JCI table of contents, January 2, 2004

12/29/03

Jaundice, the yellowing of the skin and whites of the eyes following accumulation of the bile pigment bilirubin, is extremely common in newborn infants. In Western nations jaundice is most commonly treated with exposure to light (phototherapy), however a drug therapy would also be desirable. In the January 2 issue of the Journal of Clinical Investigation, David Moore and colleagues from Baylor College of Medicine, Texas, demonstrate that a Chinese herbal tea remedy for jaundice called Yin Zhi Huang (YZH) activates a liver receptor that enhances the clearance of bilirubin. YZH was "boiled down" to one component: 6,7-dimethylesculetin, which binds to and activates the hepatic nuclear receptor CAR and its target genes, leading to increased clearance of bilirubin.

The report could lead to improved pharmaceutical treatments for neonatal jaundice and also helps close the gap between Western-style medical care and Eastern herbal remedies. In an accompanying commentary, Mitchell Lazar from the University of Pennsylvania discusses some of the differences in Western and Eastern medical philosophies and practices. He states "This is a wonderful example of knowledge gained by applying the Western scientific method to an Eastern herbal remedy. It will be very exciting if a pure compound emerges from the tea leaves as a pharmacological therapy for neonatal jaundice that is complementary to the current Western practice of phototherapy."

TITLE: A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR

AUTHOR CONTACT:
David D. Moore
Baylor College of Medicine, Houston, Texas, USA.
Phone: 713-798-3313
Fax: 713-798-3017
E-mail: moore@bcm.tmc.edu

View the PDF of this article at: https://www.the-jci.org/press/18385.pdf

ACCOMPANYING COMMENTARY: East meets West: an herbal tea finds a receptor

AUTHOR CONTACT:
Mitchell A. Lazar
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215-898-0198
Fax: 215-898-5408
E-mail: lazar@mail.med.upenn.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20661.pdf

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A viral cure for type 1 diabetes

Viruses can both cause and prevent autoimmune disease. In order to understand this dualism, Matthias von Herrath and colleagues from the La Jolla Institute for Allergy and Immunology in California exposed prediabetic mice to viral infections. In the January 2 issue of the Journal of Clinical Investigation the authors report that infection with lymphocytic choriomeningitis virus (LCMV) during the prediabetic period completely abolished the diabetic process in two distinct mouse models.

This protection against the development of type 1 diabetes correlated with a reduced number of autoaggressive CD8 T cells in pancreatic islets. Increased production of the chemokine CXCL-10 in pancreatic lymph nodes redirected cells of the immune response away from the beta cells. Once in the pancreatic lymph node, CD8 lymphocytes underwent increased apoptosis, which was directly dependent on TNF-alpha and indirectly on IFN-gamma production. The data indicate that proinflammatory cytokines and chemokines induced by viral infection can influence ongoing autoaggressive processes beneficially at the preclinical stage if produced at the correct time, location, and level. Therefore viruses that do not directly destroy beta cells may actually enhance the course of autoimmune diabetes.

TITLE: Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient

AUTHOR CONTACT:
Matthias von Herrath
La Jolla Institute for Allergy and Immunology, San Diego, California, USA.
Phone: 858-558-3571
Fax: 858-558-3579
E-mail: matthias@liai.org

View the PDF of this article at: https://www.the-jci.org/press/17005.pdf

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What do bad breath, hot dogs, and gastric blood flow have in common? The nitrite anion

While it has long been known that the reduction of nitrite to nitric oxide is involved in the process of meat curing and bad breath, a greater biological role for the nitrite anion has only recently been appreciated. Salivary nitrate is reduced to nitrite by oral bacteria. In the acidic environment of the stomach, nitrite is further reduced to nitric oxide, which has broad biological activity. In the January 2 issue of the Journal of Clinical Investigation, Jon Lundberg and colleagues from the Karolinska Institute in Sweden tested the effects of human saliva on the blood flow and thickness of rat mucosa. The saliva was collected from individuals following high or low nitrite diets. Rat mucosal blood flow and thickness were found to increase after application of nitrite-rich saliva, while fasting saliva had no effect. The results support a gastroprotective role of salivary nitrate/nitrite.

In an accompanying commentary, Mark Gladwin from the National Institutes of Health discusses the broad biology of the nitrite anion and its potential utility in the treatment of gastric ulcers, or conditions associated with scavenging of nitric oxide, such as sickle cell anemia. Gladwin suggests "At the very least, perhaps we should avoid mouthwash and feel less guilty about eating hot dogs at the ball park."

