JCI table of contents November, 2005

10/06/05

EDITOR'S PICK
Have a taste for fat? Yes! A sensor in the mouth promotes preference for fatty foods

The sense of taste informs the organism about the quality of ingested food. It comprises five sub-modalities that perceive sweet, salt, sour, bitter, and umami stimuli. The possibility for an additional taste modality directed to lipid has often been suggested because many animals exhibit a spontaneous attraction for fats, but the existence of an actual sensor remained a matter of debate.

In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, Phillipe Besnard and colleagues identify the first candidate for lipid detection in the oral cavity.

The authors combine genetic, morphological, behavioral and physiological approaches to pinpoint the multifunctional glycoprotein CD36 (also termed fatty acid transporter, FAT) as the sensor for fat. They show that lingual stimulation of CD36 by fatty acids influences behavioral and digestive physiology. CD36 gene inactivation fully abolishes both the spontaneous preference for fat and the changes in gastrointenstinal secretions mediated by oral delivery of lipids. These findings unveil one potential pathway mediating fat taste.

The data suggest that an alteration in the fat perception system might increase obesity risk through feeding dysregulation.

TITLE: CD36 involvement in orosensory detection of dietary lipids : impact on spontaneous fat preference and digestive secretions

AUTHOR CONTACT:
Phillippe Besnard
Physiologie de la Nutrition ENSBANA, Dijon, France
Phone: +33 380 396 691; Fax: +33 380 396 691; E-mail: pbesnard@u-bourgogne.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=25299

EDITOR'S PICK
Got milk? How breastfeeding affects HIV transmission

Mother to child transmission of HIV accounts for a large proportion of HIV infections in children, with many infected as a result of breastfeeding, which requires transfer of the virus across mucosal barriers. DC-SIGN, a DC lectin receptor, interacts with HIV and is found at high expression levels in tonsillar tissue.

In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, William Paxton and colleagues from the University of Amsterdam clarify how human milk affects the HIV interactions with DC-SIGN that occur during breastfeeding.

The authors show that human milk can block the binding of HIV to the DC-SIGN molecule expressed on dendritic cells and potently inhibit the transfer of HIV-1 to CD4+ T-lymphocytes. The authors identify the component present in human milk that binds to DC-SIGN. The inhibitory effect can be fully alleviated with an antibody recognizing the Lewis X sugar epitope on this factor. Other major milk proteins do not bind to DC-SIGN nor inhibit viral transfer. These results demonstrate that protein associated Lewis X is necessary and sufficient to interact withDC-SIGN and block the interaction of DC-SIGN and HIV.

The identification of a factor in human milk that can block HIV-1 transmission, the ability of the factor to inhibit the virus from binding to DCs, and the potential immunomodulatory implications of such a compound has major implications for the development of agents that can block HIV transmission.

TITLE: Lewis X component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4+ T-lymphocytes

AUTHOR CONTACT:
William Paxton
University of Amsterdam, Amsterdam, Netherlands
Phone: +31 20 566 4739; Fax: +31 20 691 6531; E-mail: w.a.paxton@amc.uva.nl

View the PDF of this article at: https://www.the-jci.org/article.php?id=25105

IMMUNOLOGY
Cytokines swing between good and bad in the war on autoimmune arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that targets the bone and cartilage. The cytokines BLyS and APRIL are present in the serum of RA patients. In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, Cornelia Weyand and colleagues from Emory University examine whether BLyS and APRIL sustain B cell function in arthritic lesions, providing a T cell-independent mechanism of autoimmunity.

The authors studied BLyS and APRIL production, and evidence for their receptors, in 72 tissue biopsies comprising 3 different types of synovitis typical of RA. While BLyS derived from macrophages, APRIL was produced by DCs. The TACI receptor for these two cytokines was expressed on plasma cells, B cells, and T cells. However, TACI positive T cells were absent in germinal-center containing RA lesions. To block the action of BLyS and APRIL in the disease lesions the authors treated human synovium-SCID mouse chimeras with the decoy receptor TACI:Fc. Treatment destroyed germinal centers, blocked immunoglobulin production and inhibited expression of the T cell cytokine IFN-_. Surprisingly, inhibition of BLyS and APRIL in other types of synovitis enhanced IFN-_ production.

