Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)-dependent glucose sensing to lower glucose production in high-fat-fed rats.

The responsiveness of glucose sensing to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake In both rodents and humans, glucose sensing is lost in diabetes and obesity, but the site(s) of impairment remains elusive. Here, we first report that short-term high-fat feeding disrupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat-fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test.

Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a.

Rationale: Inflammation is a key contributor to atherosclerosis. MicroRNA-146a (miR-146a) has been identified as a critical brake on proinflammatory nuclear factor κ light chain enhancer of activated B cells signaling in several cell types, including endothelial cells and bone marrow (BM)-derived cells. Importantly, miR-146a expression is elevated in human atherosclerotic plaques, and polymorphisms in the precursor have been associated with risk of coronary artery disease.

Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice.

Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis promotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive.

Up-regulation of leukocyte CXCR4 expression by sulfatide: an L-selectin-dependent pathway on CD4+ T cells.

CXCR4 plays significant roles in immune and inflammatory responses and is important for selective recruitment of leukocytes. We previously showed that CXCR4 surface expression of human lymphocytes was affected by sulfatide, an in vivo ligand for L-selectin. Increased CXCR4 expression was shown to promote biologically relevant functions such as integrin-dependent adhesion and transmigration.

Monocyte-induced endothelial calcium signaling mediates early xenogeneic endothelial activation.

Hallmarks of delayed xenograft rejection include monocyte infiltration, endothelial cell activation and disruption of the endothelial barrier. The monocyte is an important initiator of this type of rejection because monocytes accumulate within hours after xenografting and prior monocyte depletion suppresses the development of this type of rejection. However, the mechanisms that mediate monocyte-induced xenograft injury are unclear at present.

Improved therapeutic outcome following combination immunogene vaccination therapy in murine myeloma.

Increasing evidence suggests a role for immunologic vaccination and therapy in the management of minimal residual myeloma. We have previously demonstrated a synergistic effect of combining the Th1 stimulating cytokine IL-12 with the co-stimulatory molecule CD80 in murine myeloma vaccination therapy. We reasoned that the efficacy of such treatment might be further improved by incorporating additional gene products which enhance the function of antigen presenting cells.

The protein tyrosine phosphatase SHP-2 regulates interleukin-1-induced ERK activation in fibroblasts.

Focal adhesion complexes are actin-rich, cytoskeletal structures that mediate cell adhesion to the substratum and also selectively regulate signal transduction pathways required for interleukin (IL)-1beta signaling to the MAP kinase, ERK. IL-1-induced ERK activation is markedly diminished in fibroblasts deprived of focal adhesions whereas activation of p38 and JNK is unaffected. While IL-1 signaling is known to involve the activity of protein and lipid kinases including MAP kinases, FAK, and PI3K, little is known about the role of phosphatases in the regulation of IL-1 signal generation and attenuation.

Conditional expression of a dominant-negative c-Myb in vascular smooth muscle cells inhibits arterial remodeling after injury.

Inhibiting activity of the c-Myb transcription factor attenuates G1 to S phase cell cycle transitions in vascular smooth muscle cells (SMCs) in vitro. To determine the effects of arterial SMC-specific expression of a dominant-negative c-Myb molecule (Myb-Engrailed) on vascular remodeling in vivo, we performed carotid artery wire-denudation in 2 independent lines of binary transgenic mice with SM22alpha promoter-defined Doxycycline-suppressible expression of Myb-Engrailed. Adult mice with arterial SMC-specific expression of Myb-Engrailed were overtly normal in appearance and did not display any changes in cardiovascular structure or physiology.

NOD2/CARD15 gene mutation is not associated with susceptibility to Wegener's granulomatosis.

Objective: Polymorphisms and mutations in the NOD2/CARD15 gene have been reported to increase susceptibility to Crohn's disease (CD) and the rare Blau syndrome, respectively. Both conditions are characterized by granuloma formation. We assessed the influence of variants in the CARD15 gene in another disorder characterized by granuloma, Wegener's granulomatosis (WG).

Regulation of the S100B gene by alpha 1-adrenergic stimulation in cardiac myocytes.

We previously reported that S100B, a 20-kDa Ca(2+)-binding homodimer, inhibited the postinfarct myocardial hypertrophic response mediated by alpha(1)-adrenergic stimulation through the protein kinase C (PKC) signaling pathway. In the present study, we examined whether the same pathway induced the S100B gene, supporting the hypothesis that S100B is a feedback negative regulator of this pathway. We transfected cultured neonatal rat cardiac myocytes with a luciferase reporter gene driven by the maximal human S100B promoter and progressively shorter segments of this promoter sequentially deleted from the 5' end.

The role of NOS in heart failure: lessons from murine genetic models.

Nitric Oxide Synthases (NOSs) are a group of related proteins that produce nitric oxide (NO). In mammals, there are three known members of this gene family: nNOS (NOS1), iNOS (NOS2) and eNOS (NOS3). Each has been disrupted by targeted gene ablation in mice and the corresponding phenotypes examined.

Protein-tyrosine phosphatase MEG2 is expressed by human neutrophils. Localization to the phagosome and activation by polyphosphoinositides.

Signaling pathways involving reversible tyrosine phosphorylation are essential for neutrophil antimicrobial responses. Using reverse transcriptase PCR, expression of the protein-tyrosine phosphatase MEG2 by peripheral neutrophilic polymorphonuclear leukocytes (PMN) was identified. Polyclonal antibodies against MEG2 were developed that confirmed expression of MEG2 protein by PMN.

Deficiency of Src homology 2-containing phosphatase 1 results in abnormalities in murine neutrophil function: studies in motheaten mice.

Neutrophils, an essential component of the innate immune system, are regulated in part by signaling pathways involving protein tyrosine phosphorylation. While protein tyrosine kinase functions in regulating neutrophil behavior have been extensively investigated, little is known about the role for specific protein tyrosine phosphatases (PTP) in modulating neutrophil signaling cascades. A key role for Src homology 2 domain-containing phosphatase 1 (SHP-1), a PTP, in neutrophil physiology is, however, implied by the overexpansion and inappropriate activation of granulocyte populations in SHP-1-deficient motheaten (me/me) and motheaten viable (me(v)/me(v)) mice.

Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs.

Background: Gene therapy provides the potential to modify donor organs to better withstand transplantation, but this has yet to be realized. In vivo gene transfer using adenoviral vectors has had limited success because of host immune response that induces inflammation and limits the amount and duration of transgene expression. We hypothesize that transplantation immunosuppression can attenuate the post-transfection host-immune response to allow for improved gene transfer following adenoviral-mediated transfection.

Targeting the angiotensin system in posttransplant airway obliteration: the antifibrotic effect of angiotensin converting enzyme inhibition.

The angiotensin system plays a role in the pathogenesis of fibrotic diseases. We used a rat heterotopic tracheal transplant model of bronchiolitis obliterans (BO) to examine the role of angiotensin converting enzyme (ACE) in development of the fibroproliferative lesion of BO. Isograft and allograft tracheal transplants were performed.

Leukocyte adhesion molecules in atherogenesis.

Functions of mononuclear leukocytes and endothelial cell leukocyte adhesion molecules in the formation of early atherosclerotic lesions is discussed. The main transgenic mouse models developed to study cholesterol metabolism and atherosclerotic lesion formation, including apolipoprotein E knockout and low density lipoprotein receptor knockout (LDLR-/-) mice, are reviewed. Differences in their dependence on dietary cholesterol supplementation is emphasized and a new semi-purified, cholate-free mouse diet for LDLR-/- mice is described.