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1.
Ann Hepatol ; 19(5): 497-506, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32673649

RESUMO

INTRODUCTION AND OBJECTIVES: Curcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fibrosis and if so, to determine the action mechanisms involved in the reduction process. MATERIALS AND METHODS: CCl4 was administered to male Wistar rats (400 mg/kg, three times a week, i. p.) for 12 weeks; curcumin (100 mg/kg body weight twice per day, p. o.) was administered from week 9-12 of CCl4 treatment. Biochemical markers of hepatic injury and oxidative stress were evaluated. Hematoxylin and eosin, Masson's trichrome stains, transmission electron microscopy; immunohistochemistry, and zymography assays were carried out. Moreover, Smad3 and α-SMA mRNA and protein levels were studied. Western blotting by TGF-ß, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, pSmad3, and pJNK proteins was developed. RESULTS AND CONCLUSIONS: Curcumin reduced liver damage, oxidative stress, fibrosis, and restored normal activity of MMP-9 and MMP-2. Besides, curcumin restored NF-κB, IL-1, IL-10, TGF-ß, CTGF, Col-I, MMP-13, and Smad7 protein levels. On the other hand, curcumin decreased JNK and Smad3 phosphorylation. Furthermore, curcumin treatment decreased α-SMA and Smad3 protein and mRNA levels. Curcumin normalized GSH, and NF-κB, JNK-Smad3, and TGF-ß-Smad3 pathways, leading to a decrement in activated hepatic stellate cells, thereby producing its antifibrotic effects.


Assuntos
Transdiferenciação Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/ultraestrutura , Fígado/metabolismo , Fígado/ultraestrutura , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos Wistar , Transdução de Sinais
2.
Eur J Pharmacol ; 865: 172730, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618621

RESUMO

There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CCl4 was given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9-12 of the CCl4 treatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-ß, CTGF, Col-I, MMP-13, NF-κB, IL-1ß, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1ß, IL-10, TGF-ß, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced by naringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-ß-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.


Assuntos
Progressão da Doença , Flavanonas/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Cirrose Hepática/patologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Colágeno/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Flavanonas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Masculino , Proteólise/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
3.
Life Sci ; 224: 187-196, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30890404

RESUMO

AIMS: Stevioside is a diterpenoid obtained from the leaves of Stevia rebaudiana (Bertoni) that exhibits antioxidant, antifibrotic, antiglycemic and anticancer properties. Therefore, we aimed to study whether stevioside has beneficial effects in liver injury induced by long-term thioacetamide (TAA) administration and investigated the possible underlying molecular mechanism using in vivo, in vitro and in silico approaches. MAIN METHODS: Liver injury was induced in male Wistar rats by TAA administration (200 mg/kg), intraperitoneally, three times per week. Rats received saline or stevioside (20 mg/kg) twice daily intraperitoneally. In addition, cocultures were incubated with either lipopolysaccharide or ethanol. Liver injury, antioxidant and immunological responses were evaluated. KEY FINDINGS: Chronic TAA administration induced significant liver damage. In addition, TAA upregulated the protein expression of nuclear factor (NF)-κB, thus increasing the expression of proinflammatory cytokines and decreasing the antioxidant capacity of the liver through downregulation of nuclear erythroid factor 2 (Nrf2). Notably, stevioside administration prevented all of these changes. In vitro, stevioside prevented the upregulation of several genes implicated in liver inflammation when cocultured cells were incubated with lipopolysaccharide or ethanol. In silico assays using tumor necrosis factor receptor (TNFR)-1 and Toll-like receptor (TLR)-4-MD2 demonstrated that stevioside docks with TNFR1 and TLR4-MD2, thus promoting an antagonistic action against this proinflammatory mediator. SIGNIFICANCE: Collectively, these data suggest that stevioside prevented liver damage through antioxidant activity by upregulating Nrf2 and immunomodulatory activity by blocking NF-κB signaling.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Diterpenos do Tipo Caurano/farmacologia , Glucosídeos/farmacologia , Fatores Imunológicos/farmacologia , Edulcorantes/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Simulação por Computador , Técnicas In Vitro , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Tioacetamida/toxicidade
4.
Hepatol Res ; 49(2): 212-223, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30338893

RESUMO

AIM: The aims of the present study were to investigate the capacity of stevia leaves to prevent experimental cirrhosis induced by chronic administration of carbon tetrachloride (CCl4 ) in rats and to explore the action mechanism involved. METHODS: Liver cirrhosis was established by CCl4 treatment (400 mg/kg i.p. three times a week for 12 weeks); stevia powder was administered (100 mg/kg by gavage daily) during the CCl4 treatment. Serum markers of liver damage and hydroxyproline were evaluated and histopathological analyses were carried out. The profibrotic pathways were analyzed by western blot and immunohistochemistry. RESULTS: We found for the first time that stevia cotreatment prevented the elevation of serum markers of necrosis and cholestasis and the occurrence of liver fibrosis. It is worth noting that stevia downregulated several profibrogenic pathways, including the reduction of hepatic myofibroblasts and decreased matrix metalloproteinase (MMP)2 and MMP13 expression, thereby blocking the liberation of transforming growth factor-ß from the extracellular matrix. Notably, stevia reduced the phosphorylation of pSmad3L, the most profibrogenic and mitogenic Smad, by inhibiting the activation of c-Jun N-terminal kinase and extracellular signal-regulated kinase. Interestingly, Smad7, an important antifibrotic molecule, was upregulated by stevia treatment in cirrhotic rats. These multitarget mechanisms led to the prevention of experimental cirrhosis. CONCLUSIONS: Because stevia possesses a reasonable safety profile, our results indicate that it could be useful in the clinical setting to treat chronic liver diseases.

