Previous studies have revealed that oleanolic acid (OA) C28-glucose conjugate displayed potent anti-influenza viral activity in vitro. However, the effect of pentacyclic triterpene scaffold coupled with glucose on anti-influenza virus activity has not been clarified. Herein, as a continuous further study, a series of pentacyclic triterpene-glucose conjugates were prepared via CuAAC reaction, and the anti-influenza activity of these compounds was evaluated in vitro. Among them, compound 4d, an betulinic acid (BA)-glucose conjugate, showed potent anti-influenza virus activity (IC50 value of 9.09 mu mol/L), and no obvious cytotoxic effect on MDCK (Madin-Darbey Canine Kidney) cells was observed (CC50>100 mu mol/L). Structure-activity relationship studies showed that both triterpene scaffolds and glucose moiety have important effects on the anti-viral activity. Overall, this finding further extends the utility of triterpene derivatives in anti-influenza virus drug design.

Inhibitors targeting the entry stage of influenza viruses are a hot spot in the development of anti-influenza drugs. Our previous studies showed that oleanolic acid (OA) C28 glycoconjugates displayed strong anti-influenza virus activity. In this paper, a series of oleanolic acid C3 glycoconjugates 7a similar to 14c were designed and synthesized via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The anti-influenza activities of all these compounds were evaluated in vitro. Among them, oleanane-12-enyl-28-benzyloxycarbonyl-3-O-(4-methylene-1,2,3-triazole-1-(2,3,4,6-tetra-O-acetyl-beta-D-galacto-side)) (12a) showed the strongest activity with an IC50 of 12.45 mu mol.L-1, and no obvious cytotoxic effect on MDCK cells was observed at 100 mu mol.L-1. Hemagglutination inhibition and molecular docking experiments indicated that compound 12a might target viral envelope hemagglutinin (HA), thus inhibiting the attachment of viruses to host cells. This study improved the structure-activity relationships of oleanolic acid and its derivatives against influenza virus, and provided a basis for further research on anti-virus by these natural products.

Kinase dysregulation is greatly associated with cell proliferation, migration and survival, indicating the importance of kinases as therapeutic targets for anticancer drug development. However, traditional kinase inhibitors binding to catalytic or allosteric sites are associated with significant challenges. The emergence of resistance and targeting difficult-to-degrade and multi-domain proteins are significant limiting factors affecting the efficacy of targeted anticancer drugs. The next-generation treatment approaches seem to have overcome these concerns, and the use of proteolysis targeting chimera (PROTAC) technology is one such method. PROTACs bind to proteins of interest and recruit E3 ligase for degrading the whole target protein via the ubiquitin-proteasome pathway. This review provides a detailed summary of the most recent signs of progress in PROTACs targeting different kinases, primarily focusing on new chemical entities in medicinal chemistry.

流感病毒(Influenza Virus,IVs)属于正黏病毒科(Orthomyyxoviridae),单股负链RNA包膜病毒,由于其传播和变异速度快,且致病力和致死率高,严重威胁人类的健康和生命.理论上,抑制流感病毒生命周期的任何一个阶段,都可以有效地抑制病毒的复制和传播.目前FDA已批准的药物主要作用于子代病毒的释放阶段,随着流感病毒耐药问题的日益严重,不同作用机制的抑制剂不断被发现,部分已经进入临床研究阶段.新技术、新思路持续推进着流感病毒抑制剂的研究,本文将对最新的流感病毒抑制剂研究进展进行综述,旨在为新型的流感病毒抑制剂的设计和研发提供参考和思路.

