Efeitos da acupressura auricular para melhoria da qualidade de vida de mulheres com câncer de mama em tratamento quimioterápico : ensaio clínico randomizado

Orientadora: Profa. Drª. Luciana Puchalski KalinkeCoorientador: Prof. Dr. Jorge Vinícius Cestari FelixDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Enfermagem. Defesa : Curitiba, 20/06/2018Inclui referências: p. 72-84Área de concentração: Prática Profissional de EnfermagemResumo: Trata-se de um ensaio clínico randomizado com o objetivo de avaliar os efeitos da acupressura auricular na melhoria da qualidade de vida de mulheres com câncer de mama em tratamento quimioterápico e teve como objetivo de intervenção realizar um protocolo para aplicação da acupressura auricular no ambulatório de hematologia e oncologia do Complexo Hospital de Clínicas da Universidade Federal do Paraná. A pesquisa foi realizada de março de 2017 até abril de 2018.Participaram 54 mulheres com câncer de mama que estavam recebendo quimioterapia, com idade igual ou superior a 18 anos, não gestantes e que tinham disponibilidade para aplicação da acupressura auricular no ambulatório. Foram excluídas aquelas em uso de medicamentos antidepressivos e/ou ansiolíticos. Foram randomizadas 27 mulheres no grupo intervenção e 27 no grupo controle ou Sham, com alocação de 1:1 (1 intervenção: 1 controle ou Sham pseudointervenção). Os pontos utilizados foram escolhidos pela equipe de pesquisa, de acordo com os principais sintomas físicos e emocionais causados pelo câncer e seu tratamento identificados na literatura. O grupo intervenção recebeu a aplicação da acupressura auricular com esferas de cristal em seis acupontos, (shenmem, rim, estômago, cárdia, tronco cerebral e endócrino), o grupo controle recebeu a aplicação do micropore® nos mesmos acupontos e ambos com aplicação semanal por 12 semanas. A qualidade de vida foi avaliada em cinco momentos diferentes, a primeira antes de iniciar a intervenção e as demais sequencialmente com intervalo de três semanas, com os questionários da European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 e Quality of Life Questionnaire - Breast Cancer BR23. Os resultados mostraram que a idade média das mulheres foi de 51,3 anos e demonstraram melhorias em todos os domínios relacionados à qualidade de vida. Porém, as significantes no grupo intervenção foram na escala de sintomas do Quality of Life Questionnaire Core 30 para náuseas e vômito, p valor= 0,0018 e no Quality of Life Questionnaire - Breast Cancer nos sintomas da mama, p valor= 0,00046. A acupressura auricular mostrou-se método seguro, eficaz, de baixo custo, sem efeitos colaterais, facilmente aplicável por enfermeiros em pacientes ambulatoriais e pode ser recomendada como terapia complementar no tratamento do câncer de mama com vistas à melhorar a QV. O resultado do objetivo de intervenção foi a elaboração do protocolo de auriculoterapia para aplicação da acupressura auricular como tratamento complementar nos pacientes com diagnóstico de câncer de mama em tratamento quimioterápico, atendidos no local da pesquisa. Palavras-Chaves: Câncer mama. Qualidade de vida. Auriculoterapia. Acupressura auricular. Enfermagem Oncológica.Abstract: This is a randomized clinical trial with the objective of evaluating the effects of auricular acupressure on the quality of life of women with breast cancer undergoing chemotherapeutic treatment and had the objective of implementing a protocol for the application of auricular acupressure in hematology and oncology of the Clinical Hospital of the Federal University of Paraná. The research was carried out from March 2017 until April 2018. Participants were 54 women with breast cancer who were receiving chemotherapy, aged 18 years or above, not pregnant and who were available to come weekly for auricular acupressure. Excluding those who were taking antidepressant and / or anxiolytic drugs. Twenty-seven women in the intervention group and 27 in the control or Sham group, with allocation of 1: 1 (1 intervention: 1 control or Sham pseudo-intervention) were randomized. The intervention group received the application of auricular acupressure with crystal beads in six acupoints (shenmem, kidney, stomach, cardia, brainstem and endocrine). The control group received the application of the micropore in the same acupoints. Both groups received weekly sessions during 12 weeks. Quality of life was assessed at five different times, the first being before the intervention and the next four every three weeks with questionnaires from the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 and Quality of Life Questionnaire - Breast Cancer BR23. The results showed that the average age of women was 51.3 years and showed improvements in all domains related to quality of life. However the signifiers in the intervention group were in the symptom scale of the Quality of Life Questionnaire Core 30 for nausea and vomiting, p value = 0.0018 and in the Quality of Life Questionnaire - Breast Cancer in breast symptoms, p value = 0.00046. Atrial acupressure has proved to be a safe, effective, low-cost, no-side-effect method easily applied by nurses in outpatients and may be recommended as a complementary therapy in the treatment of breast cancer to improve QoL in these women.The result of the intervention was the elaboration of anauriculotherapy protocol for the application of auricular acupressure as a complementary treatment in patients with breast cancer diagnosis undergoing chemotherapy, treated at the research site. Keywords: Breast cancer. Quality of life. Auriculotherapy. Auricular acupressure. Oncology Nursing

Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis.

Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Under conditions of excess cholesterol, LXR activation induces the expression of several genes involved in cholesterol efflux, facilitates cholesterol esterification by promoting fatty acid synthesis, and inhibits cholesterol uptake by the low-density lipoprotein receptor. The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways are incompletely understood. Here we show that ligand activation of LXRs in mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as a mediator of this effect. Hepatic LeXis expression is robustly induced in response to a Western diet (high in fat and cholesterol) or to pharmacological LXR activation. Raising or lowering LeXis levels in the liver affects the expression of genes involved in cholesterol biosynthesis and alters the cholesterol levels in the liver and plasma. LeXis interacts with and affects the DNA interactions of RALY, a heterogeneous ribonucleoprotein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the mouse liver. These findings outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis

Inhibition of Cholesterol Biosynthesis Through RNF145-Dependent Ubiquitination of SCAP

Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways

Auriculotherapy With Needles to Improve the Quality of Life of Cancer Patients: An Integrative Literature Review / Auriculoterapia com Agulhas para Melhora da Qualidade de Vida em Pacientes com Câncer: Revisão Integrativa

Objetivo: Identificar a produção disponível relacionada ao uso da acupuntura auricular como intervenção para a melhoria da qualidade de vida de pacientes com câncer. Método: Revisão integrativa de literatura com busca em fontes eletrônicas de dados (BVS, CAPES, CINHAL, PUBMED, WEB of SCIENCE e SCOPUS) no período de janeiro de 2017 com os descritores câncer, neoplasia, auriculoterapia, acupuntura orelha e acupuntura auricular. A revisão integrativa proposta aconteceu em seis etapas distintas e complementares. Resultados: Foram identificados seis artigos com evidências satisfatórias das intervenções nos sintomas clínicos inerentes ao câncer e seu tratamento que demonstraram impactos positivos da auriculoterapia como intervenção. Conclusão: Os estudos relacionados ao tema são escassos, apontam uma realidade cientifica pouco explorada. Um número maior de estudos clínicos deve ocorrer para fortalecer as evidencias das intervenções terapêuticas efetivas, subsidiar a prática e assegurar assistência qualificada

Auriculotherapy With Needles to Improve the Quality of Life of Cancer Patients: An Integrative Literature Review / Auriculoterapia com Agulhas para Melhora da Qualidade de Vida em Pacientes com Câncer: Revisão Integrativa

Objetivo: Identificar a produção disponível relacionada ao uso da acupuntura auricular como intervenção para a melhoria da qualidade de vida de pacientes com câncer. Método: Revisão integrativa de literatura com busca em fontes eletrônicas de dados (BVS, CAPES, CINHAL, PUBMED, WEB of SCIENCE e SCOPUS) no período de janeiro de 2017 com os descritores câncer, neoplasia, auriculoterapia, acupuntura orelha e acupuntura auricular. A revisão integrativa proposta aconteceu em seis etapas distintas e complementares. Resultados: Foram identificados seis artigos com evidências satisfatórias das intervenções nos sintomas clínicos inerentes ao câncer e seu tratamento que demonstraram impactos positivos da auriculoterapia como intervenção. Conclusão: Os estudos relacionados ao tema são escassos, apontam uma realidade cientifica pouco explorada. Um número maior de estudos clínicos deve ocorrer para fortalecer as evidencias das intervenções terapêuticas efetivas, subsidiar a prática e assegurar assistência qualificada

