RESUMO
Hepatitis is one of earlier, but serious, signs of liver damage. High doses of statins for a long time can induce hepatitis. This study aimed to evaluate and compare the therapeutic potential of thymoquinone (TQ) and bee pollen (BP) on fluvastatin (F)-induced hepatitis in rats. Rats were randomly divided into: group 1 (G1, control), G2 (F, hepatitis), G3 (F + TQ), G4 (F + BP), and G5 (F + TQ + BP). Single treatment with TQ or BP relieved fluvastatin-induced hepatitis, with best effect for the combined therapy. TQ and/or BP treatment significantly (1) reduced serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, and total bilirubin, (2) decreased malondialdehyde levels and increased level of reduced glutathione, and activities of glutathione peroxidase and catalase in the liver, (3) improved liver histology with mild deposition of type I collagen, (4) increased mRNA levels of transforming growth factor beta 1, nuclear factor Kappa B, and cyclooxygenase 1 and 2, and (5) decreased tumor necrosis factor alpha and upregulated interleukin 10 protein in the liver. These data clearly highlight the ability of TQ and BP combined therapy to cause better ameliorative effects on fluvastatin-induced hepatitis than individual treatment by each alone.
Assuntos
Abelhas , Benzoquinonas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fluvastatina/efeitos adversos , Hepatite Animal/tratamento farmacológico , Pólen , Animais , Antioxidantes/metabolismo , Biomarcadores , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Expressão Gênica , Hepatite Animal/diagnóstico , Hepatite Animal/etiologia , Hepatite Animal/metabolismo , Imuno-Histoquímica , Testes de Função Hepática , Estresse Oxidativo/efeitos dos fármacos , Ratos , Resultado do TratamentoRESUMO
BACKGROUND: Nodakenin, a coumarin glucoside isolated from the roots of Angelica biserrata, has been reported to have anti-inflammatory, antibacterial, anticancer effects. However, despite these studies, the potential liver protective effects of nodakenin in inflammatory liver injury models have not been reported. METHODS: A mouse model of inflammatory liver injury was induced by injection of lipopolysaccharide (LPS) (15 mg/kg, intraperitoneally (i.p)). Liver tissue AST, ALT, ROS, T-GSH and T-SOD were analyzed by ELISA. The concentrations of TNF-α, IL-6, and IL-1ß in serum of LPS-induced inflammatory liver injury mice were analyzed. The mRNA expression levels of GPx1, catalase, SOD1, SOD2, TNF-α, IL-6, IL-1ß, iNOS and COX-2 were analyzed using real-time PCR. The expressions of MAPK, IRF3, NF-κB, Nrf2, HO-1, caspase-3 and caspase-7 were analyzed using western blotting. Liver tissue was stained with IHC to confirm NF-κB, Nrf-2, HO-1, caspase-3, Bax, and Bcl2. Tunnel analysis was performed to confirm the fragmented nuclear DNA characteristics of apoptosis. RESULTS: The administration of nodakenin (10 and 30 mg/kg) reduced serum aminotransferase levels compared to LPS-induced liver damage and significantly improved the oxidative state of liver tissue and pathological damage. Moreover, inhibited the phosphorylation of transforming growth factor beta (TGF-ß)-activated kinase (TAK)-1 in LPS-induced inflammatory liver injury model, and significantly inhibited the transcriptional of nuclear factor-kappa B (NF-kB) and the secretion of pro-inflammatory mediators. In addition nodakenin pre-treatment also attenuated hepatocyte death by regulating apoptosis-related mitochondrial proteins, such as cysteinyl aspartate specific proteinase 3 (caspase 3), poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). CONCLUSION: Our findings suggest that nodakenin has anti-inflammatory, anti-oxidant and anti-apoptotic activity and may be an adjunctive prevention agent for liver injury.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cumarínicos/farmacologia , Glucosídeos/farmacologia , Hepatite Animal/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/sangue , Citocinas/genética , Enzimas/metabolismo , Hepatite Animal/metabolismo , Hepatite Animal/patologia , Masculino , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologiaRESUMO
