Efeitos do diabetes gestacional moderado e da reposição com insulina na lactação sobre a próstata ventral do rato Wistar

Pós-graduação em Biologia Geral e Aplicada - IBB

Spatial memory in sedentary and trained diabetic rats: Molecular mechanisms

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Citral: A monoterpene with prophylactic and therapeutic anti-nociceptive effects in experimental models of acute and chronic pain

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Produção e imobilização de celulases em matriz de agarose com diferentes ativações químicas

Pós-graduação em Biotecnologia - IQ

Participação das NETs (neutrophil extracellular traps) na atividade fungicida de neutrófilos humanos contra o Paracoccidioides brasiliensis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Determinação de fatores angiogênicos e anti-angiogênicos em plasma de gestantes portadoras de pré-eclâmpsia precoce e tardia

Changes in circulating angiogenic factors have been implicated in the pathogenesis of preeclampsia. Thus, evaluation of angiogenesis agonist and antagonist factors is of greater importance to understand the mechanisms responsible for this disorder. The objective of the present study was to evaluate whether circulating angiogenic and anti-angiogenic factors may differentiate early-onset from late-onset preeclampsia. The study was conducted in 86 women with preeclampsia diagnosed in the third trimester of pregnancy. Preeclampsia was classified according to the onset of clinical manifestation in early-onset (before 34 weeks of gestation; n=31) or in late-onset (from 34 weeks of gestation on; n=55) preeclampsia. Serum was obtained from the patients in the moment of the diagnosis and assayed for placental growth factor (PlGF), vascular endothelial growth factor (VEGF), soluble Endoglin (sEng) and soluble form of vascular endothelial growth factor receptor (sVEGFR-1) determination by enzyme-linked immunosorbent assay. The results showed that early-onset preeclampsia was characterized by significant lower levels of PlGF (median 38.3 vs 123.5 pg/mL) and VEGF (median 23.1 vs 35.3 pg/mL) in serum as well as by higher serum levels of sEng (median 54.7 vs 42.1 pg/mL) and sVEGFR-1 (median 5211.0 vs 4657.6 pg/mL) compared with late-onset preeclampsia. In this study serum levels of angiogenic and anti-angiogenic factors prove useful in differentiating early-onset from late-onset preeclampsia in the third trimester of pregnancy. Therefore, these findings suggest that angiogenic factors determination may indicate that early- and late-onset preeclampsia have different pathophysiology

Aspectos biológicos, morfometria e técnica de criação de Abaris basistriata Chaudoir, 1873 e Selenophorus seriatoporus Putzeys, 1878 (Coleoptera: carabidae)

Pós-graduação em Agronomia (Entomologia Agrícola) - FCAV

Efeitos da pré-exposição ao etanol nos comportamentos relacionados à dependência desta substância e na expressão de CRF1 na amídala em ratos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of omega-3 on metabolic markers in postmenopausal women with metabolic syndrome

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Role of alpha1 and alpha2-adrenoceptors of the lateral hypothalamic area on urinary excretion caused by centrally administered angiotensin II

To determine whether central α1 and α2-adrenergic mechanisms are involved in urinary sodium and potassium excretion and urine volume induced by angiotensin II (ANGII), these renal parameters were measured in volume-expanded Holtzman rats with cannulas implanted into lateral ventricle (LV) and lateral hypothalamus (LH). The injection of ANGII into LV in rats with volume expansion reduced the sodium, potassium and urine excretion in comparison to the control injections of isotonic saline, whereas prazosin (α1 antagonist) potentiated these effects. Clonidine (α2 agonist) and yohimbine (α2 antagonist) injected into LH previous to injection of ANGII into LV also abolished the inhibitory effect of ANGII. These results suggest that the discharge of central alpha-adrenergic receptors has dual inhibitory and excitatory effect on antinatriuretic, antikaliuretic and antidiuretic effect induced by central ANGII in volume-expanded rats. © 1995.

Clonidine and phenylephrine injected into the lateral preoptic area reduce water intake in dehydrated rats

