An overview of targets and therapies for glioblastoma multiforme.

Glioblastoma multiforme (GBM) affects individuals above 65 years of age and has low median survival rate. Due to limited treatment options, lack of effective diagnosis, and palliative care, there is an urgent need to develop new therapeutic strategies to combat GBM. This review provides an overview of the current clinical trial scenario with a special focus on new targets, repurposed drugs, and technologies in the field of GBM.

A structural basis for lithium and substrate binding of an inositide phosphatase.

Inositol polyphosphate 1-phosphatase (INPP1) is a prototype member of metal-dependent/lithium-inhibited phosphomonoesterase protein family defined by a conserved three-dimensional core structure. Enzymes within this family function in distinct pathways including inositide signaling, gluconeogenesis, and sulfur assimilation. Using structural and biochemical studies, we report the effect of substrate and lithium on a network of metal binding sites within the catalytic center of INPP1.

Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome.

Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.

Genes involved in pancreatic islet cell rejuvenation.

Pancreas plays an important role in maintaining the glucose homeostasis. The deterioration of β-cells in the pancreas is a crucial factor in the progression of diabetes mellitus; therefore, the restoration of β-cell mass and its function is of vital importance for effective therapeutic strategies. The precise mechanism for increase in functional β-cell mass is still unknown.

Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model.

Aim: Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent.

Material And Methods: DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source.

Antihyperglycemic effect of Annona squamosa hexane extract in type 2 diabetes animal model: PTP1B inhibition, a possible mechanism of action?

Aim: The mechanism of action of Annona squamosa hexane extract in mediating antihyperglycemic and antitriglyceridimic effect were investigated in this study.

Materials And Methods: The effects of extract on glucose uptake, insulin receptor-β (IR-β), insulin receptor substrate-1 (IRS-1) phosphorylation and glucose transporter type 4 (GLUT4) and phosphoinositide 3-kinase (PI3 kinase) mRNA expression were studied in L6 myotubes. The in vitro mechanism of action was tested in protein-tyrosine phosphatase 1B (PTP1B), G-protein-coupled receptor 40 (GPR40), silent mating type information regulation 2 homolog 1 (SIRT1) and dipeptidyl peptidase-IV (DPP-IV) assays.

RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes.

Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent.

Discovery of conformationally rigid 3-azabicyclo[3.1.0]hexane-derived dipeptidyl peptidase-IV inhibitors.

The induction of conformationally restricted N-(aryl or heteroaryl)-3-azabicyclo[3.1.0]hexane derivatives at P(2) region of compounds of 2-cyanopyrrolidine class was explored to develop novel DPP-IV inhibitors.

From a glucocentric to a lipocentric approach towards metabolic syndrome.

Insulin resistance, the essential component of metabolic syndrome, has traditionally been defined from a glucocentric viewpoint, with glucotoxicity playing a lead role. However, as overabundant circulating fatty acids are now known to be overt contributors, there is a paradigm shift in the understanding of metabolic syndrome acknowledging the importance of lipotoxicity as a major perpetuator of insulin resistance. Ectopic accumulation of fat in liver, adipose, muscle and pancreatic islets, provokes insulin resistance through various mechanisms.

Topiramate and type 2 diabetes: an old wine in a new bottle.

Topiramate, a marketed antiepileptic drug, has been used to treat seizures and allied neurological problems since 1999. Recently, a series of newer findings for the use of topiramate have cropped up, which include Type 2 diabetes and obesity. In a series of clinical studies, a subset of neurological patients with Type 2 diabetes mellitus (T2DM) serendipitously showed better glycaemic control when treated with topiramate.

Combination of dipeptidylpeptidase IV inhibitor and low dose thiazolidinedione: preclinical efficacy and safety in db/db mice.

Thiazolidinediones (TZDs) are currently the most efficacious class of oral antidiabetics. However, they carry the burden of weight gain and haemodilution, which may lead to cardiovascular complications. The present study was designed to ascertain whether a combination of dipeptidyl peptidase IV (DPP IV) inhibitor with low dose of a thiazolidinedione absolves TZD associated weight gain and oedema without compromising its efficacy.

Fatty acid receptors as new therapeutic targets for diabetes.

G-protein-coupled receptors (GPCRs) are key regulators of several physiological functions. Their roles in cellular signal transduction have made them the target for majority of all currently prescribed drugs. Additionally, there are many orphan GPCRs that provide potential novel therapeutic targets.

Small molecule antagonists of complement receptor type 3 block adhesion and adhesion-dependent oxidative burst in human polymorphonuclear leukocytes.

The leukocyte integrin complement receptor type 3 (CR3, Mac-1, CD11b/CD18) is the predominant beta(2) integrin receptor of polymorphonuclear leukocytes (PMNs). This cell surface receptor plays a central role in innate immunity against pathogens as well as being a major cellular effector of inflammation and tissue injury. Two small molecules, compounds 1 and 2, have been identified, that interact with CR3 and prevent CR3 from binding to its natural ligand, C3bi.