Hepatitis and hepatocellular carcinoma are serious human diseases. Here, we examined the in vivo and in vitro inhibitory effect of extracts of Qizhu decoction (a traditional Chinese medicine) on hepatitis caused by diethylnitrosamine or hepatitis B virus and on diethylnitrosamine-induced hepatocellular carcinoma. The results showed that both the aqueous and ethanol extracts (QC and QS, respectively) of Qizhu decoction significantly inhibited hepatic inflammation and liver cancer induced by diethylnitrosamine or hepatitis B virus by suppressing NF-κB signaling and decreasing the levels of TNF-α and IL-1ß. Both QC and QS inhibited the proliferation and migration of primary cancer hepatocytes by reducing cyclin B1, cyclin D1 and N-cadherin expression and increasing E-cadherin expression. QC and QS also promoted the apoptosis of primary cancer hepatocytes by upregulating caspase-3 and downregulating BCL-2 expression. The knockdown of p65 in NF-κB signaling inhibited the ability of QC and QS to significantly reduce the colony formation ability of liver cancer cells. Additionally, QC and QS might significantly inhibit the DNA replication of hepatitis B virus in vivo and in vitro, and we found that corilagin and polydatin were the active compounds of QC and QS. Taken together, our in vitro findings and our results in C57BL/6 mice showed that extracts of Qizhu decoction might inhibit hepatitis and hepatocellular carcinoma by suppressing NF-κB signaling.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite Animal/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fator de Transcrição RelA/metabolismo , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/farmacologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Técnicas de Silenciamento de Genes , Células Hep G2 , Hepatite B Crônica/virologia , Hepatite Animal/induzido quimicamente , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , TransfecçãoRESUMO
BACKGROUND AND AIM: Recent investigation revealed that dysbiosis in the gut flora and disruption of permeability of intestinal barrier are possible causes for the development of autoimmune hepatitis. Supplementation of sodium butyrate has been suggested to protect liver injury from disrupted permeability of small intestine. In current study, we employed S100/Freund's complete adjuvant induced autoimmune hepatitis to investigate therapeutic efficacy of sodium butyrate and its mechanism in the liver and upper small intestine. METHODS: C57BL/6 mice were employed and divided into three groups - control group (n=8), autoimmune hepatitis group (n=12) and autoimmune hepatitis with treatment of sodium butyrate group (n=12). Histological staining and western blot analyses were employed to evaluate liver and upper small intestine morphology and gene expression respectively. RESULTS: The findings revealed that S100/Freund's complete adjuvant caused liver injury and disruption of upper small intestine villi. Sodium butyrate attenuated the injuries and prevented migration of Escherichia coli into the liver. Moreover, the effect of sodium butyrate on protection of injuries of the liver and upper small intestine could be due to inhibition of toll-like receptor 4 signaling pathway, as well as its down-regulation of inflammatory cytokines - interleukin-6 and tumor necrosis factor-a. CONCLUSIONS: Sodium butyrate can prevent liver injury by maintaining the integrity of small intestine and inhibiting inflammatory response in S100/Freund's complete adjuvant induced autoimmune hepatitis.