BACKGROUND:Glucagon-like peptide-1 (GLP-1) and its based agents improve glycemic control. Although their attenuating effect on hepatic glucose output has drawn our attention for decades, the potential mechanisms remain unclear.METHODS:Cytokine array kit was used to assess cytokine profiles in db/db mice and mouse primary hepatocytes treated with exenatide (exendin-4). Two diabetic mouse models (db/db and Pax6m/+) were treated with a GLP-1 analog exenatide or liraglutide. The expression and secretion of fibroblast growth factor 21 (FGF21) in the livers of diabetic mice, primary mouse and human hepatocytes, and the human hepatic cell line HepG2 treated with or without GLP-1 analog were measured. Blockage of FGF21 with neutralizing antibody or siRNA, or hepatocytes isolated from Fgf21 knockout mice were used, and the expression and activity of key enzymes in gluconeogenesis were analyzed. Serum FGF21 level was evaluated in patients with type 2 diabetes (T2D) receiving exenatide treatment.FINDINGS:Utilizing the cytokine array, we identified that FGF21 secretion was upregulated by exenatide (exendin-4). Similarly, FGF21 production in hepatocytes was stimulated by exenatide or liraglutide. FGF21 blockage attenuated the inhibitory effects of the GLP-1 analogs on hepatic glucose output. Similar results were also observed in primary hepatocytes from Fgf21 knockout mice. Furthermore, exenatide treatment increased serum FGF21 level in patients with T2D, particularly in those with better glucose control.INTERPRETATION:We identify that function of GLP-1 in inhibiting hepatic glucose output is mediated via the liver hormone FGF21. Thus, we provide a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis. FUND: National Key Research and Development Program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Beijing and Peking University Medicine Seed Fund for Interdisciplinary Research.

Peroxisome proliferator-activated receptor γ (PPARγ) is expressed in various types of human cancer cells including leukaemia cells, and activation of PPARγ can inhibit cancer cell growth. However, whether PPARγ is expressed in Jurkat cells, a human T-lymphocyte leukaemia cell line, and whether activation of PPARγ affects cell biological behaviors remains to be clarified. In this study, we investigated the effect of a PPARγ activator rosiglitazone, under clinically relevant pharmacological concentrations, on the growth and apoptosis of Jurkat cells in vitro and explored the possible mechanism. Metformin was also included as a positive control for the anti-proliferative and pro-apoptotic effects. We found that PPARγ mRNA was transcribed in Jurkat cells. Treatment with rosiglitazone (5 µM, 10 µM, and 20 µM) or metformin (1 mM and 10 mM) inhibited cell proliferation, and induced cell cycle arrest at G0/G1 or S phase, respectively, in a dose-dependent manner. Although metformin significantly upregulated the protein levels of the pro-apoptotic markers cleaved-caspase 3 and Bax in Jurkat cells, rosiglitazone did not have such an effect. Moreover, rosiglitazone significantly upregulated the level of PPARγ, and downregulated the expression of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) in a dose-dependent manner. Our data indicate that rosiglitazone has an anti-proliferative effect in Jurkat cells, which may be at least partly mediated via downregulating IR and IGF-1R expression. Therefore, rosiglitazone may have a potential role not only for management of hyperglycaemia but also for control of tumor progression in patients with T-lymphocyte leukaemia and diabetes.

Background This study aimed to explore whether or not mothers with higher educational and wealth status report lower rate of child mortality compared to those with less advantageous socioeconomic situation. Methods Data used were cross-sectional and collected from Multiple Indicator Cluster Survey in Kazakhstan conducted in 2015. Subjects experiencing childbirth were 9278 women aging between 15 and 49 years. The associations between maternal education and household wealth status with child mortality were examined by multivariate analytical methods. Results The overall prevalence of child mortality was 6.7%, with noticeable variations across the different regions. Compared with women who had the highest educational status, those with upper and lower secondary were 1.47 and 1.89 times more likely to experience child death. Women in the lowest and second lowest wealth quintile had 2.74 and 2.68 times higher odds of experiencing child death compared with those in the richest wealth status households. Conclusions Policy makers pay special attention to improving socioeconomic status of the mothers in an effort to reduce child mortality in the country. Women living in the disadvantaged regions with poor access to quality health care services should be regarded as a top priority.

Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively. RT-PCR and western blot analyses were used to determine the mRNA and protein levels of related molecules. Results showed that combination treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) significantly decreased cell viability and colony formation, caused cell cycle arrest, upregulated the level of pro-apoptotic proteins Bax and cleaved caspase-3, and inhibited cell migration in the cells, although their single treatment did not exhibit such effects. Combination index value for cell viability indicated a synergistic interaction of liraglutide and metformin. Moreover, the combined treatment with liraglutide and metformin could activate the phosphorylation of AMP-activated protein kinase (AMPK) more potently than their single treatment in the cells. These results suggest that liraglutide in combination with metformin has a synergistic anti-tumor effect on the pancreatic cancer cells, which may be at least partly due to activation of AMPK signaling. Our study provides new insights into the treatment of patients with type 2 diabetes and pancreatic cancer.

