and pancreatic injury independent of fasting plasma glucose level. Of note, dapagliflozin-induced glycosuria apparently triggered the up-regulation of hepatic gluconeogenic enzymes to prevent hypoglycemia.

Lipid-lowering effects of Coffea arabica pulp aqueous extract in Caco-2 cells and hypercholesterolemic rats.

BACKGROUND: Coffea arabica pulp (CP) is the first by-product obtained from coffee berries during coffee processing. The major constituents of CP, including chlorogenic acid, caffeine, and epicatechin exhibit anti-hyperlipidemic effects in in vitro and in vivo models. Whether Coffea arabica pulp aqueous extract (CPE) has a lipid-lowering effect remains unknown. PURPOSE: This study examined the effect of CPE on cholesterol absorption, and identified the mechanisms involved in lowered cholesterol in in vitro and in vivo models. METHODS: Uptake of [3H]-cholesterol micelles and the mode of CPE inhibition were determined using human intestinal Caco-2 cells, and subsequently, confirmed using isolated rat jejunal loops. In addition, the 12-week high-fat diet-induced hypercholesterolemic rats (HF) received either CPE (1000  mg/kg BW), a sole and high dose which was selected because it contained approximately 12  mg of CGA that was previously shown to have lipid-lowering effects, or ezetimibe (10  mg/kg BW), a cholesterol inhibitor. The rats were divided into HF, HF  ++ CPE, and HF  ++ ezetimibe groups for the next 12 weeks. Normal rats received a normal diet (ND) and CPE (ND  +  CPE). Body weights and lipid profiles were evaluated. Cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), protein expression and liver X receptor alpha (LXRα) mRNA expression were determined. In vitro micellar complex properties were also investigated. RESULTS: CPE inhibited [3H]-cholesterol micelle transport in Caco-2 cells and rat jejunal loops in a dose-dependent, non-competitive manner partly by decreasing membrane NPC1L1 expression. Congruently, CPE and its major constituents activated LXRα which, in turn, down-regulated NPC1L1. Furthermore, CPE interfered with physicochemical characteristics of cholesterol mixed micelles. These data were consistent with decreased body weight and slowed body weight gain and improved lipid profiles by CPE in hypercholesterolemic rats while no change occurred in these parameters in normal rats. Down-regulated intestinal NPC1L1 expression mediated by increased LXRα mRNA were also observed in HF  ++ CPE and ND  +  CPE rats. CONCLUSION: CPE has a cholesterol-lowering effect in in vitro and in vivo via inhibition of intestinal cholesterol absorption by down-regulating NPC1L1 mediated LXRα activation and interfering with micellar complex formation. Accordingly, CPE could be developed as nutraceutical product to prevent dyslipidemia-induced obesity and insulin resistance.

Molecular signaling mechanisms of renal gluconeogenesis in nondiabetic and diabetic conditions.

The kidneys are as involved as the liver in gluconeogenesis which can significantly contribute to hyperglycemia in the diabetic condition. Substantial evidence has demonstrated the overexpression of rate-limiting gluconeogenic enzymes, especially phosphoenolpyruvate carboxykinase and glucose 6 phosphatase, and the accelerated glucose release both in the isolated proximal tubular cells and in the kidneys of diabetic animal models and diabetic patients. The aim of this review is to provide an insight into the mechanisms that accelerate renal gluconeogenesis in the diabetic conditions and the therapeutic approaches that could affect this process in the kidney. Increase in gluconeogenic substrates, reduced insulin concentration or insulin resistance, downregulation of insulin receptors and insulin signaling, oxidative stress, and inappropriate activation of the renin-angiotensin system are likely to participate in enhancing renal gluconeogenesis in the diabetic milieu. Several studies have suggested that controlling glucose metabolism at the renal level favors effective overall glycemic control in both type 1 and type 2 diabetes. Therefore, renal gluconeogenesis may be a promising target for effective glycemic control as a therapeutic strategy in diabetes.

Probiotic Lactobacillus paracasei HII01 protects rats against obese-insulin resistance-induced kidney injury and impaired renal organic anion transporter 3 function.