5.
Oxid Med Cell Longev ; 2018: 3823426, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849889

RESUMO

The effect of stevia on liver cirrhosis has not been previously investigated. In the present study, the antioxidant and anti-inflammatory properties of stevia leaves were studied in male Wistar rats with carbon tetrachloride- (CCl4-) induced acute and chronic liver damage. Acute and chronic liver damage induced oxidative stress, necrosis, and cholestasis, which were significantly ameliorated by stevia. Chronic CCl4 treatment resulted in liver cirrhosis, as evidenced by nodules of hepatocytes surrounded by thick bands of collagen and distortion of the hepatic architecture, and stevia significantly prevented these alterations. Subsequently, the underlying mechanism of action of the plant was analyzed. Our study for the first time shows that stevia upregulated Nrf2, thereby counteracting oxidative stress, and prevented necrosis and cholestasis through modulation of the main proinflammatory cytokines via NF-κB inhibition. These multitarget mechanisms led to the prevention of experimental cirrhosis. Given the reasonable safety profile of stevia, our results indicated that it may be useful for the clinical treatment of acute and chronic liver diseases.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Fígado/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Stevia/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Projetos Piloto , Ratos , Ratos Wistar , Regulação para Cima
6.
World J Gastroenterol ; 24(16): 1679-1707, 2018 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-29713125

RESUMO

Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor (TGF-ß) pathway and the prevention of the transdifferentiation of hepatic stellate cells (HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase (MAPK), toll-like receptor (TLR) and TGF-ß non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease (NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-ß and vascular endothelial growth factor (VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticarcinógenos/uso terapêutico , Antioxidantes/uso terapêutico , Flavanonas/uso terapêutico , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Anticarcinógenos/efeitos adversos , Anticarcinógenos/farmacocinética , Antioxidantes/efeitos adversos , Antioxidantes/farmacocinética , Colágeno/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Flavanonas/efeitos adversos , Flavanonas/farmacocinética , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Hepatopatias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
7.
Fundam Clin Pharmacol ; 31(6): 610-624, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28802065

RESUMO

The ability of quercetin to reverse an established cirrhosis has not yet been investigated. Therefore, the aim of this study was to examine the efficacy of this flavonoid in reversing experimental cirrhosis. Cirrhosis was induced by intraperitoneal administration of TAA (200 mg/kg of body weight) three times per week for 8 weeks or by intraperitoneal petrolatum-CCl4 (400 mg/kg of body weight) administration three times per week for 8 weeks. To determine the capacity of quercetin to prevent liver fibrosis, the flavonoid (50 mg/kg of body weight, p.o.) was administered daily to rats during the CCl4 or TAA treatment. To evaluate the ability of quercetin to reverse the previously induced cirrhosis, we first treated rats with CCl4 for 8 weeks, as previously described and then the flavonoid was administered for four more weeks. We found that the liver anti-inflammatory and antinecrotic effects of quercetin are associated with its antioxidant properties, to the ability of the flavonoid to block NF-κB activation and in consequence to reduce cytokine IL-1. The ability of quercetin to reverse fibrosis may be associated with the capacity of the flavonoid to decrease TGF-ß levels, hepatic stellate cell activation, and to promote degradation of the ECM by increasing metalloproteinases. The main conclusion is that quercetin, in addition to its liver protective activity against TAA chronic intoxication, is also capable of reversing a well-stablished cirrhosis by blocking the prooxidant processes and by downregulating the inflammatory and profibrotic responses.


Assuntos
Antioxidantes/farmacologia , Cirrose Hepática Experimental/imunologia , Cirrose Hepática/imunologia , Quercetina/farmacologia , Animais , Modelos Animais de Doenças , Imunomodulação , Cirrose Hepática Experimental/patologia , Masculino , NF-kappa B/efeitos dos fármacos , Ratos , Ratos Wistar
8.
World J Gastroenterol ; 23(24): 4354-4368, 2017 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-28706418

RESUMO

AIM: To study the molecular mechanisms involved in the hepatoprotective effects of naringenin (NAR) on carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Thirty-two male Wistar rats (120-150 g) were randomly divided into four groups: (1) a control group (n = 8) that received 0.7% carboxy methyl-cellulose (NAR vehicle) 1 mL/daily p.o.; (2) a CCl4 group (n = 8) that received 400 mg of CCl4/kg body weight i.p. 3 times a week for 8 wk; (3) a CCl4 + NAR (n = 8) group that received 400 mg of CCl4/kg body weight i.p. 3 times a week for 8 wk and 100 mg of NAR/kg body weight daily for 8 wk p.o.; and (4) an NAR group (n = 8) that received 100 mg of NAR/kg body weight daily for 8 wk p.o. After the experimental period, animals were sacrificed under ketamine and xylazine anesthesia. Liver damage markers such as alanine aminotransferase (ALT), alkaline phosphatase (AP), γ-glutamyl transpeptidase (γ-GTP), reduced glutathione (GSH), glycogen content, lipid peroxidation (LPO) and collagen content were measured. The enzymatic activity of glutathione peroxidase (GPx) was assessed. Liver histopathology was performed utilizing Masson's trichrome and hematoxylin-eosin stains. Zymography assays for MMP-9 and MMP-2 were carried out. Hepatic TGF-ß, α-SMA, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, Smad3, pSmad3 and pJNK proteins were detected via western blot. RESULTS: NAR administration prevented increases in ALT, AP, γ-GTP, and GPx enzymatic activity; depletion of GSH and glycogen; and increases in LPO and collagen produced by chronic CCl4 intoxication (P < 0.05). Liver histopathology showed a decrease in collagen deposition when rats received NAR in addition to CCl4. Although zymography assays showed that CCl4 produced an increase in MMP-9 and MMP-2 gelatinase activity; interestingly, NAR administration was associated with normal MMP-9 and MMP-2 activity (P < 0.05). The anti-inflammatory, antinecrotic and antifibrotic effects of NAR may be attributed to its ability to prevent NF-κB activation and the subsequent production of IL-1 and IL-10 (P < 0.05). NAR completely prevented the increase in TGF-ß, α-SMA, CTGF, Col-1, and MMP-13 proteins compared with the CCl4-treated group (P < 0.05). NAR prevented Smad3 phosphorylation in the linker region by JNK since this flavonoid blocked this kinase (P < 0.05). CONCLUSION: NAR prevents CCl4 induced liver inflammation, necrosis and fibrosis, due to its antioxidant capacity as a free radical inhibitor and by inhibiting the NF-κB, TGF-ß-Smad3 and JNK-Smad3 pathways.


Assuntos
Flavanonas/farmacologia , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Tetracloreto de Carbono/toxicidade , Flavanonas/uso terapêutico , Glutationa/sangue , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/sangue , Cirrose Hepática Experimental/induzido quimicamente , Masculino , Metaloendopeptidases/metabolismo , NF-kappa B/metabolismo , Necrose/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , gama-Glutamiltransferase/sangue
9.
Nutr Res ; 40: 65-74, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28473062

RESUMO

Investigations demonstrated that oxidative stress plays an important role in injury promotion in cholestatic liver disease. We hypothesized that coffee attenuates cholestasis-induced hepatic necrosis and fibrosis via its antioxidant, anti-inflammatory, and antifibrotic properties. The major aim of this study was to evaluate the hepatoprotective properties of coffee and caffeine in a model of chronic bile duct ligation (BDL) in male Wistar rats. Liver injury was induced by 28-day BDL, and conventional coffee, decaffeinated coffee, or caffeine was administered daily. After treatment, the hepatic oxidative status was estimated by measuring lipid peroxidation, the reduced to oxidized glutathione ratio, and glutathione peroxidase. Fibrosis was assessed by measuring the liver hydroxyproline content. The transforming growth factor-ß, connective tissue growth factor, α-smooth muscle actin, collagen 1, and interleukin-10 proteins and mRNAs were measured by Western blot and polymerase chain reaction, respectively. Conventional coffee suppressed most of the changes produced by BDL; however, caffeine showed better antifibrotic effects. Coffee demonstrated antioxidant properties by restoring the redox equilibrium, and it also prevented the elevation of liver enzymes as well as hepatic glycogen depletion. Interestingly, coffee and caffeine administration prevented collagen increases. Western blot assays showed decreased expression levels of transforming growth factor-ß, connective tissue growth factor, α-smooth muscle actin, and collagen 1 in the coffee- and caffeine-treated BDL groups. Similarly, coffee decreased the mRNA levels of these proteins. We conclude that coffee prevents liver cirrhosis induced by BDL by attenuating the oxidant processes, blocking hepatic stellate cell activation, and downregulating the main profibrotic molecules involved in extracellular matrix deposition.


Assuntos
Cafeína/farmacologia , Café/química , Cirrose Hepática Biliar/prevenção & controle , Actinas/metabolismo , Animais , Antioxidantes/farmacologia , Ductos Biliares/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Modelos Animais de Doenças , Fibrose , Glutationa Peroxidase/metabolismo , Células Estreladas do Fígado/metabolismo , Hidroxiprolina/metabolismo , Peroxidação de Lipídeos/fisiologia , Fígado/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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