Cognitive decline, Aß pathology, and blood-brain barrier function in aged 5xFAD mice.

BACKGROUND: Patients with Alzheimer's disease (AD) develop blood-brain barrier dysfunction to varying degrees. How aging impacts Aß pathology, blood-brain barrier function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice to investigate changes in Aß levels, barrier function, and cognitive decline over time. METHODS: 5xFAD and wild-type (WT) mice were aged between 9.5 and 15.5 months and tested for spatial learning and reference memory with the Morris Water Maze (MWM). After behavior testing, mice were implanted with acute cranial windows and intravenously injected with fluorescent-labeled dextrans to assess their in vivo distribution in the brain by two-photon microscopy. Images were processed and segmented to obtain intravascular intensity, extravascular intensity, and vessel diameters as a measure of barrier integrity. Mice were sacrificed after in vivo imaging to isolate brain and plasma for measuring Aß levels. The effect of age and genotype were evaluated for each assay using generalized or cumulative-linked logistic mixed-level modeling and model selection by Akaike Information Criterion (AICc). Pairwise comparisons were used to identify outcome differences between the two groups. RESULTS: 5xFAD mice displayed spatial memory deficits compared to age-matched WT mice in the MWM assay, which worsened with age. Memory impairment was evident in 5xFAD mice by 2-threefold higher escape latencies, twofold greater cumulative distances until they reach the platform, and twice as frequent use of repetitive search strategies in the pool when compared with age-matched WT mice. Presence of the rd1 allele worsened MWM performance in 5xFAD mice at all ages but did not alter the rate of learning or probe trial outcomes. 9.5-month-old 15.5-month-old 5xFAD mice had twofold higher brain Aß40 and Aß42 levels (p < 0.001) and 2.5-fold higher (p = 0.007) plasma Aß40 levels compared to 9.5-month-old 5xFAD mice. Image analysis showed that vessel diameters and intra- and extravascular dextran intensities were not significantly different in 9.5- and 15.5-month-old 5xFAD mice compared to age-matched WT mice. CONCLUSION: 5xFAD mice continue to develop spatial memory deficits and increased Aß brain levels while aging. Given in vivo MP imaging limitations, further investigation with smaller molecular weight markers combined with advanced imaging techniques would be needed to reliably assess subtle differences in barrier integrity in aged mice.

Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway.

Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.

Resistant starch from black rice, Oryza sativa L. var. ameliorates renal inflammation, fibrosis and injury in insulin resistant rats.

It has recently been reported that black rice (BR) extract has anti-obesity, anti-diabetic, and anti-osteoporosis effects. It has been shown to reduce obese-related kidney dysfunction in animal models. This study aimed to investigate the effect of resistant starch from BR (RS) on renal inflammation, oxidative stress, and apoptosis in obese insulin resistant rats. Male Wistar rats were divided into six groups: normal diet (ND), ND treated with 150 mg of RS (NDRS150), high-fat (HF) diet, HF treated with 100 and 150 mg of RS (HFRS100), (HFRS150), and HF treated with metformin as a positive control. Insulin resistance was shown in the HF rats by glucose intolerance, increased insulin, total area under the curve of glucose and homeostasis model assessment of insulin resistance and dyslipidemia. The resulting metabolic disturbance in the HF rats caused renal inflammation, fibrosis and apoptosis progressing to kidney injury and dysfunction. Prebiotic RS including anthocyanin from BR at doses of 100 and 150 mg ameliorated insulin resistance, dyslipidemia and liver injury. Treatment with RS reduced TGF-ß fibrotic and apoptotic pathways by inhibition of NF-κB and inflammatory cytokines which potentially restore kidney damage and dysfunction. In conclusion, prebiotic RS from BR ameliorated obesity induced renal injury and dysfunction by attenuating inflammatory, fibrotic, and apoptotic pathways in insulin resistant rats induced by HF.