Assuntos
Ácido Butírico/uso terapêutico , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/fisiologia , Hepatite Animal/tratamento farmacológico , Hepatite Autoimune/tratamento farmacológico , Intestino Delgado/imunologia , Fígado/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Adjuvante de Freund/imunologia , Humanos , Interleucina-6/metabolismo , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Fígado/microbiologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas S100/imunologia , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Chlorogenic acid (CGA), one of the most abundant dietary polyphenolic compounds, has been reported to exhibit anti-inflammatory ability. However, the hepatoprotective effects and molecular mechanisms of CGA on concanavalin A (Con A)-induced hepatitis have not been explored. In the present study, we found that pretreatment with CGA dose-dependently inhibited the elevation of plasma aminotransferases and alleviated hepatic pathological damage as well as hepatocyte apoptosis in Con A-exposed mice. Additionally, CGA markedly suppressed the production of serum tumor necrosis factor (TNF)-α and interferon (IFN)-γ, alleviated the infiltration of hepatic macrophages, neutrophils, and activated CD4+ T lymphocytes in Con A-primed mice. Moreover, CGA downregulated Con A-induced hepatic expression of adhesion molecules (ICAM-1, VCAM-1 and ELAM-1) mRNA and protein, and inhibited Con A-activated Toll-like receptor (TLR) 4 signal molecules including TLR4, p-IRAK1, p-IκB, and p-p38. Finally, our results also showed that CGA exhibited a therapeutic effect, which CGA posttreatment improved hepatic damage at 1, 3, and 6h after Con A. Taken together, these data suggested that CGA could effectively prevent mice from Con A-induced hepatitis, which might be through suppressing the activation of TLR4 signaling, downregulating the expression of adhesion molecules, and alleviating the infiltration and activation of hepatic leukocytes and the production of pro-inflammatory cytokines.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Ácido Clorogênico/uso terapêutico , Hepatite Animal/tratamento farmacológico , Células de Kupffer/efeitos dos fármacos , Fígado/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Adesão Celular , Concanavalina A/imunologia , Hepatite Animal/imunologia , Humanos , Interferon gama/metabolismo , Células de Kupffer/imunologia , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The renin-angiotensin system is classically regarded as a crucial regulator of circulatory homeostasis, but recent studies also revealed its pro-inflammatory roles. The beneficial effects of the angiotensin-converting enzyme inhibitor (ACEI) in severe inflammatory injury in the lung and heart have been previously reported, but its potential effects on lethal hepatitis were unknown. In this study, a mouse model with LPS/d-galactosamine (GalN)-induced fulminant hepatitis were used to test the protective potential of captopril, a representative ACEI. The results indicated that treatment with captopril significantly decreased the plasma level of alanine aminotransferase and aspartate aminotransferase, alleviated the histopathological damage of the liver tissue and improve the survival rate of LPS/GalN-challenged mice. These effects were accompanied by reduced mRNA levels of TNF-α and IL-6 in the liver, and decreased protein level of TNF-α and IL-6 in the plasma. In addition, the activation of caspases 3, 8 and 9, and the presence of TUNEL-positive apoptotic cells, were also suppressed by captopril treatment. The above evidence suggested that the renin-angiotensin system might be involved in the development of LPS/GalN-induced fulminant hepatitis and ACEI might have potential value in lethal hepatitis.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Captopril/uso terapêutico , Hepatite Animal/tratamento farmacológico , Fígado/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Galactosamina/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite Animal/induzido quimicamente , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The AMP-activated protein kinase (AMPK)-mediated energy-sensing signals play important roles in reprogramming the expression of inflammatory genes. In the present study, the potential effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) were investigated in a mouse model with LPS/D-Gal-induced acute hepatitis. Our experimental data indicated that treatment with AICAR suppressed the elevation of plasma aminotransferases and alleviated the histopathological abnormalities in mice exposed to LPS/D-Gal. Treatment with AICAR also inhibited the LPS/D-Gal-induced up-regulation of TNF-α, NO and myeloperoxidase. In addition, the LPS/D-Gal-induced expression of pro-apoptotic factor Bax, cleavage of caspase-3, elevation of hepatic caspase-3, caspase-8, caspase-9 activities and induction of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive cells were all suppressed by AICAR. These results suggested that the AMPK activator AICAR could attenuate LPS/D-Gal-induced acute hepatitis, which implies that AMPK might become a novel target for the treatment of inflammation-based liver disorders.
Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Hepatite Animal/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Ribonucleotídeos/administração & dosagem , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Aminoimidazol Carboxamida/administração & dosagem , Aminoimidazol Carboxamida/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Modelos Animais de Doenças , Galactose/imunologia , Hepatite Animal/induzido quimicamente , Hepatite Animal/imunologia , Humanos , Lipopolissacarídeos/imunologia , Fígado/patologia , Masculino , Camundongos , Terapia de Alvo Molecular , Óxido Nítrico/metabolismo , Ribonucleotídeos/farmacologia , Transaminases/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND/PURPOSE OF THE STUDY: Vitamin D3-deficiency is common in patients with chronic liver-disease and may promote disease progression. Vitamin D3-administration has thus been proposed as a therapeutic approach. Vitamin D3 has immunomodulatory effects and may modulate autoimmune liver-disease such as primary sclerosing cholangitis. Although various mechanisms of action have been proposed, experimental evidence is limited. Here we test the hypothesis that active 1,25-(OH)2-vitamin D3 inhibits activation of hepatic stellate cells (HSC) in vitro and modulates liver-injury in vivo. METHODS: Proliferation and activation of primary murine HSC were assessed by BrdU- and PicoGreen(®)-assays, immunoblotting, immunofluorescence-microscopy, quantitative-PCR, and zymography following calcitriol-treatment. Wild-type and ATP-binding cassette transporter b4(-/-) (Abcb4(-/-))-mice received calcitriol for 4 weeks. Liver-damage, inflammation, and fibrosis were assessed by serum liver-tests, Sirius-red staining, quantitative-PCR, immunoblotting, immunohistochemistry and hydroxyproline quantification. RESULTS: In vitro, calcitriol inhibited activation and proliferation of murine HSC as shown by reduced α-smooth muscle actin and platelet-derived growth factor-receptor-ß-protein-levels, BrdU and PicoGreen®-assays. Furthermore, mRNA-levels and activity of matrix metalloproteinase 13 were profoundly increased. In vivo, calcitriol ameliorated inflammatory liver-injury reflected by reduced levels of alanine aminotransferase in Abcb4(-/-)-mice. In accordance, their livers had lower mRNA-levels of F4/80, tumor necrosis factor-receptor 1 and a lower count of portal CD11b positive cells. In contrast, no effect on overall fibrosis was observed. CONCLUSION: Calcitriol inhibits activation and proliferation of HSCs in vitro. In Abcb4(-/-)-mice, administration of calcitriol ameliorates inflammatory liver-damage but has no effect on biliary fibrosis after 4 weeks of treatment.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Calcitriol/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Hepatite Animal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/patologia , Hepatite Animal/imunologia , Hepatite Animal/patologia , Fatores Imunológicos/farmacologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
A 9-year-old female Yorkshire terrier was presented for vomiting and diarrhea. Blood chemistry tests revealed hepatic dysfunction, cholestasis, and inflammation. Liver ultrasonography and liver biopsy were consistent with cholangiohepatitis. Fine-needle aspiration of the gallbladder revealed the presence of bacteria later identified as Clostridium spp. The cholangiohepatitis was successfully treated.
Assuntos
Colangite/veterinária , Colestase Intra-Hepática/veterinária , Infecções por Clostridium/veterinária , Doenças do Cão/diagnóstico , Hepatite Animal/diagnóstico , Animais , Antibacterianos/uso terapêutico , Colangite/diagnóstico , Colangite/tratamento farmacológico , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/tratamento farmacológico , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Hepatite Animal/tratamento farmacológico , Resultado do TratamentoRESUMO
The goal of this study was to evaluate the effect of Ingavirin on the morphological features of the foci of adenovirus hepatitis in Syrian hamsters by electron microscopy. The use of the drug was shown to cause a substantial reduction in the rate of destructive processes and inflammatory reactions in the liver, by normalizing its structure at the levels of both tissue and individual hepatocytes. After administration of Ingavirin, the morphogenesis of adenovirus infection in the infected hepatocytes did not differ from that in the controls; however, the infected cells were fewer. The proportion of morphologically inadequate virions in the presence of Ingavirin increased from 35 to 46%. The findings suggest that Ingavirin is an effective drug that has antiviral, anti-inflammatory, and cytoprotective activities in the focus of adenovirus tissue involvement.
