JCI table of contents, December 15 2004

12/09/04

Oxidants link obesity to diabetes

Individuals with the metabolic syndrome are at risk of coronary heart disease, stroke, vascular disease, and type 2 diabetes. Although risk factors for this syndrome are known to include obesity, physical inactivity, and genetic factors, the mechanistic role of obesity is not completely understood. In the December 15 issue of the Journal of Clinical Investigation, Iichiro Shimomura and researchers from Osaka University, Japan, show that fat cells of obese mice produce increased levels of toxic oxygen molecules known as reactive oxygen species (ROS) as well as the enzyme NADPH oxidase. Furthermore, these cells express decreased levels of antioxidative enzymes that are responsible for destroying these toxic forms of oxygen. The effect of this oxidative stress causes changes in the production of fat-derived hormones known as adipocytokines.

The authors found that treatment of these mice with apocynin – an antioxidant that inhibits NADPH oxidase – reduced ROS production in fat cells, restored adipocytokine production to normal, improved diabetes, and reduced the levels of fat present in the blood and liver.

The results suggest that accumulated fatty tissue is a major source of ROS in obesity and acts as an early trigger of the metabolic syndrome. While it is too early to suggest that taking antioxidants may counter the development of obesity-associated metabolic syndrome, the steps leading to excess ROS generation may represent a potentially useful therapeutic target.

TITLE: Increased oxidative stress in obesity and its impact on metabolic syndrome

AUTHOR CONTACT:
Iichiro Shimomura
Department of Internal Medicine and Molecular Science, Osaka University, Osaka, Japan.
Phone: 81-6-6879-3730; Fax: 81-6-6879-3739; E-mail: ichi@imed2.med.osaka-u.ac.jp.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1752.


How platelets help cancer invade other tissues

Malignant tumors have the ability to transfer disease from organ to another. The depletion of blood platelets by many mechanisms has been shown to result in a reduction of metastases to lung and bone in experimental tumor transplant models. This effect has long been attributed to platelet-mediated enhancement of tumor cell survival and tumor cell escape from the blood into the surrounding tissue, as well as the development of new blood vessels to support tumor growth. In the December 15 issue of the Journal of Clinical Investigation, Olivier Peyruchaud and colleagues from Université Claude Bernard Lyon, France, describe two additional roles of platelets in the metastasis of breast and ovarian cancer cells to the bone. They show that platelets act as: (i) a direct source of lysophosphatidic acid (LPA), which promotes tumor cell division; and (ii) indirect activators of bone breakdown.

The authors demonstrate in mice that tumor cells encourage platelet aggregation and activation and the subsequent release from platelets of LPA. LPA causes tumor cells to release the immune cell–growth stimulants IL-6 and IL-8 into the bone marrow, causing bone breakdown to exceed bone formation. Treatment of these mice after initial bone metastasis with Intergrilin, an inhibitor of platelet aggregation, resulted in decreased circulating LPA levels and a significant reduction in bone metastasis formation. However the authors did not interfere specifically with LPA signaling, leaving open the possibility that this anti-metastatic effect could be due to an LPA-independent pathway.

These findings in addition to other data suggest that platelet inhibition may slow the rate of tumor progression and metastasis. However to date, clinical trials of the antiplatelet agents aspirin and heparin have yielded inconclusive, albeit promising, evidence that platelet inhibition may enhance the survival of cancer patients. One major reason for the difficulty in translating these results into effective anticancer therapies is the need to consider the important role that platelets play in arresting bleeding, for example in the event of a nosebleed or following injury or surgery.

In an accompanying commentary, Gaorav Gupta and Joan Massagué from Memorial Sloan-Kettering Cancer Center in New York discuss the implications of this study. These authors remind us that "cancer patients receiving cytotoxic chemotherapy who suffer from bleeding due to platelet toxicity are regularly transfused with large numbers of platelets from healthy donors." Leading us to question "[is] this life-saving therapy…simultaneously facilitating metastasis of their cancerous cells?" Gutpa and Massagué stress that any effective therapies that modulate platelet activity will need to be specific for the pathological tumor cell–platelet interaction, without effecting normal platelet function. Platelet-specific integrin inhibitors like Integrilin fall into this category. The study also suggests that drug-mediated inhibition of platelet-derived LPA and LPA receptors present on tumor cells may be another promising target for reducing or preventing bone metastasis.

