Anxiolytic and antidepressant-like activities of aqueous extract of Azadirachta indica A. Juss. flower in the stressed rats.

The aim of this study was to evaluate whether an aqueous extract of Azadirachta indica A. Juss. (A. indica) flower had anxiolytic and antidepressant-like effects in the stressed rats. Male Wistar rats were randomly allocated to one of two experimental groups: control or stress. The stress groups were received restraint stress for 3 h. The stressed rats were administered a vehicle, diazepam, fluoxetine, and A. indica at doses of 250, 500, and 1000 mg/kg BW for 30 days. The elevated plus-maze test (EPMT), the forced swimming test (FST), and the open field test (OFT) were used to assess anxiolytic and antidepressant-like behaviors. In the EPMT, the percentage of the number of open arm entries and the duration spent in open arms were measured. These measurements were considerably enhanced in the stressed rats treated with diazepam and A. indica flower extract at a dose of 500 mg/kg BW. Furthermore, the stressed rats given fluoxetine and A. indica flower extract at all doses employed in this study showed a significant reduction in the amount of time the rats were immobilized in the FST. However, there was no significant difference in spontaneous locomotor activity between any of the groups. Additionally, the stressed rats treated with either positive control medications or A. indica flower extract exhibited significantly higher brain dopamine (DA) and serotonin (5-HT) levels, but lower blood cortisol levels as compared to the stressed rats treated with vehicle. Moreover, A. indica flower extract had no harmful effect on the stressed rats' liver tissue.

Effects of probiotics, prebiotics or synbiotics on jawbone in obese-insulin resistant rats.

PURPOSE: Chronic high-fat diet (HFD) consumption results in gut dysbiosis, systemic inflammation, obese-insulin resistance, and osteoporosis of the jawbones. The probiotics, prebiotics or synbiotics alleviated gut dysbiosis and the metabolic disturbance in HFD-induced obesity. However, the effects on jawbone properties have not been investigated. This study aimed to investigate the effects of probiotic Lactobacillus paracasei HII01, prebiotic xylooligosaccharide (XOS), and synbiotics on the jawbone properties along with metabolic parameters, gut and systemic inflammation in HFD-fed rats. METHODS: Forty-eight male Wistar rats were fed with either a HFD or normal diet for 12 weeks. Rats in each group were subdivided into four subgroups to be treated with either vehicle, probiotics, prebiotics, or synbiotics for the additional 12 weeks. Blood samples, gut, bone marrows, and jawbones were collected to determine metabolic parameters, inflammation, and bone properties. RESULTS: The HFD-fed rats developed obese-insulin resistance, as indicated by increased body weight, dyslipidemia and decreased insulin sensitivity. Serum lipopolysaccharide levels and interleukin-6 mRNA expression in the ileum and bone marrows were elevated. Altered bone metabolism and the impaired jawbone properties were evident as indicated by decreased bone mineral density with increased trabecular separation. Reduced ultimate load and stiffness were observed in HFD-fed rats. Treatments with probiotics, prebiotics or synbiotics in HFD-fed rats improved metabolic parameters and reduced inflammation. However, no alterations in jawbone properties were found in all treatments. CONCLUSION: The osteoporosis of the jawbone occurred in obese-insulin resistance, and treatments with probiotics, prebiotics and synbiotics were not sufficient to improve the jawbone properties.

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.

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.

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.

Estrogen attenuates AGTR1 expression to reduce pancreatic ß-cell death from high glucose.

Chronic exposure of pancreatic ß-cells to high glucose levels results in ß-cell dysfunction and death. These effects can be protected by estrogen. The local pancreatic renin-angiotensin system (RAS) has been shown as a novel pathological pathway of high-glucose-induced cell death. The effect of estrogen on pancreatic RAS is still unknown. This study examines whether estrogen protects against pancreatic ß-cell death caused by glucotoxicity via a decrease in the pancreatic ß-cell RAS pathway. When INS-1 cells were cultured in a high glucose medium, cell death was significantly higher than when the cells were cultured in a basal glucose medium; similarly, there were also higher levels of AGTR1 and p47 ph ° x mRNA, and protein expression. Moreover, the addition of 10-8 M 17ß-estradiol to INS-1 cells cultured in a high glucose medium markedly reduced cell death, AGTR1 and p47 ph ° x mRNA levels, and protein expression. Similar results were demonstrated in the pancreatic islets. The presence of 10-8 M 17ß-estradiol, losartan, or a combination of both, in a high glucose medium had similar levels of reduction of p47 ph ° x mRNA and protein expression, compared with those cultured in high glucose. Taken together, estrogen protected pancreatic ß-cells from high-glucose-induced cell death by reducing the AGTR1 pathway.

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.

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 (TGFß1), 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 TGFß1 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.