Thus, BLyS and APRIL regulate both B and T cell function and have both pro- and anti-inflammatory actions in RA. These data help explain why RA encompasses several types of synovial inflammation, with distinct disease mechanisms and differential responsiveness to therapy.

TITLE: BLyS and APRIL in Rheumatoid Arthritis

AUTHOR CONTACT:
Cornelia Weyand
Emory University School of Medicine, Atlanta, GA USA
Phone: (404) 727-7310; Fax: (404) 727-7371; E-mail: cweyand@emory.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25265

PHYSIOLOGY
New role for hemin in pancreatic injury

In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, M. Bishr Omary and colleagues from Stanford University identify a novel protective role for hemin in experimental mouse pancreatitis and provide a cellular mechanistic basis for such protection. These studies provide a foundation for further studies towards a potential new therapeutic approach for the treatment of human pancreatitis.

TITLE: Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via HO-1 induction

AUTHOR CONTACT:
M. Bishr Omary
Stanford University, Palo Alto, CA USA
Phone 1: 650-493-5000 x63140; E-mail: mbishr@stanford.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24912

PHYSIOLOGY
Knowing more about pneumonia and its relation to bad bacteria

In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, Laurent Genestier and colleagues from INSERM demonstrate that Panton-Valentine leukocidin (PVL) induces polymorphonuclear neutrophils (PMN) apoptosis by directly targeting mitochondria. PVL is a toxin secreted by Staphylococcus aureus that is associated with necrotizing pneumonia.

The authors show that PVL creates pores in the mitochondrial outer membrane. Furthermore the apoptosis detected in vivo in patients who died from necrotizing pneumonia suggests that apoptosis could be directly involved in the pathology of necrotizing pneumonia. This is important since S. aureus necrotizing pneumonia is rapidly and highly lethal in young immunocompetent patients and antibiotic therapy frequently fails.

TITLE: Staphylocccus aureus Panton-Valentine leukocidin directly targets mitochondria and induces Bax-independent apoptosis of human neutrophils

AUTHOR CONTACT:
Laurent Genestier
INSERM, Lyon, France
Phone: 33 (0)4 72116792; Fax: 33 (0)4 72110764; E-mail: genestier@cervi-lyon.inserm.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=22684

PHYSIOLOGY
New therapy for inflammatory bowel flares up

Inflammatory bowel disorders may be due to excessive responses to antigens present in normal bacteria. In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, Stefan Fichtner-Feigl and colleagues from the NIH successfully treat both murine colitis and murine Crohn disease with NF-kappaB decoy oligodeoxynucleotides. The authors find that blockade of NF-kappaB activity is useful for both major forms of inflammatory bowel disease. This suggests a new therapeutic approach for treating human inflammatory bowel disorders.

TITLE: Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-kappaB decoy oligonucleotides

AUTHOR CONTACT:
Stefan Fichtner-Feigl
National Institutes of Health, Bethesda, MD USA
Phone: 301-496-9662; Fax: 301-402-2240; E-mail: sfichtner@niaid.nih.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=24792

PHYSIOLOGY
New tumor vessels require macrophages to bud

Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1beta promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remained unclear.

In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, Mayumi Ono and colleagues from Kyushu University examined the association between IL-1beta-induced angiogenesis and cell inflammation.

The authors found that IL-1beta induced neovascularization in the mouse cornea at rates comparable to VEGF, with neutrophil and macrophage infiltration. Lewis lung carcinoma tumors expressing human IL-1beta developed neovasculature with macrophage infiltration and enhanced tumor growth in wild-type but not MCP-1–/– mice lacking macrophages. A COX2 inhibitor reduced tumor growth, angiogenesis, and macrophage infiltration. Thus, macrophage involvement might be a prerequisite for IL-1beta-induced neovascularization and tumor progression.

TITLE: Infiltration of COX2-expressing macrophages is a prerequisite for IL-1beta-induced neovascularization and tumor growth

AUTHOR CONTACT:
Mayumi Ono
Kyushu University, Fukuoka, Japan
Phone: 81 92 642 6098; Fax: 81 92 642 6203; E-mail: mayumi@biochem1.med.kyushu-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=23298

METABOLIC DISEASE
Fattening up the targets for obesity and diabetes treatment

Gs-alpha is a G protein alpha-subunit required for hormone-stimulated cAMP production, which is important for glucose and lipid metabolism. In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, Lee Weinstein and colleagues from the NIH examined the metabolic roles of Gs signaling pathways in liver by generating mice with liver- specific Gs-alpha deficiency (LGsKO mice).