TITLE: Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer

AUTHOR CONTACT:
Olivier Peyruchaud
INSERM Research Unit 403, Université Claude Bernard Lyon 1, Lyon, France.
Phone: 33-478-78-57-38; Fax: 33-478-77-86-63; E-mail: peyruchaud@lyon.inserm.fr.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1714.

ACCOMPANYING COMMENTARY:

TITLE: Platelets and metastasis revisited: a novel fatty link

AUTHOR CONTACT:
Joan Massagué
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 212-639-8975; Fax: 212-717-3298; E-mail: j-massague@ski.mskcc.org.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1691.


Return of the Staphylococcus aureus "superbug"

Staphylococcus aureus causes a wide variety of diseases including boils and furuncles and more serious diseases such as septicemia and pneumonia, and a debate has long raged about the existence of S. aureus "superbugs" – more dangerous strains that may be associated with particularly invasive disease.

In the December 15 issue of the Journal of Clinical Investigation, Damian Melles and colleagues from University Medical Center Rotterdam examined 829 S. aureus strains from healthy donors from the city of Rotterdam. The genetic relatedness of the strains was compared and revealed the existence of 3 major and 2 minor genetic clusters. These clusters corresponded to the predominant genetic groups identified in a similar analysis recently performed in the United Kingdom, indicating that the same clonal lineages of the organism appear to be dominant in 2 distinct geographic locations.

Surprisingly, while the 2003 UK-based study found no evidence of hypervirulent clones or "superbugs" assocated with particularly invasive forms of disease, Melles et al. examined isolates from individuals with bacteriemia, deep-seated abscesses, or impetigo and found clear evidence that some strains of S. aureus are more virulent that others in that they appear more frequently in people with serious S. aureus–related disease that healthy individuals that simply carry the organism without falling prey to infection.

In an accompanying commentary, Timothy Foster from Trinity College, Dublin, discusses some potential reasons for the discrepancies between the Dutch and UK studies, the growing problem of antibiotic resistance, and reiterates the conclusion that while all strains of S. aureus have the potential to cause infection, some appear to be more virulent that others.

TITLE: Natural population dynamics and expansion of pathogenic clones of Staphylococcus aureus

AUTHOR CONTACT:
Damian C. Melles
Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Phone: 31-10-463-3510; Fax: 31-10-463-3875; E-mail: d.melles@erasmusmc.nl.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1732.

ACCOMPANYING COMMENTARY:

TITLE: The Stapylococcus aureus "superbug"

AUTHOR CONTACT:
Timothy J. Foster
Microbiology Department, Moyne Institute of Preventative Medicine, Trinity College, Dublin, Ireland.
Phone: 353-1-6082014; Fax: 353-1-6799294; E-mail: tfoster@tdc.ie.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1693.


Caspase-3 inhibitors accelerate osteoporosis

When our cells reach a certain age or state of cell health they undergo a programmed form of cell death known as apoptosis. This normal process, mediated by the enzyme caspase-3, helps maintain a balance between cell growth and cell death. Excessive apoptosis of osteoblasts and osteocytes – cells that aid the growth and development of bone – has been implicated as an important process that causes a loss of bone mineral density in patients with osteoporosis.

In the December 15 issue of the Journal of Clinical Investigation, Songtao Shi and colleagues from the Craniofacial and Skeletal Diseases Branch of the National Institutes of Health examined mice deficient in caspase-3 or mice treated with a drug that inhibits caspase-3 activity, in addition to human bone marrow stromal stem cells (BMSSCs) treated with a caspase-3 inhibitor. Bone defects, including decreased bone mineral density, observed in caspase-3–deficient mice were due to decreased BMSSC maturation. The caspase-3 inhibitor was found to accelerate bone loss in mice and also block the formation of human BMSSCs.

