A team of researchers, led by Serge Przedborski, at Columbia University in New York, have demonstrated that infusion of D-beta-hydroxybutyrate (D-beta-HB) to mice suffering from Parkinson disease restored impaired brain function and protected against neurodegeneration and motor skill abnormalities. D-beta-HB, already utilized in the treatment of epilepsy, may represent a cheap and easy way to treat Parkinson disease.
Parkinson disease is the second most common neurodegenerative disorder after Alzheimer disease. Sufferers experience motor skill abnormalities including tremor, muscle stiffness, and unstable voluntary movements and posture. The main pathological feature of the Parkinson brain is the loss of dopaminergic neurons.
Reported in an article in the September 15 issue of the Journal of Clinical Investigation, Przedborski and colleagues administered the neurotoxin MPTP to mice, which caused dopaminergic neurodegeneration and deficits in the mitochondrial electron transport chain reminiscent of Parkinson disease. Using this model of disease, the authors showed that the infusion of the ketone body D-beta-HB restored mitochondrial respiration and protected against MPTP-induced neurodegeneration and motor deficits. The study supports a critical role for mitochondrial defect in Parkinson disease.
Ketone bodies are already successfully used in the treatment of epilepsy. They are also able to penetrate the blood-brain barrier that often prevents potentially beneficial drugs from entering the brain.
D-beta-HB may therefore be considered as a novel form of neuroprotective therapy in the treatment of Parksinson disease.
TITLE: D-beta-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease
AUTHOR CONTACT:
Serge Przedborski
Columbia University, New York, New York, USA.
Phone: (212) 305-1540
Fax: (212) 305-5450
E-mail: SP30@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/18797.pdf
T cell lifespan during HIV infection
Scientists have long held the prevailing view that during HIV infection the depletion of T cells is the result of direct HIV virus–mediated killing. In the September 15 issue of the Journal of Clinical Investigation, Marc Hellerstein and colleagues at the University of California in Berkeley report that it is the chronic activation of the host immune system in response to HIV infection that primarily contributes to T cell loss.
A series of influential studies published in the mid-1990s described the rapid decay of viral load following administration of highly active antiretroviral therapy (HAART), and proposed that HIV infection was associated with a high rate of virus turnover and short lifespan of infected cells. This suggested that HIV infection of susceptible CD4+ T cells led to such high rates of cell death, that compensatory T cell proliferation was inadequate to maintain sufficient T cell numbers and therefore compromised the ability of the immune system to fight the virus.
This view was recently challenged by observations that not only were virus-infected cells dying, but a greater number of uninfected bystander T cells underwent programmed cell death that was not a direct result of HIV infection. Therefore, a new theory has been proposed in which high levels of T cell proliferation reflects a state of chronic immune activation following HIV infection as opposed to simple compensatory proliferation.
Hellerstein and colleagues used a highly innovative technique for measuring the dynamics of T cell turnover in 3 groups of individuals: (i) HIV-infected; (ii) HIV-infected HAART-treated; and (iii) uninfected. They authors found that most of the increased T cell turnover during HIV infection involved a subset of memory T cells – those cells which have encountered prior infection and can rapidly mobilize and clone themselves should the same foreign antigen be encountered during a subsequent infection. The authors concluded that the increased degree of proliferation of this T cell subset was the result of chronic immune activation and not the result of a mechanism striving to compensate for the loss of T cells directly killed by the virus. The increased degree of memory T cell turnover results in a lack of long-lived memory T cells available to assist newly infected cells. The authors did however demonstrate that HAART was able to ameliorate the defect in the production of these long-lived cells.
This identification of this fast-replicating but short-lived subset of T cells aids our understanding of how the body reacts to HIV infection and how HIV wields its destructive power. In an accompanying commentary Guido Silvestri and Mark Feinberg from the Emory Vaccine Center in Atlanta, Georgia, discuss how the dynamics of the T cell population effects the progression of HIV disease. These authors add that the present study "provides important clues as to how HIV infection leads to CD4+ T cell depletion and AIDS". It is still not clear how HIV induces this chronic state of immune activation and why this is so disruptive to the proper overall functioning of the host immune system. Silvestri and Feinberg continue, "some of these questions can be resolved with future application of the innovative and informative labeling techniques pioneered by Hellerstein and colleagues".