Noninvasive NMR/MRS Metabolic Parameters to Evaluate Metabolic Syndrome in Rats.

(1) Background: Ectopic fat deposition and its effects, metabolic syndrome, have been significantly correlated to lifestyle and caloric consumption. There is no specific noninvasive evaluation tool being used in order to establish clinical markers for tracing the metabolic pathway implicated in obesity-related abnormalities that occur in the body as a result of a high-fat diet (HFD). The purpose of this work is to investigate in vivo ectopic fat distribution and in vitro metabolite profiles given by HFDs, as well as how they are inter-related, in order to find surrogate metabolic biomarkers in the development of metabolic syndrome utilizing noninvasive approaches. (2) Methods: Male Wistar rats were divided into a standard normal chow diet, ND group, and HFD group. After 16 weeks of different diet administration, blood samples were collected for proton nuclear magnetic resonance (1H NMR) and biochemical analysis. Magnetic resonance imaging/proton magnetic resonance spectroscopy (MRI/1H MRS) was performed on the abdomen, liver, and psoas muscle of the rats. (3) Results: Visceral fat showed the strongest relationship with blood cholesterol. Although liver fat content (LFC) was not associated with any biophysical profiles, it had the highest correlation with metabolites such as (-CH2)n very-low-density lipoprotein/low-density lipoprotein (VLDL/LDL), lactate, and N-acetyl glycoprotein of serum 1H NMR. HFD showed no obvious influence on muscle fat accumulation. Acetoacetate, N-acetyl glycoprotein, lactate, (-CH2)n VLDL/LDL, and valine were the five possible metabolic biomarkers used to differentiate HFD from ND in the present study. (4) Conclusions: Our study has validated the influence of long-term HFD-induced ectopic fat on body metabolism as well as the metabolic profile deterioration both in vivo and in vitro.

Agomelatine, a structural analog of melatonin, improves kidney dysfunction through regulating the AMPK/mTOR signaling pathway to promote autophagy in obese rats.

This study aimed to investigate the renoprotective effect of agomelatine on kidney injury in an obese rat model and to understand the underlying mechanisms involving the AMPK-mTOR-autophagy signaling pathway. Male Wistar rats were fed either a normal (ND) or a high-fat diet (HF) for 16 weeks. The HF rats were divided into 4 groups: (1) HF control; (2) AGOM20 receiving agomelatine 20 mg. kg-1 day-1; (3) AGOM40 receiving agomelatine 40 mg. kg-1 day-1; and (4) NAC receiving N-acetylcysteine 100 mg. kg-1 day-1 by oral gavage for 4 weeks. HF rats demonstrated insulin resistance, impaired renal function and oxidative stress as evidenced by the elevation of MDA levels and expression of PKCα and NOX4. These alterations correlated with impaired autophagy, renal fibrosis and apoptosis. Agomelatine showed a greater efficacy than NAC treatment with regard to improving insulin resistance, dyslipidemia and renal dysfunction through alleviation of oxidative stress, fibrosis and apoptosis in kidney cells. Impaired autophagy was blunted after agomelatine or NAC administration, as demonstrated by the increased in Beclin-1, LC3B, Atg5, LAMP2, and AMPK, and decreased mTOR and CTSB expression. These data revealed that agomelatine protected against obesity-induced kidney injury via the regulation of ROS and AMPK-mTOR-autophagy signaling pathways.

Chitosan oligosaccharide mitigates kidney injury in prediabetic rats by improving intestinal barrier and renal autophagy.

