Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática

Detalhes bibliográficos
Autor(a) principal: Reghelin, Camille Kirinus
Data de Publicação: 2022
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da PUC_RS
Texto Completo: https://tede2.pucrs.br/tede2/handle/tede/10601
Resumo: Hepatic fibrosis (FH) is characterized by the healing process that represents the hepatic response to injuries, through the deposition of collagen and other constituents of the extracellular matrix. This process occurring repeatedly can culminate in liver cirrhosis, in which the architectural organization of the liver changes to the point of interfering with blood flow and its functions. Among the most serious complications of the disease, this included portal hypertension, liver failure and cancer. The main cells involved in hepatic fibrosis that produce extracellular matrix are hepatic stellate cells. This population of resident cells contains a quiescent phenotype that functions as the body's vitamin A store. And when activated, they transform to adopt a myofibroblast phenotype. The present study sought new treatment options based on concepts already applied, established and related to drug repositioning, in which we directed our analysis to bezafibrate. This is a drug commonly used to reduce the levels of cholesterol and triglycerides in the blood, acting through the activation of Peroxisome proliferator-activated receptors (PPARs). Therefore, we sought to verify the potential antifibrotic effect of BZF in experimental models in vitro and in vivo. as a possible new therapy for the treatment of liver fibrosis. The parameters evaluated in vitro were cell proliferation, cytotoxicity index, identification of acidic vesicular organelles (AVOs), quantification of lipid droplets, collagen gel contraction and analysis of molecular markers related to phenotypic activation and reversion. Subsequently, hepatic injury markers was investigated in vivo, as well as histological and molecular aspects. After 72 hours of in vitro treatment, BZF decreased cell proliferation, reversed phenotype, reduced cell contraction and induced autophagy. In addition, BZF demonstrated a protective effect on tetrachloride-induced liver fibrosis in mice, confirmed by serum, liver tissue and molecular analysis.
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spelling Melo, Denizar Alberto da SilvaOliveira, Jarbas Rodrigues deReghelin, Camille Kirinus2023-01-26T13:57:09Z2022-08-30https://tede2.pucrs.br/tede2/handle/tede/10601Hepatic fibrosis (FH) is characterized by the healing process that represents the hepatic response to injuries, through the deposition of collagen and other constituents of the extracellular matrix. This process occurring repeatedly can culminate in liver cirrhosis, in which the architectural organization of the liver changes to the point of interfering with blood flow and its functions. Among the most serious complications of the disease, this included portal hypertension, liver failure and cancer. The main cells involved in hepatic fibrosis that produce extracellular matrix are hepatic stellate cells. This population of resident cells contains a quiescent phenotype that functions as the body's vitamin A store. And when activated, they transform to adopt a myofibroblast phenotype. The present study sought new treatment options based on concepts already applied, established and related to drug repositioning, in which we directed our analysis to bezafibrate. This is a drug commonly used to reduce the levels of cholesterol and triglycerides in the blood, acting through the activation of Peroxisome proliferator-activated receptors (PPARs). Therefore, we sought to verify the potential antifibrotic effect of BZF in experimental models in vitro and in vivo. as a possible new therapy for the treatment of liver fibrosis. The parameters evaluated in vitro were cell proliferation, cytotoxicity index, identification of acidic vesicular organelles (AVOs), quantification of lipid droplets, collagen gel contraction and analysis of molecular markers related to phenotypic activation and reversion. Subsequently, hepatic injury markers was investigated in vivo, as well as histological and molecular aspects. After 72 hours of in vitro treatment, BZF decreased cell proliferation, reversed phenotype, reduced cell contraction and induced autophagy. In addition, BZF demonstrated a protective effect on tetrachloride-induced liver fibrosis in mice, confirmed by serum, liver tissue and molecular analysis.A fibrose hepática (FH) se caracteriza pelo processo de cicatrização que representa a resposta hepática a lesões, através da deposição do colágeno e outros constituintes da matriz extracelular. Este processo ocorrendo repetidas vezes pode vir a culminar em uma cirrose hepática, na qual a organização arquitetônica do fígado se altera a ponto de interferir no fluxo de sangue e nas suas funções. Dentre as mais graves complicações da doença, está incluída hipertensão portal, insuficiência e câncer hepático. As principais células envolvidas na fibrose hepática que produzem matriz extracelular são as células estreladas hepáticas. Esta população de células residentes contém um fenótipo quiescente que funciona como armazenamento de vitamina A do organismo. Uma vez ativadas, elas se transformam de forma a adotar um fenótipo de miofibroblasto. O presente estudo buscou novas opções de tratamentos baseado em conceitos já