15d-prostaglandin J(2) inhibits inflammatory hypernociception: Involvement of peripheral opioid receptor

The 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous ligand of peroxisome proliferator-activated receptors gamma (PPAR-gamma) and is now recognized as a potent anti-inflammatory mediator. However, information regarding the influence of 15d-PGJ(2) on inflammatory pain is still unknown. In this study, we evaluated the effect of 15d-PGJ(2) upon inflammatory hypernociception and the mechanisms involved in this effect. We observed that intraplantar administration of 15d-PGJ(2) (30-300 ng/paw) inhibits the mechanical hypernociception induced by both carrageenan (100 mu g/paw) and the directly acting hypernociceptive mediator, prostaglandin E-2 (PGE(2)). Moreover, 15d-PGJ(2) [100 ng/temporomandibular joint (TMJ)] inhibits formalininduced TMJ hypernociception. On the other hand, the direct administration of 15d-PGJ(2) into the dorsal root ganglion was ineffective in blocking PGE(2)- induced hypernociception. In addition, the 15d-PGJ(2) antinociceptive effect was enhanced by the increase of macrophage population in paw tissue due to local injection of thioglycollate, suggesting the involvement of these cells on the 15d-PGJ(2)-antinociceptive effect. Moreover, the antinociceptive effect of 15d-PGJ(2) was also blocked by naloxone and by the PPAR-gamma antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662), suggesting the involvement of peripheral opioids and PPAR-gamma receptor in the process. Similar to opioids, the 15d-PGJ(2) antinociceptive action depends on the nitric oxide/cGMP/protein kinase G (PKG)/K-ATP(+) channel pathway because it was prevented by the pretreatment with the inhibitors of nitric-oxide synthase (N-G-monomethyl-L-arginine acetate), guanylate cyclase] 1H-(1,2,4)-oxadiazolo(4,2-alpha) quinoxalin-1- one[, PKG [indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycone (KT5823)], or with the ATP-sensitive potassium channel blocker glibenclamide. Taken together, these results demonstrate for the first time that 15d-PGJ(2) inhibits inflammatory hypernociception via PPAR-gamma activation. This effect seems to be dependent on endogenous opioids and local macrophages.

The role of tumor hypoxia in MUC1-positive breast carcinomas

Mucin 1 (MUC1) is a glycoprotein that is expressed on apical cell membranes in a variety of normal tissues. MUC1 is involved in cell signaling, inhibition of cell-cell and cell matrix adhesion, apoptosis, proliferation, and transcription. Hypoxia is an important factor that promotes cancer metastasis and stimulates angiogenesis and tumor progression. Hypoxia inducible factor 1 (HIF-1 alpha) and carbonic anhydrase IX (CAIX) are two molecules that are involved in this process. The role of hypoxia in MUC1+ invasive ductal breast carcinomas is not well established. In this study, the expression of MUC1 was correlated with the hypoxia-associated markers HIF-1 alpha and CAIX, as well as several immunohistochemical markers and clinicopathologic features of prognostic significance in 243 invasive ductal carcinomas. MUC1 was overexpressed in 37.0% of patients and correlated with the expression of estrogen receptor (p = 0.0001), progesterone receptor (p = 0.0001), HIF-1 alpha (p = 0.006), VEGF (p = 0.024), and p53 (p = 0.025). In breast cancer, MUC1 expression has been associated with increased degradation of inhibitor of NF-kappa B (I kappa B alpha), driving NF-kappa B to the nucleus and blocking apoptosis and promoting cell survival. We analyzed NF-kappa B expression in MUC1+ breast carcinoma and found a very significant relationship between these proteins (p = 0.0001). Our findings indicate that MUC1 may play a role in the regulation of hormone receptors by increasing the inactivation of p53 and targeting NF-kappa B to the nucleus. Our data also support the notion that activation of HIF-1 alpha in MUC1+ breast carcinomas may modulate VEGF expression, allowing a metabolic adaptation to hypoxia.