In the present study, we investigated the effect of phenylephrine and clonidine (α1- and α2-adrenoceptor agonists, respectively) injected into the lateral preoptic area (LPOA) on the water intake induced by water deprivation in rats. In addition, the effects of prior injections of prazosin and yohimbine (α1- and α2-adrenoceptor antagonists, respectively) into the LPOA on the antidipsogenic action of phenylephrine and clonidine were investigated. After 30 h of water deprivation, the water intake of rats in a control experiment (saline injection) was 10.5 ± 0.8 ml/h. Injection of clonidine (5, 10, 20, and 40 nmol) into the LPOA reduced water intake to 6.3 ± 0.9, 4.9 ± 0.8, 3.6 ± 1.0, and 2.2 ± 0.7 ml/h, respectively. Similar reductions occurred after injection of 80 and 160 nmol phenylephrine into the LPOA (6.2 ± 1.6 and 4.8 ± 1.3 ml/h, respectively). Pretreatment with prazosin (40 nmol) abolished the antidipsogenic action of an 80-nmol dose of phenylephrine (11.3 ± 1.1 ml/h) and reduced the effect of a 20-nmol dose of clonidine (7.4 ± 1.4 ml/h). Yohimbine (20, 40, and 80 nmol), previously injected, produced no significant changes in the effects of either phenylephrine or clonidine. The present results show that phenylephrine and clonidine injected into the LPOA induce an antidipsogenic effect in water-deprived rat. They also suggest an involvement of α1-adrenoceptors in this effect. A possible participation of imidazole receptors in the effect of clonidine should also be taken into account. © 1993.

Involvement of PGE(2) and RANTES in Staphylococcus aureus-induced fever in rats

Martins JM, Longhi-Balbinot DT, Soares DM, Figueiredo MJ, Malvar D do C, de Melo MC, Rae GA, Souza GE. Involvement of PGE(2) and RANTES in Staphylococcus aureus-induced fever in rats. J Appl Physiol 113: 1456-1465, 2012. First published August 30, 2012; doi:10.1152/japplphysiol.00936.2011.-This study investigated the involvement of prostaglandins and regulated on activation, normal T cell expressed and secreted (RANTES), in fever induced by live Staphylococcus aureus (no. 25923, American Type Culture Collection) injection in rats. S. aureus was injected intraperitoneally at 10(9), 10(10), and 2 x 10(10) colony-forming units (CFU)/cavity, and body temperature (T-b) was measured by radiotelemetry. The lowest dose of S. aureus induced a modest transient increase in T-b, whereas the two higher doses promoted similar long-lasting and sustained T-b increases. Thus, the 10(10) CFU/cavity dose was chosen for the remaining experiments. The T-b increase induced by S. aureus was accompanied by significant decreases in tail skin temperature and increases in PGE(2) levels in the cerebrospinal fluid (CSF) and hypothalamus but not in the venous plasma. Celecoxib (selective cyclooxygenase-2 inhibitor, 2.5 mg/kg po) inhibited the fever and the increases in PGE(2) concentration in the CSF and hypothalamus induced by S. aureus. Dipyrone (120 mg/kg ip) reduced the fever from 2.5 to 4 h and the PGE(2) increase in the CSF but not in the hypothalamus. S. aureus increased RANTES in the peritoneal exudate but not in the CSF or hypothalamus. Met-RANTES (100 mu g/kg iv), a chemokine (C-C motif) receptor (CCR)1/CCR5 antagonist, reduced the first 6 h of fever induced by S. aureus. This study suggests that peripheral (local) RANTES and central PGE(2) production are key events in the febrile response to live S. aureus injection. As dipyrone does not reduce PGE(2) synthesis in the hypothalamus, it is plausible that S. aureus induces fever, in part, via a dipyrone-sensitive PGE(2)-independent pathway.

Vorapaxar in the Secondary Prevention of Atherothrombotic Events

BACKGROUND Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)

Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters

This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO) and endocannabinoids (eCBs) play an important role in the regulation of aversive responses in the periaqueductal gray (PAG). Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid receptor type 1 (CB1) receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA) that control PAG activity. We propose that they exert a R16;fine-tuningR17; regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1) receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.