Insulin-producing cells (IPCs) derived from human embryonic stem cells (hESCs) hold great potential for cell transplantation therapy in diabetes. Tremendous progress has been made in inducing differentiation of hESCs into IPCs in vitro, of which definitive endoderm (DE) protocol mimicking foetal pancreatic development has been widely used. However, immaturity of the obtained IPCs limits their further applications in treating diabetes. Forkhead box O1 (FoxO1) is involved in the differentiation and functional maintenance of murine pancreatic β cells, but its role in human β cell differentiation is under elucidation. Here, we showed that although FoxO1 expression level remained consistent, cytoplasmic phosphorylated FoxO1 protein level increased during IPC differentiation of hESCs induced by DE protocol. Lentiviral silencing of FoxO1 in pancreatic progenitors upregulated the levels of pancreatic islet differentiation-related genes and improved glucose-stimulated insulin secretion response in their progeny IPCs, whereas overexpression of FoxO1 showed the opposite effects. Notably, treatment with the FoxO1 inhibitor AS1842856 displayed similar effects with FoxO1 knockdown in pancreatic progenitors. These effects were closely associated with the mutually exclusive nucleocytoplasmic shuttling of FoxO1 and Pdx1 in the AS1842856-treated pancreatic progenitors. Our data demonstrated a promising effect of FoxO1 inhibition by the small molecule on gene expression profile during the differentiation, and in turn, on determining IPC maturation via modulating subcellular location of FoxO1 and Pdx1. Therefore, we identify a novel role of FoxO1 inhibition in promoting IPC differentiation of hESCs, which may provide clues for induction of mature β cells from hESCs and clinical applications in regenerative medicine.

Oleanolic acid (OA), a naturally occurring triterpene, was found to have a variety of biological and pharmacological properties. To expand its structural diversity, a series of oleanolic acid derivatives, including ring A and/or ring C expansion, were performed via Baeyer-Villiger reaction using m-CPBA and urea-hydrogen peroxide. The structures of all products were characterized by H NMR, C NMR and HRMS.

Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3-100 nmol/L) in the presence of PA (0.5 mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis. Results showed that liraglutide ameliorated endothelial tube formation impaired by PA in HUVECs in a dose-dependent manner. Meanwhile, liraglutide increased the phosphorylation of Akt and forkhead box O1 (Foxo1), and upregulated the levels of guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and endothelial nitric oxide synthase (eNOS) in PA-impaired HUVECs. Notably, addition of the PI3K inhibitor LY294002, Foxo1 nuclear export inhibitor trifluoperazine dihydrochloride (TFP), GTPCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) or NOS inhibitor N-nitro-L-arginine-methyl ester (L-NAME) eliminated the angiogenic effect of liraglutide. Moreover, either LY294002 or TFP abolished the liraglutide-induced upregulation of GTPCH1 and eNOS protein levels. In conclusion, liraglutide restores angiogenesis in PA-impaired HUVECs. The effect is mediated via upregulation of GTPCH1 and eNOS levels in a PI3K/Akt-Foxo1-dependent mechanism. (C) 2016 Elsevier Inc. All rights reserved.

With the aim of broadening the versatility of lentiviral vectors as a tool in nucleic acid research, we expanded the genetic code in the propagation of lentiviral vectors for site-specific incorporation of chemical moieties with unique properties. Through systematic exploration of the structure-function relationship of lentiviral VSVg envelope by site-specific mutagenesis and incorporation of residues displaying azide- and diazirine-moieties, the modifiable sites on the vector surface were identified, with most at the PH domain that neither affects the expression of envelope protein nor propagation or infectivity of the progeny virus. Furthermore, via the incorporation of such chemical moieties, a variety of fluorescence probes, ligands, PEG and other functional molecules are conjugated, orthogonally and stoichiometrically, to the lentiviral vector. Using this methodology, a facile platform is established that is useful for tracking virus movement, targeting gene delivery and detecting virus-host interactions. This study may provide a new direction for rational design of lentiviral vectors, with significant impact on both basic research and therapeutic applications.

The invention relates to application triterpenoid derivatives to produce medicines for preventing or treating influenza diseases, and the triterpenoid derivatives have the formula shown in the specification, wherein substituted groups are defined in the specification. The triterpenoid derivatives provided by the invention has obvious inhibition effect on influenza virus, and is capable of obviously preventing influenza virus from entering cells, and is applicable to prevent or treat influenza.