The relationship between gut dysbiosis and obesity is currently acknowledged to be a health topic which causes low-grade systemic inflammation and insulin resistance and may damage the kidney. Organic anion transporter 3 (Oat3) has been shown as a transporter responsible for renal handling of gut microbiota products which are involved in the progression of metabolic disorder. The present study investigated the effect of probiotic supplementation on kidney function, renal Oat3 function, inflammation, endoplasmic reticulum (ER) stress, and apoptosis in obese, insulin-resistant rats. After 12 weeks of being provided with either a normal or a high-fat diet (HF), rats were divided into normal diet (ND); ND treated with probiotics (NDL); HF; and HF treated with probiotic (HFL). Lactobacillus paracasei HII01 1 × 108 colony forming unit (CFU)/ml was administered to the rats daily by oral gavage for 12 weeks. Obese rats showed significant increases in serum lipopolysaccharide (LPS), plasma lipid profiles, and insulin resistance. Renal Oat 3 function was decreased along with kidney dysfunction in HF-fed rats. Obese rats also demonstrated the increases in inflammation, ER stress, apoptosis, and gluconeogenesis in the kidneys. These alterations were improved by Lactobacillus paracasei HII01 treatment. In conclusion, probiotic supplementation alleviated kidney inflammation, ER stress, and apoptosis, leading to improved kidney function and renal Oat3 function in obese rats. These benefits involve the attenuation of hyperlipidemia, systemic inflammation, and insulin resistance. The present study also suggested the idea of remote sensing and signaling system between gut and kidney by which probiotic might facilitate renal handling of gut microbiota products through the improvement of Oat3 function.

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats.

AIM: To evaluate the renoprotective roles of dapagliflozin in prediabetic rats in order to elucidate the effects of this sodium-glucose co-transporter-2 (SGLT2) inhibitor on the renal complications associated with metabolic dysfunction in diet-induced obesity. METHODS: Obesity was induced by feeding a high-fat diet (HFD) to male Wistar rats for 16 weeks. HFD-fed rats were treated with dapagliflozin (1 mg/kg/d) or metformin (30 mg/kg/d) by oral gavage for 4 weeks after insulin resistance had been established. The metabolic characteristics and renal function associated with lipid accumulation, inflammation, fibrosis, endoplasmic reticulum (ER) stress and apoptosis in the renal tissue were examined. RESULTS: The results showed that HFD-fed rats developed both obesity and impaired renal function, along with increased renal triglyceride accumulation. Importantly, dapagliflozin had greater efficacy in improving renal function and reducing both body weight and visceral fat accumulation than metformin treatment. Dapagliflozin and metformin were found to have similar effects regarding the suppression of renal triglycerides, superoxide dismutase (SOD) expression and malondialdehyde (MDA) levels, subsequently leading to a decrease in renal inflammation and fibrosis. Renal ER stress and apoptosis were increased in HFD-fed rats and were effectively reduced after administration of dapagliflozin. The expression of renal SGLT2 was not affected by administration of dapagliflozin or metformin. CONCLUSION: Collectively, these findings indicate that dapagliflozin exerts renoprotective effects by alleviating obesity-induced renal inflammation, fibrosis, ER stress, apoptosis and lipid accumulation in the prediabetic condition.

Lactobacillus paracasei HII01, xylooligosaccharides, and synbiotics reduce gut disturbance in obese rats.

OBJECTIVES: The beneficial effects of pro-, pre-, and synbiotics on obesity with insulin resistance have been reported previously. However, the strain-specific effect of probiotics and the combination with various types of prebiotic fiber yield controversial outcomes and limit clinical applications. Our previous study demonstrated that the probiotic Lactobacillus paracasei (L. paracasei) HII01, prebiotic xylooligosaccharide (XOS), and synbiotics share similar efficacy in attenuating cardiac mitochondrial dysfunction in obese-insulin resistant rats. Nonetheless, the roles of HII01 and XOS on gut dysbiosis and gut inflammation under obese-insulin resistant conditions have not yet, to our knowledge, been investigated. Our hypothesis was that pro-, pre-, and synbiotics improve the metabolic parameters in obese-insulin resistant rats by reducing gut dysbiosis and gut inflammation. METHODS: Male Wistar rats were fed with either a normal or high-fat diet that contained 19.77% and 59.28% energy from fat, respectively, for 12 wk. Then, the high-fat diet rats were fed daily with a 108 colony forming unit of the probiotic HII01, 10% prebiotic XOS, and synbiotics for 12 wk. The metabolic parameters, serum lipopolysaccharide levels, fecal Firmicutes/Bacteroidetes ratios, levels of Enterobacteriaceae, Bifidobacteria, and gut proinflammatory cytokine gene expression were quantified. RESULTS: The consumption of probiotic L. paracasei HII01, prebiotic XOS, and synbiotics for 12 wk led to a decrease in metabolic endotoxemia, gut dysbiosis (a reduction in the Firmicutes/Bacteroidetes ratio and Enterobacteriaceae), and gut inflammation in obese-insulin resistant rats. CONCLUSIONS: Pro-, pre-, and synbiotics reduced gut dysbiosis and gut inflammation, which lead to improvements in metabolic dysfunction in obese-insulin resistant rats.