Mitochondrial dysfunction in a cell model of thyroid oncocytoma

The role of mitochondrial dysfunction in cancer has long been a subject of great interest. In this study, such dysfunction has been examined with regards to thyroid oncocytoma, a rare form of cancer, accounting for less than 5% of all thyroid cancers. A peculiar characteristic of thyroid oncocytic cells is the presence of an abnormally large number of mitochondria in the cytoplasm. Such mitochondrial hyperplasia has also been observed in cells derived from patients suffering from mitochondrial encephalomyopathies, where mutations in the mitochondrial DNA(mtDNA) encoding the respiratory complexes result in oxidative phosphorylation dysfunction. An increase in the number of mitochondria occurs in the latter in order to compensate for the respiratory deficiency. This fact spurred the investigation into the presence of analogous mutations in thyroid oncocytic cells. In this study, the only available cell model of thyroid oncocytoma was utilised, the XTC-1 cell line, established from an oncocytic thyroid metastasis to the breast. In order to assess the energetic efficiency of these cells, they were incubated in a medium lacking glucose and supplemented instead with galactose. When subjected to such conditions, glycolysis is effectively inhibited and the cells are forced to use the mitochondria for energy production. Cell viability experiments revealed that XTC-1 cells were unable to survive in galactose medium. This was in marked contrast to the TPC-1 control cell line, a thyroid tumour cell line which does not display the oncocytic phenotype. In agreement with these findings, subsequent experiments assessing the levels of cellular ATP over incubation time in galactose medium, showed a drastic and continual decrease in ATP levels only in the XTC-1 cell line. Furthermore, experiments on digitonin-permeabilised cells revealed that the respiratory dysfunction in the latter was due to a defect in complex I of the respiratory chain. Subsequent experiments using cybrids demonstrated that this defect could be attributed to the mitochondrially-encoded subunits of complex I as opposed to the nuclearencoded subunits. Confirmation came with mtDNA sequencing, which detected the presence of a novel mutation in the ND1 subunit of complex I. In addition, a mutation in the cytochrome b subunit of complex III of the respiratory chain was detected. The fact that XTC-1 cells are unable to survive when incubated in galactose medium is consistent with the fact that many cancers are largely dependent on glycolysis for energy production. Indeed, numerous studies have shown that glycolytic inhibitors are able to induce apoptosis in various cancer cell lines. Subsequent experiments were therefore performed in order to identify the mode of XTC-1 cell death when subjected to the metabolic stress imposed by the forced use of the mitochondria for energy production. Cell shrinkage and mitochondrial fragmentation were observed in the dying cells, which would indicate an apoptotic type of cell death. Analysis of additional parameters however revealed a lack of both DNA fragmentation and caspase activation, thus excluding a classical apoptotic type of cell death. Interestingly, cleavage of the actin component of the cytoskeleton was observed, implicating the action of proteases in this mode of cell demise. However, experiments employing protease inhibitors failed to identify the specific protease involved. It has been reported in the literature that overexpression of Bcl-2 is able to rescue cells presenting a respiratory deficiency. As the XTC-1 cell line is not only respiration-deficient but also exhibits a marked decrease in Bcl-2 expression, it is a perfect model with which to study the relationship between Bcl-2 and oxidative phosphorylation in respiratory-deficient cells. Contrary to the reported literature studies on various cell lines harbouring defects in the respiratory chain, Bcl-2 overexpression was not shown to increase cell survival or rescue the energetic dysfunction in XTC-1 cells. Interestingly however, it had a noticeable impact on cell adhesion and morphology. Whereas XTC-1 cells shrank and detached from the growth surface under conditions of metabolic stress, Bcl-2-overexpressing XTC-1 cells appeared much healthier and were up to 45% more adherent. The target of Bcl-2 in this setting appeared to be the actin cytoskeleton, as the cleavage observed in XTC-1 cells expressing only endogenous levels of Bcl-2, was inhibited in Bcl-2-overexpressing cells. Thus, although unable to rescue XTC-1 cells in terms of cell viability, Bcl-2 is somehow able to stabilise the cytoskeleton, resulting in modifications in cell morphology and adhesion. The mitochondrial respiratory deficiency observed in cancer cells is thought not only to cause an increased dependency on glycolysis but it is also thought to blunt cellular responses to anticancer agents. The effects of several therapeutic agents were thus assessed for their death-inducing ability in XTC-1 cells. Cell viability experiments clearly showed that the cells were more resistant to stimuli which generate reactive oxygen species (tert-butylhydroperoxide) and to mitochondrial calcium-mediated apoptotic stimuli (C6-ceramide), as opposed to stimuli inflicting DNA damage (cisplatin) and damage to protein kinases(staurosporine). Various studies in the literature have reported that the peroxisome proliferator-activated receptor-coactivator 1(PGC-1α), which plays a fundamental role in mitochondrial biogenesis, is also involved in protecting cells against apoptosis caused by the former two types of stimuli. In accordance with these observations, real-time PCR experiments showed that XTC-1 cells express higher mRNA levels of this coactivator than do the control cells, implicating its importance in drug resistance. In conclusion, this study has revealed that XTC-1 cells, like many cancer cell lines, are characterised by a reduced energetic efficiency due to mitochondrial dysfunction. Said dysfunction has been attributed to mutations in respiratory genes encoded by the mitochondrial genome. Although the mechanism of cell demise in conditions of metabolic stress is unclear, the potential of targeting thyroid oncocytic cancers using glycolytic inhibitors has been illustrated. In addition, the discovery of mtDNA mutations in XTC-1 cells has enabled the use of this cell line as a model with which to study the relationship between Bcl-2 overexpression and oxidative phosphorylation in cells harbouring mtDNA mutations and also to investigate the significance of such mutations in establishing resistance to apoptotic stimuli.