Consumption of a high-fat diet (HFD) not only increases the risk of metabolic syndrome but also initiates kidney injury. Lipid accumulation-induced systemic low-grade inflammation is an upstream mechanism of kidney injury associated with prediabetes. Chitosan oligosaccharide (COS) provides potent anti-obesity effects through several mechanisms including fecal lipid excretion. In this study, we investigated the effects of COS on the prevention of obesity-related complications and its ability to confer renoprotection in a prediabetic model. Rats fed on a HFD developed obesity, glucose intolerance and kidney dysfunction. COS intervention successfully ameliorated these conditions (p < 0.05) by attenuating intestinal lipid absorption and the renal inflammation-autophagy-apoptosis axis. A novel anti-inflammatory effect of COS had been demonstrated by the strengthening of intestinal barrier integrity via calcium-sensing receptor (p < 0.05). The use of COS as a supplement may be useful in reducing prediabetic complications especially renal injury and the risk of type 2 diabetes.

The combination of dapagliflozin and statins ameliorates renal injury through attenuating the activation of inflammasome-mediated autophagy in insulin-resistant rats.

Long-term use of a high-fat diet with high-fructose (HFF) intake could promote insulin resistance and induce lipid accumulation leading to kidney injury possibly via impairment of the autophagy process and enhancement of the inflammasome pathway. We investigated whether dapagliflozin as a monotherapy or combined with atorvastatin could restore kidney autophagy impairment and reduce inflammasome activation associated with kidney injury induced by HFF consumption. Male Wistar rats were given an HFF for 16 weeks and then treated with dapagliflozin with or without atorvastatin for 4 weeks. Impaired glucose tolerance, dyslipidemia, renal lipid accumulation along with impaired renal autophagy and activated inflammasome pathway promoted renal injury were exhibited in HFF rats. Dapagliflozin with or without atorvastatin treatment could partially restore disrupted metabolic parameters and reduce kidney injury. In particular, the combination treatment group showed significant amelioration of inflammasome activation and autophagy impairment. In conclusion, the combination therapy of dapagliflozin and atorvastatin has a positive effect on renal injury associated with autophagy and inflammasome activation induced by HFF in insulin-resistant rats. This study is the first report demonstrating the underlying mechanism associated with a combination treatment of dapagliflozin and atorvastatin on autophagy and inflammasome pathways in an insulin-resistant condition. Therefore, dapagliflozin in combination with atorvastatin may be a further preventive or therapeutic strategy for chronic kidney disease in an insulin-resistant or diabetic condition.

Anthocyanin-rich fraction from black rice, Oryza sativa L. var. indica "Luem Pua," bran extract attenuates kidney injury induced by high-fat diet involving oxidative stress and apoptosis in obese rats.

Obesity is acknowledged as being a world health problem and increases the risk of several chronic diseases including chronic kidney disease. High-fat diet consumption and obesity-related renal disease show a close correlation with increased oxidative stress. Black rice bran extract, (BRE) Oryza sativa L. variety "Luem Pua" contains a high anthocyanin content. This study evaluated the effects of an anthocyanin-rich fraction from BRE on renal function and oxidative stress in obese rats. Male Wistar rats were fed a normal diet (ND) or high-fat diet (HF) for 16 weeks. After this, the rats were given either vehicle (HF), BRE 100 (HF100) or BRE 200 mg/kg/day (HF200) orally for 8 weeks. The HF rats had increased body weight, visceral fat weight, plasma glucose, cholesterol and triglycerides. These parameters were normalized following HF100 administration and showed a decreasing trend with HF200. Serum creatinine and renal cortical MDA were increased in the HF group but these effects were attenuated by BRE. Negative kidney injury and histopathology changes were observed following a HF, but treatment with BRE reversed these deleterious effects. These results suggest that BRE could be used as a food supplement to improve metabolic disturbance and prevent kidney dysfunction in cases of obesity.

Agomelatine protects against obesity-induced renal injury by inhibiting endoplasmic reticulum stress/apoptosis pathway in rats.

