Carbon monoxide inhibits T cell activation in target organs during systemic lupus erythematosus

International audienceSystemic lupus erythematosus is characterized by the presence of circulating anti-nuclear antibodies (ANA) and systemic damage that includes nephritis, haematological manifestations and pulmonary compromise, among others. Although major progress has been made in elucidating the molecular mechanisms responsible for autoimmunity, current therapies for lupus have not improved considerably. Because the exposure of carbon monoxide (CO) has been shown to display beneficial immunoregulatory properties in different immune-mediated diseases, we investigated whether CO therapy improves lupus-related kidney injury in lupus mice. MRL-Fas lpr lupus mice were exposed to CO and disease progression was evaluated. ANA, leucocyte-infiltrating populations in spleen, kidney and lung and kidney lesions, were measured. CO therapy significantly decreased the frequency of activated B220 1 CD4 2 CD8 2 T cells in kidneys and lungs, as well as serum levels of ANA. Furthermore, we observed that CO therapy reduced kidney injury by decreasing proliferative glomerular damage and immune complexes deposition, decreased proinflammatory cytokine production and finally delayed the impairment of kidney function. CO exposure ameliorates kidney and lung leucocyte infiltration and delays kidney disease in MRL-Fas lpr lupus mice. Our data support the notion that CO could be explored as a potential new therapy for lupus nephritis

A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance

Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC

Phenolic composition of Nebbiolo grape (Vitis vinifera L.) from Piedmont: characterization during ripening of grapes selected in different geographic areas and comparison with Uva Rara and Vespolina cv

Grapes (Vitis vinifera L.) are rich in polyphenols; the phenolic composition of grape is very complex and depends on several factors, including grape varieties, ripening stage and pedoclimatic conditions. In this work the amount of total polyphenols, anthocyanins and tannins, the antioxidant activity and the chromatic characteristics of Nebbiolo grapes from Piedmont were determined. Four different cultivation areas and three different ripening stages (starting of veraison, veraison completion and physiological ripeness) were considered. The quantification of individual polyphenols and hydroxycinnamates was performed by RP-HPLC/DAD. In a general way, anthocyanins and flavonols increased during ripening, while antioxidant activity and tannin content remained constant. Differences in specific phenolic composition were observed depending on the sample origin. Nebbiolo samples at different maturity stages were compared among them and with Uva Rara and Vespolina cv: overall Nebbiolo showed the lowest anthocyanin content, evidencing a different profile in respect to the other cultivars (major relative content of peonidin-3-O-glucoside). Multivariate statistical methods (principal components analysis and hierarchical clustering) further permitted recognition of Nebbiolo samples of different geographic origin, particularly those dedicated to \u201cBarolo\u201d winemaking