Cup a 3 is a PR-5 protein derived from C. arizonica pollen. The expression of the protein under polluted conditions has a direct incidence on the pollen allergenicity, as has been demonstrated by skin tests and Radioallergosorbent test inhibition.
We previously demonstrated that treatment of acute asthmatic rats with gene therapy using plasmid-encoding Galectin-3 (Gal-3) resulted in an improvement of cellular and functional respiratory parameters. The next question that we wanted to clarify was if in a chronic situation where the treated animal continues to inhale the Ag, does this procedure prevent the chronicity and the remodeling? Chronic inflammation was induced by intranasal administration of OVA over a period of 12 wk. In the treated group, the Gal-3 gene was introduced by intranasal instillation in 50 mul of plasmid-encoding Gal-3. Noninvasive airway responsiveness to methacholine was tested at different times. Cells were obtained by bronchoalveolar lavage and used for RNA extraction and cytometric studies. Eosinophils were counted in blood and bronchoalveolar lavage fluid. Real-time PCR was used to measure Gal-3 and cytokine mRNA expression in lung. Lungs were paraffined and histologic analyses were performed (H&E, periodic acid-Schiff, and Masson Trichrome stain). Our results showed that 12 wk after the first intranasal Ag instillation in chronically asthmatic mice, treatment with the Gal-3 gene led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion and subepithelial fibrosis in the chronically asthmatic mice, with a quantitatively measured reduction in lung collagen, a prominent feature of airway remodeling. Plasmid-encoding Gal-3 acts as a novel treatment for chronic asthma in mice producing nearly complete blockade of Ag responses with respect to eosinophil airway accumulation, airway hyperresponsiveness, and remodeling.
BackgroundSitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor used in type 2 diabetes therapy, has demonstrated protective effects in diabetic chronic kidney disease, in part due to its pleiotropic actions. However, its potential direct effects on the kidney are still not completely defined. Here, by means of proteomics and miRNA profiling, we have further unveiled the role of sitagliptin in oxidative stress, as well as the underlying mechanisms.MethodsRenal cortex samples from 9-month-old wild-type (Wistar), type II diabetic Goto-Kakizaki (GK) and sitagliptin-treated GK rats (GK+Sita) (10 mg kg−1 per day) were subjected to quantitative miRNA transcriptomic array, immunohistochemistry and Western blot studies. Renal GK and GK+Sita samples were also analyzed by differential in-gel electrophoresis. Bioinformatic tools were used to find out the relationships between altered proteins and related miRNA expression. Studies were also carried out in cultured tubular cells to confirm in vivo data.ResultsDiabetic GK rats exhibited proteinuria, renal interstitial inflammatory infiltrates and fibrosis, which improved by 20 weeks of sitagliptin treatment. Proteomic analysis of diabetic GK and Wistar rats showed a differential expression of 39 proteins mostly related to oxidative stress and catabolism. In addition, 15 miRNAs were also significantly altered in GK rats.ConclusionTreatment with sitagliptin was associated with modulation of antioxidant response in the diabetic kidney, involving a downregulation of miR-200a, a novel Keap-1 inhibitor and miR-21, coincidentally with the clinical and the morphological improvement. These data further support the concept that DPP-4 inhibitors could exert a direct reno-protective effect in patients with diabetic nephropathy.
The pathophysiology of asthma involves an intricate network of molecular and cellular interactions. Elevated Th2 cytokines (interleukin [IL]-5 and IL-4) associated with eosinophilic inflammation characterize allergic diseases and provide potential targets for immunomodulation. Recent evidence has demonstrated that galectin-3 induces selective downregulation of IL-5 gene expression in several cell types (eosinophils, T cell lines, and antigen specific T cells). Accordingly, we sought to elucidate whether in vivo intratracheal instillation of plasmid DNA encoding galectin-3 would inhibit an experimental asthmatic reaction in a rat model with increased eosinophils and T cells in bronchoalveolar fluid and impaired pulmonary function. We found that instillation of galectin-3 gene in these rats led to normalization of the eosinophil and T cell count in bronchoalveolar lavage fluid and that there was a strong concomitant inhibition of IL-5 mRNA in the lungs. As a consequence, galectin-3-treated rats showed recovery of pulmonary functional parameters, such as pulmonary pressure and expiratory flows. These data emphasize the potential utility of galectin-3 as a novel therapeutic approach for treatment of allergic asthma.
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