Obesity is recognized as a risk for the development of chronic kidney disease. Excessive fat accumulation in obesity is associated with the overproduction of reactive oxygen species with the underproduction of antioxidant mechanisms generating oxidative stress together with chronic low-grade inflammation which subsequently leads to the development of several obesity-related complications. It has been suggested that the abnormal lipid accumulation can induce endoplasmic reticulum (ER) stress and cellular apoptosis in several tissue types. Agomelatine is a relatively new antidepressant which is a synthetic agonist of melatonin. Previous study reported the antioxidant and anti-inflammatory effects of agomelatine. In this study, we investigated the therapeutic effects of agomelatine in obesity-related renal injury. Male Wistar rats were fed with normal diet or high-fat diet (HF) for 16 weeks. After that, vehicle or agomelatine or vildagliptin was orally administered to HF rats for 4 weeks. Our results indicated that HF rats demonstrated insulin resistance which was accompanied by an impairment of renal function and renal organic anion transporter 3 (Oat3) function as well as renal oxidative stress, ER stress, and apoptosis. Interestingly, agomelatine treatment not only improved the metabolic parameters, renal function and renal Oat3 function but also attenuated renal oxidative stress, ER stress and subsequent apoptosis. Therefore, agomelatine exerted renoprotective effects in obese insulin-resistant condition. These results suggested that agomelatine could be used as a drug to improve metabolic disturbance and prevent kidney dysfunction in obese condition.

Dapagliflozin ameliorates pancreatic injury and activates kidney autophagy by modulating the AMPK/mTOR signaling pathway in obese rats.

Chronic consumption of a high-fat diet induces obesity and impairs the ultra-structure of organs and tissues. We examined the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor-dapagliflozin on renal and pancreatic injuries in obese condition. Rats were fed a high-fat diet for 16 weeks to induce obesity. After that, dapagliflozin or vildagliptin, 1.0 or 3.0 mg/kg/day, respectively, was administered by oral gavage for 4 weeks. The effects of dapagliflozin on insulin resistance, kidney autophagy, pancreatic oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis in high-fat diet-induced obese rats were elucidated. High-fat-diet fed rats demonstrated metabolic abnormalities including increased body weight, visceral fat weight, plasma insulin, plasma cholesterol, homeostasis model assessment (HOMA) index, and TAUCg, indicating the obese-insulin resistant and glucose intolerance conditions. Also, high-fat-diet fed rats exhibited significant pancreatic injury accompanied by decreased kidney autophagy. Dapagliflozin or vildagliptin treatment for 4 weeks ameliorated pancreatic oxidative stress, ER stress, inflammation, and apoptosis and restored kidney autophagy in obese rats. Moreover, the morphology changes of the pancreas and kidney were improved in the treated groups. Interestingly, dapagliflozin showed higher efficacy than vildagliptin in improving body weight, visceral fat weight, plasma cholesterol level, and pancreatic oxidative stress in our model. Taken together, the present study demonstrated that the therapeutic effects of dapagliflozin attenuated pancreatic injury, pancreatic oxidative stress, ER stress, inflammation, apoptosis, and exerted renoprotective effects by restoring autophagic signaling in obese rats.

The roles of melatonin on kidney injury in obese and diabetic conditions.

Obesity is a common and complex health problem worldwide and can induce the development of Type 2 diabetes. Chronic kidney disease (CKD) is a complication occurring as a result of obesity and diabetic conditions that lead to an increased mortality rate. There are several mechanisms and pathways contributing to kidney injury in obese and diabetic conditions. The expansion of adipocytes triggers proinflammatory cytokines release into blood circulation and bind with the receptors at the cell membranes of renal tissues leading to kidney injury. Obesity-mediated inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction are the important causes and progression of CKD. Melatonin (N-acetyl-5-methoxytryptamine) is a neuronal hormone that is synthesized by the pineal gland and plays an essential role in regulating several physiological functions in the human body. Moreover, melatonin has pleiotropic effects such as antioxidant, anti-inflammation, antiapoptosis. In this review, the relationship between obesity, diabetic condition, and kidney injury and the renoprotective effect of melatonin in obese and diabetic conditions from in vitro and in vivo studies have been summarized and discussed.

Pinocembrin attenuates gentamicin-induced nephrotoxicity in rats.