Objective: To perform meta-analyses evaluating the efficacy of adding Liuwei Dihuang Pills (a...a(3)ae degrees e >>"a, LDP) to Western medicine in improving treatment outcomes for type 2 diabetes. Medline, PubMed, Cochrane Library, and Chinese databases, including the Chinese National Knowledge Infrastructure were searched to identify eligible studies; i.e., if the study involved a randomized clinical trial in which the experimental group combined LDP with Western drugs and the control group used the corresponding Western drugs alone to treat type 2 diabetes. Outcomes were measured in terms of fasting blood glucose (FBG), postprandial blood glucose (2hPG) and HbA1c level. Efficacy was also measured by using control and response rates. The combined odds ratio (OR), mean difference (MD), and 95% confidence intervals (95% CI) were calculated. Studies included in the analysis were less adequate than expected in terms of methodological quality. A total of 1,609 patients from 18 studies were included. We found that adding LDP can lower patients' FBG (MD=0.54 mmol/L, 95% CI [0.15, 0.93], P=0.007), 2hPG (MD=1.05 mmol/L, 95% CI [0.29, 1.81], P < 0.01) and HbA1c (MD=0.23, 95% CI [0.02, 0.45], P=0.008). There were also improvements in treatment response rates (OR=3.41, 95% CI [2.38, 4.90], P < 0.01) and control rates (OR=2.47, 95% CI [1.91, 3.20], P < 0.01). Adding LDP to Western medicine might improve treatment outcomes of diabetes, including FBG, 2hPG, response rates and control rates.

A novel series of compounds, derived from [1,2,3]triazolo[4,5-d]pyrimidines with a guanidyl group or amino group-terminated side chain was designed and synthesized as HIV-1 trans-activator of transcription–trans-activation responsive region (Tat–TAR) interaction inhibitors. Their ability to inhibit Tat–TAR RNA interaction was determined by a Tat-dependent HIV-1 long terminal repeat (LTR)-driven chloramphenicol acetyltransferase (CAT) assay and simian immunodeficiency virus (SIV)-induced syncytium evaluation. The binding of the compounds with TAR RNA was conducted by molecular modeling and capillary electrophoresis (CE) analysis. The results showed that all the compounds could block the Tat–TAR interaction and have antiviral activities.

HIV-1 capsid (CA) and human cyclophilin A (CypA) play important roles in HIV-1 assembly and disassembly processes, which are critical in HIV-1 replication. Based on the discovery of thiourea derivatives targeting both of the two proteins and indicating effective inhibitory activities in our group, we designed and synthesized a new class of thiourea derivatives. Their abilities to bind to capsid and cyclophilin A were determined by ultraviolet spectroscopic analysis, fluorescence binding affinity, and PPIase inhibition assay. Furthermore, the newly synthesized compounds were tested for their antiviral activities and cytotoxicities using CEM cells. According to the biological evaluation and subsequent molecular docking analyses, we studied the structure-activity relationships of thiourea derivatives. Three optimal compounds (K17, K24, K25) based on the achieved structure-activity relationships would be the basis for future optimization.

Quercetin greatly enhanced luminol electrochemiluminescence of quercetin in alkaline solution. When the concentration of luminol was 0.1 mol L(-1), the detection limit for quercetin was 2.0x10(-8) mol L(-1) with a linear range from 1.0x10(-7) to 2x10(-5) mol L(-1). The pH and buffer substantially affected ECL intensity. Quercetin was autoxidized in alkaline aqueous solution. The rate of autoxidation of quercetin in various pH buffers and borate concentrations were measured. Borate was found to inhibit quercetin autoxidation and compromise quercetin enhancement effect on luminol ECL to some extent. Two final autoxidation products were identified with LC-MS methods. Autoxidation process was associated with enhancement of ECL intensity. The ROS generated during quercetin autoxidation enhanced the ECL intensity.

A spectrophotometric method was developed to measure antioxidant free-radical scavenging capacity. Rhodamine B (RhB) was oxidized by hydroxyl radical generated via the Fenton reaction to yield a photoinactive RhB product. RhB absorption at 550 nm was restored when antioxidant agents scavenged hydroxyl radical to protect RhB from oxidation. On the basis of the dose response of antioxidant recovery capacity, a model was developed to calculate the free-radical scavenging ability. This method was sensitive to a wide range of antioxidant activity with ascorbic acid reference set as one; the antioxidant recovery capacity of quercetin was 635 compared to 2 for benzoic acid.