Journal Of Clinical Investigation Early Table Of Contents: Nov. 13, 2008

Main Category: Biology / Biochemistry
Also Included In: Genetics;  Liver Disease / Hepatitis;  Cardiovascular / Cardiology
Article Date: 14 Nov 2008 - 7:00 PDT

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The protein TRPA1 feels the pain of alkaline pH

Many biological conditions cause a rise in the pH of the environment in which cells in our body exist (i.e., the environment becomes alkaline). Some of these conditions, e.g., respiratory alkalosis due to hyperventilation and the high blood pH caused by urinary tract infection, cause pain sensation, but the mechanisms by which sensory nerve cells detect alkaline pH are not well defined. However, new research, by Makoto Tominaga and colleagues, at the National Institutes of Natural Sciences, Japan, has now shown that alkaline pH activates a protein known as TRPA1 in human cell lines and mouse nerve cells. Furthermore, injection of an alkaline reagent (ammonium chloride) into the underside of the hindpaw of normal mice and mice lacking TRPA1 caused pain-related behaviors in normal mice only. As these results indicate that alkaline pH causes pain sensation in mice through activation of TRPA1, the authors suggest that activation of this protein might be the mechanism underlying some of the human alkaline pH-related pain sensations whose mechanisms are currently unknown.

TITLE: Intracellular alkalization causes pain sensation through activation of TRPA1 in mice

AUTHOR CONTACT:
Makoto Tominaga
National Institutes of Natural Sciences, Okazaki, Japan.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35957

How the APOE gene can modify your risk for Alzheimer disease

One of the hallmarks of the brain of an individual with Alzheimer disease is the accumulation of amyloid-beta peptide (A-beta), something that is believed to be toxic to many brain cells (specifically neurons) and to therefore contribute to the underlying cause of disease. Berislav Zlokovic and colleagues, at the University of Rochester Medical School, have now generated data in mice that mechanistically links a genetic risk factor for Alzheimer disease with accumulation of A-beta in the brain.

Individuals carrying one form of the APOE gene, APOE4, have a greater risk of developing Alzheimer disease than individuals with other forms of the APOE gene (APOE2 and APOE3). In the study, the proteins generated by the different forms of the APOE gene were found to differentially affect the clearance of A-beta from the brain of mice. Specifically, A-beta binding to apoE4 led to substantially slower clearing of A-beta from the brain than A-beta binding to either apoE2 or apoE3. The authors therefore suggest that a decreased rate of A-beta clearance from the brain might contribute to the increased risk of developing Alzheimer disease observed for individuals carrying the APOE4 form of the APOE gene.

TITLE: apoE isoform-specific disruption of amyloid-beta peptide clearance from mouse brain

AUTHOR CONTACT:
Berislav V. Zlokovic
University of Rochester Medical School, Rochester, New York, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36663

Understanding how environmentally relevant levels of arsenic cause liver disease

Arsenic is a common contaminant of drinking water, and consuming arsenic-contaminated water increases an individual's risk of developing a number of diseases, including serious liver diseases. Aaron Barchowsky and colleagues, at the University of Pittsburgh, have now characterized in mice some of the molecular changes that cause liver damage after consumption of arsenic-contaminated water.

The authors studied changes in the liver of mice that drank water containing low doses of arsenite and observed damage to cells known as liver sinusoidal endothelial cells (SECs), a key event in liver disease caused by arsenic. Similar damage was observed when SECs were cultured in vitro in the presence of arsenic. Further analysis revealed a crucial role for a protein complex that contains the proteins p47 and Nox2. This protein complex generates chemicals known as reactive oxygen species, which damage cells. As inhibiting either the function of this complex or the reactive oxygen species it generated blocked the ability of arsenic to damage cultured SECs, the authors suggest that reactive oxygen species generated by the protein complex containing p47 and Nox2 have a central role in damaging SECs following exposure to environmentally relevant levels of arsenic.

TITLE: Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase-generated superoxide

AUTHOR CONTACT:
Aaron Barchowsky
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35092

Sealed with a KISs: how the protein KIS controls repair of blood vessels

Damage to the lining of our blood vessels triggers a repair process that seeks to restore the integrity and function of the vessels. Sometimes this repair process is over zealous and causes diseases known as vascular diseases; e.g., pulmonary hypertension, which occurs when blood pressure in the blood vessels near the lungs increases dramatically causing shortness of breath, dizziness, and ultimately (in many cases) heart failure. One characteristic of vascular diseases is that cells in the blood vessel wall known as VSMCs move to the site of the injury and start growing and dividing (proliferating). Elizabeth Nabel and colleagues, at the National Institutes of Health, Bethesda, have now provided new insight into the molecular control of VSCM migration and proliferation in mice, providing potential new therapeutic targets for vascular diseases.

In the study, mice lacking the protein KIS exhibited an accelerated damaging repair process after blood vessels were injured, and this was associated with increased numbers of VSCMs at the site of injury. More detailed analysis revealed that in the absence of KIS the VSCMs showed increased migration to the site of injury, but they were unable to proliferate. The propensity to migrate was a result of increased levels of the protein stathmin, and stathmin-deficient mice were partially protected from the damaging repair process. The authors therefore suggest that VSCM migration has a crucial role in the process of repairing injured blood vessels and that the molecular pathways that control this might provide new targets for the treatment of vascular diseases.

TITLE: KIS protects against adverse vascular remodeling by opposing stathmin-mediated VSMC migration in mice

AUTHOR CONTACT:
Elizabeth G. Nabel
National Institutes of Health, Bethesda, Maryland, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33206

MSDCs and iNKT cells: immune cells with opposing effects after influenza A virus infection

Some individuals who become infected with the influenza A virus, in particular those who are very young or elderly and those whose immune systems are compromised, die from the infection. Although inflammatory responses are thought to contribute to death from infection with influenza A virus, the mechanisms underlying this are not well defined. Now, however, Vincenzo Cerundolo and colleagues, at the Weatherall Institute of Molecular Medicine, United Kingdom, have used a mouse model of influenza A infection to provide evidence that immune cells known as iNKT cells have a beneficial immunomodulatory role.

In the study, mice lacking iNKT cells died more frequently following infection with influenza A virus than did mice with iNKT cells. This increased mortality was associated with expansion of a population of immune cells known as myeloid-derived suppressor cells (MDSCs), which suppressed the antiviral immune response. Infusion of iNKT cells into the mice normally lacking these cells abolished the effects of MDSCs, restoring the antiviral immune response and increasing the survival rate. As cells similar to MDSCs were found in the blood of individuals infected with influenza A virus and their in vitro suppressive activity could be diminished by agents that activate iNKT cells, the authors suggest that harnessing iNKT cells to diminish the suppressive activity of MDSCs during infection with influenza A virus might be beneficial.

TITLE: Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans

AUTHOR CONTACT:
Vincenzo Cerundolo
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36264

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Article adapted by Medical News Today from original press release.
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Source: Karen Honey
Journal of Clinical Investigation