Renal outcomes with sodium glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, in obese insulin-resistant model.

A growing body of evidence indicates that obesity and insulin resistance contribute to the progression of renal disease. This study was performed to determine the effects of dapagliflozin, a novel sodium glucose cotransporter 2 (SGLT2) inhibitor, on renal and renal organic anion transporter 3 (Oat3) functions in high-fat diet fed rats, a model of obese insulin-resistance. Twenty-four male Wistar rats were divided into two groups, and received either a normal diet (ND) (n = 6) or a high-fat diet (HFD) (n = 18) for 16 weeks. At week 17, the HFD-fed rats were subdivided into three subgroups (n = 6/subgroup) and received either a vehicle (HFD), dapagliflozin (HFDAP; 1.0 mg/kg/day) or metformin (HFMET; 30 mg/kg/day), by oral gavage for four weeks. Metabolic parameters, renal function, renal Oat3 function, renal oxidative stress, and renal morphology were determined. The results showed that obese insulin-resistant rats induced by HFD feeding had impaired renal function and renal Oat3 function together with increased renal oxidative injury. Dapagliflozin or metformin treatment decreased insulin resistance, hypercholesterolemia, creatinine clearance and renal oxidative stress leading to improved renal function. However, dapagliflozin treatment decreased blood pressure, serum creatinine, urinary microalbumin and increased glucose excretions, and showed a greater ability to ameliorate impaired renal insulin signaling and glomerular barrier damage than metformin. These data suggest that dapagliflozin had greater efficacy than metformin for attenuating renal dysfunction and improving renal Oat3 function, at least in part by reducing renal oxidative stress and modulating renal insulin signaling pathways, and hence ameliorating renal injury.

Prebiotic prevents impaired kidney and renal Oat3 functions in obese rats.

Obesity is health issue worldwide, which can lead to kidney dysfunction. Prebiotics are non-digestible foods that have beneficial effects on health. This study aimed to investigate the effects of xylooligosaccharide (XOS) on renal function, renal organic anion transporter 3 (Oat3) and the mechanisms involved. High-fat diet was provided for 12 weeks in male Wistar rats. After that, the rats were divided into normal diet (ND); normal diet treated with XOS (NDX); high-fat diet (HF) and high-fat diet treated with XOS (HFX). XOS was given daily at a dose of 1000 mg for 12 weeks. At week 24, HF rats showed a significant increase in obesity and insulin resistance associated with podocyte injury, increased microalbuminuria, decreased creatinine clearance and impaired Oat3 function. These alterations were improved by XOS supplementation. Renal MDA level and the expression of AT1R, NOX4, p67phox, 4-HNE, phosphorylated PKCα and ERK1/2 were significantly decreased after XOS treatment. In addition, Nrf2-Keap1 pathway, SOD2 and GCLC expression as well as renal apoptosis were also significantly reduced by XOS. These data suggest that XOS could indirectly restore renal function and Oat3 function via the reduction of oxidative stress and apoptosis through the modulating of AT1R-PKCα-NOXs activation in obese insulin-resistant rats. These attenuations were instigated by the improvement of obesity, hyperlipidemia and insulin resistance.

Atorvastatin and insulin equally mitigate brain pathology in diabetic rats.