Assuntos
Infecções por Adenoviridae , Amidas/administração & dosagem , Ácidos Dicarboxílicos/administração & dosagem , Hepatite Animal , Hepatócitos , Imidazóis/administração & dosagem , Fígado , Infecções por Adenoviridae/tratamento farmacológico , Adenovírus Humanos/efeitos dos fármacos , Adenovírus Humanos/genética , Animais , Caproatos , Cricetinae , Hepatite Animal/tratamento farmacológico , Hepatite Animal/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/ultraestrutura , Humanos , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Mesocricetus , Microscopia EletrônicaRESUMO
The anti-inflammatory properties of the flavonol quercetin have been intensively investigated using in vitro cell systems and are to a great extent reflected by changes in the expression of inflammatory markers. However, information relating to the degree at which quercetin affects inflammatory gene expression in vivo is limited. Recently, micro RNAs (miRNAs) have been identified as powerful post-transcriptional gene regulators. The effect of quercetin on miRNA regulation in vivo is largely unknown. Laboratory mice were fed for six weeks with control or quercetin enriched high fat diets and biomarkers of inflammation as well as hepatic levels of miRNAs previously involved in inflammation (miR-125b) and lipid metabolism (miR-122) were determined. We found lower mRNA steady state levels of the inflammatory genes interleukin 6, C-reactive protein, monocyte chemoattractant protein 1, and acyloxyacyl hydrolase in quercetin fed mice. In addition we found evidence for an involvement of redox factor 1, a modulator of nuclear factor κB signalling, on the attenuation of inflammatory gene expression mediated by dietary quercetin. Furthermore, the results demonstrate that hepatic miR-122 and miR-125b concentrations were increased by dietary quercetin supplementation and may therefore contribute to the gene-regulatory activity of quercetin in vivo.
Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Quercetina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Proteína C-Reativa/genética , Hidrolases de Éster Carboxílico/genética , Quimiocina CCL2/genética , Suplementos Nutricionais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite Animal/tratamento farmacológico , Hepatite Animal/genética , Hepatite Animal/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
In this paper, we reported the synthesis of bifendate derivatives and evaluation of anti-inflammatory activity by detecting the production of the Nitric Oxide (NO) in the lipopolysaccharide(LPS)-stimulated RAW 264.7 cell lines. Among the newly derivatives, compound 7k was the most potent one and two other compounds (7e and 7f) also exhibited greater anti-inflammatory activity than bifendate. Further in vivo studies confirmed that 7k significantly and dose-dependently inhibited carrageenan-induced paw edema and decreased the serum levels of alanine aminotransaminase, and aspartate aminotransaminase in concanavalin A-induced hepatitis model. Histopathological evaluation demonstrated that 7k has better hepatoprotective effect on acute liver injury induced by concanavalin A than bifendate, suggesting that 7k is a potential drug candidate for the treatment of hepatic injuries.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Hepatite Animal/tratamento farmacológico , Fígado/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Linhagem Celular , Concanavalina A , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Feminino , Hepatite Animal/induzido quimicamente , Hepatite Animal/patologia , Lipopolissacarídeos/imunologia , Fígado/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/imunologia , RatosRESUMO
Immobilized hyaluronidase (nanotechnology method of electron-beam synthesis) exhibited high hepatoprotective activity on the model of Cl4-induced hepatitis. This agent produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects were shown to accompany stimulation of multipotent bone marrow precursors, mobilization of these cells into the peripheral blood, and cell migration to the target organ increasing the number of parenchymal progenitor cells in the liver. The mechanisms for targeted migration of progenitor cells suggest a decrease in SDF-1 production by bone marrow stromal cells and increase in the synthesis of this factor by microenvironmental cells of the liver tissue.
