Design, synthesis and antidiabetic activity studies of purine derivatives / 药学学报

Based our previous work, twelve purine derivatives were designed and synthesized as dual modulators of GPR119 and DPP-4by conjugating the GPR119 activating and DPP-4 inhibiting fragments with the position 6 and 9 of purine core via an approach of merged pharmacophores. Compound 11, bearing 2-fluoro-4-methylsulphonyl anilide and cyanopyrrolidine moieties, exhibited the most potent GPR119 agonistic activities (EC50 = 0.33 μmol·L-1, IA = 71.1%) and DPP-4 inhibitory (58.4% inhibition at 10 μmol·L-1, 21.2% inhibition at 1 μmol·L-1) activities in the in vitro antidiabetic study. Subsequently, we performed studies on structure activity relationships and molecular docking to guide the further drug design.

Hypoglycemic Mechanism of Gegen Qinliantang： An Exploration Based on GPR119/cAMP/GLP-1 Pathway / 中国实验方剂学杂志

ObjectiveTo explore the effects of Gegen Qinliantang（GGQL） on the proliferation and apoptosis of intestinal epithelial cells as well as on the expression of cyclic adenosine monophosphate （cAMP）， G protein-coupled receptor 119 （GPR119）， and glucagon-like peptide-1 （GLP-1）， so as to explore its potential hypoglycemic mechanism. MethodTwenty-five Wistar rats were gavaged with GGQL at the dose of 23 g·kg-1 crude drug， twice a day， which meant that 6 mL was administered into each rat per day for preparing the GGQL-containing serum. After seven consecutive times of administration， the intestinal epithelial L （NCI-H716） cells were cultured with different concentrations （1%， 2.5%， 5%， 7.5%， and 10%） of GGQL. The cell proliferation was evaluated using cell counting kit-8 （CCK-8） and the apoptosis by flow cytometry. The GLP-1 and cAMP contents in cell supernatant were determined by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein GLP-1 and GPR119 levels were assayed by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. ResultCompared with the control group， GGQL significantly reduced the proliferation of NCI-H716 cells（P<0.05）. As the GGQL concentration increased， its inhibitory effect became more obvious. GGQL at each concentration significantly promoted the apoptosis of NCI-H716 cells （P<0.05）. Compared with the control group， GGQL significantly up-regulated the expression of cAMP， GLP-1， and GPR119 （P<0.05）. The results showed that the effect of GGQL was positively correlated with its concentration， and 10% GGQL exhibited the best effect. ConclusionGGQL effectively inhibits the proliferation of NCI-H716 cells and promotes their apoptosis， and it may promote the secretion of GLP-1 by up-regulating the expression of cAMP and GPR119.

Clinical Usefulness of ¹⁸F-FC119S Positron-Emission Tomography as an Auxiliary Diagnostic Method for Dementia: An Open-Label, Single-Dose, Evaluator-Blind Clinical Trial

Recent advances in G protein coupled receptor 119 agonists / 药学学报

G protein-coupled receptor 119 (GPR119) has been a promising target for the treatment of type 2 diabetes. It can not only directly promote insulin secretion, but also indirectly increase insulin secretion by stimulating the release of glucose-dependent GIP/CLP-1 without causing hypoglycemia. The remarkable advantages of small molecule GPR119 agonists make it one of the research hotspots for the development of type 2 diabetes drugs. This article reviews the anti-diabetic small molecules based on the GPR119 target in the past five years.

Preliminary study on dosimetry verification of VMAT on the basis of TG119 report / 中华放射肿瘤学杂志

Objective To preliminarily verify the feasibility of utilizing TG119 report to commission the volumetric modulated arc therapy (VMAT) plans.Methods Based on the test cases mentioned in TG119 report,7-/9-field intensity-modulated radiation therapy (IMRT) and dual-arc VMAT plans were devised by using two types of beam energy (6 MV and 10 MV) in the Eclipse TPS system according to the requirement of this report.All the plans were verified using 0.125cc semiflex thimble ionization chamber,MatriXX and Delta 4,respectively.The final results were statistically compared with the results measured by multiple institutions in the TG119 report.Results The resuhs of both IMRT and VMAT plans met the requirement of the TG119 report.The discrepancy of point dose in the high/low dose region of VMAT plans using different photon beams was ranged from-2.55％ to 2.55％,and ± 1.85％ for the IMRT plans.The percentage of γ passing points (±3％/3 mm) for the IMRT plans using 6 MV and 10 MV photon beams was 99.38％ and 99.53％,99.32％ and 99.46％ for the VMAT plans.The γ passing rate of the compound field exceeded 98％.Conclusions The VMAT plans with 6 MV and 10 MV photon beams meet the requirement of the TG119 report.TG119 report provides certain guidance for establishing a benchmark for dosimetry verification of the VMAT plans.

