Keerati Wanchai

Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity.

Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.

Role of Gastrointestinal Microbiota on Kidney Injury and the Obese Condition

Abstract 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.

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.

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

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.

PREBIOTICS, PROBIOTICS OR SYNBIOTICS THERAPY RESTORES COGNITIVE DECLINE IN OBESE RATS

(Ph&M) maintain cognitive functions and protect against dementia but their role versus risk factors needs more attention. Epigallocatechin-3-gallate (EGCG) act as an antioxidant and anti-inflammatory against b-amyloid aggregation in hippocampus thus may exhibit neuroprotective effects. Vitamin E (VE), Vitamin C (VC) and Selenium (Se) are antioxidant and have ability to counteract free radicals that contribute to pathological process in AD. Methods: Four major groups of rats were daily received (for 5 weeks): Saline (for normal groups), 10% casein diet with SI (for SI&PM-model groups) or 70mg/kg of AlCl3 (IP) either alone (for AD-model groups) or with SI&PM (for AD-associated SI&PM model groups). Each of them was subdivided to 3 subgroups: One as control for each of them and 2 were exposed/week to Ph&M (Swimming and Y-maze tests) either alone or with combination of EGCG (10 mg/kg, IP), VC (400mg/kg, PO), VE (100mg/kg, PO) and Se (1 mg/kg, PO). Biochemical parameters (AChE, Ab, Tau, b-secretase, monoamins, oxidative stress and inflammatory markers) were measured in the brain as well as brain derived neurotrophic factor (BDNF), DNA fragmentation and histopathological changes in different brain regions. Results: Combination of EGCG, VE, VC and Se together with Ph&M showed higher protection than Ph&M alone against hazards of AlCl3 and/or SI&PM especially in AD-associated SI&PM group. Their protection was indicated by the increase in brain monoamins, SOD, TAC and BDNF together with the decrease in AChE, Ab, Tau, b-secretase, MDA, TNF-a, IL-1b, DNA fragmentation and confirmed by the histopathological examinations. Conclusions: Combination of EGCG with VE, VC and Se together with Ph&M have more pronounced protective effect against risk of SI and PM inducing progression of AD than Ph&M alone. Consequently, their use is advisable to enhance the power of Ph&M especially in elderly and with risk conditions.