Post-Transcriptional Changes in Serum Albumin: Role in the Pathogenesis of Bacterial Infections in Cirrhosis

Besides the oncotic function Human serum Albumin (HSA) is also endowed with many other non-oncotic properties among which the antioxidant activity. Beside quantitative changes, during cirrhosis extensive post-transcriptional alterations, likely promoted by pro-inflammatory and pro-oxidant state occur to the HSA molecule.In this study we evaluated the structural and functional integrity of HSA in a large series of hospitalized patients with advanced cirrhosis. We also evaluated the relationship between alterations to the HSA molecule and clinical features as well as 1-year prognosis of patients included in the study. By using an LC-ESI-MS approach we identified several HSA isoforms characterized by one or more structural defects. These alterations mainly involved the cysteine-34 residue, the main antioxidant site of the molecule, and were mainly promoted by a pro-oxidant environment. Specific patterns of molecular alterations were found associated to the severity of cirrhosis and to the presence of clinical complication of disease, while the residual amount of the native HSA emerged as a potent predictor of 1-year mortality. The functional integrity of the N-terminal portion of the HSA molecule, provided with an indirect antioxidant activity, was evaluated by measuring the circulating level of Ischemia Modified Albumin (IMA) and IMA to serum albumin ratio (IMAr). IMA and IMAr were not associated to the severity of cirrhosis nor to the patients prognosis. Contrariwise IMA and IMAr were specifically associated to bacterial infection,showing a discriminating performance comparable to that of C-reactive protein. In conclusion this study provided evidences of clinical and prognostic relevance of HSA structural and functional alteration in patients with cirrhosis, strengthening the concept that the global function of the HSA molecule, resulting from both oncotic and non-oncotic properties, is related not only to its absolute circulating level, but also,and perhaps mainly, to its structural and functional integrity

Strategies to Restore Adenosine Triphosphate (ATP) Level After More than 20 Hours of Cold Ischemia Time in Human Marginal Kidney Grafts

BACKGROUND The persisting organ shortage in the field of transplantation recommends the use of marginal kidneys which poorly tolerate ischemic damage. Adenosine triphosphate (ATP) depletion during cold ischemia time (CIT) is considered crucial for graft function. We tested different strategies of kidney perfusion before transplantation in the attempt to improve the technique. MATERIAL AND METHODS Twenty human discarded kidneys from donors after brain death and with at least 20 hours of CIT were randomized to the following experimental groups (treatment time three-hours at 4\ub0C): a) static cold storage (CS); b) static cold hyperbaric oxygenation (Hyp); c) hypothermic perfusion (PE); d) hypothermic perfusion in hyperbaric oxygenation (PE-Hyp); and e) hypothermic oxygenated perfusion (PE-O2). RESULTS Histological results showed that perfusion with or without oxygen did not produce any endothelial damage. A depletion of ATP content following the preservation procedure was observed in CS, PE, and Hyp, while PE-Hyp and PE-O2 were associated with a net increase of ATP content with respect to baseline level. In addition, PE-Hyp was associated with a significant downregulation of endothelial isoform of nitric oxide synthase (eNOS) gene expression and of hypoxia inducible factor-1\u3b1 (HIF-1\u3b1). CONCLUSIONS Hyperbaric or normobaric oxygenation with perfusion improves organ metabolic preservation compared to other methods. This approach may prevent the onset of delayed graft function, but clinical trials are needed to confirm this

Circulating Inflamma-miRs as Potential Biomarkers of Cognitive Impairment in Patients Affected by Alzheimer's Disease

none17noAlzheimer's disease (AD), the most prevalent neurodegenerative disease in the growing population of elderly people, is still lacking minimally-invasive circulating biomarkers that could facilitate the diagnosis and the monitoring of disease progression. MicroRNAs (miRNAs) are emerging as tissue-specific and/or circulating biomarkers of several age-related diseases, but evidence on AD is still not conclusive. Since a systemic pro-inflammatory status was associated with an increased risk of AD development and progression, we focused our investigation on a subset of miRNAs modulating the inflammatory process, namely inflamma-miRNAs. The expression of inflamma-miR-17-5p, -21-5p, -126-3p, and -146a-5p was analyzed in plasma samples from 116 patients with AD compared with 41 age-matched healthy control (HC) subjects. MiR-17-5p, miR-21-5p, and miR-126-3p plasma levels were significantly increased in AD patients compared to HC. Importantly, a strong inverse relationship was observed between miR-21-5p and miR-126-3p, and the cognitive impairment, assessed by Mini-Mental State Examination (MMSE). Notably, miR-126-3p was able to discriminate between mild and severe cognitive impairment. Overall, our results reinforce the hypothesis that circulating inflamma-miRNAs could be assessed as minimally invasive tools associated with the development and progression of cognitive impairment in AD.restrictedGiuliani, Angelica; Gaetani, Simona; Sorgentoni, Giulia; Agarbati, Silvia; Laggetta, Maristella; Matacchione, Giulia; Gobbi, Mirko; Rossi, Tommaso; Galeazzi, Roberta; Piccinini, Gina; Pelliccioni, Giuseppe; Bonfigli, Anna Rita; Procopio, Antonio Domenico; Albertini, Maria Cristina; Sabbatinelli, Jacopo; Olivieri, Fabiola; Fazioli, FrancescaGiuliani, Angelica; Gaetani, Simona; Sorgentoni, Giulia; Agarbati, Silvia; Laggetta, Maristella; Matacchione, Giulia; Gobbi, Mirko; Rossi, Tommaso; Galeazzi, Roberta; Piccinini, Gina; Pelliccioni, Giuseppe; Bonfigli, Anna Rita; Procopio, Antonio Domenico; Albertini, Maria Cristina; Sabbatinelli, Jacopo; Olivieri, Fabiola; Fazioli, Francesc

Strategies to Restore Adenosine Triphosphate (ATP) Level After More than 20 Hours of Cold Ischemia Time in Human Marginal Kidney Grafts

BACKGROUND The persisting organ shortage in the field of transplantation recommends the use of marginal kidneys which poorly tolerate ischemic damage. Adenosine triphosphate (ATP) depletion during cold ischemia time (CIT) is considered crucial for graft function. We tested different strategies of kidney perfusion before transplantation in the attempt to improve the technique. MATERIAL AND METHODS Twenty human discarded kidneys from donors after brain death and with at least 20 hours of CIT were randomized to the following experimental groups (treatment time three-hours at 4°C): a) static cold storage (CS); b) static cold hyperbaric oxygenation (Hyp); c) hypothermic perfusion (PE); d) hypothermic perfusion in hyperbaric oxygenation (PE-Hyp); and e) hypothermic oxygenated perfusion (PE-O2). RESULTS Histological results showed that perfusion with or without oxygen did not produce any endothelial damage. A depletion of ATP content following the preservation procedure was observed in CS, PE, and Hyp, while PE-Hyp and PE-O2 were associated with a net increase of ATP content with respect to baseline level. In addition, PE-Hyp was associated with a significant downregulation of endothelial isoform of nitric oxide synthase (eNOS) gene expression and of hypoxia inducible factor-1α (HIF-1α). CONCLUSIONS Hyperbaric or normobaric oxygenation with perfusion improves organ metabolic preservation compared to other methods. This approach may prevent the onset of delayed graft function, but clinical trials are needed to confirm this