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Osteosarcoma (OS) is a primary malignant bone tumor most commonly affecting children and adolescents and is characterized by loss of differentiation. Bone morphogenetic protein/retinoic acid inducible neural-specific 3 (BRINP3) has been reported to regulate the differentiation of osteoblasts. However, the role that BRINP3 plays in the progression of osteosarcoma remains unknown. We found in this study that BRINP3 was highly expressed in 64.13% of human osteosarcoma tissues and it was associated with histological grade, tumor recurrence, and poor clinical prognosis of osteosarcoma. In vitro, downregulation of BRINP3 was able to inhibit the proliferation and invasion of osteosarcoma cell lines. Furthermore, BRINP3 interacted with microtubule-associated protein 4 (MAP4) at the protein level, and overexpression of MAP4 could partially reverse the inhibitory effect of downregulated BRINP3 on the proliferation and invasion of osteosarcoma cells, which indicates that downregulation of BRINP3 might suppress the proliferation and invasion of osteosarcoma cells by inhibiting MAP4 expression. Overall, our results demonstrate that BRINP3 functions as an oncogene within osteosarcoma through MAP4 and could therefore be used as a potential biomarker for osteosarcoma diagnostics and therapeutics.

Ischaemia-reperfusion injury (IRI) is closely related to cardiovascular disease (CVD), which is the leading cause of death and disability. Exosomes appear to be involved in several diseases, including CVD. However, the role of mesenchymal stem cell (MSC)-derived exosomes in IRI remains unclear. miRNA expression levels in exosomes from rat normal MSCs or hypoxia-reoxygenation (H/R) MSCs were determined by qPCR and the two significantly upregulated miRNAs were selected for further investigation. Rat cardiomyoblasts (H9c2) were transfected with either miRNA mimics or scramble controls, followed by H/R induction. The effects of miRNA overexpression and exosome administration on H/R damage were then investigated. H/R increased Faslg, suppressed β-catenin, inhibited cell proliferation and migration, and stimulated apoptosis and reactive oxygen species (ROS) production. miR-149 or Let-7c mimics or exosomes reversed H/R-induced damage. The luciferase reporter assay proved the targeted regulation of Faslg by both miR149 and Let-7c. Inhibition of β-catenin suppressed cell migration, proliferation, and ΔΨm but increased apoptosis and ROS. Overall, bone marrow MSC-derived exosomes protected rat cardiomyoblasts from H/R injury

Recent studies have reported that aberrant PR domain zinc finger protein 14 (PRDM14) expression is associated with the therapeutic sensitivity of cancer cells to drugs. However, its role in lung adenocarcinoma (LUAD) remains unclear. The present study aimed to determine the functions of knockdown or overexpression of PRDM14 in the chemosensitivity and glycolysis of LUAD cells. PRDM14 expression was analyzed in lung cancer tissues from patients resistant and sensitive to cisplatin (DDP), as well as in LUAD cell lines A549 and DDP‑resistant A549 (A549/DDP) using reverse transcription quantitative‑PCR and western blotting. Additionally, apoptosis was analyzed by flow cytometry, and flow cytometry and biochemical analysis was used to analyze glycolysis, indicated by glucose uptake and lactate release. The results of the present study demonstrated that PRDM14 expression was upregulated in patients with DDP‑resistant LUAD and DDP‑resistant cell lines. Overexpression of PRDM14 suppressed the sensitivity of A549 cells to DDP and silencing of PRDM14 using shRNA targeting PRDM14 promoted the sensitivity of A549/DDP cells to DDP, compared with that in the respective control groups. In mice with xenograft tumors, knockdown of PRDM14 using shRNA targeting PRDM14 inhibited the A549/DDP cell‑derived tumor growth compared with scramble shRNA. The results of the glycolysis assays demonstrated that PRDM14 silencing inhibited glucose uptake, lactate release and glucose transporter 1 expression in A549/DDP cells compared with those in the control cells. PRDM14 overexpression relieved the inhibitory effects of 3‑bromopyruvate, a potent glycolytic inhibitor for glycolysis, on glucose uptake and lactate release in A549 cells compared with those in the control cells. Therefore, the results of the present study suggested that PRDM14 may inhibit the chemosensitivity and promote glycolysis in human LUAD cells.

The ischemia-reperfusion (I/R)-caused damage in human brain microvascular endothelial cells (BMECs) is associated with the disruption of blood-brain barrier (BBB). CXC chemokine ligand 5 (CXCL5) is reported upregulated in ischemia stroke. However, the detailed function of CXCL5 in this pathological process remains largely unclear. To further analyze the function of CXCL5 in ischemia stroke, we constructed oxygen-glucose deprivation (OGD) model on human BMECs to mimic ischemic stroke condition in vitro. Cell proliferation was analyzed using cell counting kit-8 (CCK-8) assay. qRT-PCR and western blot were utilized to determine gene expression. The barrier function of BMECs was assessed using fluorescently labeled dextran (FITC-Dextran) assay and Trans-epithelial/endothelial electrical resistance (TEER) technique. Our results indicated that CXCL5 antibody (anti-CXCL5) promoted the proliferation of model cells, whereas reduced its permeability. Moreover, the TEER value of model cells was enhanced in the presence of anti-CXCL5. Therefore, these findings demonstrated that CXCL5 silencing attenuated the ischemic/hypoxic-induced injury in human BMECs. Importantly, human recombinant protein CXCL5 (Re-CXCL5) deeply disrupted the function of BMECs in normoxic condition. Furthermore, p38 inhibitor SB203580 significantly abolished the function of CXCL5 in model cells. Much importantly, the similar results were also obtained in BMECs with normoxic conditions in the presence of Re-CXCL5. These results indicated CXCL5 might regulate the function of BMECs via mediating p38 pathway. This investigation not only enhanced the understanding into the biological effect of CXCL5 in human BMECs with ischemic/hypoxic conditions but also indicated its potential value as a therapeutic target for ischemic-induced brain disease. This article is protected by copyright. All rights reserved.

Background. Jiangzhi Decoction (JZD), a traditional herb mixture, has shown significant clinical efficacy against nonalcoholic fatty liver disease (NAFLD). However, its multicomponent and multitarget characteristics bring difficulty in deciphering its pharmacological mechanisms. Our study is aimed at identifying the core molecular mechanisms of JZD against NAFLD. Methods. The active ingredients were searched from Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Traditional Chinese Medicine Integrated Database (TCMID). The targets of those ingredients were identified using ChemMapper database based on 3D structure similarity. NAFLD-related genes were searched from DisGeNET database and Gene Expression Omnibus (GEO) database. Then, we performed protein-protein interaction (PPI) analysis, functional enrichment analysis, and constructed pathway networks of “herbs-active ingredients-candidate targets” and identified the core molecular mechanisms and key active ingredients in the network. Also, molecular docking was carried out to predict the ligands of candidate targets using SwissDock. Finally, the human hepatic L02 cell line was used to establish the NAFLD model in vitro. The effect and key molecules were validated by Oil Red O staining, biochemical assays, and quantitative real-time PCR (qRT-PCR). Results. We found 147 active ingredients in JZD, 1285 targets of active ingredients, 401 NAFLD-related genes, and 59 overlapped candidate targets of JZD against NAFLD. 22 core targets were obtained by PPI analysis. Finally, nuclear receptor transcription and lipid metabolism regulation were found as the core molecular mechanisms of JZD against NAFLD by functional enrichment analysis. The candidate targets PPARα and LXRα were both docked with hyperin as the most favorable interaction, and HNF4α was docked with linolenic acid ethyl ester. According to in vitro experiments, it was found that JZD had an inhibitory effect on lipid accumulation and regulatory effects on cholesterol and triglycerides. Compared with OA group, the mRNA expression levels of PPARα and HNF4α were significantly upregulated in JZD group ( P < 0.05 ), and LXRα was significantly downregulated ( P < 0.001 ). Conclusion. JZD might alleviate hepatocyte steatosis by regulating some key molecules related to nuclear receptor transcription and lipid metabolism, such as PPARα, LXRα, and HNF4α. Our study will provide the scientific evidences of the clinical efficacy of JZD against NAFLD.

Background Aging is associated with a decrease in appetite, energy intake and glucose tolerance. Experimental studies have suggested that ghrelin and obestatin play a role in glucose homeostasis and in the regulation of energy metabolism. However, few studies have been performed on the role of ghrelin and obestatin in middle-aged and old adults. Methods In the present study, we investigated the plasma concentrations of ghrelin and obestatin in middle-aged (41-64 years) and old (65-76 years) subjects with newly diagnosed type 2 diabetes mellitus (NDD) and normal glucose tolerance (NGT). We also characterized the relationship among plasma ghrelin and obestatin levels and glucose/lipid metabolism. The fasting plasma ghrelin and obestatin concentrations were analyzed using enzyme immunoassay method. Results Plasma obestatin concentrations in diabetic subjects were significantly lower than those in NGT subjects. Plasma ghrelin were negatively associated with fasting glucose, hemoglobin A1c, urine albumin-to-creatinine ratio (UACR) and positively correlated with high-density lipoprotein cholesterol. In addition, plasma obestatin level was correlated negatively with systolic blood pressure, triglycerides and total cholesterol. Furthermore, multiple regression analysis indicated that UACR was a significantly independent predictor of fasting plasma ghrelin levels. Conclusions Collectively, ghrelin and obestatin levels may be markers reflecting glucose and lipid conditions in NDD. The lower ghrelin levels may be a potential indicator for renal dysfunction in patients with type 2 diabetes mellitus.

To investigate the correlation between serum liver enzymes and onset of type 2 diabetes mellitus (T2DM).A total of 8 779 individuals subjected to a Zhengzhou community survey were enrolled in the study and were tested for the following serum biochemical parameters, including ALT, AST, γ-glutamyl transferase (GGT), TC, TG and blood glucose. All subjects were divided into four groups (Q1-Q4) according to the quartiles of their liver enzyme levels. Logistic regression was performed to explore the odd ratio (OR) for the onset of T2DM in groups of Q2-Q4 compared with the group of Q1.ROC curve was used to analyze the predictive value of elevated liver enzymes for the onset of T2DM.When the quartiles were defined by the GGT level, compared with the group of Q1, the OR for the group of Q4 was 4.043 (95%CI 2.759-5.924) in the male and 4.239 (95%CI 3.172-5.664) in the female, which was higher than the OR when the quartiles were defined by the ALT level. In the ROC curve, the AUC of GGT was larger than those of ALT, AST, BMI, waist circumference and TG, with 0.63 for the male and 0.68 for the female.Serum level of GGT is more closely correlated with the onset of T2MD than the level of ALT or AST. Even the increase of serum GGT within physiological range is a risk factor for the onset of T2DM.