Antibothropic action of Casearia sylvestris Sw. (flacourtiaceae) extracts

Casearia sylvestris Sw., popularly known in Brazil as `guacatonga`, has been used as antitumor, antiseptic, antiulcer, local anaesthetic and healer in folk medicine. Snakebite envenomation by Bothrops jararacussu (Bjssu) constitutes a relevant public health hazard capable of inducing serious local damage in victims. This study examined the pharmacological action of apolar and polar C sylvestris leaf extracts in reverting the neuromuscular blockade and myonecrosis, which is induced by Bjssu venom and its major toxin bothropstoxin-I on the mouse phrenic nerve-diaphragm preparations. The polar methanol extract (ME) was by far the most efficacious. ME not only prevented myonecrosis and abolished the blockade, but also increased ACh release. Such facilitation in neuromuscular transmission was observed with ME alone, but was accentuated in preparations incubated with ME plus venom or toxin. This established synergy opens an interesting point of investigation because the venom or toxin in contact with ME changes from a blocking to a facilitating effect. It is suggested that rutin, known to have potent antioxidant properties, and one of the components present in the ME, could have a role in the observed effects. Since commercial rutin did not reproduce the ME effects, it is likely that a rutin-containing phytocomplex is neutralizing the bothropic envenoming effects. Copyright (C) 2008 John Wiley & Sons, Ltd.

Protein requirements for Blue-fronted Amazon (Amazona aestiva) growth

The objective of this study was to evaluate the protein requirements for hand-rearing Blue-fronted Amazon parrots (Amazona aestiva). Forty hatchlings were fed semi-purified diets containing one of four (as-fed basis) protein levels: 13%, 18%, 23% and 28%. The experiment was carried out in a randomized block design with the initial weight of the nestling as the blocking factor and 10 parrots per protein level. Regression analysis was used to determine relationships between protein level and biometric measurements. The data indicated that 13% crude protein supported nestling growth with 18% being the minimum tested level required for maximum development. The optimal protein concentration for maximum weight gain was 24.4% (p = 0.08; r(2) = 0.25), tail length 23.7% (p = 0.09; r(2) = 0.19), wing length 23.0% (p = 0.07; r(2) = 0.17), tarsus length 21.3% (p = 0.06; r(2) = 0.10) and tarsus width 21.4% (p = 0.07; r(2) = 0.09). Tarsus measurements were larger in males (p < 0.05), indicating that sex must be considered when studying developing psittacines. These results were obtained using a highly digestible protein and a diet with moderate metabolizable energy levels.

STAT3 expression in salivary gland tumours

The aim of the present study was to evaluate the signal transducer and activator of transcription (STAT3) expression, which is constitutively active in different types of malignant tumours, in salivary gland tumours. Fifty biopsies of salivary gland tumours (9 pleomorphic adenomas, 12 adenoid cystic carcinomas, 7 epithelial-myoepithelial carcinomas, 10 polymorphous low-grade adenocarcinomas and 12 mucoepidermoid carcinomas) and 10 normal. salivary glands were immunohistochemically labeled for STAT3 and Phospho-STAT3 (STAT3P). The labeled sections were quatitatively and quantitatively evaluated. The results showed that, in normal salivary gland, STAT3 was expressed in cytoplasm and STAT3P in nuclei of all tissue cells, except in large mucous acinar cells for which both antibodies were negative. In pleomorphic adenoma, the expression was the same as in normal glands. In malignant tumours, there were variations in the expression of these antibodies. The most important one was the presence of STAT3 in the nuclei of the malignant tumour cells, most evident in the cribriform-type of adenoid cystic carcinoma. Both toss and variation of STAT3P expression were also observed. The presence of STAT3 in the nuclei of malignant salivary gland tumours may represent an important event in oncogenesis probably contributing to tumour cell proliferation white blocking apoptosis. However, further investigation will. be necessary to support this hypothesis. (c) 2007 Pubtished by Elsevier Ltd.

Regulation of Trypanosoma cruzi-Induced Myocarditis by Programmed Death Cell Receptor

Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1(-/-) mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas` disease.