ABSTRACT
Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.
ABSTRACT
Gene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood-brain barrier (BBB) penetration and QSH peptide for -amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against -site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of A production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the A deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as A and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.
ABSTRACT
The leading cause of drug withdrawal from market and clinical trials failure is drug-induced liver injury (DILI). Varying clinical, histological and laboratory features of DILI, as well as undefined underlying mechanisms, hinder patients to be diagnosed in the early-stage of the disease and receive effective treatments. Conventional indicators, like serum transaminases and bilirubin, have inevitable limitations referring to sensitive prediction and specific detection of DILI. In order to reduce the occurrence of DILI, researchers have attempted to discover potential biomarkers with higher specificity and sensitivity from blood and urine in recent years. This article aims to review recent advances in biomarkers of DILI.
ABSTRACT
Objective: To study the pharmacokinetics and brain/plasma concentration ratio of nortriptyline at multiple doses in mice which were pre-treated with physiological saline, piperine and verapamil. Methods: A total of 216 male Kun Ming mice[(25±3) g] were equally divided into 4 groups randomly. Each group was intragastrically administered physiological saline (B), piperine (170 μg/kg), piperine (5 mg/kg) and verapamil (5 mg/kg) for 8 days. On the 8th day, 1 h atfer giving the above drugs, each mice was intraperitoneally injected nortriptyline (13 mg/kg). The mice were sacriifced by picking off eyeballs at the time intervals of 5, 15, 30 min, and 1, 2, 4, 6, 8 and 12 h, andthe cerebra were collected and weighted. Nortriptyline in mouse plasma and brain was determined by HPLC-MS/MS. The pharmacokinetic properties of the plasma, brain and brain/plasma were calculated. Results: hTe AUC0-12 h of brain/plasma concentration ratio in the 170 μg/kg piperine group was significantly lower than that in the other groups (P<0.05), while the AUC0-12 h of brain/plasma concentration ratios in the 5 mg/kg piperine group and the verapamil group were not signiifcantly different from those of untreated mice. Conclusion: Piperine (170 μg/kg) may induce P-glycoprotein expression in the blood-brain barrier, while piperines at 5 mg/kg has no influence on P-glycoprotein expression in the blood-brain barrier.
ABSTRACT
Objective To investigate the efficacy of Saxagliptin on the glucose and lipids metabolism and adipokines levels in diet-induced insulin resistance rat,and to explore the regulatory mechanism of saxagliptin in insulin resistance.Methods 36 4-week-old male Wistar rats were randomly divided into two groups:control group (n=12) and high-glucose and fat diet group(HF,n =24).The HF rats were randomly divided into two subgroups:HF group and saxagliptin group,and continued the treatment for 8 weeks.Levels of blood glucose,insulin,triglyceride (TG),total cholesterol (TC),TNF-α and adiponectin were determined.Results After four months,serum levels of fasting glucose,insulin,TG,TC were significantly increased in HF group as compared with control group [(7.07±1.61) mmol/L vs.(5.10±0.44) mmol/L,(23.70±7.37) mU/L vs.(19.35 ± 6.38) mU/L],[(3.21± 1.44) mmol/L vs.(0.83 ± 0.39) mmol/L,(3.04 ± 1.62) mmol/L vs.(1.14±0.24) mmol/L,all P＜0.05],and were all decreased after the treatment of saxagliptin.The glucose infusion rate was lower in HF group than in control group and was higher in saxagliptin group than in HF group [(18.80±1.57) mg · kg-1 · min-1 vs.(24.31±2.65) mg · kg 1 · min 1,(21.45 ±1.80) mg· kg-1 · min-1 vs.(18.80±1.57) mg· kg 1 · min-1,P＜0.01 or 0.05].Compared with the control group,serum THF-α was higher and adiponectin level was lower in HF group [(1.38 ±0.18) μg/L vs.(2.33±0.21)μg/L,(2.65±0.29) mg/L vs.(1.38±0.20)mg/L,both P＜0.01].Saxagliptin can significantly increase the serum level of adiponectin and decrease the level of TNF-α in HF group (P＜0.01 or 0.05).Conclusions Saxagliptin treatment can improve high-fat dietinduced insulin resistance,decrease blood lipids levels and regulate the levels of adipokines in HF rats.
ABSTRACT
Aim To investigate the extent of systemic absorption and uptake of meptazinol (MEP) hydrochloride in cerebrospinal fluid (CSF) after intranasal administration on rats and compare with oral administration. Methods CSF samples were collected by a serial sampling method. The concentration of MEP in the biological samples was measured by HPLC with fluorescence detector. Results Rapid and significant levels of MEP in plasma and CSF can be achieved after nasal administration whereas the oral administration resulted in considerably lower drug concentrations. AUC in plasma and CSF from the nasal route are 7.375 and 15.6 folds compared with those of the oral route, respectively. Conclusion Intranasal MEP is able to show quick absorption and improve the bioavailability, which could be a promising alternative to oral administration.