JCI table of contents March 1, 2005

02/17/05

EDITOR PICK

Licorice licks herpes virus infection

Many of the viruses that infect people can sit suppressed in cells for long periods of time, but when they are reactivated can cause painful symptoms and distress. While treatment for active infections is progressing nicely, it remains very challenging to treat latent infections. In particular, progress in treating herpesvirus latency has lagged behind.

Appearing in the March 1 print edition of the Journal of Clinical Investigation, Ornella Flore and colleagues from New York University School of Medicine show, for the first time, that it is possible to interfere with herpesvirus latency by inhibiting the expression of Kaposi sarcoma–associated herpes virus (KSHV) latent genes. KSHV is the virus that is associated with Kaposi sarcoma, a disease characterized by tumors in tissues below the surface of the skin, often found in patients with immunodeficiencies like HIV and AIDS.

These investigators demonstrate that a compound found in licorice, glycyrrhizic acid (GA), can kill cells that are latently infected with KSHV. GA induces cell death by altering levels of proteins involved in latency like LANA and v-cyclin.

The possibility that GA-like compounds might be useful in treating clinical KSHV infections is of considerable interest. GA represents the first example of an anti-viral agent that specifically targets the expression of a herpesvirus gene required to maintain the virus in the latent state. The discovery of such drugs provides an opportunity for developing novel anti-herpesvirus agents to control, and perhaps eradicating latent viral infections.

In an accompanying commentary, Jeffrey Cohen states, "a compound present in licorice may seem like an unlikely candidate for the treatment of virus-associated cancers…derivates of GA might be used in the future for treating human diseases caused by latent virus infections."

TITLE: Glycyrrhizic acid alters of Kaposi sarcoma–associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes

AUTHOR CONTACT:
Ornella Flore
NYU School of Medicine, New York, NY USA
Phone: 212-263-5313; Fax: 212-263-7933; E-mail: ornella.flore@med.nyu.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/642

ACCOMPANYING COMMENTARY:

TITLE: Licking latency with licorice

AUTHOR CONTACT:
Jeffrey I. Cohen
National Institutes Of Health, Bethesda, MD USA
Phone: 301-496-5265; Fax: 301-496-7383; E-mail: jcohen@niaid.nih.gov

This article is available at: http://www.jci.org/cgi/content/full/115/3/591

EDITOR PICK

A new route for treatment of IBD

Crohn disease and ulcerative colitis are two major inflammatory bowel disorders resulting from a variety of genetic, immunological, and environmental factors. Toll-like receptors (TLRs) work to protect the immune system by recognizing foreign microbes and defending against them by regulating proteins called cytokines and chemokines to boost host survival.

Previous data had shown that TLR9, in particular, could set into motion an anti-inflammatory program to ease colitis in experimental animals. In a study appearing in the March 1 issue of the Journal of Clinical Investigation, Eyal Raz and colleagues from the University of California San Diego, explored how TLR9 eased inflammation and offered relief in colitis.

In this study, researchers administered TLR9 activators to two different groups of mice that appear similar because both of them do not produce T or B immune cells, but are actually genetically different, because they come from different strains. TLR9 activators, given to one group of mice, called RAG mice, inhibited the severity of experimental colitis but had no effect on the other group of mice, called SCID mice.

This differential response to TLR9 prompted the investigators to explore the cellular and the molecular events that caused one strain to respond to therapy and the other to be resistant. Using a variety of approaches, the investigators found that TLR9-induced protection is mediated through the induction of a protein called type I IFN, which suppresses inflammation. The resistance to protection in the SCID mice is due to defective induction of type I IFN by TLR stimulation in mice of this genotype.

Further, they show that the inability of SCID to produce IFN is due to a mutation that impairs TLR9 signaling in this strain. Thus, type I IFN has a protective role in colon injury and protects against colonic inflammation.

In an accompanying commentary, Stefan Wirtz and Marcus Neurath state that, "These results underscore a potentially important protective role for type I IFNs in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for intestinal inflammatory conditions."