TITLE: Nitrite in saliva increases gastric mucosal blood flow and mucus thickness

AUTHOR CONTACT:
Jon Lundberg
Karolinska Institutet, Stockholm, Sweden.
Phone: 46-8-7287952
Fax: 46-8-332278
E-mail: jon.lundberg@fyfa.ki.se

View the PDF of this article at: https://www.the-jci.org/press/19019.pdf

ACCOMPANYING COMMENTARY: Haldane, hot dogs, halitosis, and hypoxic vasodilation: the emerging biology of the nitrite anion

AUTHOR CONTACT:
Mark T. Gladwin
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-435-2310
Fax: 301-402-1213
E-mail: mgladwin@nih.gov

View the PDF of this commentary at: https://www.the-jci.org/press/20664.pdf

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ONLINE FIRST ARTICLE

Distinct roles for VEGF isoforms in bone development

During bone formation, epiphyseal cartilage is avascular until secondary ossification occurs. Vascularization of this maturing tissue relies on angiogenic recruitment from surrounding vessels. The growth factorVEGF has previously been shown to be critical for metaphyseal bone vascularization and is now implicated as an angiogenic factor for epiphyseal vascularization. By generating mice that express specific splice forms of VEGF, Geert Carmeliet and colleagues from Katholike Universiteit Leuven, Belgium determined that the soluble forms of VEGF are indispensable for proper epiphyseal cartilage development, and chondrocyte development and survival. In the January 2 issue of the Journal of Clinical Investigation, Carmeliet et al. demonstrate that mice expressing only the matrix-bound form (VEGF188) but neither of the soluble forms (VEGF120 or VEGF164) had increased hypoxia and massive chondrocyte apoptosis in the epiphyseal cartilage, as well as dwarfed skeletal defects. Metaphyseal development appeared normal in these mice, demonstrating that different molecular processes requiring specific VEGF isoforms regulate epiphyseal and metaphyseal vascularization.

TITLE: Soluble VEGF isoforms are essential to establish epiphyseal vascularization and regulate chondrocyte development and survival

AUTHOR CONTACT:
Geert Carmeliet
Katholieke Universiteit Leuven, Leuven, Belgium
Phone: 32-16-345974
Fax: 32-16-345934
E-mail: geert.carmeliet@med.kuleuven.ac.be

View the PDF of this article at: https://www.the-jci.org/press/19383.pdf

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Kaposi-sarcoma herpesvirus: a new paradigm for infection

Kaposi-sarcoma–associated herpesvirus (KSHV) infection is linked to the development of Kaposi sarcoma (KS). Other cancer-causing herpesviruses undergo lytic replication early in infection, which encompasses host cell infection, utilization of host cell machinery to manufacture virus, and host cell lysis to release new virus particles. These viruses then mature to a latent state, where infected host cells survive and the virus persists within them with little expression of its genes and without the production of progeny virus. In the case of KSHV, lytic replication is required throughout the entire natural history of infection in order to produce a KS lesion, however the reason for this is unknown. Current theories have suggested that lytically infected cells secrete substances that promote angiogenesis and inflammation: hallmarks of KS. In the January 2 issue of the Journal of Clinical Investigation, Don Ganem and colleagues from the University of California, San Francisco demonstrate that latency in KSHV is unstable and results in segregation of the viral episome. The data indicate that acquisition of stable KSHV latency is a multistep process that is successful to varying degrees in different cell types. The report also demonstrates that lytic replication is important in the recruitment of new cells to latency in order to balance the loss of viral plasmids and maintain the virus in cancer cells.

In an accompanying commentary, Bill Sugden and Chen-Yu Wang from the University of Wisconsin-Madison discuss the contribution of the lytic cycle to oncogenesis and how this finding impacts our current understanding of herpesvirus infection.

TITLE: Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis

AUTHOR CONTACT:
Don E. Ganem
Howard Hughes Medical Institute, and Department of Microbiology, University of California San Francisco, San Francisco, California, USA.
Phone: 415-476-2826
Fax: 415-476-0939
E-mail: ganem@cgl.ucsf.edu

View the PDF of this article at: https://www.the-jci.org/press/17803.pdf

ACCOMPANYING COMMENTARY: New viruses shake old paradigms

AUTHOR CONTACT:
Bill Sugden
University of Wisconsin, Madison, Wisconsin, USA.
Phone: 608-262-6697
Fax: 608-262-2824
E-mail: sugden@oncology.wisc.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20662.pdf

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Caspase-3 activation triggers muscle breakdown

Loss of muscle mass is a serious consequence of catabolic conditions such as cancer, uremia, sepsis, and diabetes. However the initial step in this breakdown process is unknown. As cytokines or insulin resistance activate caspases, and are common in catabolic states, William Mitch and colleagues from the University of Texas examined whether caspase-3 was capable of breaking down actomyosin – the essential contractile substance of muscle. In the January 2 issue of the Journal of Clinical Investigation, the authors demonstrate that recombinant caspase-3 cleaves actomyosin resulting in a unique actin fragment and other proteins that are degraded by the ubiquitin-proteasome system. Cleaved actin fragments are present in muscles of rates with muscle atrophy from diabetes or uremia and fragment accumulation and the rate of muscle breakdown could be suppressed by a caspase-3 inhibitor. The report suggests that therapeutic strategies targeting caspase-3 activation may prevent muscle breakdown.

