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1.
Cells ; 13(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474385

RESUMO

Increased production of extracellular matrix is a necessary response to tissue damage and stress. In a normal healing process, the increase in extracellular matrix is transient. In some instances; however, the increase in extracellular matrix can persist as fibrosis, leading to deleterious alterations in organ structure, biomechanical properties, and function. Indeed, fibrosis is now appreciated to be an important cause of mortality and morbidity. Extensive research has illustrated that fibrosis can be slowed, arrested or even reversed; however, few drugs have been approved specifically for anti-fibrotic treatment. This is in part due to the complex pathways responsible for fibrogenesis and the undesirable side effects of drugs targeting these pathways. Natural products have been utilized for thousands of years as a major component of traditional medicine and currently account for almost one-third of drugs used clinically worldwide. A variety of plant-derived compounds have been demonstrated to have preventative or even reversal effects on fibrosis. This review will discuss the effects and the underlying mechanisms of some of the major plant-derived compounds that have been identified to impact fibrosis.


Assuntos
Matriz Extracelular , Compostos Fitoquímicos , Humanos , Fibrose , Matriz Extracelular/metabolismo , Compostos Fitoquímicos/farmacologia
2.
Am J Physiol Cell Physiol ; 313(5): C487-C500, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768641

RESUMO

IL-6 and leukemia inhibitory factor (LIF), members of the IL-6 family of cytokines, play recognized paradoxical roles in skeletal muscle mass regulation, being associated with both growth and atrophy. Overload or muscle contractions can induce a transient increase in muscle IL-6 and LIF expression, which has a regulatory role in muscle hypertrophy. However, the cellular mechanisms involved in this regulation have not been completely identified. The induction of mammalian target of rapamycin complex 1 (mTORC1)-dependent myofiber protein synthesis is an established regulator of muscle hypertrophy, but the involvement of the IL-6 family of cytokines in this process is poorly understood. Therefore, we investigated the acute effects of IL-6 and LIF administration on mTORC1 signaling and protein synthesis in C2C12 myotubes. The role of glycoprotein 130 (gp130) receptor and downstream signaling pathways, including phosphoinositide 3-kinase (PI3K)-Akt-mTORC1 and signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3), was investigated by administration of specific siRNA or pharmaceutical inhibitors. Acute administration of IL-6 and LIF induced protein synthesis, which was accompanied by STAT3 activation, Akt-mTORC1 activation, and increased SOCS3 expression. This induction of protein synthesis was blocked by both gp130 siRNA knockdown and Akt inhibition. Interestingly, STAT3 inhibition or Akt downstream mTORC1 signaling inhibition did not fully block the IL-6 or LIF induction of protein synthesis. SOCS3 siRNA knockdown increased basal protein synthesis and extended the duration of the protein synthesis induction by IL-6 and LIF. These results demonstrate that either IL-6 or LIF can activate gp130-Akt signaling axis, which induces protein synthesis via mTORC1-independent mechanisms in cultured myotubes. However, IL-6- or LIF-induced SOCS3 negatively regulates the activation of myotube protein synthesis.


Assuntos
Interleucina-6/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/metabolismo , Biossíntese de Proteínas/fisiologia , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Citocinas/farmacologia , Citocinas/fisiologia , Interleucina-6/farmacologia , Fator Inibidor de Leucemia/farmacologia , Fator Inibidor de Leucemia/fisiologia , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos
3.
Alcohol Clin Exp Res ; 37(8): 1286-94, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23528014