TITLE: Toll-like receptor 9-–induced type I IFN protects mice from experimental colitis

AUTHOR CONTACT:
Eyal Raz
University of California, San Diego La Jolla, CA USA
Phone: 858-534-5444; Fax: 858-534-5399; E-mail: eraz@ucsd.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/695

ACCOMPANYING COMMENTARY:

TITLE: Illuminating the role of type I IFNs in colitis

AUTHOR CONTACT:
Markus Neurath
University of Mainz, Mainz, Germany
Phone: 49-6131-172374; Fax: 49-6131-39175508; E-mail: neurath@1-med.klinik.uni-mainz.de

This article is available at: http://www.jci.org/cgi/content/full/115/3/586

EDITOR PICK

Boosting blood vessels with BDNF

When an artery or blood vessel is blocked or narrowed, the consequence is decreased blood flow, and therefore decreased oxygen, to the target organ. This is called ischemia and can result in serious, permanent damage. A goal in ischemia therapy is to induce formation of new blood vessels (called angiogenesis) in order to revascularize an area (neovascularization), be it the heart, the limbs, the brain, or some other organ.

The most widely used agents to promote angiogenesis are growth factors known as VEGF and FGF. However, in clinical settings, these have only been able to form new and stable blood vessels for a limited time. VEGF may also cause abnormal vascular leaks and aberrant masses of blood vessels. Recently, another factor – a neurotrophic factor called BDNF (brain derived neurotrophic factor) – has been shown to regulate the vasculature of the developing heart, but the mechanism for this interesting action was unclear.

In the March 1 issue of the Journal of Clinical Investigation, Shahin Rafii and Barbara Hempstead along with colleagues from Cornell University, delve into the mechanisms underlying the angiogenic effects of BDNF in adult blood vessels.

The researchers show that BDNF and VEGF have comparable efficacy in inducing growth of tiny blood vessels in organs that contain cells that express the BDNF receptor TrkB. The also show that BDNF is as effective as VEGF in promoting recovery of the blood flow and vessel density in ischemic limbs. BDNF has local effects on TrkB expressing cells and also recruits a subset of blood stem cells that contribute to neo-angiogenesis. This special population of cells responds specifically to BDNF and contributes to neovascularization.

In an accompanying commentary, Dan Duda and Rakesh Jain write, "This work establishes that neurotrophins are novel proangiogenic factors. Understanding the molecular and cellular underpinnings of this interaction may prove to be crucial for both regenerative medicine and cancer therapy."

Therapy with BDNF may increase the number of functional and stable blood vessels in patients with insufficient blood supply to various organs -– diseases of vascular insufficiency. The selective angiogenic activity of BDNF compared to other growth factors, could lead to the development of organ specific angiogenesis therapy. BDNF now is a novel therapeutic protein to induce organ specific angiogenesis to increase the number of functional and stable vessels.

TITLE: Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors

AUTHOR CONTACT:
Shahin Rafii
Cornell Medical School, New York, NY USA
Phone: 212-746-2070; Fax: 212-746-8866; E-mail: srafii@med.cornell.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/653

ACCOMPANYING COMMENTARY:

TITLE: Pleiotropy of tissue-specific growth factors: from neurons to vessels via bone marrow

AUTHOR CONTACT:
Rakesh K. Jain
Harvard Medical School, Boston, MA USA
Phone: 617-726-4083; Fax: 617-724-1819; E-mail: jain@steele.mgh.harvard.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/596

MICROBIOLOGY

A fungus among us

Cryptococcosis is a human disease characterized by inflammation of the brain. It is caused by inhalation of a fungus called Cryptococcus neoformans. In the March 1 issue of the Journal of Clinical Investigation, John Panepinto and colleagues from the University of Illinois at Chicago describe a new class of proteins and a signaling network used by the fungus to wreak havoc. They pinpoint a protein called Vad1 (virulence-associated DEAD box RNA helicase-encoding protein) as a regulator of virulence genes. The paper provides new and important information on how the fungus Cryptococcus neoformans causes disease. In an accompanying commentary, Lena Heung and Maurizio Del Poeta state, "results from future studies…may be the key to effectively clearing cryptococcal infections and improving quality of life for many patients."