Assuntos
Citoproteção , Enzimas Imobilizadas/uso terapêutico , Hepatite Animal/tratamento farmacológico , Hialuronoglucosaminidase/uso terapêutico , Fígado/efeitos dos fármacos , Células-Tronco Multipotentes/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Tetracloreto de Carbono , Movimento Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Enzimas Imobilizadas/administração & dosagem , Enzimas Imobilizadas/química , Hepatite Animal/metabolismo , Hepatite Animal/patologia , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/química , Fígado/metabolismo , Fígado/patologia , Camundongos , Células-Tronco Multipotentes/citologia , Nanotecnologia , Ratos , Células Estromais/citologia , Células Estromais/efeitos dos fármacosRESUMO
18Beta-glycyrrhetinic acid (GA), the major bioactive component of licorice root extract, has a protective effect on hepatic injury and exhibits antiinflammatory activity. Here, we investigate the effect of GA in Propionibacterium acnes-induced acute inflammatory liver injury. C57BL/6 mice were primed with P. acnes followed by lipopolysaccharide challenge to induce fulminant hepatitis. GA (75 mg/kg) or vehicle control was administered intraperitoneally daily 1 day after P. acnes priming, and GA significantly improved mouse mortality. Then, to investigate the underlying mechanisms of GA in this acute inflammatory liver injury model, we primed C57BL/6 mice with P. acnes only. We propose that GA ameliorates acute P. acnes-induced liver injury through reduced macrophage inflammatory protein (MIP)-1alpha expression in Kupffer cells by down-regulating MyD88 expression and inhibiting NF-kappaB activation. Reduced MIP-1alpha expression lowered the recruitment of CD11c(+)B220(-) dendritic cell precursors into the liver. Consequently, GA treatment inhibits the activation and proliferation of liver-infiltrating CD4(+) T cells and reduces the production of serum alanine aminotransferase and proinflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha. Moreover, anti-MIP-1alpha treatment in P. acnes-primed mice inhibits the recruitment of dendritic cell precursors into the liver and suppresses mouse mortality as GA does. Taken together, our results suggest that GA exhibits antiinflammatory effects through inhibition of MIP-1alpha in a mouse model of acute P. acnes-induced inflammatory liver injury.
Assuntos
Anti-Inflamatórios/farmacologia , Quimiocina CCL3/imunologia , Ácido Glicirretínico/análogos & derivados , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Hepatite Animal/tratamento farmacológico , Células de Kupffer/imunologia , Falência Hepática Aguda/tratamento farmacológico , Propionibacterium acnes/imunologia , Animais , Anti-Inflamatórios/química , Antígeno CD11c/imunologia , Linfócitos T CD4-Positivos/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Células Dendríticas/imunologia , Medicamentos de Ervas Chinesas/química , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Glycyrrhiza/química , Infecções por Bactérias Gram-Positivas/imunologia , Hepatite Animal/imunologia , Interferon gama/imunologia , Antígenos Comuns de Leucócito/imunologia , Lipopolissacarídeos/farmacologia , Fígado/imunologia , Falência Hepática Aguda/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Fator 88 de Diferenciação Mieloide/imunologia , Raízes de Plantas/química , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Tumor necrosis factor-alpha (TNF-alpha) is critically involved in a wide variety of inflammatory pathologies, such as hepatitis, via the TNF receptor-1 (TNFR1). To develop TNFR1-targeted anti-inflammatory drugs, we have already succeeded in creating a TNFR1-selective antagonistic mutant TNF-alpha (R1antTNF) and shown that R1antTNF efficiently inhibits TNF-alpha/TNFR1-mediated biological activity in vitro. In this study, we examined the therapeutic effect of R1antTNF in acute hepatitis using two independent experimental models, induced by carbon tetrachloride (CCl(4)) or concanavalin A (ConA). In a CCl(4)-induced model, treatment with R1antTNF significantly inhibited elevation in the serum level of ALT (alanine aminotransferase), a marker for liver damage. In a ConA-induced T-cell-mediated hepatitis model, R1antTNF also inhibited the production of serum immune activated markers such as IL-2 and IL-6. These R1antTNF-mediated therapeutic effects were as good as or better than those obtained using conventional anti-TNF-alpha antibody therapy. Our results suggest that R1antTNF may be a clinically useful TNF-alpha antagonist in hepatitis.
Assuntos
Hepatite Animal/tratamento farmacológico , Receptores Tipo I de Fatores de Necrose Tumoral , Fator de Necrose Tumoral alfa/uso terapêutico , Alanina Transaminase/sangue , Animais , Tetracloreto de Carbono/farmacologia , Linhagem Celular , Concanavalina A/farmacologia , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Hepatite Animal/sangue , Hepatite Animal/induzido quimicamente , Hepatite Animal/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, the main pharmacologically active component of Salvia miltiorrhiza. The aim of this study was to investigate the effect of STS on concanavalin A (ConA)-induced hepatitis (CIH) in mice, an experimental model of immune-mediated liver injury. RESULTS: C57BL/6 mice pretreated with STS released much less alanine transaminase into plasma in response to ConA challenge and had reduced inflammatory infiltration and hepatocyte apoptosis in the liver compared with control mice pretreated with vehicle solutions. Thus, STS protected mice from CIH. In STS-pretreated mice induced with CIH, we found abrogated tumor necrosis factor-alpha and interferon (IFN)-gamma production. Moreover, mRNA expressions of IFN-inducible protein-10 and macrophage inflammatory protein-1alpha in these mice were decreased. The mechanism of anti-inflammatory effects of STS may be attributed to its modulation of crucial inflammatory signaling pathways, including NF-kappaB and IFN-gamma/STAT1. CONCLUSION: In conclusion, STS was capable of protecting mice from immune-mediated liver injury in vivo, and the protection was associated with its suppressive effect on the production of important inflammatory mediators through modulating NF-kappaB and IFN-gamma/STAT1 signaling pathways.