Oxidative stress mediated apoptosis of renal tubular cells is a major pathology of gentamicin-induced nephrotoxicity, which is one of the prevailing causes of acute renal failure. Pinocembrin is a major flavonoid found in rhizomes of fingerroot (Boesenbergia pandurata). It has pharmacological and biological activities including antimicrobial, anti-inflammatory, and antioxidant effects. Preclinical studies have suggested that pinocembrin protects rat brain and heart against oxidation and apoptosis induced by ischemia-reperfusion. The aim of the current study was to investigate the mechanisms of renoprotection elicited by pinocembrin in gentamicin-induced nephrotoxicity. Nephrotoxicity was induced in rats by intraperitoneal injection (i.p.) of gentamicin, and pinocembrin was administered via i.p. 30 min before gentamicin treatment for 10 days. Gentamicin-induced nephrotoxicity was indicated by the reduced renal function and renal Oat3 function and expression. Gentamicin treatment also stimulated Nrf2, HO-1, and NQO1, as well as the pro-apoptotic proteins Bax and caspase-3, concomitant with the attenuation of Bcl-XL expression in the renal cortical tissues. Pinocembrin pretreatment improved renal function and renal Oat3 function and reduced oxidative stress and apoptotic conditions. These findings indicate that pinocembrin has a protective effect against gentamicin-induced nephrotoxicity, which may be due in part to its antioxidant and anti-apoptotic effects, subsequently leading to improved renal function.

Atorvastatin improves renal organic anion transporter 3 and renal function in gentamicin-induced nephrotoxicity in rats.

What is the central question of this study? This study was designed to determine the renoprotective effects of atorvastatin treatment in an experimental model of gentamicin-induced nephrotoxicity through modulating the Nrf2 pathway by decreasing the oxidative stress. What is the main finding and its importance? Atorvastatin exerts a nephroprotective effect by attenuating oxidative stress, protecting renal function and renal organic anion transporter 3 function from the effects of gentamicin. Atorvastatin might protect the tissues via its antioxidant property and by modulating the antioxidant enzymes through the Nrf2 signalling pathway, which may be the underlying mechanisms of these protective effects. Recent evidence demonstrates that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exert not only lipid-lowering effects but also antioxidant, anti-inflammatory and anti-apoptotic effects. Nephrotoxicity, a serious side-effect of gentamicin, is related to an increase in reactive oxygen species in the kidney. This study was designed to determine the renoprotective effects of atorvastatin treatment in an experimental model of gentamicin-induced nephrotoxicity. Male Sprague-Dawley rats were used. Nephrotocixity was induced by i.p. injection of gentamicin, 100 mg kg(-1)  day(-1) , for 15 days. Atorvastatin, 10 mg kg(-1)  day(-1) , was administered by gavage 30 min before gentamicin injection (pretreatment) for 15 days or only on days 10-15 (post-treatment). Renal function and renal organic anion transporter 3 (Oat3) function and expression were examined. Gentamicin-treated rats demonstrated impaired renal function by attenuation of creatinine clearance and increased oxidative stress. Gentamicin treatment also decreased renal Oat3 function and expression as shown by decreased [(3) H]estrone sulfate uptake into renal cortical slices and decreased expression. The protein expressions of protein kinase C, Nrf2, NAD(P)H:quinone oxidoreductase 1, haeme oxygenase 1 and glutamate-cysteine ligase were markedly increased in gentamicin-treated rats, indicating the increase in oxidative stress. Administration of atorvastatin improved renal function and alleviated oxidative stress, and atorvastatin pretreatment had a greater ability to decrease oxidative stress than atorvastatin post-treatment. These effects helped to preserve renal function and Oat3 function and expression. These results indicate that atorvastatin has a renoprotective effect against gentamicin-induced nephrotoxicity by decreasing overoxidation in the kidney, and might be used in conjunction with gentamicin to protect against renal damage.