Mechanism of GPR119 in regulating lipid metabolism and anti-atherosclerosis by hypoxia-inducible factor-1α/ vascular endothelial growth factor pathway / 中华内分泌代谢杂志

Objective To investigate the effect and mechanism of G protein coupled receptor 119 ( GPR119) in regulating lipid metabolism. Methods ( 1) Macrophage THP-1 was induced by oxidized low density lipoprotein ( oxLDL) to the formation of lipid foam cells, protein expression of GPR119, hypoxia-inducible factor-1α(HIF-1α), vascular endothelial growth factor (VEGF) were detected by Western blotting. (2) Constructing GPR119 over-expressed and low-expressed plasmids, the plasmids were transfected into THP-1 cells which induced by oxLDL. The lipid content in macrophages was observed by oil red O staining. Cholesterol efflux was detected by liquid scintillation counter. The mRNA and protein expressions of HIF-1α, VEGF were detected by reverse transcription PCR and Western blotting. (3) Constructing GPR119, HIF-1α, and VEGF over-expressed plasmids, then co-transfection of GPR119 and HIF-1α/VEGF plasmids. The lipid content in macrophages was observed by oil red O staining. Cholesterol efflux was detected by liquid scintillation counter. Results Compared with the control group, the lipid droplets were densely distributed in macrophages, with a large number and volume. The protein expression of GPR119 was significantly decreased and HIF-1α, VEGF were significantly increased in macrophages induced by oxLDL ( P<0.05). After over-expression of GPR119, the lipid droplets were sparsely distributed and the number was significantly reduced in macrophages, the lipid droplets were mostly located in the area around the cells. The cholesterol efflux was significantly increased ( P<0. 01 ) . The mRNA and protein expressions of HIF-1α and VEGF were significantly decreased ( P<0.01) . On the contrary, in the GPR119 inhibition group, the lipid droplets were densely distributed in macrophages, with a large number and volume. The lipid droplets even covered the nuclei. The cholesterol efflux was significantly reduced (P<0.05). The mRNA and protein expression of HIF-1α, VEGF were significantly increased ( P<0.05) . After GPR119 were co-expressed with HIF-1αand VEGF, the number of lipid droplets was increased, lipid droplets were dense and bulky in oxLDL-induce macrophages. The cholesterol efflux was inhibited. Conclusion GPR119 can regulate lipid metabolism and possibly by down-regulating the expression of HIF-1αand VEGF.

Mechanism of GPR119 in regulating lipid metabolism and anti-atherosclerosis by hypoxia-inducible factor-1α/ vascular endothelial growth factor pathway / 中华内分泌代谢杂志

Objective@#To investigate the effect and mechanism of G protein coupled receptor 119 (GPR119) in regulating lipid metabolism.@*Methods@#(1) Macrophage THP-1 was induced by oxidized low density lipoprotein (oxLDL) to the formation of lipid foam cells, protein expression of GPR119, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) were detected by Western blotting. (2) Constructing GPR119 over-expressed and low-expressed plasmids, the plasmids were transfected into THP-1 cells which induced by oxLDL. The lipid content in macrophages was observed by oil red O staining. Cholesterol efflux was detected by liquid scintillation counter. The mRNA and protein expressions of HIF-1α, VEGF were detected by reverse transcription PCR and Western blotting. (3) Constructing GPR119, HIF-1α, and VEGF over-expressed plasmids, then co-transfection of GPR119 and HIF-1α/VEGF plasmids. The lipid content in macrophages was observed by oil red O staining. Cholesterol efflux was detected by liquid scintillation counter.@*Results@#Compared with the control group, the lipid droplets were densely distributed in macrophages, with a large number and volume. The protein expression of GPR119 was significantly decreased and HIF-1α, VEGF were significantly increased in macrophages induced by oxLDL (P<0.05). After over-expression of GPR119, the lipid droplets were sparsely distributed and the number was significantly reduced in macrophages, the lipid droplets were mostly located in the area around the cells. The cholesterol efflux was significantly increased (P<0.01). The mRNA and protein expressions of HIF-1α and VEGF were significantly decreased (P<0.01). On the contrary, in the GPR119 inhibition group, the lipid droplets were densely distributed in macrophages, with a large number and volume. The lipid droplets even covered the nuclei. The cholesterol efflux was significantly reduced (P<0.05). The mRNA and protein expression of HIF-1α, VEGF were significantly increased (P<0.05). After GPR119 were co-expressed with HIF-1α and VEGF, the number of lipid droplets was increased, lipid droplets were dense and bulky in oxLDL-induce macrophages. The cholesterol efflux was inhibited.@*Conclusion@#GPR119 can regulate lipid metabolism and possibly by down-regulating the expression of HIF-1α and VEGF.

YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

Eficiencia del Gasto Total en Salud: Análisis no paramétrico en una muestra amplia de países / Total health expenditure efficiency: non-parametric analysis in a large sample of countries

RESUMEN Objetivo Mostrar la utilidad de una herramienta estadística no paramétrica para medir la eficiencia de 190 países en la producción de status de salud, así como conocer los determinantes de dicha eficiencia. Métodos Con datos de 2009, y utilizando la técnica de Envolvente de Datos, se estima la frontera de eficiencia, utilizando como insumo al gasto total en salud per cápita y como productos la tasa de mortalidad infantil y la esperanza de vida al nacer. Se realiza un análisis de los determinantes de la eficiencia del gasto mediante el uso de modelos Tobit. Resultados Las naciones del continente africano presentan menor eficiencia técnico-asignativa, aunque mayor eficiencia de escala. La calidad de las instituciones muestra un impacto estadísticamente significativo sobre los niveles de eficiencia técnico-asignativa y de escala. El porcentaje de financiamiento del gasto por parte de aseguradoras privadas incide sobre la eficiencia técnico-asignativa mientras que el porcentaje de urbanización lo hace sobre la eficiencia de escala. Discusión El hecho de que más del 70 % de los países presente rendimientos decrecientes del gasto en salud sugeriría que, una vez alcanzados ciertos estándares mínimos de calidad de vida, el efecto marginal de cada dólar adicional destinado a salud no es sustancial. En países pobres donde el gasto en salud presenta rendimientos crecientes, el desempeño sanitario podría mejorar significativamente con incrementos marginales del gasto. Las estructuras de financiamiento del gasto en salud podrían estar influyendo sobre la eficiencia técnico-asignativa y el grado de urbanización podría hacerlo sobre la eficiencia de escala.(AU)

Objective To measure the efficiency of 190 countries in producing health results and the factors that determine such efficiency. Methodology A data envelopment analysis was conducted on worldwide data from the year 2009 in order to estimate the efficient frontier, based on total health expenditure per capita, as well on infant mortality rate and life expectancy at birth. At the same time, an analysis of the determinants of expenditure efficiency was performed through Tobit models. Results African nations have lower technical and allocative efficiency, but higher scale efficiency. The quality of institutions has a statistically significant impact on the levels of technical and allocative efficiency and on the levels of scale efficiency. The percentage of health expenditure financed by private insurers has an impact on technical and allocative efficiency, while urbanization rates affect the scale efficiency. Discussion the fact that more than 70 % of countries show decreasing returns suggest that, once certain minimal standards of life quality are achieved, the marginal effect of each additional dollar assigned to health is not substantial. Conversely, in poor countries, where the expenditure in health presents increasing returns, the health performance could be substantially better by marginally raising the expenditure. On the other hand, financing structures of health expenditures may influence technical-allocative efficiency, while urbanization levels may impact scale efficiency (source: MeSH, NLM).(AU)

Changes of Poison Data Characteristics Collected from Telephone Response in 1339 and 119: Discrepancy in Characteristics of Post-toxin Exposure Data Obtained through Telephone Counselling Provided by 1339 and 119

PURPOSE: The aim of this study was to compare the toxicologic profiles and outcome of poisoned patients by comparing the data obtained through telephone counselling, each provided by emergency medical information center (1339) and emergency dispatch center (119). METHODS: We analyzed the telephone-based poison exposure data before and after Seoul 1339 merged to 119. We compared the Seoul 1339 call response data in 2008 with Seoul and Busan 119 call response data between 2014 and 2016. We analyzed the changes in the trend and quality of data obtained, as well as the quality of service provided by each center before and after this reallocation, by comparing the data each obtained through telephone counselling. RESULTS: The data was collected for a total of 2260 toxin exposure related calls made to Seoul 1339 in 2009, and 1657 calls to 119 in Seoul and Busan between 2014 and 2016. Significant difference was observed for age, sex, and reason for exposure to toxic substance between the two groups. CONCLUSION: After the integration of 1339 with 119, 119 focused on role of field dispatch and hospital transfer, lacking the consulting on drug poisoning. Moreover, data on exposure to toxic substances at the pre-hospital stage indicate that drug information and counseling are missing or unknown. In addition, first aid or follow-up instructions are not provided. Thus, systematic approach and management are required.

