Immunephenotype Predicts Response to Vedolizumab: Integrating Clinical and Biochemical Biomarkers in the Treatment of Inflammatory Bowel Diseases

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Orientación sobre sexualidad para estudiantes de enfermería

OBJECTIVE: To identify the perception of students at the Nursing undergraduate course about sexual orientation activities; to establish how these activities should be developed towards the students. METHODS: This is a descriptive study using content analysis, performed with a population consisting of 193 students of the Nursing undergraduate course of Universidade Federal de São Paulo (UNIFESP). RESULTS: 93% of the respondents agreed with sexual orientation activities and 80% justified the necessity through the following categories: contribution for professional education (9%), stereotypes (1%), necessity of information (26%), prevention (4%), taking care of oneself in order to care for the other (13%), self-knowledge (8%) and difficulties with the topic (19%). CONCLUSION: Nursing students are interested in activities focused on the discussion of human sexuality within the academic universe.OBJETIVO: Identificar la percepción de estudiantes del Pregrado en Enfermería sobre actividades dirigidas a la orientación sexual; establecer la forma de desarrollo de estas actividades junto a los estudiantes. MÉTODOS: Se trata de un estudio descriptivo en el cual se utilizó el análisis de contenido, realizado junto a una población conformada por 193 estudiantes del pregrado en Enfermería de la Universidad Federal de São Paulo. RESULTADOS: el 93% de los entrevistados concordaron con actividades dirigidas a la orientación sexual, y el 80% justificaron la necesidad por medio de las categorías: contribución a la formación profesional (9%), estereotipos (1%), necesidad de información (26%), prevención (4%), cuidar de sí para cuidar del otro (13%), autoconocimiento (8%) y dificultades con el asunto (19%). CONCLUSIÓN: Existe interés de los estudiantes de enfermería por actividades orientadas a la discusión de la sexualidad humana en el espacio académico.OBJETIVO: Identificar a percepção de estudantes do Curso de graduação em Enfermagem sobre atividades voltadas à orientação sexual; estabelecer a forma de desenvolvimento destas atividades junto aos estudantes. MÉTODOS: Trata-se de um estudo descritivo em que se utilizou a análise de conteúdo, realizado junto a uma população constituída por 193 estudantes do Curso de graduação em Enfermagem da Universidade Federal de São Paulo (UNIFESP). RESULTADOS: 93% dos entrevistados concordaram com atividades voltadas à orientação sexual, e 80% justificaram a necessidade por meio das categorias: contribuição para formação profissional (9%), estereótipos (1%), necessidade de informação (26%), prevenção (4%), cuidar de si para cuidar do outro (13%), autoconhecimento (8%) e dificuldades com o assunto (19%). CONCLUSÃO: Existe interesse dos estudantes de enfermagem por atividades voltadas à discussão da sexualidade humana no espaço acadêmico.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Abstract The 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a NO-releasing derivative of aspirin. In this study, we provide evidence that NCX-4016 delivered to PMBC-derived T lymphocytes and monocytes causes a transitory inhibition of cell respiration and ≈50% reduction of cellular ATP, which translates in a time-reversible inhibition of cell proliferation and IL-2, IL-4, IL-5, and IFN-γ secretion. Exposure of lymphocytes and monocytes to aspirin, 2-(acetyloxy)benzoic acid 3-(hydroxymethyl)phenyl ester (NCX-4017), a non-NO-releasing analog of NCX-4016, and cyclooxygenase inhibitors, reduced PG formation, but has no effect on cytokine/chemokine release. In contrast, delivering NO with (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) reproduced most of the metabolic and anti-cytokine activities of NCX-4016. Scavenging NO with hemoglobin or adding selective substrates of complex II, III, and IV of the mitochondrial respiratory chain reverses NCX-4016′ inhibitory activities. Exposure to DETA-NO and NCX-4016 enhances glucose uptake, glycolytic rate, and lactate generation in CD3/CD28-costimulated lymphocytes, while reduced citric acid cycle intermediates. These effects were not reproduced by selective and nonselective cyclooxygenase 2 inhibitors. In summary, we demonstrated that exposure of lymphocytes to NCX-4016 causes a metabolic hypoxia that inhibits lymphocyte reactivity to costimulatory molecules, providing a potential counteregulatory mechanism to control activated immune system

