Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events

Background: Breast cancer outcome, including response to therapy, risk of metastasis and survival, is difficult to predict using currently available methods, highlighting the urgent need for more informative biomarkers. Androgen receptor (AR) has been implicated in breast carcinogenesis however its potential to be an informative biomarker has yet to be fully explored. In this study, AR protein levels were determined in a cohort of 73 Grade III invasive breast ductal adenocarcinomas

Kaurenoic Acid from Sphagneticola trilobata Inhibits Inflammatory Pain: Effect on Cytokine Production and Activation of the NO-Cyclic GMP-Protein Kinase G-ATP-Sensitive Potassium Channel Signaling Pathway

Kaurenoic acid [ent-kaur-16-en-19-oic acid (1)] is a diterpene present in several plants including Sphagneticola trilobata. The only documented evidence for its antinociceptive effect is that it inhibits the writhing response induced by acetic acid in mice. Therefore, the analgesic effect of 1 in different models of pain and its mechanisms in mice were investigated further. Intraperitoneal and oral treatment with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid. Oral treatment with 1 also inhibited overt nociception-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), and both phases of the formalin test. Compound 1 also inhibited acute carrageenin- and PGE(2)-induced and chronic CFA-induced inflammatory mechanical hyperalgesia. Mechanistically, 1 inhibited the production of the hyperalgesic cytokines TNF-alpha and IL-1 beta. Furthermore, the analgesic effect of 1 was inhibited by L-NAME, ODQ, KT5823, and glybenclamide treatment, demonstrating that such activity also depends on activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that 1 exhibits an analgesic effect in a consistent manner and that its mechanisms involve the inhibition of cytokine production and activation of the NO-cyclic GMP-protein lcinase G-ATP-sensitive potassium channel signaling pathway.Fundacao de Amparo a Pesquisa do Estado de So Paulo (FAPESP, Brazil)Fundacao de Amparo a Pesquisa do Estado de So Paulo (FAPESP, Brazil)Conselho Nacional de Pesquisa (CNPq, Brazil)Conselho Nacional de Pesquisa (CNPq, Brazil)Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), BrazilCoordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brazil)Fundacao Araucaria and Governo do Estado do Parana (Brazil)Fundacao Araucaria and Governo do Estado do Parana (Brazil

Pimaradienoic Acid Inhibits Carrageenan-Induced Inflammatory Leukocyte Recruitment and Edema in Mice: Inhibition of Oxidative Stress, Nitric Oxide and Cytokine Production.

Pimaradienoic acid (PA; ent-pimara-8(14),15-dien-19-oic acid) is a pimarane diterpene found in plants such as Vigueira arenaria Baker (Asteraceae) in the Brazilian savannas. Although there is evidence on the analgesic and in vitro inhibition of inflammatory signaling pathways, and paw edema by PA, its anti-inflammatory effect deserves further investigation. Thus, the objective of present study was to investigate the anti-inflammatory effect of PA in carrageenan-induced peritoneal and paw inflammation in mice. Firstly, we assessed the effect of PA in carrageenan-induced leukocyte recruitment in the peritoneal cavity and paw edema and myeloperoxidase activity. Next, we investigated the mechanisms involved in the anti-inflammatory effect of PA. The effect of PA on carrageenan-induced oxidative stress in the paw skin and peritoneal cavity was assessed. We also tested the effect of PA on nitric oxide, superoxide anion, and inflammatory cytokine production in the peritoneal cavity. PA inhibited carrageenan-induced recruitment of total leukocytes and neutrophils to the peritoneal cavity in a dose-dependent manner. PA also inhibited carrageenan-induced paw edema and myeloperoxidase activity in the paw skin. The anti-inflammatory mechanism of PA depended on maintaining paw skin antioxidant activity as observed by the levels of reduced glutathione, ability to scavenge the ABTS cation and reduce iron as well as by the inhibition of superoxide anion and nitric oxide production in the peritoneal cavity. Furthermore, PA inhibited carrageenan-induced peritoneal production of inflammatory cytokines TNF-α and IL-1β. PA presents prominent anti-inflammatory effect in carrageenan-induced inflammation by reducing oxidative stress, nitric oxide, and cytokine production. Therefore, it seems to be a promising anti-inflammatory molecule that merits further investigation