Surveillance of antiviral resistance markers in Argentina: detection of E119V neuraminidase mutation in a post-treatment immunocompromised patient

Although vaccines are the best means of protection against influenza, neuraminidase inhibitors are currently the main antiviral treatment available to control severe influenza cases. One of the most frequent substitutions in the neuraminidase (NA) protein of influenza A(H3N2) viruses during or soon after oseltamivir administration is E119V mutation. We describe the emergence of a mixed viral population with the E119E/V mutation in the NA protein sequence in a post-treatment influenza sample collected from an immunocompromised patient in Argentina. This substitution was identified by a real-time reverse transcriptase polymerase chain reaction (RT-PCR) protocol and was confirmed by direct Sanger sequencing of the original sample. In 2014, out of 1140 influenza samples received at the National Influenza Centre, 888 samples (78%) were A(H3N2) strains, 244 (21.3%) were type B strains, and 8 (0.7%) were A(H1N1)pdm09 strains. Out of 888 A(H3N2) samples, 842 were tested for the E119V substitution by quantitative RT-PCR: 841 A(H3N2) samples had the wild-type E119 genotype and in one sample, a mixture of viral E119/ V119 subpopulations was detected. Influenza virus surveillance and antiviral resistance studies can lead to better decisions in health policies and help in medical treatment planning, especially for severe cases and immunocompromised patients.

Effect of TWS119 on the activities of human SGC-7901 and γδ T cells in vitro and its mechanism / 中国药学杂志

OBJECTIVE: To study the antitumor activity of TWS119 and its effect on the killing activity of γδT cells in vitro. METHODS: CCK-8 assay was used for detecting the influence of TWS119 on the proliferation of SGC-7901 and γδT cells and the cytotoxic activity of γδT cells to SGC-7901 cells. The cell apoptosis was measured by flow cytometric analysis. The protein expression was examined by Western blot analysis. RESULTS: It was found that TWS119 could inhibit the growth and induce the apoptosis of SGC-7901 cells. The expression of Bcl-2 in SGC-7901 cells treated with TWS119 was downregulated, while p-ERK1/2 and p-STAT3 were up-regulated. In addition, TWS119 at 0.5-4.0μmol · L-1 could promote the growth of γδT cells and enhance the cytotoxic activity of γδT cells to SGC-7901 cells especially at 4.0 μmol · L-1 for 72 h. Furthermore, TWS119 could upregulate the expression of Bcl-2 and inhibit the expression of p-ERK1/2 and p-STAT3. CONCLUSION: TWS119 in some concentrations can inhibit the growth of SGC-7901 cells, promote the 78T cells growth and enhance the cytotoxic activity of γδT cells to SGC-7901 cells, and the mechanism may be involve in Wnt, ERK1/2, Bcl-2 and p-STAT3 signaling pathways.

Synergistic Effects of Chios Gum Mastic Extract and Low Level Laser Therapy on Osteoblast Differentiation

In the present study, we evaluated the effect of CGM on osteogenic differentiation of cultured osteoblasts, and determined whether combination treatment with LLLT had synergistic effects on osteogenic differentiation. The results indicated that CGM promoted proliferation, differentiation, and mineralization of osteoblasts at the threshold concentration of 10 µg/ml; whereas, CGM showed cytotoxic properties at concentrations above 100 µg/ml. ALP activity and mineralization were increased at concentrations above 10 µg/ml. CGM in concentrations up to 10 µg/ml also increased the expression of osteoblast-activated factors including type I collagen, BMP-2, RUNX2, and Osterix. The CGM (50 µg/ml) and LLLT (80 mW for 15 sec) combination treatment group showed the highest proliferation levels, ALP activity, and mineralization ratios. The combination treatment also increased the levels of phosphorylated forms of p38, ATF2, PKD, ERK, and JNK. In addition, the osteoblast differentiation factors including type I collagen, BMP-2, RUNX2, and Osterix protein levels were clearly increased in the combination treatment group. These results suggested that the combination treatment of CGM and LLLT has synergistic effects on the differentiation and mineralization of osteoblastic cells.

