Novel sulfonyl(thio)urea derivatives act efficiently both as insulin secretagogues and as insulinomimetic compounds.

Glibenclamide is widely used in the management of non-insulin dependent diabetes mellitus, but numerous risks limit its use in therapy. In the search for novel structures that are safer and more efficient than glibenclamide, we obtained new chemical analogs based on bioisosterism, through the treatment of benzenesulfonamide derivatives with isothiocyanates and isocyanates, affording (thio)ureas with good yield. We also verified the hypoglycemic activity, through an in vivo approach. Most of these synthesized compounds improved glucose tolerance, and the mechanism of action of the best compound (7) suggests that its effect is mediated by insulin secretion, while its hypoglycemic action is triggered by glucose uptake involving GLUT4 expression and translocation through PI-3K and PKA activity and active de novo protein synthesis in skeletal muscle. Taking all these factors together, sulfonylthiourea 7 acts as an insulin secretagogue and insulinomimetic agent on glucose homeostasis, and does not exhibit toxicity in acute treatment.

Congenital hypothyroidism alters the oxidative status, enzyme activities and morphological parameters in the hippocampus of developing rats.

Congenital hypothyroidism is associated with delay in cell migration and proliferation in brain tissue, impairment of synapse formation, misregulation of neurotransmitters, hypomyelination and mental retardation. However, the mechanisms underlying the neuropsychological deficits observed in congenital hypothyroidism are not completely understood. In the present study we proposed a mechanism by which hypothyroidism leads to hippocampal neurotoxicity. Congenital hypothyroidism induces c-Jun-N-terminal kinase (JNK) pathway activation leading to hyperphosphorylation of the glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits from hippocampal astrocytes and neurons, respectively. Moreover, hyperphosphorylation of the cytoskeletal proteins was not reversed by T3 and poorly reversed by T4. In addition, congenital hypothyroidism is associated with downregulation of astrocyte glutamate transporters (GLAST and GLT-1) leading to decreased glutamate uptake and subsequent influx of Ca(2+) through N-methyl-D-aspartate (NMDA) receptors. The Na(+)-coupled (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation into hippocampal cells also might cause an increase in the intracellular Ca(2+) concentration by opening voltage-dependent calcium channels (VDCC). The excessive influx of Ca(2+) through NMDA receptors and VDCCs might lead to an overload of Ca(2+) within the cells, which set off glutamate excitotoxicity and oxidative stress. The inhibited acetylcholinesterase (AChE) activity might also induce Ca(2+) influx. The inhibited glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyl transferase (GGT) activities, associated with altered glutamate and neutral amino acids uptake could somehow affect the GSH turnover, the antioxidant defense system, as well as the glutamate-glutamine cycle. Reduced levels of S100B and glial fibrillary acidic protein (GFAP) take part of the hypothyroid condition, suggesting a compromised astroglial/neuronal neurometabolic coupling which is probably related to the neurotoxic damage in hypothyroid brain.

1α,25-dihydroxyvitamin D(3) mechanism of action: modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats.

The involvement of calcium-mediated signaling pathways in the mechanism of action of 1α,25-dihydroxyvitamin D(3) (1,25D) is currently demonstrated. In this study we found that 1,25D induces nongenomic effects mediated by membrane vitamin D receptor (VDRm) by modulating intermediate filament (IF) phosphorylation and calcium uptake through L-type voltage-dependent calcium channels (L-VDCC) in cerebral cortex of 10 day-old rats. Results showed that the mechanism of action of 1,25D involves intra- and extracellular calcium levels, as well as the modulation of chloride and potassium channels. The effects of L-VDCCs on membrane voltage occur over a broad potential range and could involve depolarizing or hyperpolarizing coupling modes, supporting a cross-talk among Ca(2+) uptake and potassium and chloride channels. Also, the Na(+)/K(+)-ATPase inactivation by ouabain mimicked the 1,25D action on (45)Ca(2+) uptake. The Na(+)/K(+)-ATPase inhibition observed herein might lead to intracellular Na(+) accumulation with subsequent L-VDCC opening and consequently increased (45)Ca(2+) (calcium, isotope of mass 45) uptake. Moreover, the 1,25D effect is dependent on the activation of the following protein kinases: cAMP-dependent protein kinase (PKA), Ca(2+)/calmodulin-dependent protein kinase (PKCaMII), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase p38 (p38(MAPK)). The modulation of calcium entry into neural cells by the 1,25D we are highlighting, might take a role in the regulation of a plethora of intracellular processes. Considering that vitamin D deficiency can lead to brain illness, 1,25D may be a possible candidate to be used, at least as an adjuvant, in the pharmacological therapy of neuropathological conditions.

Propylthiouracil-induced congenital hypothyroidism upregulates vimentin phosphorylation and depletes antioxidant defenses in immature rat testis.

Congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water from day 9 of gestation, and continually up to postnatal day 15. Structural alterations observed by light microscopy of seminiferous tubules and by transmission electron microscopy of Sertoli cells of treated animals were consistent with hypothyroid condition. Hypothyroidism was also associated with high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase 1/2 levels. Furthermore, the phosphorylation and the immunoreactivity of cytoskeletal-associated vimentin were increased without altering vimentin expression, suggesting an accumulation of insoluble and phosphorylated vimentin. These alterations in intermediate filament dynamics could result in loss of Sertoli cell cytoskeletal integrity and be somewhat related to the deleterious effects of hypothyroidism in testis. In addition, the mitochondrial alterations observed could also be related to defective cytoskeletal dynamics implying in cell damage. Moreover, we observed decreased oxygen consumption and unaltered lipid peroxidation in hypothyroid testis. However, we demonstrated decreased enzymatic and non-enzymatic antioxidant defenses, supporting an increased mitochondrial reactive oxygen species (ROS) generation, contributing to biochemical changes in hypothyroid testis. In addition, the changes in the testis histoarchitecture could be ascribed to cytoskeletal alterations, decreased antioxidant defenses, and increased ROS generation, leading to oxidative stress in the organ.

Hyperthyroidism in the developing rat testis is associated with oxidative stress and hyperphosphorylated vimentin accumulation.

Hyperthyroidism was induced in rats and somatic indices and metabolic parameters were analyzed in testis. In addition, the morphological analysis evidenced testes maturation and intense protein synthesis and processing, supporting the enhancement in vimentin synthesis in hyperthyroid testis. Furthermore, vimentin phosphorylation was increased, indicating an accumulation of phosphorylated vimentin associated to the cytoskeleton, which could be a consequence of the extracellular-regulated kinase (ERK) activation regulating the cytoskeleton. Biomarkers of oxidative stress demonstrated an increased basal metabolic rate measured by tissue oxygen consumption, as well as, increased TBARS levels. In addition, the enzymatic and non-enzymatic antioxidant defences appeared to respond according to the augmented oxygen consumption. We observed decreased total glutathione levels, with enhancement of reduced glutathione, whereas most of the antioxidant enzyme activities were induced. Otherwise, superoxide dismutase activity was inhibited. These results support the idea that an increase in mitochondrial ROS generation, underlying cellular oxidative damage, is a side effect of hyperthyroid-induced biochemical changes by which rat testis increase their metabolic capacity.

Follow-up studies on glycosylated flavonoids and their complexes with vanadium: their anti-hyperglycemic potential role in diabetes.

The present study sought to evaluate the hypoglycemic activities of free glycosylated flavonoids and flavonoid complexes with vanadium(IV), (VO(IV)), on glycemia in experimental diabetic rats. Besides free kaempferol-3,7-O-(alpha)-dirhamnoside and kaempferol-3-neohesperidoside, complexes of these flavonoids with VO(IV) were administered by different routes in order to compare the potency of the compounds as well as the efficacy of insulin or VO(IV) in lowering serum glucose. Wistar rats were made diabetic by alloxan. The glycemia was assessed at different times after the administering of compounds. The equilibrium constants were determined by potentiometric study and two species with VO(IV) are proposed at physiological pH, VOH(2)L(2) for kaempferitrin and VOHL for kaempferol-3-neohesperidoside. The latter exhibited hypoglycemic activity at all times examined with 50 and 100 mg/kg and the former reduced the glycemia from 0 to 6h by i.p. route. The administering of the complexes or 0.0146 mmol/kg VO(IV) resulted in a serum glucose-lowering effect over time in the case of i.p. treatment. A marked hypoglycemic effect was observed for 0.5IU of insulin (67.5%); 0.0146 mmol VO(IV) (16.8%); 0.0294 mmol kaempferitrin-VO(IV) (17.8%) and 0.0286 mmol kaempferol-3-neohesperidoside-VO(IV) (56.0%) at 3h after i.p. treatment when compared with respective zero time in diabetic groups. Kaempferol-3-neohesperidoside-VO(IV) was 2.5 times more effective than VO(IV), twice as effective as the free compound and three times more effective than kaempferitrin-VO(IV). This is of particular interest since kaempferol-3-neohesperidoside appears to represent a suitable ligand for VO(IV) to mimic the efficacy of insulin in lowering serum glucose levels.

Implante em aorta abdominal de suíno de artéria pulmonar heteróloga conservada em glicerina / Replacement of porcine abdominal aorta using pulmonary artery heterograft

A correção cirúrgica de várias doenças vasculares requer a implantação de próteses. Neste estudo, foi avaliado o comportamento da artéria pulmonar de cão conservada em glicerina a 98 por cento implantada na aorta abdominal de dois suínos, acompanhados por cinco meses de pós-operatório. Ao exame macroscópico, um dos implantes apresentou dilatação e o outro estenose, em relação à aorta adjacente. Microscopicamente, o tecido hospedeiro e o implante estavam íntegros e a cicatrização se apresentou adequada. Apesar das diferenças de diâmetro encontradas (estenose e dilatação), ambos os animais tiveram desenvolvimento normal e não demonstraram problemas clínicos.