Lymphoma therapy could deliver a double punch | Back to top
B cell lymphomas are a group of cancers of that originate in lymphoid tissue from B cells, the specialized immune cell type that produces antibodies. The development of B cell lymphoma is associated with several known genetic changes, including increased expression of MYC, a transcription factor that promotes cell growth and division. In this issue of the JCI, Andrei Thomas-Tikhonenko and his colleagues at the University of Pennsylvania in Philadelphia report on their studies to better understand the molecular pathways that interact with MYC and contribute to B cell lymphoma development. Using a mouse model of lymphoma, they found that a transcription factor in B cells known as PAX5 controls the level of MYC in cells. They showed that PAX5 stabilizes MYC protein levels through a previously undescribed pathway involving CD19, a surface protein expressed on B cells. When the research team looked in patient samples, they found that high levels of CD19 correlated with high MYC activity, and that both predicted poor patient survival time. Their findings uncover a CD19-dependent pathway that contributes to the cancerous growth of B cell lymphomas. Their work has direct implications for therapies targeting CD19 that are currently in clinical trials, and suggest that these therapies may reduce cancer-promoting signaling in addition to depleting total B cell numbers.
CD19 is a major B cell receptor–independent activator of MYC-driven B-lymphomagenesis
University of Pennsylvania & Children's Hospital of Philadelphia, Philadelphia, PA, USA
Phone: 267-426-9699; Fax: 267-426-8125; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/45851?key=2d28704cb4fae4c2cc5e
Driving the preference for fatty foods | Back to top
The World Health Organization recognizes obesity as global pandemic that threatens the health of millions of people. A number of factors contribute to the development of obesity, including complex changes in cellular pathways. Improving our understanding of the molecular events that contribute to obesity could potentially improve treatment options. Naim Akhtar Khan and fellow researchers at the Universite de Bourgogne in France recently experimentally addressed how signaling pathways in taste bud cells influence the detection of dietary fat. They report that stromal interaction molecule 1 (STIM1) is a key regulatory protein that determines fat preference. The Khan team showed that STIM1 regulates calcium signaling in response to fatty acids. Further, they found that elimination of STIM1 in mice reduced the fat-induced release of serotonin in taste bud cells and the decreased the preference mice showed for dietary fat. Their results highlight the importance of STIM1 in controlling preference for dietary fat, and suggest that modulation of this pathway could be developed as a therapy for obesity.
STIM1 regulates calcium signaling in taste bud cells and preference for fat in mice
Naim Akhtar Khan
Université de Bourgogne, Dijon, UNK, FRA
Phone: +33 3 80 39 63 12; Fax: +33 3 80 39 63 30; E-mail: Naim.email@example.com
View this article at: http://www.jci.org/articles/view/59953?key=157f32bb1feb4812a0a3
Understanding increased infection risk in diabetics | Back to top
In addition to problems with blood sugar management, diabetics suffer from a host of complications including atherosclerosis, glaucoma, and increased risk of infections. The underlying cause for many of these complications, including increased susceptibility to infections, remains unclear. Dr. Yunn-Hwen Gan and colleagues at the National University of Singapore wanted to understand why diabetics are more likely to acquire meliodosis, a disease caused by infection with Burkholderia pseudomallei, which is commonly found in southeast Asia and parts of Australia. They found that diabetic patients with B. pseudomallei infection had decreased production of a cytokine called IL-12 in infected cells. IL-12 normally activates the immune system to kill bacteria through the interferon γ pathway. Decreased IL-12 production was also observed M. tuberculosis infection. They further showed that IL-12 levels were correlated with intracellular reduced glutathione (GSH) levels, and that treatment of cells with GSH could restore normal IL-12 production. Their results suggest treatment options that increase intracellular GSH could potentially protect diabetic patients against some types of bacterial infections.
Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria
National University of Singapore, Singapore, , SGP
Phone: 6565163678; Fax: 6567791453; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/57817?key=a72a852f4021a52d471d
Protecting against cellular aging in chronic obstructive pulmonary disease | Back to top
Smokers are at a greatly increased risk of developing chronic obstructive pulmonary disease (COPD), which results in impaired lung function associated with increased inflammation and accelerated aging in lung tissue. Current treatment options can help manage COPD symptoms, but cannot cure the disease. Researchers at the University of Rochester Medical Center in Rochester, NY wanted to better understand the molecular determinants of COPD. Led by Dr. Irfan Rahman, the team identified a novel cellular pathway that induces premature aging in lung cells. Using a mouse model system, they showed that activation of sirtuin 1 (SIRT1), an enzyme that removes acetyl group modifications from proteins, plays a critical role in protecting lung tissue from damage. Mice with reduced SIRT1 activity showed a decline in lung function and airspace enlargement, which is consistent with observations of reduce SIRT1 in COPD patients. They went on to show that SIRT1 influences lung function by deacetylating FOXO3, a transcription factor that controls the expression of multiple genes in lung tissue. Their results suggest that the development of therapies that boost SIRT1 function may be an efficacious treatment option for COPD patients.
SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice
University of Rochester Medical Center, Rochester, NY, USA
Phone: 1-585-275-6911; E-mail: Irfan_Rahman@urmc.rochester.edu
View this article at: http://www.jci.org/articles/view/60132?key=528b4aa2c24de25fe852
Counterbalances keep blood cell proliferation in check | Back to top
Blood cells are continually generated throughout our lifetime in a process called hematopoiesis. Hematopoietic stem cells and progenitor cells (HSPCs) have the capacity to divide and specialize into multiple different blood cell types. This process must be tightly regulated to ensure proper production of the various blood cell lineages. A signaling protein called JAK2 is critical for cellular signaling in HSPCs and promoting cell division. JAK2 is kept in check by LNK, a protein that inhibits JAK2 function and limits cellular division of HSPC. Myeloproliferative neoplasm, a disorder characterized excess production of myeloid lineage cells, can be caused by mutation of LNK in patients. Wei Tong and colleagues at the Children's Hospital of Philadelphia wanted to understand how the interaction between JAK2 and LNK is regulated in HSPCs. They identified a protein family called 14-3-3 proteins that disrupt JAK2-LNK interaction, which relieves inhibition on the JAK2 signaling pathway and promotes cell growth. They further showed in mice that 14-3-3 is required to restrain LNK for proper hematopoiesis. Their results improve our understanding of the molecular pathways that govern HSCPs proliferation.
14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells
Children's Hospital of Philadelphia, philadelphia, PA, USA
Phone: 267-426-0930; Fax: 267-426-5476; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/59719?key=276fbbab303f5b24fa0b
Getting to the root of psoriasis | Back to top
Psoriasis is very common skin disorder characterized by redness, irritation and the appearance of scaly patches. An autoimmune response, in which the body's immune system triggers inflammatory response in the absence of pathogens, can trigger psoriasis in patients, though the molecular mechanisms that drive this reaction are unclear. Dr. Burkhard Becher and colleagues at the University of Zurich in Switzerland wanted to understand which immune cells initiate psoriasis in an inducible mouse model of the disease. They found that specialized cells of the innate immune system, known as Rorγ+ cells, and of the adaptive immune system, known as γδ T cells, are responsible for producing cytokines that trigger inflammation in skin. Their findings were unexpected because previous work implicated a different immune cell type, known as TH17 cells in triggering psoriasis in this mouse model. Their results provide a new basis for designing therapeutics for psoriasis and suggest further study of the roll of Rorγ+ cells and γδ T cells in psoriasis is warranted.
Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice
University of Zurich, Zurich, , CHE
Phone: +41446353703; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/61862?key=60cab272f933a7b1f656
High blood pressure induced by elevated aldosterone production | Back to top
High blood pressure is a significant health risk for a number of diseases including cardiovascular disease and renal failure. One of the key regulators of blood pressure is a peptide hormone known as aldosterone, which is produced in the adrenal gland. Elevated aldosterone levels contribute to high blood pressure in as many as 20% of patients with resistant hypertension. Paula Barrett and colleagues at the University of Virginia in Charlottesville wanted to better understand the cellular mechanisms that contribute to aldosterone production. Aldosterone is produced by specialized cells in the adrenal gland known as zona glomerulosa cells. However, it was generally unclear how the zona glomerulosa cells transduce the appropriate signals to drive aldosterone production. The Barrett research group showed that zona glomerulosa cells have an innate electrical excitability that sustains calcium signaling that leads to the eventual production of aldosterone by these cells. There identifies as previously unappreciated property of zona glomerulosa cells as electrical oscillators that facilitates calcium signaling and subsequent aldosterone production.
Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators
University of Virginia School of Medicine, Charlottesville, VA, USA
Phone: 434-924-5454; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/61996?key=60a69ddb4a1bd26301c1
Muscle building: miRNA-206 regulates muscle regeneration | Back to top
Scientists at the University of Texas Southwestern Medical Center are exploring how muscle tissue is regenerated and the underlying molecular pathways. Skeletal muscle regeneration is initiated following muscle injury when specialized stem cells, known as satellite cells, are activated. The UT Southwestern research team, led by Eric Olson, discovered an important role for a regulatory RNA called miRNA-206 in satellite cells. They found that miRNA-206 levels were increased following muscle injury, and that mice without miRNA-206 substantially delayed skeletal muscle repair. In addition, they found in a mouse model system of Duchenne muscular dystrophy that loss of miRNA-206 accelerated both the onset time and the severity muscular dystrophy. Their results indicate that miRNA-206 is an important regulator of gene expression in satellite cells during muscle regeneration.
microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice
UT Southwestern Medical Center, Dallas, TX, USA
Phone: 214 648-1187; Fax: 214 648-1196; E-mail: Eric.Olson@utsouthwestern.edu
View this article at: http://www.jci.org/articles/view/62656?key=ce2ddf6ea8493b52ea52
Nonalcoholic fatty liver disease: which came first, insulin insensitivity or excess triglycerides? | Back to top
Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element–binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.
The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans
Institut Cochin Inserm U1016, paris, 75014 FRA, UNK, FRA
Phone: 1: 33-1-53-73-27-07; Fax: 1: 33-1-53-73-27-03; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/41636?key=c60105c1e771f3709051
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