TWS119 upregulates CCR5 expression of γδT cells by inhibiting STAT3 phos-phorylation / 中国免疫学杂志

Objective:To investigate the mechanisms of TWS119 induced CCR5 expression in hunman γδT cells. Methods:After treatment with various concentrations of TWS119 for 48h, the expression of CCR5 in γδT cells were detected by flow cytometry. The p-STAT3 and GAPDH expression were examined by Western blot analysis. Results: TWS119 could upregulate the expression of CCR5 in dose dependent manner. Western blot analysis revealed that TWS119 inhibit phosphorylation of STAT3,but had no significant impact on GAPDH. In addition, pretreatment of γδT cells with 0. 5 μmol/L STAT3 specific phosphorylation inhibitor Stattic could upregulate the expression of CCR5 and enhance the TWS119 induced CCR5 expression. Conclusion: TWS119 could upregulate CCR5 expression of γδT cells by inhibiting STAT3 phosphorylation in vitro.

Pharmacology and pharmacokinetics studies of MBX-2982, a novel GPR119 agonists / 中国药学杂志

OBJECTIVE: To observe the glucose tolerance and evaluate the hypoglycemic effect of MBX-2982 respectively in the normal mice and in the KK-Ay mice. And further pharmacokinetics investigation was experimented in rats. METHODS: The influence of glucose tolerance was evaluated in KM mice which underwent a single dose of MBX-2982. Body weight, fasting blood glucose, glucose tolerance, triglyceride, serum insulin were all tested in order to evaluate the hypoglycemic effect on KK-Ay mice. The pharmacokinetics of MBX-2982 suspension and solution were investigated in rats to calculate the oral bioavailability. RESULTS: The blood glucose of each test point were all reduced after MBX-2982 (3, 10, 30 mg · kg-1) were administered orally to KM mice. After MBX-2982 (10, 30 mg · kg-1) treatment to KK-Ay mice for 4 weeks, the fasting blood glucose and triglyceride were significantly reduced and the serum insulin was remarkably increased. Meanwhile the area under glucose curve was significant reduced of 30 mg · kg-1. After oral administration of MBX-2982 (4 mg · kg-1) in rats, the oral bioavailability of suspension (0.4% CMC) and solution (DMSO-Cremopor EL-NS = 1:1:8) were 35.2% and 98.2% receptively. CONCLUSION: Animal experiment results show that the MBX-2982 as a GPR119 agonists had a good hypoglycemic effect. The absolute bioavailability of the solution is closed to 100%, which is higher than that of suspension.

Advances of anti-diabetic drugs based on new targets / 中国药科大学学报

@#With the deepening of research, different new anti-diabetic drug targets have been discovered and reported, several categories of anti-diabetic drugs(linagliptin, exenatide, dapagliflozin, etc. )have been brought to the market and some new drugs acting on different targets are in late-stage clinical trials. All these progresses provide new means for overcoming diabetes. GPR119, GPR120, GPR40, AMPK, apelin receptor and GSK3β are anti-diabetic targets with great research values in current days and the future. This article reviews the mechanisms, drugs and research advances with respect to the above-mentioned targets.

Quercus infectoria Gall Extract Enhanced the Proliferation and Activity of Human Fetal Osteoblast Cell Line (hFOB 1.19)

Background: The present study investigated the effects of Quercus infectoria (QI) gall extract on the proliferation, alkaline phosphatase (ALP), osteocalcin, and the morphology of a human fetal osteoblast cell line (hFOB 1.19). Methods: The cells were cultured in Dulbecco’s modified eagle medium F12 supplemented with a 10% fetal bovine serum, a 1% penicillin/streptomycin and were treated with QI at various concentrations (0.1 to 99.0 μg/mL) for 72 hours. The levels of ALP and osteocalcin were measured at day 1, 3, 7, 10, and 14 and were compared among the negative control, pamidronate and QI groups. Results: The median effective concentration (EC50) of hFOB 1.19 treated with QI was 10.30 μg/mL. This concentration was more effective compared to the control drug, pamidronate (EC50 at 16.09 μg/mL). The ALP and osteocalcin levels of hFOB 1.19 treated with QI from day 7 and onwards were significantly increased in a time and concentration-dependent manner. Interestingly, from day 7 until day 14, the ALP and osteocalcin levels were highest in the cells treated with QI compared to the other two groups. The morphology of cells treated with QI was uniformly elongated, higher in number and over-confluent. Conclusion: After treatment with QI, cell proliferation enhanced and ALP and osteocalcin levels increased.

