RESUMO
The bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), VO(dmpp)2, has shown anti-diabetic effects by in vitro studies in Wistar (W) rat adipocytes and in vivo in obese Zucker rats. The aim of this work is to confirm the therapeutic properties of VO(dmpp)2 in non-obese type 2 diabetic Goto-Kakizaki (GK) rats. An in vivo study was carried out, treating W and GK rats during 21 days with a daily dose of VO(dmpp)2 (44 µmol/kg). It was shown that VO(dmpp)2 doesn't affect the normal increase of body weight of both W and GK rats, after 8 days of treatment ameliorates glycemia in GK rats (8.4 ± 0.3 vs 10.1 ± 0.2 mM in GK control, P<0.001) but doesn't interfere with glucose levels in W rats and, after 21 days of treatment, improves the glucose intolerant profile of GK rats (13.1 ± 0.5 vs 20.6 ± 0.7 mM/min in GK control, P<0.001), despite no increase of plasma insulin levels during glucose tolerance test. Additionally, it was demonstrated that VO(dmpp)2 significantly enhances [3-(3)H]-glucose uptake by W and GK rat adipocytes (non-toxic concentration of 100 µM: respectively 193 ± 20 and 254 ± 21%, P<0.001, relative to the basal value) showing an efficacy similar to insulin 1.72 nM and better than the same concentration of BMOV (P<0.01). Western blotting revealed that in W and GK rats VO(dmpp)2 significantly promotes IRS2 (P<0.05) and p-AKT expression (P<0.001 and P<0.05, respectively, relative to the respective controls) and in GK animals reduces the increase of PTP1ß expression (P<0.001, relative to GK control).
Assuntos
Complexos de Coordenação/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Compostos Organometálicos/farmacologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Mimetismo Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos WistarRESUMO
Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.