Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats.

Brexpiprazole (Bre) is a new multi-target antipsychotic drug (APD) approved by the US FDA in 2015, and shows good therapeutic potential. But it lacks assessments on the metabolic side effects, which obstructs the treatment of schizophrenia. Glucagon-like peptide 1 (GLP1), an incretin associated with insulin action and metabolism, is involved in the metabolic syndrome (MS) caused by most APDs. In this study, we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS. In the first part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 28 days with aripiprazole (1.0 mg· kg-1· d-1) or olanzapine (1.0 mg· kg-1· d-1) as the controls. Compared to vehicle, Bre administration significantly increased the weight gain, serum lipid (TG, TC, LDL, FFA), and blood glucose levels accompanied by the hormonal (insulin, glucagon, GLP1) imbalance, and the impaired glucose tolerance and insulin sensitivity. Moreover, we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKIIα, AMPK, and ß-catenin; Bre administration also caused islet dysfunction with decreased GLP1R, PI3K, IRß expression in pancreas, and the interference of IRS1, PI3K, p-AKT, and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance. In the second part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 42 days. We showed that co-administration with the GLP1 receptor (GLP1R) agonist liraglutide (0.125 mg· kg-1· d-1, ip) could ameliorate Bre-caused metabolic abnormalities. Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms.

Preparation of tilmicosin-resin complex microsphere and its Pharmacokinetics study in rat.

The objective of this study is to mask the extremely bitter taste of tilmicosin, and the tilmicosin-resin complex (DRC) microsphere were prepared by entrapping tilmicosin into resins (Tulsion® 339 and Eudragit® RS/ RL 100) for further pharmacokinetics study in rat. The DRC was characterized by FTIR and X-ray diffraction, and the microsphere containing DRC and Eudragit® RS/RL 100 were characterized by scanning electron microscopy (SEM). The rats were orally administrated with tilmicosin phosphate (10 mg/kg) and the microsphere containing the same dose of tilmicosin, respectively. These microspheres do not taste bitter and the kinetics study suggests that the drug released from microsphere meet the first order kinetics (r = 0.9911). The experimental results showed that T½ and Tmax of microsphere were much longer than tilmicosin phosphate, which indicates that the oral microsphere can be a promising long-active formulation for taste masking of tilmicosin.

Medical intelligence using PPG signals and hybrid learning at the edge to detect fatigue in physical activities.

The educational environment plays a vital role in the development of students who participate in athletic pursuits both in terms of their physical health and their ability to detect fatigue. As a result of recent advancements in deep learning and biosensors benefitting from edge computing resources, we are now able to monitor the physiological fatigue of students participating in sports in real time. These devices can then be used to analyze the data using contemporary technology. In this paper, we present an innovative deep learning framework for forecasting fatigue in athletic students following physical exercise. It addresses the issue of lack of precision computational models and extensive data analysis in current approaches to monitoring students' physical activity. In our study, we classified fatigue and non-fatigue based on photoplethysmography (PPG) signals. Several deep learning models are compared in the study. Using limited training data, determining the optimal parameters for PPG presents a significant challenge. For datasets containing many data points, several models were trained using PPG signals: a deep residual network convolutional neural network (ResNetCNN) ResNetCNN, an Xception architecture, a bidirectional long short-term memory (BILSTM), and a combination of these models. Training and testing datasets were assigned using a fivefold cross validation approach. Based on the testing dataset, the model demonstrated a proper classification accuracy of 91.8%.

Olanzapine induces weight gain in offspring of prenatally exposed poly I:C rats by reducing brown fat thermogenic activity.