The study offers a novel concept of how caspase-3 deficiency alters the development of stem cells leading to osteoporosis.

Given the demonstrated influence of the caspase-3 inhibitor on bone mineral density, the authors highlight the necessity for careful consideration of any future application of caspase-3 inhibitors – some of which are currently being assessed in animal studies for the treatment of some degenerative diseases – in the treatment of human disease. This caution would apply particularly to postmenopausal women as such treatment may adversely affect their bone mineral density.

TITLE: A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells

AUTHOR CONTACT:
Songtao Shi
National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-435-4584; Fax: 301-402-0824; E-mail: sshi@dir.nidcr.nih.gov.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1704.


Immune cooperation foils influenza A virus infection

Influenza A virus (fluA) is a major human pathogen. The role of certain white bloods cells, known as natural killer (NK) cells, in the innate immune response to fluA is not well understood. In the December 15 issue of the Journal of Clinical Investigation, Xiao-Song He and colleagues from the VA Medical Center in Palo Alto demonstrate that upon exposure of adult cells to fluA, NK cells produce IFN-gamma, which stimulates the immune system to destroy foreign material. The authors further demonstrate that T cells previously exposed to fluA (known as virus-specific memory T cells), express IL-2, which is required in order to initiate subsequent IFN-gamma secretion by NK cells. Taken together, these data and results of previous work support the notion that a number of reciprocal interactions exist between components of the innate and adaptive immune response, which collectively facilitate a successful immune response to clear an infection.

TITLE: T cell–dependent production of IFN-gamma by NK cells in response to influenza A virus

AUTHOR CONTACT:
Xiao-Song He
Veteran's Administration Medical Center, Palo Alto, California, USA.
Phone: 650-493-5000, ext. 66135; Fax: 650-852-3259; E-mail: xiaosong@stanford.edu.

A PDF of this article is available at: : http://www.jci.org/cgi/content/full/114/12/1812.


Eph affects T cell function

The erythropoietin-producing hepatocyte (Eph) kinases are the largest family of receptor tyrosine kinases in the immune system. The Eph kinases and their ligands are known to direct neural outgrowth, the growth of new blood vessels, and epithelial cell migration in the intestine. In the December 15 issue of the Journal of Clinical Investigation, Jiangping Wu and colleagues from Notre Dame Hospital, Montreal, now delve further into the role of Eph kinases in the immune system by showing that EphB6 modulates immune function. The authors demonstrated that mice genetically deficient for EphB6 have compromised T cell responses. On the other hand, immune responses mediated by antibodies were normal in the mutant mice. This study is the first to describe roles for an Eph kinase in in vivo immunological function and the data suggest that EphB6 is important for T cell–T cell cooperation during T cell activation.

TITLE: EphB6-null mutation results in compromised T cell function

AUTHOR CONTACT:
Jiangping Wu
Laboratory of Immunology, Notre Dame Hospital, Montreal, Quebec, Canada.
Phone: 514-890-8000 ext. 25164; Fax: 514-412-7596; E-mail: jianping.wu@umontreal.ca.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1762.


Use of iNKT cells boosts tumor vaccination strategy

T cell responses to natural infection are orders of magnitude greater than those observed in cancer patients in response to current vaccination protocols. Optimizing tumor vaccination protocols will require a deeper understanding of the signals that the immune system coordinates in order to respond to pathogenic infection. In the December 15 issue of the Journal of Clinical Investigation, Vincenzo Cerundolo and colleagues from the University of Oxford report a vaccination approach in mice in which intravenous delivery of a protein antigen plus a type of NK T cells, known as iNKT cells, enhanced the immune response and cleared an established tumor. The authors demonstrate that the approach is effective when the vaccine is delivered orally or intravenously and could be exploited in future vaccination protocols aimed at eliciting immune responses against cancer and infectious diseases.

TITLE: Utilizing the adjuvant properties of Cd1d-dependent NK T cells in T cell–mediated immunotherapy

AUTHOR CONTACT:
Vincenzo Cerundolo
Tumor Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Phone: 44-1865-222412; Fax: 44-1865-222502; E-mail: vincenzo.cerundolo@imm.ox.ac.uk.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1800.