The nitroxyl donor Angeli's salt ameliorates Staphylococcus aureus-induced septic arthritis in mice

Septic arthritis is a severe and rapidly debilitating disease associated with severe joint pain, inflammation and oxidative stress. Nitroxyl (HNO) has become a nitrogen oxide of significant interest due to its pharmacological endpoints that are potentially favorable for treating varied diseases. However, whether HNO also serves as a treatment to septic arthritis is currently unknown. The aim of this study was to investigate the effect of the HNO donor, Angeli's salt (AS), in the outcome of chronic Staphylococcus aureus (S. aureus)-induced septic arthritis in mice. Daily treatment with AS inhibited mechanical hyperalgesia and inflammation (edema, leukocyte migration, cytokines release and NF-κB activation, and oxidative stress) resulting in reduced disease severity (clinical course, histopathological changes, proteoglycan levels in the joints, and osteoclastogenesis). In addition, AS decreased the number of S. aureus colony forming unities in synovial tissue, enhanced the bactericidal effect of macrophages and inhibited the worsening of systemic inflammatory response (leukocyte counts in the lung and systemic proinflammatory cytokine concentration). Our results suggest for the first time the therapeutic potential of AS in a model of septic arthritis by mechanisms involving microbicidal effects, anti-inflammatory actions and reduction of disease severity.CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico); MCTI/SETI/Fundacao Araucaria (Ministerio da Ciencia, Tecnologia e Inovacao/Secretaria da Ciencia, Tecnologia, e Ensino Superior do Parana/Fundacao Araucaria); Decit/SCTIE/MS (Departamento de Ciencia e Tecnologia da Secretaria de Ciencia, Tecnologia e Insumos Estrategicos, Ministerio da Saude); Fundacao Araucaria; Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); INCT (National Institutes of Science and Technology) - MCTI/CNPq/CAPES/Fundacao Araucaria, Brazil; CAPES [PDSE - 99999.007507/2014-03]; CNPq [161279/2015-5]; CAPES/Fundacao Araucaria; CAPES12 month embargo; available online 15 April 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Acetic acid- and phenyl-p-benzoquinone-induced overt pain-like behavior depends on spinal activation of MAP kinases, PI3K and microglia in mice

The acetic acid and phenyl-p-benzoquinone are easy and fast screening models to access the activity of novel candidates as analgesic drugs and their mechanisms. These models induce a characteristic and quantifiable overt pain-like behavior described as writhing response or abdominal contortions. The knowledge of the mechanisms involved in the chosen model is a crucial step forward demonstrating the mechanisms that the candidate drug would inhibit because the mechanisms triggered in that model will be addressed. Herein, it was investigated the role of spinal mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated kinase), JNK (Jun N-terminal Kinase) and p38, PI3K (phosphatidylinositol 3-kinase) and microglia in the writhing response induced by acetic acid and phenyl-p-benzoquinone, and flinch induced by formalin in mice. Acetic acid and phenyl-p-benzoquinone induced significant writhing response over 20 min. The nociceptive response in these models were significantly and in a dose-dependent manner reduced by intrathecal pre-treatment with ERK (PD98059), JNK (SB600125), p38 (SB202190) or PI3K (wortmannin) inhibitors. Furthermore, the co-treatment with MAP kinase and PI3K inhibitors, at doses that were ineffective as single treatment, significantly inhibited acetic acid- and phenyl-p-benzoquinone-induced nociception. The treatment with microglia inhibitors minocycline and fluorocitrate also diminished the nociceptive response. Similar results were obtained in the formalin test. Concluding. MAP kinases and PI3K are important spinal signaling kinases in acetic acid and phenyl-p-benzoquinone models of overt pain-like behavior and there is also activation of spinal microglia indicating that it is also important to determine whether drugs tested in these models also modulate such spinal mechanisms. (C) 2012 Elsevier Inc. All rights reserved.Fundacao AraucariaFundacao AraucariaFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), BrazilCoordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), BrazilPIBITI/UEL, BrazilPIBITI/UEL, Brazi