TITLE: Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection
AUTHOR CONTACT:
Marc Hellerstein
University of California, Berkeley, California, USA.
Phone: (510) 642-0646
Fax: (510) 642-0535
E-mail: march@nature.berkeley.edu
View the PDF of this article at: https://www.the-jci.org/press/17533.pdf
ACCOMPANYING COMMENTARY:
Turnover of lymphocytes and conceptual paradigms in HIV infection
AUTHOR CONTACT:
Mark B. Feinberg
Emory Vaccine Center, Atlanta, Georgia, USA.
Phone: (404) 727-4374
Fax: (404) 727-8199
E-mail: mbf@sph.emory.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19799.pdf
BMPs and bone loss: get it through your noggin
A study by Etsuko Abe and colleagues at Mount Sinai School of Medicine in New York has revealed that the balance between the expression of the bone-building protein BMP, and the BMP inhibitor noggin, plays a crucial role in regulating bone formation and loss. The overproduction of noggin may ultimately result in the net bone loss associated with conditions such as osteoporosis. The study suggests that recombinant BMP may prove useful in reversing age-related bone loss.
Bone morphogenetic proteins (BMPs) 2 and 4 are known to regulate hair follicle growth and skeletal development. These effects are inhibited by a protein called noggin, yet little was known about the role of noggin in the differentiation of bone-building cells (osteoblasts) and adult skeletal remodeling. In an article in the September 15 issue of the Journal of Clinical Investigation, Abe and colleagues have found that noggin is expressed in osteoblasts, chondrocytes, and macrophages. Infection of preosteoblastic cells with a retrovirus containing noggin inhibited osteoblast differentiation. A transgenic mouse that overexpressed noggin in mature osteoblasts displayed dramatic osteoporosis, decreased trabecular and calvarial bone, diminished bone formation rates, and reduced osteoblast differentiation.
These studies provide strong evidence that the balance between the expression of BMPs and noggin may determine the extent of bone building and breakdown, and ultimately bone mass in adult mice. The overproduction of noggin during aging may result in impaired bone building and function and hence, net bone loss.
Following the recent FDA approval of recombinant BMP2 for specific uses, there remains great clinical interest in the role of BMPs and noggin in the regulation of bone formation and repair in a variety of conditions, including osteoporosis. Abe and colleagues suggest that recombinant BMP may prove useful in reversing age-related bone loss.
TITLE: Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice
AUTHOR CONTACT:
Etsuko Abe
Mount Sinai School of Medicine, New York, New York, USA.
Phone: (212) 241-8735
Fax: (212) 534-4820
E-mail: etsuko.abe@mssm.edu
View the PDF of this article at: https://www.the-jci.org/press/15543.pdf
Tracking autoimmune T cells in diabetes
Insulin-dependent diabetes mellitus is usually caused by autoimmune destruction of pancreatic beta cells by T cells. Methodologies to track the development, migration, and functional activation of one class of such T cells (CD4 T cells) have been limited. This is an important issue for studies designed to monitor the efficacy of potential intervention protocols. Luc Teyton and colleagues at The Scripps Research Institute in California, introduce an exciting new tetramer technology that allows a particular set of diabetogenic CD4 T cells to be quantified and tracked.
In an accompanying commentary, Edward Leiter from The Jackson Laboratory in Bar Harbor, Maine, discusses the potential uses of this technology that may help researchers design appropriate intervention protocols that may inhibit progression to overt insulin-dependent diabetes in humans at risk for this debilitating disease.
TITLE: Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity
AUTHOR CONTACT:
Luc Teyton
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-2728
Fax: (858) 784-8166
E-mail: lteyton@scripps.edu
View the PDF of this article at: https://www.the-jci.org/press/18337.pdf
ACCOMPANYING COMMENTARY
Tracking autoimmune T cells in diabetes
AUTHOR CONTACT:
Edward H. Leiter
Jackson Laboratory, Bar Harbor, Maine, USA.
