New insights into irritable bowel syndrome pathophysiological mechanisms: contribution of epigenetics

Irritable bowel syndrome (IBS) is a complex multifactorial condition including alterations of the gut-brain axis, intestinal permeability, mucosal neuro-immune interactions, and microbiota imbalance. Recent advances proposed epigenetic factors as possible regulators of several mechanisms involved in IBS pathophysiology. These epigenetic factors include biomolecular mechanisms inducing chromosome-related and heritable changes in gene expression regardless of DNA coding sequence. Accordingly, altered gut microbiota may increase the production of metabolites such as sodium butyrate, a prominent inhibitor of histone deacetylases. Patients with IBS showed an increased amount of butyrate-producing microbial phila as well as an altered profile of methylated genes and micro-RNAs (miRNAs). Importantly, gene acetylation as well as specific miRNA profiles are involved in different IBS mechanisms and may be applied for future diagnostic purposes, especially to detect increased gut permeability and visceromotor dysfunctions. In this review, we summarize current knowledge of the role of epigenetics in IBS pathophysiology

Adipose-derived Stem Cells Added to Platelet-rich Plasma for Chronic Skin Ulcer Therapy

Adipose-derived stem cells (ASCs) hold great promise for regenerative medicine applications due to their ability to promote the healing process through in situ differentiation and secretion of paracrine factor. The aim of this paper is to present a clinical adjunct for chronic skin wound therapy based on ASCs added to platelet-rich plasma (PRP), to obtain an enhanced PRP (e-PRP)

Cellular Targeting of Engineered Heterologous Antigens Is a Determinant Factor for Bovine Herpesvirus 4-Based Vaccine Vector Development▿

In a previous study, an apathogenic strain of bovine herpesvirus 4 (BoHV-4) cloned as a bacterial artificial chromosome and expressing a chimeric peptide (gE2/gD) as a secreted form was described. Recombinant virus-inoculated animals produced antibodies against bovine viral diarrhea virus (BVDV) gE2 and BoHV-1 gD. However, neutralizing antibodies were produced only against BVDV, not against BoHV-1. In the present work a recombinant BoHV-4 expressing a membrane-linked form of gE2/gD chimeric peptide was constructed, and inoculated rabbits produced serum-neutralizing antibodies against both BVDV and BoHV-1. Protein cell sorting and targeting are a very important issue when immunodominant antigens are engineered for recombinant virus vaccine development

Pioglitazone Improves In Vitro Viability and Function of Endothelial Progenitor Cells from Individuals with Impaired Glucose Tolerance

BACKGROUND: Evidence suggests that the PPARγ-agonist insulin sensitizer pioglitazone, may provide potential beneficial cardiovascular (CV) effects beyond its anti-hyperglycaemic function. A reduced endothelial progenitor cell (EPC) number is associated with impaired glucose tolerance (IGT) or diabetes, conditions characterised by increased CV risk. AIM: To evaluate whether pioglitazone can provide benefit in vitro in EPCs obtained from IGT subjects. MATERIALS AND METHODS: Early and late-outgrowth EPCs were obtained from peripheral blood mononuclear cells of 14 IGT subjects. The in vitro effect of pioglitazone (10 µM) with/without PPARγ-antagonist GW9662 (1 µM) was assessed on EPC viability, apoptosis, ability to form tubular-like structures and pro-inflammatory molecule expression. RESULTS: Pioglitazone increased early and late-outgrowth EPC viability, with negligible effects on apoptosis. The capacity of EPCs to form tubular-like structures was improved by pioglitazone in early (mean increase 28%; p=0.005) and late-outgrowth (mean increase 30%; p=0.037) EPCs. Pioglitazone reduced ICAM-1 and VCAM-1 adhesion molecule expression in both early (p=0.001 and p=0.012 respectively) and late-outgrowth (p=0.047 and p=0.048, respectively) EPCs. Similarly, pioglitazone reduced TNFα gene and protein expression in both early (p=0.034;p=0.022) and late-outgrowth (p=0.026;p=0.017) EPCs compared to control. These effects were prevented by incubation with the PPARγ-antagonist GW9662. CONCLUSION: Pioglitazone exerts beneficial effects in vitro on EPCs isolated from IGT subjects, supporting the potential implication of pioglitazone as a CV protective agents

Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis

Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2—one of the most potent immunomodulatory chemokines—to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications