The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis

<p>Abstract</p> <p>Background</p> <p>We previously showed that mice lacking the high mobility group A1 gene (<it>Hmga1</it>-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the <it>Hmga1</it>-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in <it>Hmga1</it>-deficient mice could be related to the deficit of an insulin resistance factor is discussed.</p> <p>Results</p> <p>We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (<it>RBP4</it>) gene and protein expression in living cells of both human and mouse origin. Then, by employing the <it>Hmga1</it>-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis <it>in vivo</it>, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in <it>Hmga1</it>-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased <it>Glut4 </it>mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.</p> <p>Conclusion</p> <p>These results indicate that HMGA1 is an important modulator of <it>RBP4 </it>gene expression <it>in vivo</it>. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.</p

Low Laser Therapy Plus Non-surgical Periodontal Treatment Reduces Interleukin-1 Beta Serum Levels

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Enrichment of CD56dimKIR+CD57+ highly cytotoxic NK cells in tumor infiltrated lymph nodes of melanoma patients

An important checkpoint in the progression of melanoma is the metastasis to lymph nodes. Here, to investigate the role of lymph node NK cells in disease progression, we analyze frequency, phenotype and functions of NK cells from tumor-infiltrated (TILN) and tumor-free ipsilateral lymph nodes (TFLN) of the same patients. We show an expansion of CD56dimCD57dimCD69+CCR7+KIR+ NK cells in TILN. TILN NK cells display robust cytotoxic activity against autologous melanoma cells. In the blood of metastatic melanoma patients the frequency of NK cells expressing the receptors for CXCL8 receptor is increased compared to healthy subjects, and blood NK cells also express the receptors for CCL2 and IL6. These factors are produced in high amount in TILN and in vitro switch the phenotype of blood NK cells from healthy donors to the phenotype associated with TILN. Our data suggest that the microenvironment of TILN generates and/or recruits a particularly effective NK cell subset

Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition

The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation

Effect of Mediterranean Diet and Antioxidant Formulation in Non-Alcoholic Fatty Liver Disease: A Randomized Study

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, characterized by liver fatty acid accumulation and fibrosis, not due to excessive alcohol consumption. Notably, nutritional habits have been reported to be implicated in the onset and severity of the hepatic damage, while the Mediterranean diet has shown beneficial effects on NAFLD. Free radicals and oxidative stress were suggested to be involved in the pathogenesis and progression of NAFLD, and several data highlighted the efficacy of antioxidant supplementation in its treatment. The aim of this study was to compare the effects of the Mediterranean diet, with or without an antioxidant complex supplement, in overweight patients suffering from NAFLD. In this prospective study, fifty Caucasian overweight patients were randomized into three groups (Groups A–C). A personalized moderately hypocaloric Mediterranean diet was prescribed to all patients included in the A and B groups. In addition to the diet, Group B was administered antioxidant supplementation daily and for the period of six months. Group C did not have any type of treatment. The study proved that the Mediterranean diet alone or in association with the antioxidant complex improved anthropometric parameters, lipid profile and reduced hepatic fat accumulation and liver stiffness. However, Group B patients, in which the diet was associated with antioxidant intake, showed not only a significant improvement in insulin sensitivity, but also a more consistent reduction of anthropometric parameters when compared with Group A patients. Taken together, these results support the benefit of antioxidant supplementation in overweight patients with NAFLD

Intra-aortic balloon pump induced pulsatile perfusion reduces endothelial activation and inflammatory response following cardiopulmonary bypass

OBJECTIVE: Intra-aortic balloon pump (IABP)-induced pulsatile perfusion has demonstrated that it can preserve organ function during cardiopulmonary bypass (CPB). We evaluated the role of IABP pulsatile perfusion on endothelial response. METHODS: Forty consecutive isolated CABG undergoing preoperative IABP were randomized to receive IABP pulsatile CPB during aortic cross-clamping (group A, 20 patients) or standard linear CPB (group B, 20 patients) during cross-clamp time. Hemodynamic results were analyzed by Swan-Ganz catheter [mean arterial pressure (MAP), cardiac index (CI), indexed systemic vascular resistances (ISVR), indexed pulmonary vascular resistances (IPVR), wedge pressure (PCWP)]. Inflammatory/endothelial response was analyzed by pro-inflammatory (IL-2, IL-6, IL-8), anti-inflammatory cytokines (IL-10), and endothelial markers [vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1)]. All measurements were recorded preoperatively (T0), before aortic declamping (T1), at the end of surgery (T2), 12h (T3) and 24h (T4) postoperatively. ANOVA for repeated measures was used to evaluate the differences of means. RESULTS: Hemodynamic response was comparable except for higher MAP (p=0.01 at T1) and lower ISVR (p=0.001 at T1, p=0.003 at T2) in group A. No differences were found in perioperative leakage of IL-2, IL-6, and IL-8 between the two groups (within-group p=0.0001 either in group A and group B; between-groups p=NS at 2-ANOVA). Group A showed significantly lower VEGF (between-groups p=0.001 at 2-ANOVA, p=0.001 at T1, T2) and MCP-1 (between-groups p=0.001 at 2-ANOVA, p=0.001 at T1, T2) with higher IL-10 secretion (between-groups p=0.001 at 2-ANOVA, p=0.01 at T1, T2, T3). CONCLUSIONS: IABP-induced pulsatile perfusion allows lower endothelial activation during CPB and higher anti-inflammatory cytokines secretion