Although insulin and atorvastatin have been shown to exert glycemic control and could improve brain function, the effects of atorvastatin or insulin as well as the combination of atorvastatin plus insulin on brain pathology in diabetes mellitus type 1 (T1DM) are unclear. Therefore, this study investigated the effect of atorvastatin, insulin or combined drugs on brain pathology in streptozotocin-induced diabetic rats. Thirty-six male rats were divided into two groups, a control group (n = 12) and a diabetic or experimental group (n = 24). Diabetic rats were further divided into four groups (n = 6/group) and the groups received either a vehicle (normal saline), atorvastatin (10 mg/kg/day), insulin (4 U/day) or a combination of the drugs for 4 weeks. The control group rats were divided into two groups (n = 6/group) to receive either just the vehicle or atorvastatin for 4 weeks. We found that streptozotocin-induced diabetic rats developed hyperglycemia, showing evidence of increased brain oxidative stress, impaired brain mitochondrial function, increased brain apoptosis, increased tau protein expression, increased phosphorylation of tau protein expression and amyloid beta levels, and decreased dendritic spine density. Although atorvastatin and insulin therapies led to an equal reduction in plasma glucose level in these diabetic rats, the combined drug therapy showed the greatest efficacy in decreasing plasma glucose level. Interestingly, atorvastatin, insulin and the combined drugs equally mitigated brain pathology. Our findings indicate that the combined drug therapy showed the greatest efficacy in improving metabolic parameters. However, atorvastatin, insulin and the combined drug therapy shared a similar efficacy in preventing brain damage in T1DM rats.

Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats.

BACKGROUND: Chronic high-fat diet (HFD) consumption caused not only obese-insulin resistance, but also cognitive decline and microglial hyperactivity. Modified gut microbiota by prebiotics and probiotics improved obese-insulin resistance. However, the effects of prebiotics, probiotics, and synbiotics on cognition and microglial activity in an obese-insulin resistant condition have not yet been investigated. We aimed to evaluate the effect of prebiotic (Xyloolidosaccharide), probiotic (Lactobacillus paracasei HII01), or synbiotics in male obese-insulin resistant rats induced by a HFD. METHODS: Male Wistar rats were fed with either a normal diet or a HFD for 12 weeks. At week 13, the rats in each dietary group were randomly divided into four subgroups including vehicle group, prebiotics group, probiotics group, and synbiotics group. Rats received their assigned intervention for an additional 12 weeks. At the end of experimental protocol, the cognitive functioning of each rat was investigated; blood and brain samples were collected to determine metabolic parameters and investigate brain pathology. RESULTS: We found that chronic HFD consumption leads to gut and systemic inflammation and impaired peripheral insulin sensitivity, which were improved by all treatments. Prebiotics, probiotics, or synbiotics also improved hippocampal plasticity and attenuated brain mitochondrial dysfunction in HFD-fed rats. Interestingly, hippocampal oxidative stress and apoptosis were significantly decreased in HFD-fed rats with all therapies, which also decreased microglial activation, leading to restored cognitive function. CONCLUSIONS: These findings suggest that consumption of prebiotics, probiotics, and synbiotics restored cognition in obese-insulin resistant subjects through gut-brain axis, leading to improved hippocampal plasticity, brain mitochondrial function, and decreased microglial activation.

Diacerein alleviates kidney injury through attenuating inflammation and oxidative stress in obese insulin-resistant rats.

A link between inflammation with obesity and metabolic syndrome has been found in patients with chronic kidney disease (CKD). Diacerein is an anthraquinone used to treat osteoarthritis that exerts anti-inflammatory action by inhibiting the synthesis and activity of proinflammatory cytokines. This study aimed to investigate the protective effect of diacerein on renal function and renal organic anion transporter 3 (Oat3) function in obese insulin-resistant condition. Obese insulin-resistant rats were induced by feeding a high-fat diet in male Wistar rats for 16 weeks. Diacerein or metformin (positive control) (30mg/kg/day) was administered orally for 4 weeks after insulin resistance had been confirmed. Obese insulin-resistant rats showed an impaired renal function as indicated by the increased serum creatinine and microalbuminuria along with the decreased renal Oat3 function and expression. Importantly, diacerein treatment not only improved insulin resistance but also restored renal function. The decreased renal malondialdehyde level, expressions of PKCα, angiotensin 1 receptor (AT1R), Nrf2, and HO-1, and increased expression of SOD2 were observed in diacerein treatment group, indicating the attenuation of renal oxidative stress condition. Moreover, renal inflammation and renal damage were also alleviated in diacerein-treated rats. Our results demonstrated for the first time that diacerein was effective to improve renal function and renal Oat3 function in obese insulin-resistance condition mediated by suppressing renal oxidative stress and inflammation. These findings suggest that anti-inflammatory agents can be used therapeutically to improve metabolic disorder and prevent organ dysfunctions in pre-diabetic condition.

