Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier.

BACKGROUND: The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom BCG (Bacillus Calmette-Guerin) has failed or is contraindicated are recently increasing due to the development of new drugs. Although agents like mitomycin C and BCG are routinely used, there is a need for more potent and/or less-toxic agents. In this scenario, a new perspective is represented by P-MAPA (Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride), developed by Farmabrasilis (non-profit research network). This study detailed and characterized the mechanisms of action of P-MAPA based on activation of mediators of Toll-like Receptors (TLRs) 2 and 4 signaling pathways and p53 in regulating angiogenesis and apoptosis in an animal model of NMIBC, as well as, compared these mechanisms with BCG treatment. RESULTS: Our results demonstrated the activation of the immune system by BCG (MyD88-dependent pathway) resulted in increased inflammatory cytokines. However, P-MAPA intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway (TRIF-dependent pathway), which was more effective in the NMIBC treatment. Interferon signaling pathway activation induced by P-MAPA led to increase of iNOS protein levels, resulting in apoptosis and histopathological recovery. Additionally, P-MAPA immunotherapy increased wild-type p53 protein levels. The increased wild-type p53 protein levels were fundamental to NO-induced apoptosis and the up-regulation of BAX. Furthermore, interferon signaling pathway induction and increased p53 protein levels by P-MAPA led to important antitumor effects, not only suppressing abnormal cell proliferation, but also by preventing continuous expansion of tumor mass through suppression of angiogenesis, which was characterized by decreased VEGF and increased endostatin protein levels. CONCLUSIONS: Thus, P-MAPA immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of patients that are refractory or resistant to BCG intravesical therapy.

Parkinsonia aculeata (Caesalpineaceae) improves high-fat diet-induced insulin resistance in mice through the enhancement of insulin signaling and mitochondrial biogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: The search for natural agents that minimize obesity-associated disorders is receiving special attention. Parkinsonia aculeata L. (Caesalpineaceae) has long been used in Brazil as a hypoglycaemic herbal medicine, without any scientific basis. AIMS OF THE STUDY: In this context, we aimed to use molecular and physiological methods to study the effect of a hydroethanolic extract partitioned with ethyl acetate from the aerial parts of Parkinsonia aculeata (HEPa/EtOAc) on insulin resistance in a mouse model of diet-induced obesity (DIO). MATERIAL AND METHODS: Firstly, C57BL/6J mice were fed either with standard rodent chow diet or a high-fat diet (HFD) for 12 consecutive weeks. Then, the animals were treated with HEPa/EtOAc at two doses (125 and 250mg/kg/day) or metformin (200mg/kg/day) for 16 days. At the end of the experiment, body weight, fat pad weight, fasting serum glucose (FSG), insulin (FSI) and leptin were measured. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was also calculated. Glucose, insulin and pyruvate tolerance tests were performed. The expression and phosphorylation of IRß(tyr), Akt(ser473), AMPKα and PGC1α in liver, muscle and adipose tissue were determined by Western blot analyses. RESULTS: Herein we demonstrate for the first time an improvement in insulin resistance following HEPa/EtOAc administration in obese mice, as shown by increased glucose, insulin and pyruvate tolerance, as well as an improvement in FSG, FSI, HOMA-IR and circulating leptin levels, which together are in part due to enhancement of the insulin signaling pathway in its main target tissues. Surprisingly, the increase in activation of the AMPKα-PGC1-α axis by HEPa/EtOAc was similar to that produced by metformin treatment in the liver and muscle tissues. CONCLUSION: In conclusion, P. aculeata appears to be a source of therapeutic agent against obesity-related complications.