Hydrogen sulphide induces μ opioid receptor-dependent analgesia in a rodent model of visceral pain

<p>Abstract</p> <p>Background</p> <p>Hydrogen sulphide (H₂S) is a gaseous neuro-mediator that exerts analgesic effects in rodent models of visceral pain by activating K_ATPchannels. A body of evidence support the notion that K_ATPchannels interact with endogenous opioids. Whether H₂S-induced analgesia involves opioid receptors is unknown.</p> <p>Methods</p> <p>The perception of painful sensation induced by colorectal distension (CRD) in conscious rats was measured by assessing the abdominal withdrawal reflex. The contribution of opioid receptors to H₂S-induced analgesia was investigated by administering rats with selective μ, κ and δ opioid receptor antagonists and antisenses. To investigate whether H₂S causes μ opioid receptor (MOR) transactivation, the neuronal like cells SKNMCs were challenged with H₂S in the presence of MOR agonist (DAMGO) or antagonist (CTAP). MOR activation and phosphorylation, its association to β arrestin and internalization were measured.</p> <p>Results</p> <p>H₂S exerted a potent analgesic effects on CRD-induced pain. H₂S-induced analgesia required the activation of the opioid system. By pharmacological and molecular analyses, a robust inhibition of H₂S-induced analgesia was observed in response to central administration of CTAP and MOR antisense, while κ and δ receptors were less involved. H₂S caused MOR transactivation and internalization in SKNMCs by a mechanism that required AKT phosphorylation. MOR transactivation was inhibited by LY294002, a PI3K inhibitor, and glibenclamide, a K_ATPchannels blocker.</p> <p>Conclusions</p> <p>This study provides pharmacological and molecular evidence that antinociception exerted by H₂S in a rodent model of visceral pain is modulated by the transactivation of MOR. This observation provides support for development of new pharmacological approaches to visceral pain.</p

The Bile Acid Sensor FXR Protects against Dyslipidemia and Aortic Plaques Development Induced by the HIV Protease Inhibitor Ritonavir in Mice

Although human immunodeficiency virus (HIV)–related morbidity and mortality rates in patients treated with a combination of high active antiretroviral therapy (HAART) have declined, significant metabolic/vascular adverse effects associated with the long term use of HIV protease inhibitors (PIs) have emerged as a significant side effect. Here we illustrate that targeting the bile acid sensor farnesoid X receptor (FXR) protects against dyslipidemia and vascular injury induced HIV-PIs in rodents. mice with gemfibrozil, a PPARα agonist. FXR activation counter-regulated induction of expression/activity of CD36 caused by HIV-PIs in circulating monocytes and aortic plaques. In macrophages cell lines, CDCA attenuated CD36 induction and uptake of acetylated LDL caused by ritonavir. Natural and synthetic FXR ligands reduced the nuclear translocation of SREBP1c caused by ritonavir.Activation of the bile acid sensor FXR protects against dyslipidemia and atherosclerotic caused by ritonavir, a widely used HIV PI. From a mechanistic stand point it appears that besides reducing the liver expression of genes involved in fatty acid synthesis, FXR activation counter-regulates the expression/activity of CD36 on monocytes. FXR ligands might hold promise in the treatment dyslipidemia induced by ritonavir

Probiotics Modulate Intestinal Expression of Nuclear Receptor and Provide Counter-Regulatory Signals to Inflammation-Driven Adipose Tissue Activation

