Cellular metabolism linked to anxiety disorders
Anxiety disorders, ranging from social phobia to post-traumatic stress disorder, are the most common psychiatric diseases in the United States. Research in mice suggests a link between the gene that encodes Glyoxylase 1 (GLO1) and increased anxiety; however, the mechanism underlying this association has remained unclear. The normal role of GLO1 is to degrade cytotoxic byproducts of glycolysis, a function which has no obvious connection to anxiety. Margaret Distler and colleagues at the University of Chicago asked whether the primary substrate of GLO1, methylglyoxal, might have undocumented neurological effects. Using a mouse model, they demonstrated that methylglyoxal stimulates robust activity from GABAA receptors, which are neuron receptors that respond to neurotransmitters. As pharmaceuticals targeting GABAA receptors are mainstays of anxiety treatment, this study provides a definitive functional link between GLO1 activity and anxiety. The team also showed that the inhibition of GLO1 in mice reduced anxious behavior, suggesting GLO1 as a potential novel therapeutic target in humans. These findings have important clinical implications not only for anxiety disorders, but also for other central nervous system diseases having proposed associations with the gene encoding GLO1, including autism, affective disorders, and schizophrenia.
Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal
University of Chicago, Chicago, IL, USA
Phone: (773) 834-2897; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/61319?key=e2db0ff64964217265c6
Hope for new treatment options for the rare disease Beare-Stevenson syndrome
Beare-Stevenson cutis gyrata syndrome is an extremely rare genetic disease that causes serious physical problems affecting the skin and skull. The disease is associated with mutations in the fibroblast growth factor receptor 2 (FGFR2), which relays signals from the extracellular environment, but how FGFR2 mutations contribute to skin and skull defects has been unclear. In this issue of the JCI, Ethylin Wang Jabs and colleagues at the Mount Sinai School of Medicine report on the development of a new mouse model of Beare-Stevenson cutis gyrata syndrome. They team showed that these mice had an increase in intracellular signaling through a stress-responsive protein called p38. Abherent signaling through p38 is also associated with certain autoimmune conditions, and pharmacological p38 inhibitors have already been developed. The Jabs team went on to show in the mouse model of Beare-Stevenson cutis gyrata syndrome that treatment with a p38 inhibitor alleviated defects in the skull and skin. These results that suggest that p38 signaling significantly contributes to the development of the disease and suggests readily available therapeutic options might be used treat Beare-Stevenson cutis gyrata syndrome and related syndromes.
p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice
Ethylin Wang Jabs
Mount Sinai School of Medicine, New York, NY, USA
Phone: 212-241-3504; E-mail: Ethylin.Jabs@mssm.edu
View this article at: http://www.jci.org/articles/view/62644?key=0be3e3be09d197cc8279
To grow or not grow: how does Angiopoietin-2 differentially regulate?
The growth of new blood vessels, called angiogenesis, is important for cell development and proliferation. Proteins that regulate angiogenesis like Angiopoietin-2 (ANG-2) are good targets for drug therapy. Pro-angiogenic drugs are used to promote wound healing and tissue repair, while anti-angiogenic drugs are used to inhibit tumor growth. Despite findings that have established the critical role of ANG-2 in angiogenesis, the signaling mechanisms underlying its pro-angiogenic and anti-angiogenic effects have been unclear until now.
Several studies have demonstrated that ANG-2 inhibits angiogenesis through down-regulation of tyrosine kinase 2 (TIE2). However, new research on tumor cells shows that ANG-2 promotes angiogenesis. These findings led Dr. Moritz Felcht and his colleagues from Heidelberg University in Germany to investigate the role of ANG-2 on angiogenesis in the absence of TIE2. Results from endothelial cell binding and adhesion assays show that ANG-2 binds to integrin receptors when TIE2 expression is low, resulting in increased cell migration and angiogenesis. Their study concluded that ANG2 inhibits and promotes angiogenesis by binding to TIE2 and integrin receptors, respectively. Their groundbreaking work provides insight on how ANG-2 differentially regulates angiogenesis, which has important implications for angiogenesis therapeutics involving ANG-2.
Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling
German Cancer Research Center (DKFZ-ZMBH Alliance) and Heidelberg Universit, Heidelberg, UNK, DEU
Phone: +49-(0)6221-42-1500; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/58832?key=c7cc0899a244305f6199
Breast cancer stem cell revealed
Not all cells within a tumor are identical, and the observation that some cells possess a greater capacity to initiate new tumors has led to a cancer stem cell hypothesis. These cancer stem cells can self-renew as well as establish new tumors when transplanted into mice. Furthermore, these cancer stem cells resist conventional cancer therapies and may serve as a reservoir for establishing metastatic cancer. However, very few biomarkers exist that can readily identify the presence of cancer stem cells. Dr. Michael Andreef and colleagues at the MD Anderson Cancer Center in Houston Texas recently identified a new marker for cancer stem cells in breast cancer. The research team found that a particular lipid molecule called ganglioside G2 was expressed on a subset of cells from patient samples and that these cells were capable of establishing tumors in mice. They further found that the enzyme that synthesizes ganglioside G2 is required for tumor formation. Thus, the research team not only identified a novel biomarker of breast cancer stem cells but also established ganglioside G2 production as a potential therapeutic target.
Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis
The Univ of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Phone: 713-792-7260; Fax: 713-794-1903; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/59735?key=a4dcacf86339b739c2ee
Too much of a good thing is bad: hormones protect from toxic inflammation
Immune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis, are mediated by a dysfunctional inflammatory response. This disease-mediating inflammation often involves the expression of an important molecule, tumor necrosis factor (TNF), whose function can be blocked by steroid hormones called glucocorticoids. However, the mechanism through which glucocorticoids block TNF-associated inflammation is not fully understood. A recent study from Claude Libert and colleagues from VIB and Ghent University in Belgium investigated the protective effect of glucocorticoids during TNF-induced inflammation in a mouse model. The team showed that mice lacking intact glucocorticoid signaling were more sensitive to TNF-associated inflammation, resulting in increased mortality and intestinal damage in the mutant mice. They demonstrated that the protective effect of glucocorticoids during inflammation is dependent on the joining of two glucocorticoid receptor molecules, which can activate anti-inflammatory molecules such as MKP-1 to protect against inflammatory damage. When the researchers stimulated mice lacking MKP-1 with TNF, they found that MKP-1-deficient mice showed increased inflammation and tissue damage compared to normal mice, further confirming the importance of MKP-1 in protecting against TNF-induced inflammation. Their study sheds light on the mechanism behind glucocorticoid-mediated protection and provides insight into better therapeutics to treat inflammatory disorders.
Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation
VIB/DMBR, Ghent, , BEL
Phone: 093313705; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/60006?key=5e53349c42253f156423
Stop the attack: new treatment options for graft versus host disease
Graft versus host disease is a serious complication that can result from transplantation of bone marrow, which is sometimes performed for patients with blood cancers such as leukemia. In graft versus host disease, immune cells from the recipient called dendritic cells, which are a component of the immune system that process antigens, activate donor called T cells that recognize antigens. Researchers at the Mount Sinai School of Medicine in New York wanted to better understand the molecular pathways that are involved in trigger the hyperactive immune response in graft versus host disease. Led by Dr. Peter Heeger, the research team found in a mouse model system that a signaling pathway in immune cells involving the proteins complement C5a and C3a was critical for inducing graft versus host disease. Genetic mutations that increase complement signaling caused an a more severe progression of graft versus host disease, whereas loss of either C5a receptor or C3a receptor in T cells reduced the severity of graft versus host disease. Further, the Heeger team showed that pharmacological inhibition of C5a markedly improved survival of mice following transplantation. Cumulatively, their results provide a better understanding of how graft versus host disease develops and provides a blueprint for an effective treatment strategy in human graft versus host disease.
Antigen presenting cell-derived complement modulates murine graft versus host disease
Peter S. Heeger
Mount Sinai School of Medicine, New York, NY, USA
Phone: 212.241.6500 (general number); Fax: ; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/61019?key=b796836c1a0d2ceed170
Keeping liver cancer in check: a new therapeutic target for hepatocellular carcinoma
Hepatocellular carcinoma is the most common form of liver cancer and is frequently resistant to conventional chemotherapy and radiotherapy. In hopes of identifying new molecular targets for pharmacological treatment of hepatocellular carcinoma, Tiebang Kang and fellow researchers at the Sun Yat-Sen University Cancer Center, in Guangzhou, China searched for genes that correlated with poor prognosis in hepatocellular carcinoma patients. They found that a protein that mediates the cellular response to DNA damage called checkpoint kinase 1 (CHK1) is frequently elevated in patients who respond poorly to treatment. They went on to show that CHK1 acts to modify a specific protein called spleen tyrosine kinase (L) (SYK(L)) and that this modification led to SYK(L) protein destruction. Further, the Kang team found in mice that treatment with a pharmacological CHK1 inhibitor increased the sensitivity of hepatocellular carcinoma cells to cell death induced by the chemotherapy agent cisplatin. Their findings suggest that CHK1 targeting combined with cisplatin may offer enhanced clinical benefits in hepatocellular carcinoma.
CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma
Sun Yat-sen University Cancer Center, Guangzhou, , CHN
Phone: +86 2087343183; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/61380?key=bc88ef0895636e0346c8
Provided by Journal of Clinical Investigation
This Phys.org Science News Wire page contains a press release issued by an organization mentioned above and is provided to you “as is” with little or no review from Phys.Org staff.