Recent data about insulin signaling system and insulin resistance states

Insulin is the key hormone regulating glucose homeostasis and has many cellular effects on metabolism, growth, and differentiation. Its action is mediated through a specific cell surface receptor. The first step following insulin binding consists of receptor autophosphorylation and stimulation of its tyrosine kinase activity. Among the multiple substrates the insulin receptor substrate-1 is the major cytoplasmic substrate. It binds several Src homology 2 proteins through its multiple tyrosine phosphorylation sites: phosphatidylinositol 3-kinase, the Ras guanine nucleotide-releasing complex growth factor receptor-bound protein-2/son of sevenless protein, the tyrosine phosphatase Syp, and the adapter protein Nek. Insulin receptor substrate-1 is essential for many, but not all of the insulin biological responses. Recently, a primary alternative substrate, insulin receptor substrate-2, was purified and cloned. Numerous biochemical abnormalities of the insulin signaling system lead to insulin resistance. The recent data about the molecular mechanisms of insulin action may provide new insights into the pathophysiology and therapy of diabetes mellitus and other insulin resistance states.Biomedical Reviews 1996; 5: 47-55

Signal transduction in keratinocyte proliferation and differentiation

Keratinocytes, a key cellular component for both homeostasis and pathology of the skin, secrete a number of growth factors and cytokines, and their proliferation and differentiation are stimulated by a variety of biological factors. The major mechanism by which keratinocytes respond to extracellular signals is change in protein phosphorylation. In this review, we focus on factors known to influence keratinocyte proliferation and differentiation, such as epidermal growth factor family, nerve growth factor, transforming growth factor-β, insulin-like growth factor-1, keratinocyte growth factor, hepatocyte growth factor, cytokines. A hypothesis for a dual role of epidermal growth factor in keratinocyte proliferation and differentiation is proposed.Biomedical Reviews 1997; 8: 73-85

Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance

Seliciclib (R-Roscovitine) was identified as an inhibitor of CDKs and has undergone drug development and clinical testing as an anticancer agent. In this review, the authors describe the discovery of Seliciclib and give a brief summary of the biology of the CDKs Seliciclib inhibits. An overview of the published in vitro and in vivo work supporting the development as an anti-cancer agent, from in vitro experiments to animal model studies ending with a summary of the clinical trial results and trials underway is presented. In addition some potential non-oncology applications are explored and the potential mode of action of Seliciclib in these areas is described. Finally the authors argue that optimisation of the therapeutic effects of kinase inhibitors such as Seliciclib could be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division

Advocating the need of a systems biology approach for personalised prognosis and treatment of B-CLL patients

The clinical course of B-CLL is heterogeneous. This heterogeneity leads to a clinical dilemma: can we identify those patients who will benefit from early treatment and predict the survival? In recent years, mathematical modelling has contributed significantly in understanding the complexity of diseases. In order to build a mathematical model for determining prognosis of B-CLL one has to identify, characterise and quantify key molecules involved in the disease. Here we discuss the need and role of mathematical modelling in predicting B-CLL disease pathogenesis and suggest a new systems biology approach for a personalised therapy of B-CLL patients

The role of CD247 polymorphisms in Bulgarian patients with systemic lupus erythematosus

Decreased expression of the TCR ζ-chain has been reportedin several autoimmune and inflammatory diseases. Recent evidence suggeststhat this deficiency may be due to polymorphisms in the CD247gene. A total 52 patients with systemic lupus erythematosus (SLE) and95 healthy controls of Bulgarian ethnicity were genotyped for 837C&gt;G,rs1052230, 844A&gt;T, and rs1052231 using a TaqMan genotyping assay.None of the two polymorphisms appeared associated with the diseases.On the other hand, we have found that the -837GG genotype and the Gallele were associated with hematological disease. The -844AA genotypeand the A allele appeared associated with the hematological disease aswell. The -843AA genotype and the A allele were found to be associatedwith antinuclear antibody (ANA) tests and immunological disease. Anassociation was found between the -837G allele and arthritis. The AGhaplotype was found to be associated with hematological disease, ANA,and immunological disease. Our preliminary data confirm the previousfindings that the CD247 polymorphisms are mainly associated with theclinical outcome of the disease and less with susceptibility.</p

Antitumor activity of Bulgarian herb Tribulus terrestris L. on human breast cancer cells

Medicinal plants have been intensively studied as a source of antitumor compounds. Due to the beneficial climate conditions Bulgarian herbs have high pharmacological potential. Currently, the antitumor effect of the Bulgarian medicinal plant Tribulus terrestris L. on human cancer cell lines is not studied. The main active compounds of the plant are the steroid saponins.The present study aims to analyze the effect on cell viability and apoptotic activity of total extract and saponin fraction of Bulgarian Tribulus terrestris L. on human breast cancer (MCF7) and normal (MCF10A) cell lines. Antitumor effect was established by МТТ cell viability assay and assessment of apoptotic potential was done through analysis of genomic integrity (DNA fragmentation assay) and analysis of morphological cell changes (Fluorescence microscopy). The results showed that total extract of the herb has a marked dose-dependent inhibitory effect on viability of MCF7 cells (half maximal inhibitory concentration is 15 μg/ml). Cell viability of MCF10A was moderately decreased without visible dose-dependent effect. The saponin fraction has increased inhibitory effect on breast cancer cells compared to total extract. Morphological changes and DNA fragmentation were observed as markers for early and late apoptosis predominantly in tumor cells after treatment. Apoptotic processes were intensified with the increase of treatment duration.The obtained results are the first showing selective antitumor activity of Bulgarian Tribulus terrestris L. on human cancer cells in vitro. Apoptotic processes are involved in the antitumor mechanisms induced by the herb. This results give directions for future investigations concerning detailed assessment of its pharmacological potential

IL-1RN VNTR Polymorphism in Adult Dermatomyositis and Systemic Lupus Erythematosus

Polymorphisms in the cytokine genes and their natural antagonists are thought to influence the predisposition to dermatomyositis (DM) and systemic lupus erythematosus (SLE). A variable number tandem repeat (VNTR) polymorphism of 86 bp in intron 2 of the interleukin-1 receptor antagonist (IL-1RN) gene leads to the existence of five different alleles which cause differences in the production of both IL-1RA (interleukin-1 receptor antagonist) and IL-1 . The aim of this case-control study was to investigate the association between the IL-1RN VNTR polymorphism and the susceptibility to DM and SLE in Bulgarian patients. Altogether 91 patients, 55 with SLE and 36 with DM, as well as 112 unrelated healthy controls, were included in this study. Only three alleles were identified in both patients and controls ((1) four repeats, (2) two repeats, and (3) five repeats). The IL-1RN * 2 allele ( = 0.02, OR 2.5, and 95% CI 1.2-5.4) and the 1/2+2/2 genotypes were found prevalent among the SLE patients ( = 0.05, OR 2.6, and 95% CI 1-6.3). No association was found between this polymorphism and the ACR criteria for SLE as well as with the susceptibility to DM. Our results indicate that the IL-1RN VNTR polymorphism might play a role in the susceptibility of SLE but not DM