siRNA knockdown of SPHK1 in vivo protects mice from systemic, type-I Allergy.

Systemic anaphylaxis is considered to be a typical immediate hypersensitivity response, determined by the activation of immune cells,
via antigen-induced aggregation of IgE-sensitized FcεRI cells. Perhaps most the important cells, in the immediate hypersensitivity responses, are mast cells. We have previously shown that SPHK1 plays a key role in the intracellular signaling pathways triggered by FceRI aggregation on human
mast cells. More recently, we performed a genome-wide gene expression profiling of human mast cells, sensitized with IgE alone, or stimulated by FcεRI aggregation. We found that sphingosine kinase 1 (SPHK1) was one
of genes activated at the earlier stages of mast cell activation, including during sensitization. Moreover, SPHK1 has been shown, by us and others, to be a key player in the intracellular signaling pathways triggered by
several immune-receptors, including fMLP, C5a, and Fcg- and Fcereceptors. Here we have investigated the in vivo role of SPHK1 in allergy, using a specific siRNA to knockdown SPHK1 in vivo. Our results support a role for
SPHK1 in the inflammatory responses that share clinical, immunological, and histological features of type I hypersensitivity. Thus, mice pretreated with the siRNA for SPHK1 were protected from the IgE mediated allergic
reactions including: temperature changes, histamine release, cytokine production, cell-adhesion molecule expression, and immune cell infiltration into the lungs

Phospholipase D1 Mediates TNFα-Induced Inflammation in a Murine Model of TNFα-Induced Peritonitis

<p><b>Background:</b> Tumor Necrosis Factor alpha (TNF alpha) is a pleiotropic cytokine extensively studied for its role in the pathogenesis of a variety of disease conditions, including in inflammatory diseases. We have recently shown that, in vitro, that TNF alpha utilizes PLD1 to mediate the activation of NF kappa B and ERK1/2 in human monocytes. The aim of this study was to investigate the role(s) played by phospholipase D1 (PLD1) in TNF alpha-mediated inflammatory responses in vivo.</p> <p><b>Methodology/Findings:</b> Studies were performed in vivo using a mouse model of TNF alpha-induced peritonitis. The role of PLD1 was investigated by functional genomics, utilizing a specific siRNA to silence the expression of PLD1. Administration of the siRNA against PLD1 significantly reduced PLD1 levels in vivo. TNF alpha triggers a rapid pyrogenic response, but the in vivo silencing of PLD1 protects mice from the TNFa-induced rise in temperature. Similarly TNF alpha caused an increase in the serum levels of IL-6, MIP-1 alpha and MIP-1 beta: this increase in cytokine/chemokine levels was inhibited in mice where PLD1 had been silenced. We then induced acute peritonitis with TNF alpha. Intraperitoneal injection of TNFa triggered a rapid increase in vascular permeability, and the influx of neutrophils and monocytes into the peritoneal cavity. By contrast, in mice where PLD1 had been silenced, the TNF alpha-triggered increase in vascular permeability and phagocyte influx was substantially reduced. Furthermore, we also show that the TNF alpha-mediated upregulation of the cell adhesion molecules VCAM and ICAM1, in the vascular endothelium, were dependent on PLD1.</p> <p><b>Conclusions:</b> These novel data demonstrate a critical role for PLD1 in TNF alpha-induced inflammation in vivo and warrant further investigation. Indeed, our results suggest PLD1 as a novel target for treating inflammatory diseases, where TNF alpha play key roles: these include diseases ranging from sepsis to respiratory and autoimmune diseases; all diseases with considerable unmet medical need.</p&gt

Mesenchymal stem cells in regenerative medicine: focus on articular cartilage and intervertebral disc regeneration

K

Current Management Strategies in Breast Cancer by Targeting Key Altered Molecular Players

Breast Cancer is second largest disease affecting women worldwide. It remains the most frequently reported and leading cause of death among women in both developed and developing countries. Chemoprevention is one the promising approaches which reduces breast cancer. Tamoxifen and raloxifene are commonly used for treatment of breast cancer in women with high risk, although resistance occurs by tamoxifen after five years of therapy and both drugs cause uterine cancer and thromboembolic events. Aromatase inhibitors are coming up as potential option for prevention in treatment with adjuvant trials in practice. The combination of aromatase inhibitors along with tamoxifen can also be beneficial. For this, clinical trials based on large number of patients with optimal dose and lesser side effects have to be more in practice. Despite the clinical trials going on, there is need of better molecular models which can identify high risk population and new agents with better benefit having less side effects and improved biomarkers for treating breast cancer