Background: Olanzapine (OLZ) is an antipsychotic with a high risk of metabolic syndrome, and its induced metabolic disturbance may be related to the thermogenic function of brown adipose tissue (BAT). Of note is that schizophrenia itself appears to be associated with a higher incidence of metabolic syndrome. However, whether OLZ affects metabolic disorders by regulating BAT function and its mechanism in animal models of schizophrenia have not been reported. Methods: We induced maternal immune activation (MIA) in pregnant rodents by injection of synthetic double-stranded RNA-poly I:C (a virus-like substance), and rats were injected with poly I:C, 10 mg/kg) or saline on day 13 of gestation. Rat offspring received OLZ (1 mg/kg, tid) or vehicle from adulthood for 28 days, and body weight and food intake were recorded. Morphological alterations of white adipose tissue (WAT) and BAT were analyzed by HE and oil red staining, and expression of BAT-specific marker proteins/genes was detected by western blot and qRT-PCR. In addition, embryonic stem cells C3H10T1/2 were used to direct differentiation into brown-like adipocytes, and C3H10T1/2 cells were treated with OLZ for the differentiation process. The effects of OLZ on brown-like adipocyte differentiation and activity were analyzed using oil red staining, immunofluorescence and flow cytometry. Results: Compared with the Veh (saline) group, the TG, pWAT weight, adipocyte size and liver weight of the Veh (poly I:C) group were significantly increased, suggesting that the offspring of Poly I:C rats had obvious dyslipidemia and lipid accumulation, which were risk factors for metabolic abnormalities such as obesity. In addition, OLZ treatment resulted in altered WAT and BAT morphology in poly I:C or saline exposed offspring, causing lipid accumulation and weight gain and reducing the expression of the BAT-specific marker molecule UCP1 protein/gene. At the same time, OLZ inhibited the directional differentiation and mitochondrial activity of C3H10T1/2 brown-like adipocytes. Conclusion: Poly I:C-elicited MIA and OLZ differentially inhibited BAT activity and mitochondrial biogenesis, leading to weight gain in adult rats, a process involving PPAR-γ/UCP1-related thermogenic proteins.

Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in vivo and in vitro.

Caffeic acid phenethyl ester (CAPE) could ameliorate myocardial ischemia/reperfusion injury (MIRI) by various mechanisms, but there hadn't been any reports on that CAPE could regulate silent information regulator 1 (SIRT1) and endothelial nitric oxide synthase (eNOS) to exert cardioprotective effect. The present study aimed to investigate the cardioprotective potential of caffeic acid o-nitro phenethyl ester (CAPE-oNO2) on MIRI and the possible mechanism based on the positive control of CAPE. The SD rats were subjected to left coronary artery ischemia /reperfusion (IR) and the H9c2 cell cultured in hypoxia/reoxygenation (HR) to induce the MIRI model. Prior to the procedure, vehicle, CAPE or CAPE-oNO2 were treated in the absence or presence of a SIRT1 inhibitor nicotinamide (NAM) and an eNOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). In vivo, CAPE and CAPE-oNO2 conferred a cardioprotective effect as shown by reduced myocardial infarct size, cardiac marker enzymes and structural abnormalities. From immunohistochemical and sirius red staining, above two compounds ameliorated the TNF-α release and collagen deposition of IR rat hearts. They could agitate SIRT1 and eNOS expression, and consequently enhance NO release and suppress NF-κB signaling, to reduce the malondialdehyde content and cell necrosis. In vitro, they could inhibit HR-induced H9c2 cell apoptosis and ROS generation by activating SIRT1/eNOS pathway and inhabiting NF-κB expression. Emphatically, CAPE-oNO2 presented the stronger cardioprotection than CAPE both in vivo and in vitro. However, NAM and L-NAME eliminated the CAPE-oNO2-mediated cardioprotection by restraining SIRT1 and eNOS expression, respectively. It suggested that CAPE-oNO2 ameliorated MIRI by suppressing the oxidative stress, inflammatory response, fibrosis and necrocytosis via the SIRT1/eNOS/NF-κB pathway.

CAPE-pNO2 ameliorated diabetic nephropathy through regulating the Akt/NF-κB/ iNOS pathway in STZ-induced diabetic mice.

Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. This study aimed to determine the effects and potential mechanism of caffeic acid para-nitro phenethyl ester (CAPE-pNO2), a derivative of caffeic acid phenethyl ester (CAPE), on DN; In vivo, intraperitoneal injections of streptozotocin (STZ) were used to induce diabetes in mice; then, the mice were intraperitoneally injected daily with CAPE or CAPE-pNO2 for 8 weeks. The mice were sacrificed, and blood samples and kidney tissues were collected to measure biological indexes. The results showed that CAPE and CAPE-pNO2 could lower serum creatinine, blood urea nitrogen, 24-h albumin excretion, malondialdehyde and myeloperoxidase levels and increase superoxide dismutase activity in diabetic mice. According to HE, PAS and Masson staining, these two compounds ameliorated structural changes and fibrosis in the kidneys. In addition, the immunohistochemical and western blot results showed that CAPE and CAPE-pNO2 inhibited inflammation through the Akt/NF-κB pathway and prevented renal fibrosis through the TGF-ß/Smad pathway. In vitro, CAPE and CAPE-pNO2 inhibited glomerular mesangial cell (GMC) proliferation, arrested cell cycle progression and suppressed ROS generation. These compounds also inhibited ECM accumulation via regulating the TGF-ß1, which was a similar effect to that of the NF-κB inhibitor PDTC. More importantly, CAPE and CAPE-pNO2 could up-regulate nitric oxide synthase expression in STZ-induced diabetic mice and HG-induced GMCs. CAPE-pNO2 had stronger effects than CAPE both in vivo and in vitro. These data suggest that CAPE-pNO2 ameliorated DN by suppressing oxidative stress, inflammation, and fibrosis via the Akt/NF-κB/ iNOS pathway.

Changes in the microstructure and properties of aspen chemithermomechanical pulp fibres during recycling.

The effects of recycling on the microstructure and properties of bleached aspen chemithermomechanical pulp (CTMP) fibres were systematically investigated. The low-temperature nitrogen adsorption and atomic force microscopy results showed that a substantial amount of large pores and most of the very small pores in the fibre wall closed and the fibre surface became less coarse and porous during recycling. The partial cocrystallisation of cellulose microfibrils took place, as reflected in the increment of the cellulose crystallinity and the width of the crystallite in the 0 0 2 lattice plane. These irreversible structural changes caused significant hornification of the recycled fibres, leading to the loss of swelling and bonding capability. The decrease of the tensile index, burst index, and tear index further demonstrated the deterioration of the fibre properties. However, the single-fibre strength considerably increased after recycling, which was mainly due to the enlarged cellulose aggregates in the fibre wall.

Effect of baicalin-copper on the induction of apoptosis in human hepatoblastoma cancer HepG2 cells.

The medical properties of baicalin have been well known for many years. However, the discovery that baicalin in the presence of metal ions is more effective than baicalin alone changed the course of drug research. The present study was designed to investigate the effect and possible mechanism of apoptosis induced by baicalin-copper in a human hepatoblastoma cancer cell line (HepG2) and in vivo. This study demonstrated that baicalin-copper suppresses the proliferation of HepG2 cells in a dose-dependent manner. Intraperitoneal injection of baicalin-copper resulted in a significant decrease in tumor growth in xenografts in nude mice. Acridine orange staining and flow cytometry analysis demonstrated that baicalin-copper induced apoptosis in HepG2 cells and caused cells to arrest in G2-M phase of the cell cycle. Furthermore, baicalin-copper treatment significantly increased the Bax/Bcl-2 ratio and p38 levels, as well as decreased the expression of caspase-3, p-PI3K, p-Akt and p-mTOR (P < 0.01). All of the evidences above indicate that baicalin-copper induces apoptosis in HepG2 cells by down-regulating the PI3K/Akt/mTOR signaling pathway.