Recent achievements in developing selective Gq inhibitors

G proteins are key mediators of G protein-coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM-254890 and FR900359 are two of the very few known selective inhibitors of the G_q subfamily, and are used as unique pharmacological tools in the study of G _q-mediated signaling. Moreover, a peptide-based G protein antagonist-2A (GP-2A), a 27-residue peptide (27mer(I860A)) derived from phospholipase C-β3 (PLC-β3), and the small molecule BIM-46187 have also been characterized as selective G _q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G _q inhibitors. The development and application of G _q-selective inhibitors will expand our knowledge of the structure and function of G protein-mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer.     

Significance of uroplakin III expression in recurrence of solitary muscle non-invasive bladder cancer

Numerous immunohistochemical biomarkers for patients with urothelial bladder cancer have been identified in order to predict their biological behavior. The aim of this present study was to examine the uroplakin III (UPIII) expression in homogenous group of non-muscle invasive bladder cancer and to correlate its value with clinico-pathological characteristics of patients and moreover with COX-2 expression and tumor infiltrating lymphocytes (TILs).     

Effects of the inhibitors of energy metabolism,lonidamine and levamisole,on 5-aminolevulinic-acid-induced photochemotherapy

The ability of endogenously synthesized protoporphyrin IX (PpIX) to damage Chinese hamster lung fibroblasts of the line V79 by exposure to light was examined. This treatment induced reduction of cellular ATP, GTP, of the NADH/NAD⁺ ratio and of oxygen consumption. The present results indicate a close relationship between inhibition of respiration of irradiated cells and their ability to survive, e.g. 1 min of light exposure induced 90% inhibition of oxygen consumption and inactivation of approximately 95% of the cells, while the cellular content of ATP was reduced by only 15%. This indicates that the mitochondria are one of the primary targets of 5-aminolevulinic acid (ALA)-mediated photochemotherapy (PCT). In the present study, ALA-PCT was combined with the modulators of the glycolysis and the respiration chain, levamisole (LEV) and Ionidamine (LND). A synergistic effect of combining ALA-PCT with non-toxic concentrations of LND was observed when LND was given prior to light exposure. This synergism was observed despite a substantial LND-induced inhibition of PpIX formation. At increasing doses of LND (>0.15 mM) the combination treatment becomes less efficient. This is due to the inhibition of PpIX synthesis induced by LND. A synergistic effect of ALA-PDT and LEV was found when LEV was given prior to light exposure. This was at least partly due to an LEV-stimulated effect on ALA-induced PpIX formation. However, it is not clear from the present results whether LEV may perturb energy metabolism in V79 cells since LEV alone did not reduce the energy charge or the NADH/NAD⁺ ratio. When LEV or LND were given after ALA-PCT, these 2 treatment modalities acted in an additive or slightly synergistic manner. © 1996 Wiley-Liss, Inc.     

Metronidazole-induced encephalopathy: a systematic review

Journal of Neurology - Metronidazole, a commonly used antibiotic drug, can cause adverse effects in the central nervous system termed metronidazole-induced encephalopathy, leading to diagnostic...     

Correlation between Body Mass Index and the Occurrence of Postoperative Complications after Surgical Removal of the Lower Third Molar

ObjectivesSwelling, pain and trismus after the surgical removal of the mandibular third molars are the most common and expected postoperative complications. The aim of this cross-sectional study was to assess the association of those postoperative complications and BMI after surgical removal of the mandibular third molars.Material and methods84 patients who required the surgical removal of their lower third molar were enrolled in this study and were divided into 4 groups dependent on their BMI. Data were tested by one-way analysis of variance (Welch''s ANOVA). The differences were tested by the intragroup using the Games-Howell test.ResultsThe effect of BMI on pain had a statistically significant difference within the first 24 postoperative hours: 4 hours (p=0.014), 6 hours (p=0.034, p=0.049), 12 hours (p= 0.00.P=0.023), and 24 hours (p=0.010). For swelling and trismus in the exception on first postoperative day between underweight and normal weight groups (p=0.026), and underweight and overweight groups (p=0.014) no statistically significant correlation was foundConclusionBMI has an impact on a patient’s early postoperative recovery     

Diagnostic and Therapeutic Implications of Type 2 Myocardial Infarction: Review and Commentary

The Task Force for the Universal Definition of Myocardial Infarction recently published updated guidelines for the clinical and research diagnosis of myocardial infarction under a variety of circumstances and in a variety of categories. A type 1 myocardial infarction (MI) is usually the result of atherosclerotic coronary artery disease with thrombotic coronary arterial obstruction secondary to atherosclerotic plaque rupture, ulceration, fissuring, or dissection, causing coronary arterial obstruction with resultant myocardial ischemia and necrosis. Patients with a type 2 MI do not have atherosclerotic plaque rupture. In this latter group of patients, myocardial necrosis occurs because of an increase in myocardial oxygen demand or a decrease in myocardial blood flow. Type 2 MI has been the subject of considerable clinical discussion and confusion. This review by knowledgeable members of the Task Force seeks to help clinicians resolve the confusion surrounding type 2 MI.