aplicados, estabelecidos e correlatos ao reposicionamento de fármacos. Neste sentido, o bezafibrato surgiu como alterativa porque apresenta potencial efeito antifibrótico. Este um medicamento comumente utilizado para reduzir os níveis de colesterol e triglicérides no sangue, atuando por meio da ativação de Receptores ativados por proliferadores de peroxissomas (PPARs). Portanto, buscamos verificar o potencial efeito antifibrótico do BZF em modelos experimentais in vitro e in vivo como uma possível nova terapia para o tratamento da fibrose hepática. Os parâmetros avaliados in vitro foram a proliferação celular, o índice de citotoxicidade, a identificação das organelas vesiculares ácidas (AVOs), quantificação de gotículas lipídicas, contração de gel de colágeno e análise dos marcadores moleculares relacionados a ativação e reversão fenotípica. Na sequência foram investigados in vivo marcadores de lesão hepática, os aspectos histológicos e também moleculares. Após 72 horas de tratamento in vitro, o BZF diminuiu a proliferação celular, reverteu o fenótipo, reduziu a contração celular e induziu autofagia. Além disso, o BZF demonstrou o efeito protetor na fibrose hepática induzida por tetracloreto em camundongos, confirmados pela avaliação do soro, no tecido hepático e análise molecular.Submitted by PPG Biologia Celular e Molecular (bcm@pucrs.br) on 2023-01-24T14:11:23Z No. of bitstreams: 1 CAMILLE KIRINUS REGHELIN.pdf: 2463376 bytes, checksum: b51e33c488f97ddaa81ca030ca9453a7 (MD5)Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2023-01-26T13:40:51Z (GMT) No. of bitstreams: 1 CAMILLE KIRINUS REGHELIN.pdf: 2463376 bytes, checksum: b51e33c488f97ddaa81ca030ca9453a7 (MD5)Made available in DSpace on 2023-01-26T13:57:09Z (GMT). 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dc.title.por.fl_str_mv Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
title Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
spellingShingle Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
Reghelin, Camille Kirinus
Bezafibrato
Células GRX
Dano Oxidativo
Célula
Fibrose Hepática
Bezafibrate
GRX Cells
Oxidative Damage
Cell
Liver Fibrosis
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL
title_short Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
title_full Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
title_fullStr Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
title_full_unstemmed Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
title_sort Avaliação do efeito antifibrótico hepático do bezafibrato em modelos in vitro e in vivo de fibrose hepática
author Reghelin, Camille Kirinus
author_facet Reghelin, Camille Kirinus
author_role author
dc.contributor.advisor1.fl_str_mv Melo, Denizar Alberto da Silva
dc.contributor.advisor-co1.fl_str_mv Oliveira, Jarbas Rodrigues de
dc.contributor.author.fl_str_mv Reghelin, Camille Kirinus
contributor_str_mv Melo, Denizar Alberto da Silva
Oliveira, Jarbas Rodrigues de
dc.subject.por.fl_str_mv Bezafibrato
Células GRX
Dano Oxidativo
Célula
Fibrose Hepática
topic Bezafibrato
Células GRX
Dano Oxidativo
Célula
Fibrose Hepática
Bezafibrate
GRX Cells
Oxidative Damage
Cell
Liver Fibrosis
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL
dc.subject.eng.fl_str_mv Bezafibrate
GRX Cells
Oxidative Damage
Cell
Liver Fibrosis
dc.subject.cnpq.fl_str_mv CIENCIAS BIOLOGICAS::BIOLOGIA GERAL
description Hepatic fibrosis (FH) is characterized by the healing process that represents the hepatic response to injuries, through the deposition of collagen and other constituents of the extracellular matrix. This process occurring repeatedly can culminate in liver cirrhosis, in which the architectural organization of the liver changes to the point of interfering with blood flow and its functions. Among the most serious complications of the disease, this included portal hypertension, liver failure and cancer. The main cells involved in hepatic fibrosis that produce extracellular matrix are hepatic stellate cells. This population of resident cells contains a quiescent phenotype that functions as the body's vitamin A store. And when activated, they transform to adopt a myofibroblast phenotype. The present study sought new treatment options based on concepts already applied, established and related to drug repositioning, in which we directed our analysis to bezafibrate. This is a drug commonly used to reduce the levels of cholesterol and triglycerides in the blood, acting through the activation of Peroxisome proliferator-activated receptors (PPARs). Therefore, we sought to verify the potential antifibrotic effect of BZF in experimental models in vitro and in vivo. as a possible new therapy for the treatment of liver fibrosis. The parameters evaluated in vitro were cell proliferation, cytotoxicity index, identification of acidic vesicular organelles (AVOs), quantification of lipid droplets, collagen gel contraction and analysis of molecular markers related to phenotypic activation and reversion. Subsequently, hepatic injury markers was investigated in vivo, as well as histological and molecular aspects. After 72 hours of in vitro treatment, BZF decreased cell proliferation, reversed phenotype, reduced cell contraction and induced autophagy. In addition, BZF demonstrated a protective effect on tetrachloride-induced liver fibrosis in mice, confirmed by serum, liver tissue and molecular analysis.
publishDate 2022
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