A new cryptic host defense peptide identified in human 11-hydroxysteroid dehydrogenase-1 ß-like: from in silico identification to experimental evidence.

BACKGROUND: Host defence peptides (HDPs) are evolutionarily conserved components of innate immunity. Human HDPs, produced by a variety of immune cells of hematopoietic and epithelial origin, are generally grouped into two families: beta structured defensins and variably-structured cathelicidins. We report the characterization of a very promising cryptic human HDP, here called GVF27, identified in 11-hydroxysteroid dehydrogenase-1 ß-like protein. METHODS: Conformational analysis of GVF27 and its propensity to bind endotoxins were performed by NMR, Circular Dichroism, Fluorescence and Dynamic Light Scattering experiments. Crystal violet and WST-1 assays, ATP leakage measurement and colony counting procedures were used to investigate antimicrobial, anti-biofilm, cytotoxicity and hemolytic activities. Anti-inflammatory properties were evaluated by ELISA. RESULTS: GVF27 possesses significant antibacterial properties on planktonic cells and sessile bacteria forming biofilm, as well as promising dose dependent abilities to inhibit attachment or eradicate existing mature biofilm. It is unstructured in aqueous buffer, whereas it tends to assume a helical conformation in mimic membrane environments as well as it is able to bind lipopolysaccharide (LPS) and lipoteichoic acid (LTA). Notably it is not toxic towards human and murine cell lines and triggers a significant innate immune response by attenuating expression levels of pro-inflammatory interleukins and release of nitric oxide in LPS induced macrophages. CONCLUSION: Human GVF27 may offer significant advantages as leads for the design of human-specific therapeutics. GENERAL SIGNIFICANCE: Human cryptic host defence peptides are naturally no immunogenic and for this they are a real alternative for solving the lack of effective antibiotics to control bacterial infections.

Amyloidogenic variant of apolipoprotein A-I elicits cellular stress by attenuating the protective activity of angiogenin.

Amyloidogenic 'gain-of-function' mutations in apolipoprotein A-I (ApoA-I) gene (APOA1) result in systemic amyloidosis characterized by aggregate deposition and eventually cell death. However, how amyloidogenic variants of ApoA-I induce cell death is unknown. Here we report that one of the mechanisms by which amyloidogenic ApoA-I induces cell death is through attenuating anti-stress activity of angiogenin (ANG), a homeostatic protein having both pro-growth and pro-survival functions. Under growth conditions, ANG is located in nucleolus where it promotes ribosomal RNA (rRNA) transcription thereby stimulating cell growth. In adverse conditions, ANG is relocated to cytoplasm to promote damage repairs and cell survival. We find that in cells overexpressing the L75P-APOA1 mutant ANG expression is decreased and normal cellular localization of ANG is altered in response to stress and growth signals. In particular, ANG does not relocate to cytoplasm under stress conditions but is rather retained in the nucleolus where it continues promoting rRNA transcription, thus imposing a ribotoxic effect while simultaneously compromising its pro-survival activity. Consistently, we also find that addition of exogenous ANG protects cells from L75P-ApoA-I-induced apoptosis.

Right ventricular performance in severe obesity. Effect of weight loss.

BACKGROUND: The effects of severe obesity on right ventricular function in the absence of associated cardiopulmonary disease are not well known. Right myocardial performance index (R-MPI) is an echocardiographic index to non-invasively assess the right ventricular function. The aim of our study was to assess R-MPI in individuals with severe but uncomplicated obesity before and after a significant weight loss induced by bariatric surgery. PATIENTS AND METHODS: Fifteen obese females (OB) without cardiovascular and pulmonary diseases were examined. In all subjects, R-MPI was calculated by Doppler echocardiography as the sum of isovolumetric contraction time and isovolumetric relaxation time divided by ejection time. Furthermore, pulmonary function test (PFT) and 6-min walking test (6mWT) were performed. Ten healthy subjects with normal weight (HS) were also evaluated as controls. R-MPI, PFT and 6mWT were also re-evaluated one year later in 12 obese subjects treated with gastric banding after a consistent weight loss (> 20%). RESULTS: A prolongation of R-MPI was found in OB before bariatric surgery in comparison to the HS (0.47 +/- 0.04 and 0.29 +/- 0.05, respectively; P < 0.001). R-MPI significantly improved in OB 12 months after surgery (0.32 +/- 0.03) and was no longer different from HS. R-MPI positively correlated to body mass index (BMI). A significant association was found between the reduction of BMI after bariatric surgery and the distance walked during the 6mWT. CONCLUSIONS: These results show a right ventricular dysfunction in severe uncomplicated obesity, associated with an impaired functional capacity which recovers after consistent weight loss.

Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics.

BACKGROUND: Postprandial plasma glucose (PPG) excursion is a significant determinant of overall metabolic control as well as an increased risk for diabetic complications. Older persons with type 2 diabetes mellitus (DM2) are more likely to have moderate cognitive deficits and neurophysiologic and structural changes in brain tissue. Considering that poor metabolic control is considered a deranging factor for tissue/organ damage in diabetics, the authors hypothesized that PPG excursion is associated with a decline in cognitive functioning and that a tighter control of PPG may prevent cognitive decline. METHODS: Two groups of aged diabetic patients were randomly selected to be treated with repaglinide (n = 77) or glibenclamide (n = 79). RESULTS: Coefficient of variation of PPG (CV-PPG) was associated with Mini-Mental State Examination (MMSE) scores (r = -0.3410; p < 0.001) and a composite score of executive and attention functioning (r = -0.3744; p < 0.001) after adjusting for multiple confounders. Both groups showed a significant decline in hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), but only the repaglinide group demonstrated a significant decline of CV-PPG over time. In models investigating the change in cognitive functioning over time, adjusted for HbA1c and CV-FPG, a decline in cognitive functioning was observed only in the glibenclamide group (p < 0.001). After adjusting for CV-PPG, the authors no longer found a decline in executive and attention functioning composite score (p = 0.085) or the MMSE (p = 0.080) with glibenclamide. CONCLUSIONS: Exaggerated postprandial glucose (PPG) excursions are associated with a derangement of both global, executive, and attention functioning. A tighter control of PPG may prevent cognitive decline in older diabetic individuals.