TITLE: Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions

AUTHOR CONTACT:
William E. Mitch
University of Texas, Galveston, Texas, USA.
Phone: 409-772-9891
Fax: 409-772-8762
E-mail: wmitch@utmb.edu

View the PDF of this article at: https://www.the-jci.org/press/18330.pdf

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Tumor-suppressing ligand TRAIL may not be so selective after all

Hepatic cell death is the leading cause of fatality in patients with liver diseases, however the molecular pathways underlying this event are unknown. The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) holds tremendous promise for cancer therapy because of its ability to selectively cause the programmed cell death (apoptosis) of tumor cells, but not most normal cells. However, some recent studies have cast doubt on this selective activity. In the January 2 issue of the Journal of Clinical Investigation, Youhai Chen and colleagues from the University of Pennsylvania investigated the role of TRAIL in hepatic cell death. Using two experimental models of hepatitis, the authors found that hepatic cell death was dramatically reduced in TRAIL-deficient mice as well as in mice in which the TRAIL receptor was blocked. Restoration of TRAIL activity restored the sensitivity of TRAIL-deficient mice to hepatitis. The report demonstrates that TRAIL plays a crucial role in hepatic cell death and liver inflammation. While further investigation is needed to comprehensively understand the in vivo functions of TRAIL, the safety and potential side effects of TRAIL-based cancer therapy in humans remain unresolved.

TITLE: Critical roles of TRAIL in hepatic cell death and hepatic inflammation

AUTHOR CONTACT:
Youhai Chen
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215-898-4671
Fax: 215-573-8606
E-mail: yhc@mail.med.upenn.edu

View the PDF of this article at: https://www.the-jci.org/press/19255.pdf

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Male/female differences in diabetic stroke recovery

Diabetic hyperglycemia is a recognized risk factor for stroke and increases brain damage after cerebral ischemia. The underlying mechanisms remain unclear but may involve increased apoptosis. While previous studies showed female diabetic mice suffered less brain damage following cerebral hypoxia-ischemia than male diabetic mice, Susan Vannucci and colleagues from Columbia University in New York investigated the effects of estrogen, an established neuroprotectant, on ischemic recovery. Female diabetic and nondiabetic mice had their ovaries removed via ovariectomy and were treated with estrogen replacement, or a control, prior to hypoxia. In the January 2 issue of the Journal of Clinical Investigation, Vannucci and colleagues report that ovariectomy increased ischemic damage in nondiabetic mice, and estrogen replacement reduced tissue injury in association with enhanced antiapoptotic gene expression. Diabetic mice showed significantly more damage, and there was no detectable protection afforded by estrogen replacement therapy. Such impaired wound healing is analogous to that seen in peripheral tissues but has never before been considered as part of the pathophysiology of ischemic stroke in the context of diabetes.

TITLE: Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice

AUTHOR CONTACT:
Susan J. Vannucci
Morgan Stanley Children's Hospital of New York, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-8458
Fax: 212-342-2293
E-mail: sv2020@columbia.edu

View the PDF of this article at: https://www.the-jci.org/press/18336.pdf

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Avicins boost the stress response

Chronic disease states develop during the aging process as cellular stress responses and repair systems are worn down. In an effort to address the broad concept of disease mechanisms during stress and aging, Jordan Gutterman and colleagues from the University of Texas examined avicins, triterpenoid electrophiles isolated from the Australian desert tree Acacia victoriae, and their ability to control gene transcription. They found that avicin-treated cells had increased nuclear localization of the redox-regulated transcription factor Nrf-2. This, in turn, activated the transcription of genes containing the antioxidant response element (ARE) and a battery of stress response genes. In vivo experiments with mouse models stressed by UV light exposure resulted in significantly less severe skin damage after avicin treatment. These studies show the potential of a new class of metabolites for the treatment of stress-associated diseases.