Understanding acid sensing in the kidney

The normal daily diet generates volatile acid (carbon dioxide) and nonvolatile acid (hydrogen ions) from carbohydrate and protein metabolism, respectively, and the kidney is responsible for maintaining an acid-base balance by excreting these acids. In this issue of the Journal of Clinical Investigation, Patricia Preisig and colleagues from the University of Texas Southwestern Medical Center have identified the kidney's elusive acid sensor. The authors examined opossum kidney cells cultured under acidic conditions and found that a 24-hour exposure to acid activates the enzyme Pyk2, which then binds to the proto-oncogene c-Src, causing c-Src activation and subsequent activation of signaling pathways that increase production of NHE3, the molecule at the surface of renal proximal tubule cells in the kidney that release hydrogen ions from the cell.

In an accompanying commentary, Steven Gluck from the University of California San Francisco discusses the broader role of Pyk2 in acid-base balance in bone and other tissues beyond the kidney.

TITLE: Pyk2 activation is integral to acid stimulation of sodium/hydrogen exchanger 3

AUTHOR CONTACT:
Patricia Preisig
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214-648-8628; Fax: 214-648-2071; E-mail: Patricia.Preisig@UTSouthwestern.edu.

A PDF of this article will be available at:

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1782.

ACCOMPANYING COMMENTARY:

TITLE: Acid sensing in renal epithelial cells

AUTHOR CONTACT:
Stephen L. Gluck
Division of Nephrology, University of California, San Francisco, USA.
Phone: 415-476-2173; Fax: 415-476-3381; E-mail: glucksl@medicine.ucsf.edu.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1696.


Alternative immunotherapy for prostate cancer bone lesions

Prostate cancer (PC) is the most commonly diagnosed malignancy and the second leading cause of death in American men. PC usually moves into the bone and the symptoms are treated by suppression of the production of male hormones known as androgens. However within 12-18 months of beginning this therapy, the disease usually becomes androgen-independent and no further effective therapies currently exist.

In the December 15 issue of the Journal of Clinical Investigation, Zelig Eshhar and colleagues from The Weizmann Institute of Science, Israel, report an alternative treatment approach. The authors used the "T body" approach, in which T cells genetically reprogrammed to be tumor antigen–specific were directly applied to confined but well-established PC tumors in mice. These mice were "preconditioned" prior to treatment, meaning that they were subjected to low-dose radiation or chemotherapy prior to T cell transfer in order to prevent the body from attacking the newly transferred T cells. The "T body" approach decreased tumor growth, prolonged survival, and even cured the treated mice. The authors suggest that patient preconditioning prior to the transfer of tumor-specific T cells offers great promise for immunotherapy of metastatic PC and other malignant tumors.

TITLE: Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lyphocytes

AUTHOR CONTACT:
Zelig Eshhar
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
Phone: 972-8-9344014; Fax: 972-8-9474030; E-mail: zelig.eshhar@weizmann.ac.il.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1774.


Gene therapy improves spinal muscular atrophy in mice

Spinal muscular atrophy is one of the most common genetic diseases leading to death in childhood. Characterized by muscle weakness caused by degeneration of motor neurons in the spinal cord and brain stem nuclei, the condition results from mutations or deletion of the SMN1 gene. In the December 15 issue of the Journal of Clinical Investigation, Mimoun Azzouz and colleagues from Oxford BioMedica report that multiple single injections of a lentivector expressing human SMN into various muscle of mice with spinal muscular atrophy was able to restore SMN to motor neurons, reduce motor neuron death, and increase life expectancy compared to untreated mice. The authors suggest that this approach may have potential as a safe and practical treatment for many of the symptoms of human spinal muscular atrophy.

TITLE: Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy

AUTHOR CONTACT:
Mimoun Azzouz or Nicholas Mazarakis
Oxford BioMedica Ltd., Oxford, United Kingdom.
Phone: 01-865-78-30-00; Fax: 01-865-78-30-01; E-mail: m.azzouz@oxfordbiomedica.co.uk or n.mazarakis@oxfordbiomedica.co.uk.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1726.