RESUMO

BACKGROUND: Alcohol abuse is the second leading cause of dilated cardiomyopathy, a disorder specifically referred to as alcoholic cardiomyopathy (ACM). Rodent and human studies have revealed cardiac fibrosis to be a consequence of ACM, and prior studies by this laboratory have associated this occurrence with elevated transforming growth factor-beta (TGF-ß) and activated fibroblasts (myofibroblasts). To date, there have been no other studies to investigate the direct effect of alcohol on the cardiac fibroblast. METHODS: Primary rat cardiac fibroblasts were cultured in the presence of ethanol (EtOH) and assayed for fibroblast activation by collagen gel contraction, alpha-smooth muscle actin (α-SMA) expression, migration, proliferation, apoptosis, collagen I and III, and TGF-ß expression. The TGF-ß receptor type 1 inhibitor compound SB 431542 and a soluble recombinant TGF-ßII receptor (RbII) were used to assess the role of TGF-ß in the response of cardiac fibroblasts to EtOH. RESULTS: Treatment for cardiac fibroblasts with EtOH at concentrations of 100 mg/dl or higher resulted in fibroblast activation and fibrogenic activity after 24 hours including an increase in contraction, α-SMA expression, migration, and expression of collagen I and TGF-ß. No changes in fibroblast proliferation or apoptosis were observed. Inhibition of TGF-ß by SB 431542 and RbII attenuated the EtOH-induced fibroblast activation. CONCLUSIONS: EtOH treatment directly promotes cardiac fibroblast activation by stimulating TGF-ß release from fibroblasts. Inhibiting the action of TGF-ß decreases the fibrogenic effect induced by EtOH treatment. The results of this study support TGF-ß to be an important component in cardiac fibrosis induced by exposure to EtOH.


Assuntos
Cardiomiopatia Alcoólica/etiologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Fibroblastos/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/efeitos dos fármacos , Comunicação Autócrina , Benzamidas , Movimento Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Dioxóis , Coração/efeitos dos fármacos , Masculino , Contração Miocárdica/efeitos dos fármacos , Comunicação Parácrina , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/antagonistas & inibidores
4.
Microsc Microanal ; 18(3): 453-61, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22571914

RESUMO

Male, wild-type, FVB strain mice were fed a nutritionally complete liquid diet supplemented with 4% ethanol v/v over a time course of 1, 2, 4, 8, 12, and 14 weeks. Controls were offered an isocaloric liquid equivalent and pair fed with their ethanol counterparts. Changes in cardiac physiology were assessed at respective time points via echocardiography. Additionally, the use of histological techniques, mRNA analysis, apoptosis determination, and immunohistochemistry were employed to determine the functional and structural changes on the heart. Echocardiograph analysis revealed a compensatory phase that occurred early in the time course (1-8 weeks) and decompensation reverting toward heart failure at weeks 12 and 14. Throughout the study, an increase in cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis, TGF-ß, and the presence of α-SMA-positive cells were determined. A compensatory period in mice treated with ethanol occurred early followed by a transition to a dilated phenotype over time. A number of factors may be involved in this process including the activation of myofibroblasts and their fibrotic activities that is correlated with the presence of transforming growth factor beta.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Etanol/toxicidade , Coração/efeitos dos fármacos , Coração/fisiopatologia , Miocárdio/patologia , Animais , Modelos Animais de Doenças , Ecocardiografia , Histocitoquímica , Masculino , Camundongos , Microscopia , Fatores de Tempo
5.
Hypertension ; 53(6): 1041-7, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19398662

RESUMO

Correlative data suggest that cardiac mast cells are a component of the inflammatory response that is important to hypertension-induced adverse myocardial remodeling. However, a causal relationship has not been established. We hypothesized that adverse myocardial remodeling would be inhibited by preventing the release of mast cell products that may interact with fibroblasts and other inflammatory cells. Eight-week-old male spontaneously hypertensive rats were treated for 12 weeks with the mast cell stabilizing compound nedocromil (30 mg/kg per day). Age-matched Wistar-Kyoto rats served as controls. Nedocromil prevented left ventricular fibrosis in the spontaneously hypertensive rat independent of hypertrophy and blood pressure, despite cardiac mast cell density being elevated. The mast cell protease tryptase was elevated in the spontaneously hypertensive rat myocardium and was normalized by nedocromil. Treatment of isolated adult spontaneously hypertensive rat cardiac fibroblasts with tryptase induced collagen synthesis and proliferation, suggesting this as a possible mechanism of mast cell-mediated fibrosis. In addition, nedocromil prevented macrophage infiltration into the ventricle. The inflammatory cytokines interferon-gamma and interleukin (IL)-4 were increased in the spontaneously hypertensive rat and normalized by nedocromil, whereas IL-6 and IL-10 were decreased in the spontaneously hypertensive rat, with nedocromil treatment normalizing IL-6 and increasing IL-10 above the control. These results demonstrate for the first time a causal relationship between mast cell activation and fibrosis in the hypertensive heart. Furthermore, these results identify several mechanisms, including tryptase, inflammatory cell recruitment, and cytokine regulation, by which mast cells may mediate hypertension-induced left ventricular fibrosis.