Phone: (207) 288-6370
Fax: (207) 288-6079
E-mail: ehl@jax.org
View the PDF of this commentary at: https://www.the-jci.org/press/19842.pdf
Antioxidants play a crucial role in estrogen-deficiency bone loss
Osteoporosis is an enormous clinical problem, yet the mechanisms through which estrogen-deficiency causes bone hyper-resorption remain controversial. A report by Timothy Chambers and colleagues at St. George's Hospital Medical School, London, may resolve these controversies by demonstrating that estrogen-deficiency sensitizes cells to oxidant signaling and stress by lowering thiol antioxidants in bone resorbing cells. This mechanism provides novel opportunities for the development of potential osteoporosis therapies.
TITLE: A crucial role for thiol antioxidants in estrogen-deficiency bone loss
AUTHOR CONTACT:
Timothy J. Chambers
St. George's Hospital Medical School, London, United Kingdom
Phone: 44-20-8725-5270
Fax: 44-20-8725-0064
E-mail: t.chambers@sghms.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/18859.pdf
Cancer and Trousseau syndrome: the missing link revealed
Ajit Varki and colleagues from the University of California, San Diego, have revealed why individuals presenting with Trousseau syndrome also mysteriously suffer from mucin-producing carcinomas and why the anti-clotting agent heparin, but not other antithrombotic agents, is capable of ameliorating Trousseau syndrome.
Trousseau syndrome involves the formation of platelet-rich aggregates (microthrombi) in small blood vessels, in individuals with mucin-rich adenocarcinomas. However, no molecular link between carcinoma mucins and thrombosis previously existed. Adenocarcinomas secrete abnormally glycosylated mucins into the bloodstream that present pathological binding sites for P- and L-selectins.
Hypothesizing that selectin interactions with circulating mucins might trigger the syndrome, Varki and colleagues injected purified carcinoma mucin preparations into mice, rapidly inducing platelet-rich microthrombi. These were diminished in P- and L-selectin–deficient mice and by the anticoagulant heparin. Inhibition of endogenous thrombin did not block platelet aggregation. The authors therefore deduced that Trousseau syndrome is likely triggered by interactions of circulating carcinoma mucins with leukocyte L-selectin and platelet P-selectin without requiring accompanying thrombin generation. The authors also suggest that heparin was likely working by directly inhibiting P- and L-selectin interactions. This may also explain why Trousseau syndrome is ameliorated by heparin but not by other antithrombotic agents.
TITLE: Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas
AUTHOR CONTACT:
Ajit Varki
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 534-2214
Fax: (858) 534-5611
E-mail: avarki@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/press/18882.pdf
Tracking T cells in Hepatitis C
The characterization of CD4 T cells populations specific for microbial antigens or self-proteins represents a major challenge in human immunology. The characterization of these populations is relevant to the outcome of chronic viral infections, such a Hepatitis C. Kai Wucherpfennig and colleagues at the Dana-Farber Cancer Institute in Boston, Massachusetts, have created fully functional MHC class II molecules for tetramer-based analysis of T cell populations. Using these MHC class II tetramers the authors were able to characterize CD4 T cell populations present at very low frequencies in subjects infected with Hepatitis C virus (HCV). The authors demonstrate that HCV-specific CD4 T cells can be isolated from subjects who resolved viremia, but not in patients suffering from chronic progressive infection, and that these T cells have a distinctive memory phenotype. This technique affords researchers the ability to study rare populations of memory CD4 T cells in human diseases.
TITLE: Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers
AUTHOR CONTACT:
Kai W. Wucherpfennig
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone (617) 632-3086
Fax: (617) 632-2662
E-mail: wucherpf@mbcrr.harvard.edu
View the PDF of this commentary at: https://www.the-jci.org/press/18509.pdf
Liver enzyme, PKC-lambda, mediates insulin sensitivity
Individuals with type 2 diabetes often exhibit impairment of insulin action in the liver. Masato Kasuga and colleagues at Kobe University, Japan, have found that mice deficient in the hepatic enzyme PKC-lambda have increased overall insulin sensitivity, yet their blood glucose concentration remained within normal limits. The authors demonstrated a link between the altered expression of the sterol regulatory element-binding protein SREBP-1c gene and its target genes, and defective PKC-lambda signaling. Restoration of PKCl expression in the liver restored SREBP-1c expression and insulin sensitivity to normal. This study suggests that reagents that block PKC-lambda signaling specifically in the liver might consequently ameliorate insulin resistance.
TITLE: PKC-lambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic liver content and overall insulin sensitivity
AUTHOR CONTACT:
Masato Kasuga
Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Phone: 81-78-382-5861
Fax: 81-78-382-2080
E-mail: kasuga@med.kobe-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/18816.pdf
HATs off to Hop in cardiac hypertrophy
Histone acetylation, regulated by two antagonistic enzymes – histone acetyltransferases (HATs) and histone deacetylases (HDACs) – results in transcriptional changes and also plays a critical role in cardiac development and disease. A new study by Jonathan Epstein and colleagues from the University of Pennsylvania shows that overexpression of the atypical transcriptional co-repressor homeodomain-only protein (Hop) causes cardiac hypertrophy via recruitment of a class I HDAC. In contrast to the body of work on transcriptional mechanisms that drive cardiac hypertrophy, including class II HDACs, this report elucidates a novel growth-suppressing transcriptional pathway in cardiac muscle that opposes hypertrophic growth.
In an accompanying commentary, Yasuo Hamamori and Michael Schneider from Baylor College of Medicine in Houston, Texas, further discuss the roles of HDACs and Hop in cardiac hypertrophy.
TITLE: Cardiac hypertrophy and histone deacetylase–dependent transcriptional repression mediated by the atypical homeodomain protein Hop
AUTHOR CONTACT:
Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-8731
Fax: (215) 573-2094
E-mail: epsteinj@mail.med.upenn.edu
View the PDF of this article at: https://www.the-jci.org/press/19137.pdf
ACCOMPANYING COMMENTARY HATs off to HOP: recruitment of a class I histone deacetylase incriminates a novel transcriptional pathway that opposes cardiac hypertrophy
AUTHOR CONTACT:
Michael D. Schneider
Center for Cardiovascular Development, Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-6683
Fax: (713) 798-7437
E-mail: michaels@bcm.tmc.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19834.pdf
Activation of adenosine receptors protects the kidney
Mark Okusa and colleagues from the University of Virginia have investigated the contribution of A2A adenosine receptors expressed on bone marrow-–derived cells to the protection of renal tissue against ischemia-reperfusion injury (IRI). The authors determined that activation of these receptors expressed on bone marrow–-derived cells is necessary for tissue protection in a mouse model of IRI.
TITLE: Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells
AUTHOR CONTACT:
Mark D. Okusa
University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.
Phone: (434) 924-2187
Fax: (434) 924-5848
E-mail: mdo7y@virginia.edu
View the PDF of this article at: https://www.the-jci.org/press/15483.pdf
CD69 and TGF-beta: double trouble in arthritis
Francisco Sánchez-Madrid and colleagues from Hospital de La Princesa in Madrid, Spain explored the role of the cytokine CD69 in a mouse model of collagen-induced arthritis (CIA). Their results strongly suggest that CD69 is a negative regulator of autoimmune reactivity and agonistic anti-CD69 antibodies may be useful in the treatment of chronic inflammation in diseases such as arthritis.
The CD69 receptor is induced following activation of leukocytes at inflammatory sites, but its physiological role during inflammation remains unknown. Sánchez-Madrid and colleagues explored the role of CD69 in autoimmune reactivity by analyzing a model of CIA in CD69-deficient mice. CD69–/– mice showed increased CIA, with exacerbated T and B cell immune responses to type II collagen. Transforming growth factor (TGF) -beta1 and TGF- beta2, which are protective in CIA, were reduced in the inflamed joints of CD69–/– mice, correlating with the increase in other proinflammatory cytokines. Local injection of blocking anti–TGF-beta antibodies increased CIA severity and proinflammatory cytokines in control but not CD69–/– mice. These results show that CD69 is a negative modulator of autoimmune reactivity and inflammation through synthesis of TGF-beta, a cytokine that in turn downregulates the production of various proinflammatory mediators.
TITLE: CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis
AUTHOR CONTACT:
Francisco Sánchez-Madrid
Hospital de La Princesa, Madrid, Spain.
Phone: 34-91-5202370
Fax: 34-91-5202374
E-mail: fsanchez.hlpr@saud.madrid.org
View the PDF of this article at: https://www.the-jci.org/press/19112.pdf
15d-PGJ2 revealed as imposter PPAR-gamma ligand
Over the past several years there has been increasing interest in the prostaglandin D2–derived product 15d-PGJ2. In 1995, evidence was reported that suggested that 15d-PGJ2 was capable of activating the transcription factor PPAR-gamma. At the time, the finding was of considerable interest because the endogenous ligand for PPAR-gamma was unknown. Since then, 15d-PGJ2 has often been referred to as the endogenous PPAR-gamma ligand. Garrett FitzGerald and colleagues at the University of Pennsylvania used a highly sensitive and specific assay to demonstrate that in vivo 15d-PGJ2 levels are actually several orders of magnitude below the levels required to induce many of the biological effects attributed to this molecule.
TITLE: Biosynthesis of 15-deoxy-?12,14-PGJ2 and the ligation of PPAR-gamma
AUTHOR CONTACT:
Garret A. FitzGerald
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-1184
Fax: (215) 573-9135
E-mail: garret@spirit.gcrc.upenn.edu
View the PDF of this article at: https://www.the-jci.org/press/18012.pdf
ACCOMPANYING COMMENTARY:
15-deoxy-?12,14-PGJ2: endogenous PPAR-gamma ligand or minor eicosanoid degradation product?
AUTHOR CONTACT:
William S. Powell
Meakins-Christie Laboratories and Department of Medicine, McGill University, Montreal, Quebec, Canada.
Phone: (514) 398-3864 ext. 094071
Fax: (514) 398-7483
E-mail: William.Powell@McGill.ca
View the PDF of this commentary at: https://www.the-jci.org/press/19796.pdf
JunD protects the kidney
Fabiola Terzi and colleagues at INSERM, Paris, have defined the role of the protein JunD in preventing renal lesions and renal failure, a devastating consequence of a loss of kidney mass.
The partial loss of kidney mass triggers the compensatory growth of remaining nephrons. In some cases, this compensatory growth becomes excessive, resulting in renal lesions and end-stage renal failure. The transcription factor AP-1 is composed of Jun and Fos proteins and plays a crucial role in the fine-tuning of cell proliferation. Terzi and colleagues used JunD–/– mice to define a key role for this transcription factor in preventing renal lesions following nephron reduction.
The model showed that nephron reduction induced a bimodal proliferative response. JunD was dispensable for the initial proliferative phase but essential for preventing a late phase that leads to kidney lesions. The regulation by JunD was found to involve upregulation of the paracrine mitogen, TGF-alpha. Expression of a transgene encoding a dominant-negative isoform of the epidermal growth factor receptor prevented hyperplasia and development of renal lesions in JunD–/– mice. Dissection of these regulatory networks opens avenues for identifying genes involved in the susceptibility to renal disease.
TITLE: JunD protects against chronic kidney disease by regulating paracrine mitogens
AUTHOR CONTACT:
Fabiola Terzi
INSERM U426, Paris, France.
Phone: 33-1-44-85-62-70
Fax: 33-1-42-28-15-64
E-mail: terzi@bichat.inserm.fr
View the PDF of this article at: https://www.the-jci.org/press/17647.pdf
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