Understanding why some diabetics feel no pain

Diabetes-associated nerve fiber damage, known as diabetic neuropathy, can result in a decreased ability of affected individuals to feel pain. Beginning with reduced sensation in the feet and legs, and in combination with poor circulation, the condition often results in the development of nonhealing ulcers. The molecular events that cause this loss of pain perception are poorly understood. In the December 15 issue of the Journal of Clinical Investigation, Peter Nawroth and colleagues from the University of Heidelberg report that levels of the RAGE receptor and its ligand, AGE, are increased at the sites of peripheral nerves in diabetic patients. AGE was shown to induce increased and sustained activation of NF-kappaB, which is closely associated with nerve dysfunction, and this could be partially reversed by blockade of the RAGE receptor.

Furthermore, the authors were able to partially reverse the loss of pain perception, associated with long-standing diabetic neuropathy, in mice treated with soluble RAGE, which is able to block the binding of AGE to the RAGE receptor. The data suggest that although RAGE has a substantial role in mechanisms leading to neuronal stress and sensory deficits in diabetes, it is certainly not the only factor. Although by revealing that the AGE-RAGE interaction impacts neuronal function, there is a strong case to support the development of AGE inhibitors for the treatment of human diabetic neuropathy.

TITLE: Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily

AUTHOR CONTACT:
Angelika Bierhaus
University of Heidelberg, Heidelberg Germany.
Phone: 49-6221-564752; Fax: 49-6221-564754; E-mail: angelika_bierhaus@med.uni-heidelberg.de.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1741.


TB, or not TB: that is the question – does TLR signaling hold the answer?

Defense against invading pathogens comes in two major forms: innate and adaptive immunity. Local barriers to infection such as the skin, and the production of stomach acid, mucous, tears, and saliva comprise what is known as innate immunity. This form of immunity is critically dependent on signaling by Toll-like receptors (TLRs) that rely heavily on an intracellular adaptor protein called myeloid differentiation factor 88 (MyD88). Acquired immunity is a form of cellular defense where foreign substances are attacked by lymphocytes and destroyed by T cells, and the adaptive immune response is also generally thought to require intact TLR-MyD88 signaling pathways. However a study by Bernhard Ryffel and colleagues from Centre National de la Recherche Scientifique, France, in the December 15 issue of the Journal of Clinical Investigation, challenges this view and instead suggests that MyD88 may not be absolutely required for a normal adaptive immune response.

The authors used mice genetically deficient in MyD88 and subjected them to Mycobacterium tuberculosis infection. While their adaptive immune response appeared to be unaffected, markedly blunted defense by innate immune mechanisms eventually proved lethal. With the support of additional data, the authors concluded that MyD88-dependent signaling is not significantly involved in T cell activation (an adaptive immune response), but in the absence of MyD88, T cell–mediated immunity is only able to provide partial protection from infection.

This study suggests that we need to reassess whether adaptive immunity is really dependent upon innate immunity, and if MyD88 is not involved in regulating the adaptive response to M. tuberculosis infection, then what is? In an accompanying commentary, Terence Doherty and Moshe Arditi from Cedars-Sinai Medical Center in Los Angeles address these and other questions that arise from this study.

TITLE: Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88

AUTHOR CONTACT:
Bernhard Ryffel
CNRS, Molecular Immunology and Embryology, Orleans, France.
Phone: 33-238-25-54-39; Fax: 33-238-25-79-79; E-mail: bryffel@cnrs-orleans.fr.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1790.

ACCOMPANYING COMMENTARY:

TITLE: TB or not TB: that is the question – does TLR signaling hold the answer?

AUTHOR CONTACT:
Moshe Arditi
Cedars-Sinai Medical Center, Los Angeles, California, USA.
Phone: 310-423-4471 Fax: 310-423-8284; E-mail: moshe.arditi@cshs.org.

A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1699.


Source: Eurekalert & others

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