TITLE: Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery

AUTHOR CONTACT:
Jordan Gutterman
The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Phone: 713-792-2676
Fax: 713-792-6554
E-mail: jgutterm@mdanderson.org

View the PDF of this article at: https://www.the-jci.org/press/18699.pdf

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Annexin II critical for angiogenesis

Endothelial cells are critical to the maintenance of hemostasis – the balance of blood flow and clotting – because they provide the site of assembly for a variety of regulatory factors, such as fibrin, involved in the response to vessel injury. Having generated annexin II–null mice in order to observe the physiologic roles of annexin II in hemostasis, Katherine Hajjar and colleagues from Cornell University in New York now show in the January 2 issue of the Journal of Clinical Investigation that annexin II does indeed participate in the regulation of fibrin homeostasis. The mice showed defective fibrinolytic function and impaired clearance of injury-induced arterial blood clots. Moreover, neoangiogenesis – the formation of new blood vessels – was abnormal in these mice, suggesting a key role for annexin II in activation of the vascularization process. This dual role in clotting and new vessel formation suggests that annexin II is an indispensable factor in hemostasis and a potential target for control of angiogenesis.

TITLE: Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo

AUTHOR CONTACT:
Katherine Hajjar
Weill Medical College of Cornell University, New York, New York, USA.
Phone: 212-746-2034
Fax: 212-746-8809
E-mail: khajjar@med.cornell.edu

View the PDF of this article at: https://www.the-jci.org/press/19684.pdf

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Stat-3 preserves lung function during oxygen injury

Acute lung injury remains a common cause of morbidity and mortality in both adults and children, however the mechanisms regulating pulmonary homeostasis are poorly understood. In the January 2 issue of the Journal of Clinical Investigation, Jeffrey Whitsett and colleagues from Cincinnati Children's Hospital Medical Center investigated the role of the signaling molecule STAT-3 in lung injury. The Stat-3 gene was selectively deleted from the respiratory endothelial cells of mice. The deletion did not affect prenatal lung morphogenesis or post-natal lung function, however exposure of adult Stat-3–deficient mice to 95% oxygen caused rapid, progressive lung injury, pulmonary capillary leakage, and respiratory distress. The report indicates that while Stat-3 is not required for lung formation it plays a critical role in the maintenance of lung function during oxygen injury.

TITLE: Stat-3 is required for pulmonary homeostasis during hyperoxia

AUTHOR CONTACT:
Jeffrey A. Whitsett
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513-636-4830
Fax: 513-636-7868
E-mail: jeff.whitsett@cchmc.org

View the PDF of this article at: https://www.the-jci.org/press/19491.pdf

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The roles of growth hormone and IGF-1 in controlling insulin sensitivity

Insuling-like growth factor-1 (IGF-1) and growth hormone (GH) interact with insulin to modulate its control of carbohydrate metabolism. In the January 2 issue of the Journal of Clinical Investigation, Derek LeRoith and colleagues from the National Institutes of Health demonstrate that blocking the effect of GH in the presence of low serum IGF-1 concentrations enhances insulin sensitivity. This suggests that chronic elevation of GH levels plays a major role in insulin resistance. IGF-1 maintains the fine balance between insulin and GH in order to promote normal carbohydrate and lipid metabolism.

In an accompanying commentary David Clemmons from the University of North Carolina discusses insulin, GH, and IGF-1 regulation and how they affect food intake and insulin sensitivity.

TITLE: Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1–deficient mice

AUTHOR CONTACT:
Derek LeRoith
National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-496-8090
Fax: 301-480-4386
E-mail: derek@helix.nih.gov

View the PDF of this article at: https://www.the-jci.org/press/17763.pdf

ACCOMPANYING COMMENTARY: The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity

AUTHOR CONTACT:
David R. Clemmons
University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Phone: 919-966-4735
Fax: 919-966-6025
E-mail: endo@medicineexch.med.unc.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20660.pdf

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Ring around the rosy CTL

Cytotoxic T lymphocytes (CTLs) kill target cells by forming an immunological synapse with these cells. The CTLs and target cells adhere using the adhesion molecules LFA-1 and its counter-receptor ICAM-1. In the January 2 issue of the Journal of Clinical Investigation, Michael Dustin and colleagues from the Skirball Institute of Biomolecular Medicine in New York describe a novel adhesive structure that is formed by CD8+ human CTLs, but not by CD4+ helper T cells, before foreign antigen complexes are recognized. The CTL ring junction acts as a presynapse, setting the stage for sensitive antigen recognition. This structure may play an important role in immune surveillance by CTLs and implies unique regulatory mechanisms in CTLs that are not shared with helper T cells.

TITLE: Cytotoxic T lymphocytes form an antigen-independent ring junction

AUTHOR CONTACT:
Michael L. Dustin
Skirball institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
Phone: 212-263-3207
Fax: 212-263-5711
E-mail: dustin@saturn.med.nyu.edu

View the PDF of this article at: https://www.the-jci.org/press/19337.pdf

Source: Eurekalert & others

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