BACKGROUND: Adipocytes from mesenteric white adipose tissue amplify the inflammatory response and participate in inflammation-driven immune dysfunction in Crohn's disease by releasing proinflammatory mediators. Peroxisome proliferator-activated receptors (PPAR)-α and -γ, pregnane x receptor (PXR), farnesoid x receptor (FXR) and liver x-receptor (LXR) are ligand-activated nuclear receptor that provide counter-regulatory signals to dysregulated immunity and modulates adipose tissue. AIMS: To investigate the expression and function of nuclear receptors in intestinal and adipose tissues in a rodent model of colitis and mesenteric fat from Crohn's patients and to investigate their modulation by probiotics. METHODS: Colitis was induced by TNBS administration. Mice were administered vehicle or VSL#3, daily for 10 days. Abdominal fat explants obtained at surgery from five Crohn's disease patients and five patients with colon cancer were cultured with VSL#3 medium. RESULTS: Probiotic administration attenuated development of signs and symptoms of colitis, reduced colonic expression of TNFα, IL-6 and IFNγ and reserved colonic downregulation of PPARγ, PXR and FXR caused by TNBS. Mesenteric fat depots isolated from TNBS-treated animals had increased expression of inflammatory mediators along with PPARγ, FXR, leptin and adiponectin. These changes were prevented by VSL#3. Creeping fat and mesenteric adipose tissue from Crohn's patients showed a differential expression of PPARγ and FXR with both tissue expressing high levels of leptin. Exposure of these tissues to VSL#3 medium abrogates leptin release. CONCLUSIONS: Mesenteric adipose tissue from rodent colitis and Crohn's disease is metabolically active and shows inflammation-driven regulation of PPARγ, FXR and leptin. Probiotics correct the inflammation-driven metabolic dysfunction

The Bile Acid Receptor GPBAR-1 (TGR5) Modulates Integrity of Intestinal Barrier and Immune Response to Experimental Colitis

BACKGROUND: GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation. AIMS: To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis. METHODS: Colitis was induced in wild type and GP-BAR1(-/-) mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies. RESULTS: GP-BAR1(-/-) mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1. CONCLUSIONS: GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand

Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite

Bisphenol AF (BPAF) is a fluorinated analog of bisphenol A (BPA), and it is a more potent estrogen receptor (ER) agonist. BPAF is mainly metabolized to BPAF-glucuronide (BPAF-G), which has been reported to lack ER agonist activity and is believed to be biologically inactive. The main goal of the current study was to examine the influence of the metabolism of BPAF via glucuronidation on its ER activity and adipogenesis. Also, as metabolites can have different biological activities, the effects of BPAF-G on other nuclear receptors were evaluated. First, in-vitro BPAF glucuronidation was investigated using recombinant human enzymes. Specific reporter-gene assays were used to determine BPAF and BPAF-G effects on estrogen, androgen, glucocorticoid, and thyroid receptor pathways, and on PXR, FXR, and PPAR gamma pathways. Their effects on lipid accumulation and differentiation were determined in murine 3T3L1 preadipocytes using Nile Red, with mRNA expression analysis of the adipogenic markers adiponectin, Fabp4, Cebp alpha, and PPAR gamma. BPAF showed strong agonistic activity for hER alpha and moderate antagonistic activities for androgen and thyroid receptors, and for PXR. BPAF-G was antagonistic for PXR and PPAR gamma. BPAF (0.1 mu M) and BPAF-G (1.0 mu M) induced lipid accumulation and increased expression of key adipogenic markers in murine preadipocytes. BPAF-G is therefore not an inactive metabolite of BPAF. Further toxicological and epidemiological investigations of BPAF effects on human health are warranted, to provide better understanding of the metabolic end-elimination of BPAF. (C) 2018 Elsevier Ltd. All rights reserved.Peer reviewe

GLP-1 Mediates Regulation of Colonic ACE2 Expression by the Bile Acid Receptor GPBAR1 in Inflammation

Background & Aims: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. Methods: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn’s disease (CD) patients and three mouse models of colitis and Gpbar1−/− mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. Results: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. Conclusions: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α-and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2