Chronic treatment with prebiotics, probiotics and synbiotics attenuated cardiac dysfunction by improving cardiac mitochondrial dysfunction in male obese insulin-resistant rats.

PURPOSE: In metabolic syndrome, the composition of gut microbiota has been disrupted, and is associated with left ventricular (LV) dysfunction. Several types of prebiotics, probiotics, and synbiotics have been shown to exert cardioprotection by restoring gut microbiota from dysbiosis and reducing systemic inflammation. However, the effects of prebiotics such as xylooligosaccharides (XOS); probiotics such as Lactobacillus paracasei STII01 HP4, and synbiotics on metabolic and LV function in obese insulin-resistant rats have not been investigated. In this study, we hypothesized that prebiotics and probiotics improve metabolic parameters, heart rate variability (HRV), blood pressure (BP), and LV function by attenuating cardiac mitochondrial dysfunction, systemic inflammation, and oxidative stress, and that synbiotics provide greater efficacy than a single regimen in obese insulin resistance. METHODS: Rats were fed with either normal diet or high-fat diet (HFD) for 12 weeks and then rats in each dietary group were randomly subdivided into four subgroups to receive either a vehicle, prebiotics, probiotics, or synbiotics for another 12 weeks. Metabolic parameters, BP, HRV, LV function, cardiac mitochondrial function, systemic inflammation, and oxidative stress were determined. RESULTS: HFD-fed rats had obese insulin resistance with markedly increased systemic inflammatory marker [Serum LPS; ND; 0.6 ± 0.1 EU/ml vs. HFD; 5.7 ± 1.2 EU/ml (p < 0.05)], depressed HRV, and increased BP and LV dysfunction [%ejection fraction; ND; 93 ± 2% vs. HFD; 83 ± 2% (p < 0.05)]. Prebiotics, probiotics, and synbiotics attenuated insulin resistance by improving insulin sensitivity and lipid profiles. All interventions also improved HRV, BP, LV function [%ejection fraction; HFV; 81 ± 2% vs. HFPE; 93 ± 3%, HFPO; 92 ± 1%, HFC; 92 ± 2% (p < 0.05)] by attenuating mitochondrial dysfunction, oxidative stress, and systemic inflammation in obese insulin-resistant rats. CONCLUSION: Prebiotics, probiotics, and synbiotics shared similar efficacy in reducing insulin resistance and LV dysfunction in obese insulin-resistant rats.

The additive effects of atorvastatin and insulin on renal function and renal organic anion transporter 3 function in diabetic rats.

Hyperglycemia-induced oxidative stress is usually found in diabetic condition. 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, statins, are widely used as cholesterol-lowering medication with several "pleiotropic" effects in diabetic patients. This study aims to evaluate whether the protective effects of atorvastatin and insulin on renal function and renal organic anion transporter 3 (Oat3) function involve the modulation of oxidative stress and pancreatic function in type 1 diabetic rats. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin (50 mg/kg BW). Atorvastatin and insulin as single or combined treatment were given for 4 weeks after diabetic condition had been confirmed. Diabetic rats demonstrated renal function and renal Oat3 function impairment with an increased MDA level and decreased SOD protein expression concomitant with stimulation of renal Nrf2 and HO-1 protein expression. Insulin plus atorvastatin (combined) treatment effectively restored renal function as well as renal Oat3 function which correlated with the decrease in hyperglycemia and oxidative stress. Moreover, pancreatic inflammation and apoptosis in diabetic rats were ameliorated by the combined drugs treatment. Therefore, atorvastatin plus insulin seems to exert the additive effect in improving renal functionby alleviating hyperglycemiaand the modulation of oxidative stress, inflammation and apoptosis.

The roles of sodium-glucose cotransporter 2 inhibitors in preventing kidney injury in diabetes.

Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) worldwide. The early effective treatment of high plasma glucose could delay or prevent the onset of DN. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are new target treatments for ameliorating high plasma glucose and help to maintain glucose homeostasis in diabetic patients. Reduced renal glucose reabsorption by SGLT2 inhibition seems to have high potential to improve glycemic control in diabetes mellitus (DM) not only through glucose lowering but also through glucose-independent effects such as blood pressure-lowering and direct renal effects in diabetes. Of note, the important events in the pathogenesis of glucose-induced renal injury and DN including oxidative stress, inflammation, fibrosis and apoptosis conditions have shown to be ameliorate after the treatment with SGLT2 inhibitors. Interestingly, SGLT2 inhibitors have been reported to reduce albuminuria in DM via an activation of renal tubuloglomerular feedback by increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction and attenuated diabetes-induced renal hyperfiltration. These effects also help to conserve glomerular integrity. Thus, the treatment of diabetes mellitus using SGLT2 inhibitors could be one of the effective approach for the management of diabetic-associated kidney disease like DN. This review summarizes the up to date information and discusses the bidirectional relationship between the SGLT2 inhibitor treatments and the renal functions that are available from both basic research and clinical reports. The details of renal outcomes of SGLT2 inhibitors in DN are also provide in this review.

Anthocyanin-rich Riceberry bran extract attenuates gentamicin-induced hepatotoxicity by reducing oxidative stress, inflammation and apoptosis in rats.

Liver plays an important role in the detoxification and metabolic elimination of various drugs and harmful substances. The damaging effects on the liver tissue treated with gentamicin are multi-factorial and their mechanisms remain unclear. This study aimed to investigate the possible protective effects of anthocyanin-rich Riceberry bran extract on gentamicin-induced hepatotoxicity in rats. Riceberry bran extract was given by oral administration 30min before gentamicin injection for 15 consecutive days. Serum levels of liver marker enzymes, AST and ALT, were significantly elevated and the total serum protein level was markedly reduced in gentamicin-treated rats. Gentamicin injection led to the significant increase in hepatic MDA level and decrease SOD expression. Liver inflammation and apoptosis were observed in gentamicin-treated rats as indicated by the increases in NF-κB, TNF-αR1, COX2, and iNOS, caspase-3, Bax, and decrease in Bcl-XL expressions. Riceberry bran extract significantly prevented gentamicin-induced the elevations of serum AST, ALT and the reduction of serum total protein. These were related to the inhibition of oxidative stress, inflammation and apoptosis in Riceberry bran extract treatment. These findings suggest that anthocyanin-rich Riceberry bran extract can prevent liver dysfunction and damage induced by gentamicin, possibly through its antioxidant, anti-inflammatory and anti-apoptotic effects.

Role of Gastrointestinal Microbiota on Kidney Injury and the Obese Condition.

Obesity is associated with kidney disease, probably due to obesity-mediated inflammation, podocyte injury and oxidative stress in the kidney It is also linked to other diseases, for example, diabetes and hypertension, which are associated with the development and progression of chronic kidney disease. Interestingly, gastrointestinal dysbiosis has been demonstrated in cases of obesity with the development and progression of kidney disease. Thus, modification of gastrointestinal microbiota using probiotics or prebiotics or both to improve the balance of bacterial flora is a potential approach for the management of obesity-associated kidney disease. This review covers information regarding the association between obesity and kidney injury, and it examines evidence for a hypothesized role of gastrointestinal microbiota in this setting. Studies describing the effects of probiotic and prebiotic treatments on kidney disease show mixed results, although several suggest benefits indicated by biomarkers associated with kidney injury, uremia and inflammation. Additional studies are needed to determine whether these interventions are clinically effective in managing kidney injury and kidney disease.

The effect of exercise on skeletal muscle fibre type distribution in obesity: From cellular levels to clinical application.

Skeletal muscles play important roles in metabolism, energy expenditure, physical strength, and locomotive activity. Skeletal muscle fibre types in the body are heterogeneous. They can be classified as oxidative types and glycolytic types with oxidative-type are fatigue-resistant and use oxidative metabolism, while fibres with glycolytic-type are fatigue-sensitive and prefer glycolytic metabolism. Several studies demonstrated that an obese condition with abnormal metabolic parameters has been negatively correlated with the distribution of oxidative-type skeletal muscle fibres, but positively associated with that of glycolytic-type muscle fibres. However, some studies demonstrated otherwise. In addition, several studies demonstrated that an exercise training programme caused the redistribution of oxidative-type skeletal muscle fibres in obesity. In contrast, some studies showed inconsistent findings. Therefore, the present review comprehensively summarizes and discusses those consistent and inconsistent findings from clinical studies, regarding the association among the distribution of skeletal muscle fibre types, obese condition, and exercise training programmes. Furthermore, the possible underlying mechanisms and clinical application of the alterations in muscle fibre type following obesity are presented and discussed.