Trimethylamine-N-Oxide, a Metabolite Associated with Atherosclerosis, Exhibits Complex Genetic and Dietary Regulation

SummaryCirculating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis

Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis

Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by sheets of curved rough endoplasmic reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated mitochondria are analyzed by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets, and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodeling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.Fil: Anastasia, Irene. Laval University; Canadá. Brain Research Center; CanadáFil: Ilacqua, Nicolò. Laval University; Canadá. Brain Research Center; CanadáFil: Raimondi, Andrea. San Raffaele Scientific Institute; ItaliaFil: Lemieux, Philippe. Brain Research Center; CanadáFil: Ghandehari-Alavijeh, Rana. Brain Research Center; CanadáFil: Faure, Guilhem. Broad Institute of MIT and Harvard; Estados Unidos. National Center For Biotechnology Information; Estados UnidosFil: Mekhedov, Sergei L.. National Center For Biotechnology Information ; Estados UnidosFil: Williams, Kevin J.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Caicci, Federico. Università di Padova; ItaliaFil: Valle, Giorgio. Università di Padova; ItaliaFil: Giacomello, Marta. Università di Padova; ItaliaFil: Quiroga, Ariel Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. University of Alberta; CanadáFil: Lehner, Richard. University of Alberta; CanadáFil: Miksis, Michael J.. Northwestern University; Estados UnidosFil: Toth, Katalin. University of Ottawa; CanadáFil: de Aguiar Vallim, Thomas Q.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Koonin, Eugene V.. National Center For Biotechnology Information ; Estados UnidosFil: Scorrano, Luca. Università di Padova; ItaliaFil: Pellegrini, Luca. Laval University; Canad

Intestinal Deletion of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Promotes Expansion of the Resident Stem Cell Compartment

BACKGROUND: The intestine occupies the critical interface between cholesterol absorption and excretion. Surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. Here, we investigate the physiological importance of this pathway through genetic deletion of the rate-limiting enzyme. METHODS: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. Plasma lipids, intestinal morphology, mevalonate pathway metabolites, and gene expression were analyzed. RESULTS: Mice with intestine-specific loss of Hmgcr were markedly smaller at birth, but gain weight at a rate similar to wild type littermates, and are viable and fertile into adulthood. Intestine lengths and weights were greater relative to body weight in both male and female Hmgcr intestinal knockout (i-KO) mice. Male i-KO had decreased plasma cholesterol levels, while fasting triglycerides were lower in both sexes. Lipidomics revealed substantial reductions in numerous non-sterol isoprenoids and sterol intermediates within the epithelial layer, but cholesterol levels were preserved. Hmgcr i-KO mice also showed robust activation of SREBP-2 target genes in the epithelium, including the low-density lipoprotein receptor (LDLR). At the cellular level, loss of Hmgcr is compensated for quickly after birth through a dramatic expansion of the stem cell compartment, which persists into adulthood. CONCLUSIONS: Loss of Hmgcr in the intestine is compatible with life through compensatory increases in intestinal absorptive surface area, LDLR expression, and expansion of the resident stem cell compartment

Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans

Bile acids are synthesized from cholesterol in the liver and subjected to multiple metabolic biotransformations in hepatocytes, including oxidation by cytochromes P450 (CYPs) and conjugation with taurine, glycine, glucuronic acid, and sulfate. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6β-position to form α-muricholic acid (MCA) and ursodeoxycholic acid (UDCA) to form β-MCA. However, MCA is not formed in humans to any appreciable degree and the mechanism for this species difference is not known. Comparison of several Cyp-null mouse lines revealed that α-MCA and β-MCA were not detected in the liver samples from Cyp2c-cluster null (Cyp2c-null) mice. Global bile acid analysis further revealed the absence of MCAs and their conjugated derivatives, and high concentrations of CDCA and UDCA in Cyp2c-null mouse cecum and feces. Analysis of recombinant CYPs revealed that α-MCA and β-MCA were produced by oxidation of CDCA and UDCA by Cyp2c70, respectively. CYP2C9-humanized mice have similar bile acid metabolites as the Cyp2c-null mice, indicating that human CYP2C9 does not oxidize CDCA and UDCA, thus explaining the species differences in production of MCA. Because humans do not produce MCA, they lack tauro-β-MCA, a farnesoid X receptor antagonist in mouse that modulates obesity, insulin resistance, and hepatosteatosis

FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption

FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids