High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound With Anti-Diabetic Efficacy in Db/db Mice.

High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound with Anti-Diabetic Efficacy in db/db Mice.

PLoS One. 2013; 8(5): e63861
Zhang M, Feng Y, Wang J, Zhao J, Li T, He M, Yang D, Nosjean O, Boutin J, Renard P, Wang MW

G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic ? cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents. HubMed – drug


Why Are Women Dying When They Reach Hospital on Time? A Systematic Review of the ‘Third Delay’

PLoS One. 2013; 8(5): e63846
Knight HE, Self A, Kennedy SH

The ‘three delays model’ attempts to explain delays in women accessing emergency obstetric care as the result of: 1) decision-making, 2) accessing services and 3) receipt of appropriate care once a health facility is reached. The third delay, although under-researched, is likely to be a source of considerable inequity in access to emergency obstetric care in developing countries. The aim of this systematic review was to identify and categorise specific facility-level barriers to the provision of evidence-based maternal health care in developing countries.Five electronic databases were systematically searched using a 4-way strategy that combined search terms related to: 1) maternal health care; 2) maternity units; 3) barriers, and 4) developing countries. Forty-three original research articles were eligible to be included in the review. Thirty-two barriers to the receipt of timely and appropriate obstetric care at the facility level were identified and categorised into six emerging themes (Drugs and equipment; Policy and guidelines; Human resources; Facility infrastructure; Patient-related and Referral-related). Two investigators independently recorded the frequency with which barriers relating to the third delay were reported in the literature. The most commonly cited barriers were inadequate training/skills mix (86%); drug procurement/logistics problems (65%); staff shortages (60%); lack of equipment (51%) and low staff motivation (44%).This review highlights how a focus on patient-side delays in the decision to seek care can conceal the fact that many health facilities in the developing world are still chronically under-resourced and unable to cope effectively with serious obstetric complications. We stress the importance of addressing supply-side barriers alongside demand-side factors if further reductions in maternal mortality are to be achieved. HubMed – drug


Brevilin A, a Novel Natural Product, Inhibits Janus Kinase Activity and Blocks STAT3 Signaling in Cancer Cells.

PLoS One. 2013; 8(5): e63697
Chen X, Du Y, Nan J, Zhang X, Qin X, Wang Y, Hou J, Wang Q, Yang J

Signal abnormalities in human cells usually cause unexpected consequences for individual health. We focus on these kinds of events involved in JAK-STAT signal pathways, especially the ones triggered by aberrant activated STAT3, an oncoprotein which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases. By establishing a STAT3 signal based high-throughput drug screening system in human lung cancer A549 cells, we have screened a library from natural products which contained purified compounds from medicinal herbs. One compound, named Brevilin A, exhibited both strong STAT3 signal inhibition and STAT3 signal dependent cell growth inhibition. Further investigations revealed that Brevilin A not only inhibits STAT3 signaling but also STAT1 signaling for cytokines induced phosphorylation of STAT3 and STAT1 as well as the expression of their target genes. In addition, we found Brevilin A could attenuate the JAKs activity by blocking the JAKs tyrosine kinase domain JH1. The levels of cytokine induced phosphorylation of STATs and other substrates were dramatically reduced by treatment of Brevilin A. The roles of Brevilin A targeting on JAKs activity indicate that Brevilin A may not only be used as a STAT3 inhibitor but also a compound blocking other JAK-STAT hyperactivation. Thus, these findings provided a strong impetus for the development of selective JAK-STAT inhibitors and therapeutic drugs in order to improve survival of patients with hyperactivated JAKs and STATs. HubMed – drug


Small Heterodimer Partner-Targeting Therapy Inhibits Systemic Inflammatory Responses through Mitochondrial Uncoupling Protein 2.

PLoS One. 2013; 8(5): e63435
Yang CS, Yuk JM, Kim JJ, Hwang JH, Lee CH, Kim JM, Oh GT, Choi HS, Jo EK

The orphan nuclear receptor, small heterodimer partner (SHP), appears to play a negative regulatory role in innate immune signaling. Emerging evidence warrants further study on the therapeutic targeting of SHP to suppress excessive and deleterious inflammation. Here we show that fenofibrate, which targets SHP, is required for inhibiting systemic inflammation via mitochondrial uncoupling protein 2 (UCP2). In vivo administration of fenofibrate ameliorated systemic inflammatory responses and increased survival upon experimental sepsis through SHP. An abundance of SHP was observed in mice fed fenofibrate and in cultured macrophages through LKB1-dependent activation of the AMP-activated protein kinase pathway. Fenofibrate significantly blocked endotoxin-triggered inflammatory signaling responses via SHP, but not via peroxisome proliferator-activated receptor (PPAR)-?. In addition to the known mechanism by which SHP modulates innate signaling, we identify a new role of fenofibrate-induced SHP on UCP2 induction, which is required for the suppression of inflammatory responses through modulation of mitochondrial ROS production. These data strongly suggest that the SHP-inducing drug fenofibrate paves the way for novel therapies for systemic inflammation by targeting SHP. HubMed – drug