Effect of glycogen synthase kinase-3β inhibitor TWS119 on proliferation and phenotypic characteristics of human γδT cells in vitro / 中国免疫学杂志

Objective:To investigate the effect of glycogen synthase kinase-3β inhibitor TWS119 on hunman γδT cells growth and phenotypic characteristics. Methods:Using γδT medium to cultivate human peripheral blood γδT cells in vitro. After co-cultured with different concentrations of glycogen synthase kinase-3β( GSK-3β) inhibitor 4, 6-disubstituted pyrrolopyrimidine ( TWS119 ) for indicated time,growth curve and Wnt/β-catenin activation of in each group were determined by CCK-8 and Western blot assays. The CD62L and CD45RA expression theγδT cells were detected using flow cytometry. Results:Wnt/β-catenin pathway ofγδT cells could activate by TWS119. In the first group,TWS119 could upregulate the expression of CD62L and CD45RA in dose dependent manner while inhibit the growth and ratio of γδT cells. In the second group,TWS119 could promote the growth and ratio of γδT cells with the increase in concentration from 0 μmol/L to 4. 0 μmol/L and decreased thereafter. Besides,TWS119 could promote the expression of CD62L in a dose-dependent and had no effect on the CD45RA. Conclusion: Human γδT cells isolated from peripheral blood treated with TWS119 gave rise to two subsets of CD45RA+CD62L+γδT cells and CD62L+γδT cells.

Conserved regions of Plasmodium vivax potential vaccine candidate antigens in Sri Lanka: conscious in silico analysis of prospective conformational epitope regions

OBJECTIVES@#To do mapping and modeling of conformational B cell epitope regions of highly conserved and protective regions of three merozoitecandidate vaccine proteins of Plasmodium vivax (P. vivax), ie. merozoite purface protein-1 (PvMSP-1), apical membrane antigen -1 domain ∏ (PvAMA1-D∏) and region ∏ of the Duffy binding protein (PvDBP∏), and to analyze the immunogenic properties of these predicted epitopes.@*METHODS@#3-D structures of amino acid haplotypes from Sri Lanka (available in GeneBank) of PvMSP-119 (n=27), PvAMA1-D∏ (n=21) and PvDBP∏ (n=33) were modeled. SEPPA, selected as the best online server was used for conformational epitope predictions, while prediction and modeling of protein structure and properties related to immunogenicity was carried out with Geno3D server, SCRATCH Protein Server, NetSurfP Server and standalonesoftware, Genious 5.4.4.@*RESULTS@#SEPPA revealed that regions of predicted conformational epitopes formed 4 clusters in PvMSP-I19, and 3 clusters each in PvAMA1-D∏ and PvDBP∏, all of which displayed a high degree of hydrophilicity, contained solvent exposed residues, displayed high probability of antigenicity and showed positive antigenic propensity values, that indicated high degree of immunogenicity.@*CONCLUSIONS@#Findings of this study revealed and confirmed that different parts of the sequences of each of the conserved regions of the three selected potential vaccine candidate antigens of P. vivax are important with regard to conformational epitope prediction that warrants further laboratory experimental investigations in in vivo animal models.

HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies

G-protein coupled receptor 119 (GPR119) has emerged as a novel target for the treatment of type 2 diabetes mellitus. GPR119 is involved in glucose-stimulated insulin secretion (GSIS) from the pancreatic beta-cells and intestinal cells. In this study, we identified a novel small-molecule GPR119 agonist, HD047703, which raises intracellular cAMP concentrations in pancreatic beta-cells and can be expected to potentiate glucose-stimulated insulin secretion from human GPR119 receptor stably expressing cells (CHO cells). We evaluated the acute efficacy of HD047703 by the oral glucose tolerance test (OGTT) in normal C57BL/6J mice. Then, chronic administrations of HD047703 were performed to determine its efficacy in various diabetic rodent models. Single administration of HD047703 caused improved glycemic control during OGTT in a dose-dependent manner in normal mice, and the plasma GLP-1 level was also increased. With respect to chronic efficacy, we observed a decline in blood glucose levels in db/db, ob/ob and DIO mice. These results suggest that HD047703 may be a potentially promising anti-diabetic agent.