These mice had lower random glucose and insulin, greater than normal glucose tolerance and insulin sensitivity, and reduced adiposity but they failed to develop fasting hypoglycemia, most likely due to increased renal gluconeogenesis. The mice had reduced expression of PGC-1 and gluconeogenic enzymes in liver, increased circulating free fatty acid levels, increased lipogenesis in liver, and increased serum triglyceride levels in the fasted state. These results show that Gs-alpha pathways in liver may be a potential therapeutic target for diabetes and obesity.

TITLE: Increased glucose tolerance and reduced adipocity in the absence of fasting hypoglycemia in mice with liver-specific Gs-alpha deficiency

AUTHOR CONTACT:
Lee Weinstein, Lee
NIDDK/NIH, Bethesda, MD USA
Phone: 301-402-2923; Fax: 301-402-0374; E-mail: leew@amb.niddk.nih.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=24196

ONCOLOGY
Melanoma gets a new NOTCH in its belt, and a new treatment strategy

Notch is a cellular receptor that is necessary for proper tissue development and maintenance. The Notch signaling pathway is involved in several cancers, but its role in melanoma was poorly characterized. In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, Meenhard Herlyn and colleagues from the Wistar Institute describe a specific role of Notch1 signaling in primary melanoma progression.

The authors show that the Notch1 pathway is activated in human melanoma. Blocking Notch signaling suppressed, while constitutive activation of the Notch1 pathway enhanced primary melanoma cell growth but had little effect on metastatic melanoma cells. Activation of Notch1 signaling enables primary melanoma cells to gain metastatic capability.

Notch effects on primary melanoma cells is mediated through beta-catenin. These findings not only define a novel role for Notch1 signaling in promoting primary melanoma progression but also unveil a beta-catenin-dependent mechanism for the stage- specific role of Notch1 signaling in melanoma progression. Therefore, members of the Notch pathway and beta-catenin pathway are potential targets for therapy in melanoma and skin cancers.

TITLE: Activation of Notch1 signaling is required for beta-catenin–mediated human primary melanoma progression

AUTHOR CONTACT:
Meenhard Herlyn
The Wistar Institute, Philadelphia, PA USA
Phone: 215-898-3950; Fax: 215-898-0980; E-mail: herlynm@wistar.upenn.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25001

NEUROBIOLOGY
Alzheimer disease and the blood brain barrier: is Abeta transport the key?

Increased production of the amyloid-beta (Abeta) peptide can lead to Abeta aggregation and buildup in the brain and rare familial forms of early onset Alzheimer disease (AD). Aggregation and buildup of Abeta also appears to contribute to the common, late-onset form of AD, which accounts for 99% of cases, however, there is not strong evidence of Abeta over-production in late-onset AD.

This suggests that there is an age-associated alteration in brain Abeta clearance that contributes to late-onset AD. There is substantial clearance of Abeta from the brain to the blood via the blood-brain-barrier (BBB). Thus, understanding which molecules at the BBB are responsible for Abeta clearance is important. Several transporters have been identified on the BBB that mediate Abeta efflux, however if and how these transporters contribute to Abeta deposition as plaques remain unclear.

In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, David Holtzman and colleagues from Washington University demonstrate that P-glycoprotein is required for Abeta transport across the BBB and that ablation of this transporter at the BBB increases Abeta deposition in a mouse model of AD.

P-glycoprotein has been a major pharmaceutical target by conferring resistance to many chemotherapy regimens, as well as its role in eliminating a wide variety of medicines via liver uptake. It is possible that chronic treatment with these types of drugs could alter P-glycoprotein function, thereby altering Abeta transport and the risk of developing AD. The findings in this manuscript, in addition to its implications in understanding Abeta transport via the BBB and its therapeutic implications, suggests that researchers should begin to explore whether drugs currently being utilized in humans that affect PgP activity, alter risk for AD.

TITLE: P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer's disease mouse model

AUTHOR CONTACT:
David Holtzman
Washington University, St. Louis, MO USA
Phone: 314-362-9872; E-mail: holtzman@neuro.wustl.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25247

Source: Eurekalert & others

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