Involvement of the Nrf2/HO‐1/CO axis and therapeutic intervention with the CO‐releasing molecule CORM‐A1, in a murine model of autoimmune hepatitis

Abstract

Concanavalin A (ConA)-induced hepatitis is an experimental model of human autoimmune hepatitis induced in rodents by i.v. injection of Con A. The disease is characterized by increase in serum levels of transaminases and massive immune infiltration of the livers. Type 1, type 2, and type 17 cytokines play a pathogenic role in the development of ConA-induced hepatitis. To understand further the immunoregulatory mechanisms operating in the development and regulation of ConA-induced hepatitis, we have evaluated the role of the anti-inflammatory pathway Nrf2/HO-1/CO (Nuclear Factor E2-related Factor 2/Heme Oxygenase-1/Carbon Monoxide) in this condition and determined whether the in vivo administration of CO via the CO-releasing molecule (CORM) CORM-A1, influences serological and histological development of Con-A-induced hepatitis. We have firstly evaluated in silico the genes belonging to the Nrf2/HO-1/CO pathway that are involved in the pathogenesis of autoimmune hepatitis (AIH). The data obtained from the in silico study demonstrate that a significant number of genes modulated in the liver of ConA-challenged mice belong to the Nrf2 pathway; on the other hand, the administration of CORM-A1 determines an improvement in several sero-immunological and histological parameters, and it is able to modulate genes identified by the in silico analysis. Collectively, our data indicate that the Nrf2/HO-1/CO pathway is fundamental for the regulation of the immune responses, and that therapeutic intervention aimed at its modulation by CORM-A1 may represent a valuable strategy to be considered for the treatment of autoimmune hepatitis in humans.

Transcriptomic analysis reveals moderate modulation of macrophage migration inhibitory factor superfamily genes in alcohol use disorders

“…In addition, we also evaluated the transcriptomic analysis of MIF, DDT and their receptors in the brains of a mouse model of alcoholism. This analysis was carried out by DNA microarray analysis that represents a useful in silico toll for the better understanding of pathogenic pathways and the possible prediction of new diagnostic therapeutic approaches in several clinical settings, including immunoinflammatory and autoimmune diseases and fibrotic diseases (45,46,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). Our analysis first demonstrated that no differences in the expression of MIF, DDT and their receptors can be found in brains of both rodent models of AUD and patients with this condition.…”

Exploratory Analysis of iPSCS-Derived Neuronal Cells as Predictors of Diagnosis and Treatment of Alzheimer Disease

“…To this aim, gene expression signatures obtained from -omics data [28] are used to discover novel mechanisms of disease and searches inverse drug-disease relationships by matching gene expression profiles. We and others have used whole-genome expression databases for the better understanding of pathogenic pathways and the prediction of diagnostic and therapeutic strategies for a series of disorders-e.g., immunoinflammatory and autoimmune diseases [29][30][31][32][33][34][35][36][37], and cancer [38,39]-which has led to the identification of potential novel therapeutic targets [40][41][42][43][44][45][46][47][48][49][50][51]. However, gene perturbation alone cannot accurately predict treatment options due to variability related to disease genetics and epigenetics, as well as, experimental settings.…”

Meta-Analysis of Transcriptomic Data of Dorsolateral Prefrontal Cortex and of Peripheral Blood Mononuclear Cells Identifies Altered Pathways in Schizophrenia

“…To our knowledge, this is the first meta-analysis to be performed exclusively on studies performed on a specific brain region from SCZ subjects and controls, rather than on studies encompassing different Brodmann areas or brain anatomical structures. The use of whole-genome expression databases has been largely exploited by our group and others [37][38][39][40][41] for the characterization of pathogenic pathways and to identify therapeutic targets for a variety of disorders, such as autoimmune diseases [42][43][44][45][46][47][48][49][50], cancer [44,51,52], and has allowed researchers to characterize pathogenic pathways [53][54][55][56], and potential therapeutic targets [57][58][59][60][61].…”