Assuntos
Hepatite Animal/tratamento farmacológico , Imunossupressores/administração & dosagem , Interferon gama/imunologia , NF-kappa B/antagonistas & inibidores , Fenantrenos/administração & dosagem , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Concanavalina A/toxicidade , Hepatite Animal/induzido quimicamente , Hepatite Animal/imunologia , Hepatite Animal/metabolismo , Imunossupressores/química , Imunossupressores/imunologia , Injeções Intraperitoneais , Interferon gama/sangue , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Fenantrenos/química , Fenantrenos/imunologia , Fitoterapia , Fator de Transcrição STAT1/imunologia , Salvia miltiorrhiza/imunologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: It has been proved that cyclo-oxygenase-2 (COX-2) is rapidly induced by inflammatory mediators. However, it is not known whether overexpression of COX-2 in the liver is sufficient to promote activation or secretion of inflammatory factors leading to hepatitis. AIM: To investigate the role forced expression of COX-2 in liver by using inducible COX-2 transgenic (TG) mice. METHODS: TG mice that overexpress the human COX-2 gene in the liver using the liver-specific transthyretin promoter and non-TG littermates were derived and fed the normal diet for up to 12 months. Hepatic prostaglandin E(2) (PGE(2)) content was determined using enzyme immunoassay, nuclear factor kappaB (NF-kappaB) activation by electrophoretic mobility shift assays, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labelling and proliferation by Ki-67 immunohistochemistry. RESULTS: COX-2 TG mice exhibited strongly increased COX-2 and PGE(2), elevated serum alanine aminotransferase level and histological hepatitis. Hepatic COX-2 expression in the TG mice resulted in activation of NF-kappaB and inflammatory cytokine cascade, with a marked expression of the proinflammatory cytokines tumour necrosis factor (TNF)-alpha (9.4-fold), interleukin (IL)-6 (4.4-fold), IL-1beta (3.6-fold), and of the anti-inflammatory cytokine IL-10 (4.4-fold) and chemokine macrophage inflammatory protein-2 (3.2-fold). The inflammatory response of the COX-2 TG mice was associated with infiltration macrophages and lymphocytes, increased cell proliferation and high rates of cell apoptosis. Administration of the COX-2 inhibitor celecoxib in TG mice restored liver histology to normal. CONCLUSION: Enhanced COX-2 expression in hepatocytes is sufficient to induce hepatitis by activating NF-kappaB, stimulating the secretion of proinflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represents a mechanism-based chemopreventive approach to hepatitis.
