News From The Journal Of Clinical Investigation: July 26, 2010

Main Category: Heart Disease
Also Included In: Immune System / Vaccines;  Cancer / Oncology
Article Date: 27 Jul 2010 - 5:00 PDT

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CARDIOVASCULAR DISEASE: Flushing out key limitations to a drug that protects against heart attack

The drug niacin is used to modulate fat levels in the blood and thereby reduce the risk of a heart attack. However, noxious effects on the skin that have been termed 'flushing' limit its use in the clinic. Understanding the mechanisms underlying flushing might identify therapeutic targets that could suppress flushing and enable wider use of niacin. Insight into this has now been provided by a team of researchers, led by Stefan Offermanns, at the Max-Planck-Institute for Heart and Lung Research, Germany, that studied in mice the mechanisms underlying flushing caused by niacin, which targets the protein GPR109A.

Specifically, the team found that different molecular pathways in different cell types in the skin mediated the two phases of niacin-induced flushing. The early phase of flushing was mediated via GPR109A on Langerhans cells and involved the protein COX-1, while the late phase was mediated via GPR109A on skin cells (keratinocytes) and involved COX-2. Inhibitors of COX-1 and COX-2 selectively blocked the anticipated phases of flushing. The authors hope that these data will lead to the development of new approaches to mitigate the skin toxicity that limits the use of niacin in the clinic.

In an accompanying commentary, Richard Dunbar and Joel Gelfand, at the University of Pennsylvania, Philadelphia, note that these data bring us closer to understanding the noxious skin effects of niacin. However, they caution that the readouts of flushing assessed in mouse models (redness) might not correlate with some of the other noxious skin effects (such as pain and itching) that niacin induces.

Title: Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice

Accompanying Commentary
Title: Seeing red: flushing out instigators of niacin-associated skin toxicity

IMMUNOLOGY: Function of rare immune cell uncovered

Basophils are immune cells that are found in very small numbers in the blood. We currently have very little understanding of their function, but such information could be obtained by the development of a basophil-deficient mouse. A team of researchers, led by Hajime Karasuyama, at Tokyo Medical and Dental University Graduate School, Japan, has now generated mice in which basophils can be selectively deleted by administration of diptheria toxin. Furthermore, using these mice, they identified an essential and nonredundant role for basophils in the immune response to ticks that mediate babesiosis, Q fever, and Russian encephalitis in humans. The authors suggest that their data might open new avenues of research for the development of strategies for controlling tick-borne diseases and that their mice will be useful in determining the functions of basophils in health and disease, a sentiment echoed in an accompanying commentary by Booki Min, at the Cleveland Clinic Foundation, Cleveland.

Title: Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks

Accompanying Commentary
Title: Mice that "conditionally" lack basophils, AT LAST

ONCOLOGY: The protein Sema3E: the black sheep in the Sema3 family

Sema3 proteins are traditionally considered to be inhibitors of tumor growth and spread (metastasis). However, a team of researchers, led by Luca Tamagnone, at the University of Torino Medical School, Italy, and Massimiliano Mazzone, at Flanders Institute for Biotechnology, Belgium, has now determined that although the Sema3 protein Sema3E inhibits the growth of human tumor cells after transplantation into mice, it actually promotes their invasiveness and metastasis to distant sites. Consistent with this, expression of Sema3E and the protein to which it binds (Plexin D1) correlated with metastatic progression of human tumors. The authors therefore suggest that targeting Sema3E and the molecules to which it binds to mediate its effects might provide a way to block tumor metastasis. However, in an accompanying commentary, Michael Klagsbrun and Akio Shimizu, at Children's Hospital Boston, Boston, caution that more clinical data are needed to confirm that Sema3E has a central role in tumor metastasis in humans.

Title: Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

Accompanying Commentary
Title: Semaphorin 3E, an exception to the rule

Source:
Karen Honey
Journal of Clinical Investigation

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