TITLE: The DEAD-box RNA helicase Vad1 regulates multiple virulence-associated genes in Cryptococcus neoformans

AUTHOR CONTACT:
John Panepinto
University of Illinois at Chicago, Chicago, IL USA
Phone: 312-996-8068; Fax: 312-996-5704; E-mail: panepijc@uic.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/632

ACCOMPANYING COMMENTARY:

TITLE: Unlocking the DEAD-box: a key to cryptococcal virulence?

AUTHOR CONTACT:
Maurizio Del Poeta
Medical University of South Carolina, Charleston, SC USA
Phone: 843-792-8381; Fax: 843-792-8565; E-mail: delpoeta@musc.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/593

PHYSIOLOGY

Kallikrein mutations make arteries abnormal

Artery function is known to depend on lipid genetics, but other genetic factors that affect arterial physiology are poorly documented. In a study appearing in the March 1 issue of the Journal of Clinical Investigation, Michel Azizi and colleagues from the Clinical Investigation Center in Paris show that human subjects with a common mutation in kallikrein that causes decreased activity, have abnormal artery function. Kallikrein is an enzyme involved in vascular physiology. Subjects carrying the kallikrein mutation may be at increased risk for progression of vascular diseases. In an accompanying commentary, Oscar Carretero states, "these findings raise the intriguing possibility that decreased kallikrein-kinin system activity may play an important role in the pathogenesis of vascular remodeling and disease, while increased activity may have a beneficial effect."

TITLE: Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans

AUTHOR CONTACT:
Michel Azizi
Clinical Investigation Center, Paris, France
Phone: 33-1-5609-2911; Fax: 33-156-09-2929; E-mail: michel.azizi@egp.ap-hop-paris.fr

This article is available at: http://www.jci.org/cgi/content/full/115/3/780

ACCOMPANYING COMMENTARY:

TITLE: Vascular remodeling and the kallikrein-kinin system

AUTHOR CONTACT:
Oscar Carretero
Henry Ford Hospital, Detroit, MI USA
Phone: 313-916-2103; Fax: 313-916-1479; E-mail: ocarret1@hfhs.org

This article is available at: http://www.jci.org/cgi/content/full/115/3/588

PHYSIOLOGY

Essential tremor gets shaken up

Essential tremor is the most common movement disorder in man, but the cause of the disease is not known. In the March 1 issue of the Journal of Clinical Investigation, Leslie Morrow and colleagues from the University of North Carolina present the first genetic animal model of essential tremor. The researchers show that mice with a specific neurotransmitter receptor subunit (GABA A receptor alpha 1) rendered inactive exhibit the clinical characteristics of genetic essential tremor and respond to the same drugs as patients with essential tremor. This provides a consistent model in which to test novel potential treatments. An accompanying commentary by Joseph Jankovic and Jeffrey Noebels stresses that this new mutant mouse "provides an excellent model for tracing the developmental cascade of signaling changes that leads to a tremulous phenotype." This paper represents the first direct demonstration that GABA A receptors help maintain proper motor function and provides evidence for the etiology of essential tremor involving loss of GABA A receptor alpha1 subunits. Alcohol withdrawal tremor is also associated with decreased expression of GABAA receptor alpha1 subunits.

TITLE: Genetic essential tremor in gamma-aminobutryric acid-A receptor alpha-1 subunit knockout mice

AUTHOR CONTACT:
A. Leslie Morrow
University of North Carolina School of Medicine, Chapel Hill, NC USA
Phone: 919-966-7682; Fax: 919-966-9099; E-mail: morrow@med.unc.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/774

ACCOMPANYING COMMENTARY:

TITLE: Genetic mouse models of essential tremor: are they essential?

AUTHOR CONTACT:
Joseph Jankovic
Baylor College of Medicine, Houston, TX USA
Phone: 713-798-5998; Fax: 713-798-6808; E-mail: josephj@bcm.tmc.edu

This article is available at: http://www.jci.org/cgi/content/full/115/3/584

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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