Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer.

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERß) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC.

Histochemical and ultrastructural analysis of the action of naproxen on tail fin regeneration in carp (Cyprinus carpio)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of rheumatoid arthritis and osteoarthritis, and are also indicated for periarticular and musculoskeletal diseases. However, the use of NSAIDs is limited by their toxicity. NSAIDs have a variable effect on the regeneration of cells and extracellular matrix that depends on the dose used. In this work, we examined the effect of naproxen, a NSAID, on tail fin regeneration in carp (Cyprinus carpio), a teleost fish that is a good model for studying the growth of connective tissue in vivo. We used histochemical, ultrastructural and morphometric analyses to assess the synthesis, deposition and organization of the lepidotrichial extracellular matrix components and the total area of regenerating fins, including lepidotrichia, epidermis and connective tissue. Naproxen (15.6 mg/L in the tank water) did not affect the formation of the epidermal cap and blastema, the differentiation of blastemal cells in scleroblasts or the synthesis, deposition, organization and mineralization of lepidotrichial matrix components. In addition, there was no significant difference in the area of regenerated tissue between control and naproxen-treated fishes. These results indicate that at the concentration tested, naproxen had no effect on tail fin regeneration.

Inhibition of caudal fin actinotrichia regeneration by acetylsalicylic acid (aspirin) in teleosts

Various substances have been used to investigate physiological and physiophatological processes in animals. In this study, we investigated the effects of acetylsalicylic acid (ASA, aspirin) on the regeneration of actinotrichia, skeletal structures of the caudal fin of teleosts. Two groups of fish (Tilapia rendalli) were maintained in aquaria with dechlorinated water at 24 graus Celsius, with one group being exposed to ASA (0.1 g/l) for 24 h. Thereafter ASA-treated and untreated (control) fishes were anesthetized and their tail fin amputated. After periods ranging from 4-12 days, the fishes were sacrified and the regeneration tissue was processed for light and transmission electron microscopy and picrosirius-hematoxylin staining. Control specimens ahowed normal regeneration of the actinotrichia, whereas all (except one) of the ASA-treated fishes showed no regeneration. The 20 ASA-treated fishes devoid of actinotrichia had varying degrees pf caudal fin regeneration. These results indicate that, as in mammal, aspirin also affects biological processes in fish. Based on reports in the literature, we hypothesize that ASA interfered with the transcripition of the fibroblast genes necessary for the synthesis of elasoidin, or altered the typical rapid turn-over of this protein, thereby affecting regeneration could be a valuable approach for instigating cell-matrix interactions. This model could also be useful for evaluating the toxic effects of river pollution and chemical damping.