Assuntos
Ciclo-Oxigenase 2/fisiologia , Hepatite Animal/enzimologia , Animais , Apoptose , Celecoxib , Proliferação de Células , Quimiocinas/metabolismo , Quimiotaxia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Citocinas/metabolismo , Dinoprostona/metabolismo , Feminino , Expressão Gênica , Substâncias de Crescimento/metabolismo , Hepatite Animal/tratamento farmacológico , Hepatite Animal/patologia , Hepatócitos/enzimologia , Técnicas Imunoenzimáticas , Fígado/enzimologia , Fígado/patologia , Linfócitos/fisiologia , Macrófagos/fisiologia , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
The present study is aimed at investigating the effect of curcumin (CMN) in salvaging endotoxin-induced hepatic dysfunction and oxidative stress in the liver of rodents. Hepatotoxicity was induced by administering lipopolysaccharide (LPS) in a single dose of 1 mg/kg intraperitoneally to the animals, which were being treated with CMN daily for 7 days. Liver enzymes serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST) and alkaline phosphatase (ALP), total bilirubin and total protein were estimated in serum. Oxidative stress in liver tissue homogenates was estimated by measuring thiobarbituric acid reactive substances (TBARS), glutathione (GSH) content and superoxide dismutase (SOD) activity. Serum and tissue nitrite was estimated using Greiss reagent and served as an indicator of NO production. A separate set of experiments was performed to estimate the effect of CMN on cytokine levels in mouse serum after LPS challenge. LPS induced a marked hepatic dysfunction evident by rise in serum levels of ALT, AST, ALP and total bilirubin (P < 0.05). TBARS levels were significantly increased, whereas GSH and SOD levels decreased in the liver homogenates of LPS-challenged rats. CMN administration attenuated these effects of LPS successfully. Further CMN treatment also regressed various structural changes induced by LPS in the livers of rats and decreased the levels of tumour necrosis factor-alpha and interleukin-6 in mouse plasma. In conclusion, these findings suggest that CMN attenuates LPS-induced hepatotoxicity possibly by preventing cytotoxic effects of NO, oxygen free radicals and cytokines.
Assuntos
Curcumina/farmacologia , Citocinas/imunologia , Hepatite Animal/tratamento farmacológico , Imunossupressores/farmacologia , Animais , Citocinas/análise , Glutationa/análise , Hepatite Animal/imunologia , Hepatite Animal/metabolismo , Interleucina-1/análise , Interleucina-6/análise , Peroxidação de Lipídeos , Lipopolissacarídeos , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Nitritos/análise , Nitritos/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/análise , Fator de Necrose Tumoral alfa/análiseRESUMO
Imatinib exerts potent antileukemic effects in vitro and in vivo. Despite its well known antitumor activity, the potential of imatinib for the treatment of inflammatory diseases remains elusive so far. Our current report provides strong evidence that imatinib has potent antiinflammatory effects. It potently inhibits LPS- and Con A-induced TNF-alpha production by human myeloid cells in vitro (peripheral blood mononuclear cells, CD14-selected monocytes, and monocyte-derived macrophages). Of note, the production of the antiinflammatory cytokine IL-10 was not significantly regulated by imatinib. In line with this observation, phosphorylation of IkappaB and subsequent DNA binding of NF-kappaB, which is critically involved in TNF-alpha, but not IL-10 expression, was reduced by imatinib. Using several murine models of acute hepatitis, we could corroborate our in vitro findings, as imatinib prevented macrophage- and TNF-alpha-dependent inflammatory damage of the liver induced by injection of either Con A or d-galactosamine/LPS by inhibition of hepatic TNF-alpha production. Of note, d-galactosamine/TNF-induced hepatitis was not affected, showing that imatinib does not directly inhibit TNF-alpha-induced hepatocellular cell death. These findings suggest a potent antiinflammatory role of imatinib by modulation of TNF-alpha production in monocytes/macrophages. This observation might be of therapeutic value for the treatment of TNF-mediated diseases.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatite Animal/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Benzamidas , Morte Celular/efeitos dos fármacos , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Concanavalina A/toxicidade , Feminino , Hepatite Animal/induzido quimicamente , Hepatite Animal/tratamento farmacológico , Humanos , Proteínas I-kappa B/metabolismo , Mesilato de Imatinib , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-10/biossíntese , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
A 12-year-old, neutered male domestic shorthair cat was evaluated with a life-long history of intermittent, predominantly small bowel diarrhea and a 3 day history of hematochezia. At presentation, the cat had increased liver enzyme activities and an inflammatory leukogram. Histopathology demonstrated inflammatory bowel disease (IBD), cholangiohepatitis and pancreatitis. The cholangiohepatitis was associated with a multi-drug resistant Enterococcus faecium. Gallbladder agenesis was also documented. Treatment with vancomycin was safely instituted for 10 days. Clinical signs resolved, however, cure of the bacterial cholangiohepatitis was not achieved. The risk of vancomycin resistant enterococci (VRE) in human and veterinary medicine is discussed.