Fermented (By <i>Monascus purpureus</i> or <i>Aspergillus oryzae</i>) and Non-Fermented Defatted Soybean Flour Extracts: Biological Insight and Mechanism Differences in Inflammatory Pain and Peritonitis

Background: Monascus purpureus and Aspergillus oryzae have been used to ferment defatted soybean flour (DSF: DSFF-Mp and DSSF-Ao, respectively) extract, improving antioxidant availability and conversion of the glycosylated isoflavones to aglycones. The aim of the present study was to evaluate the biological activity of fermented and non-fermented DSF extracts in pain and inflammation, which has not yet been explored. Methods: Phenolic compounds of extracts were determined. Non-fermented DSF (DSF-Non), DSFF-Mp, and DSFF-Ao (10–100 mg/kg) were administrated i.p., 30 min before i.pl. or i.p. carrageenan stimulus. Mechanical and thermal hyperalgesia, edema, histopathology, leukocyte recruitment, and oxidative stress in the paw tissue, and inflammatory cell recruitment, NFκB activation, and cytokine production were assessed in the peritoneum. Stomach and kidney toxicity were evaluated. Results: DSF-Non, DSFF-Mp, and DSFF-Ao extracts inhibited mechanical and thermal hyperalgesia, paw edema, histopathology, neutrophil recruitment, and oxidative stress, as well as inhibited peritoneal leukocyte recruitment. DSF-Non increased IL-10, and DSFF-Ao reduced IL-33 levels. DSFF-Mp increased IL-10 and reduced IL-33 production, and NFκB activation in CD45+ cells, without inducing toxicity. Conclusions: The present data reveal for the first time that fermented/non-fermented DSF extracts are analgesic and anti-inflammatory, showing differences in the mechanism of action depending on fungi applied for fermentation

Pimaradienoic acid (PA) inhibits carrageenan-induced nitric oxide (NO) production.

<p>Mice were treated per oral (p.o.) with PA (10 mg/kg) or vehicle (DMSO 2% diluted in saline) 30 minutes before the intraperitoneal (i.p.) injection of carrageenan (300 μg/paw). Nitrite production in peritoneal exudates was determined 3 hours after carrageenan injection. Results are means ± SEM of six mice per group per experiment, and are representative of two separate experiments. [*p<0.05 compared with the saline group, and #p< 0.05 compared to the vehicle group (One-way ANOVA followed by Tukey’s test)].</p

Pimaradienoic acid (PA) inhibits carrageenan-induced oxidative stress.

<p>Mice were treated per oral (p.o.) with PA (10 mg/kg) or vehicle (DMSO 2% diluted in saline) 30 minutes before the intraplantar (i.pl.) injection of carrageenan (300 μg/paw). Paw skin (A) GSH levels, (B) ABTS⁺ scavenging activity, (C) the ability to reduce iron (FRAP), and (D) superoxide anion production were determined 3 hours after carrageenan injection. Results are means ± SEM of six mice per group per experiment, and are representative of two separate experiments. [*p<0.05 compared to the saline group; #p<0.05 compared to inflammatory stimulus group. (One-way ANOVA followed by Tukey’s test)].</p

Pimaradienoic acid (PA) structure.

<p>Chemical structure of PA[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149656#pone.0149656.ref029" target="_blank">29</a>].</p

Pimaradienoic acid (PA) inhibits carrageenan-induced total leukocyte and neutrophil recruitment in the peritoneal cavity.

<p>Mice were treated per oral (p.o.) with PA (0.1–10 mg/kg) or vehicle (DMSO 2% diluted in saline) 30 minutes before carrageenan (500 μg/ cavity) intraperitoneal (i.p.) injection. The (A) total number of leukocytes, (B) neutrophils and (C) mononuclear cells was evaluated 6 hours after carrageenan injection. Results are means ± SEM of six mice per group per experiment and are representative of two separate experiments. [*p < 0.05 compared to the saline group; #p < 0.05 compared to the vehicle group (One-way ANOVA followed by Tukey’s test)].</p