Assuntos
Hipertensão/patologia , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/patologia , Mastócitos/fisiologia , Nedocromil/farmacologia , Análise de Variância , Animais , Western Blotting , Proliferação de Células , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Fibrose , Hipertensão/tratamento farmacológico , Imuno-Histoquímica , Masculino , Mastócitos/efeitos dos fármacos , Probabilidade , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Valores de Referência , Sensibilidade e Especificidade
6.
In Vitro Cell Dev Biol Anim ; 43(8-9): 297-305, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17849168

RESUMO

Exposure of fibroblasts to high glucose levels promotes a fibrotic response characterized by increased expression of extracellular matrix components including interstitial collagens. Little is known about the effects of glucose levels on other aspects of fibroblast function. Fibroblasts in the myocardium are surrounded by an extensive extracellular matrix composed predominantly of type I collagen. Interactions between fibroblasts and the myocardial extracellular matrix are thought to affect heart function by altering ventricular diastolic properties. The purpose of the present study was to determine the effects of elevated glucose levels on the interactions between heart fibroblasts and the collagenous extracellular matrix. Studies were performed to determine the effects of relative glucose levels on the ability of fibroblasts to migrate on and contract a three-dimensional collagenous substratum. These experiments illustrated that exposure of cardiac fibroblasts to high glucose levels (25 mM) resulted in decreased migratory activity of fibroblasts on a collagen matrix and decreased fibroblast proliferation. In addition, high glucose stimulated collagen and collagen-binding integrin expression and contraction of three-dimensional collagen gels by cardiac fibroblasts. These studies illustrate that altered glucose levels induce important changes in the interactions of cardiac fibroblasts with the collagenous extracellular matrix.


Assuntos
Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Glucose/farmacologia , Miocárdio/citologia , Actinas/metabolismo , Animais , Bromodesoxiuridina/metabolismo , Agregação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Géis , Integrinas/metabolismo , Ratos , Ratos Sprague-Dawley , Vinculina/metabolismo
7.
J Mol Cell Cardiol ; 41(1): 97-107, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16765374

RESUMO

The ovarian hormone, 17beta-estradiol, has been suggested to play an important role in gender-specific differences in cardiovascular diseases. One possible cardioprotective mechanism involves the interaction between 17beta-estradiol and the renin-angiotensin system. Previous studies demonstrated that fibroblast function and gene expression are regulated by biochemical factors including growth factors, hormones, and cytokines, but little is known regarding the integration of these diverse signals. Therefore, the purpose of this study was to determine the ability of 17beta-estradiol to modulate angiotensin II (AngII) effects on integrin-induced collagen gel contraction, matrix metalloproteinase (MMP) activity and expression, and signal transduction pathways in isolated neonatal cardiac fibroblasts. 17beta-estradiol significantly attenuated AngII-stimulated collagen gel contraction and significantly diminished the effect of AngII on the expression of beta1 and not alpha1integrins. Active MMP-2 levels were decreased by AngII and addition of 17beta-estradiol resulted in further reductions. Relative MMP-2 mRNA levels showed essentially identical patterns to protein levels. 17beta-estradiol pretreatment increased AngII-mediated mitogen-activated protein (MAP) kinase p42/44 activation and slightly decreased p38 activation compared to non-pretreated fibroblasts. Simultaneous addition of 17beta-estradiol and AngII had little to no effect on AngII activation of p42/44 or p38 MAP kinase. The current studies demonstrate the inhibitory role of estrogen on AngII-induced fibroblast-mediated ECM remodeling, gene expression, and signal transduction. These studies begin to elucidate the mechanisms of estrogen effects on myocardial remodeling and function.


Assuntos
Angiotensina II/farmacologia , Estradiol/farmacologia , Fibroblastos/metabolismo , Coração/efeitos dos fármacos , Miocárdio/citologia , Angiotensina II/metabolismo , Animais , Células Cultivadas , Colágeno/efeitos dos fármacos , Estradiol/metabolismo , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Fibroblastos/efeitos dos fármacos , Géis , Integrinas/efeitos dos fármacos , Integrinas/metabolismo , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais
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