RESUMEN
Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.
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Antiinflamatorios/uso terapéutico , Hepatitis Animal/tratamiento farmacológico , Fosfotransferasas (Aceptor de Grupo Alcohol)/inmunología , Animales , Antiinflamatorios/farmacología , Hepatitis Animal/sangre , Hepatitis Animal/inmunología , Hepatitis Animal/patología , Interferón gamma/sangre , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Transducción de Señal , Esfingosina/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunologíaRESUMEN
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.
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Abejas , Benzoquinonas/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Fluvastatina/efectos adversos , Hepatitis Animal/tratamiento farmacológico , Polen , Animales , Antioxidantes/metabolismo , Biomarcadores , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Expresión Génica , Hepatitis Animal/diagnóstico , Hepatitis Animal/etiología , Hepatitis Animal/metabolismo , Inmunohistoquímica , Pruebas de Función Hepática , Estrés Oxidativo/efectos de los fármacos , Ratas , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Cumarinas/farmacología , Glucósidos/farmacología , Hepatitis Animal/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/sangre , Citocinas/genética , Enzimas/metabolismo , Hepatitis Animal/metabolismo , Hepatitis Animal/patología , Masculino , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacologíaRESUMEN
OBJECTIVE: The present work aimed to investigate the effects of AdipoRon against acute hepatitis and liver fibrosis induced by carbon tetrachloride (CCl4) in mice. METHODS: C57BL/6 mice were randomly divided into five groups: control, model, AdipoRon groups (three different dosages), CCl4 was administered to induce acute hepatitis or liver fibrosis except for control group. The liver function, inflammatory and fibrotic profiles were evaluated by histology, immunohistochemistry and expression analysis, respectively. RESULTS: AdipoRon pretreatment effectively attenuated oxidative stress and hepatocellular damage in acute CCl4 intoxication, demonstrated by marked reduction in peroxidation indexes [hepatic malonaldehyde (MDA), total nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS)] and serum transaminases [alanine aminotransferase (ALT), aspartate transaminase (AST)]. Moreover, AdipoRon attenuated the severity of fibrosis induced by sustaining CCl4 challenge, with the alleviation of fibrous deposit and architecture distortion. The levels of canonical fibrosis markers (aminotransferases, hydroxyproline, hyaluronic acid, laminin) were also dose-dependently modulated by AdipoRon. Immunochemistry and expression analysis showed AdipoRon restrained the proinflammatory and profibrotic cytokines (TNF-α, TGF-ß1, α-SMA, COL1A1), which somehow, ascribed the anti-fibrotic action to inhibiting hepatic stellate cells (HSCs) activation and quenching specific inflammation-fibrogenesis pathways. CONCLUSIONS: AdipoRon demonstrates a remedial capacity against hepatitis and fibrosis induced by CCl4, potentially by inflammation restraint and HSC deactivation, which might pave the way for its therapeutical application in hepatic fibrosis.
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Antiinflamatorios/uso terapéutico , Fibrosis/tratamiento farmacológico , Células Estrelladas Hepáticas/metabolismo , Hepatitis Animal/tratamiento farmacológico , Hígado/patología , Piperidinas/uso terapéutico , Animales , Células Cultivadas , Citocinas/metabolismo , Femenino , Fluorocarburos , Células Estrelladas Hepáticas/patología , Humanos , Mediadores de Inflamación/metabolismo , Hígado/efectos de los fármacos , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health concern worldwide. Ilex hainanensis Merr. extract was proved to have anti-inflammation effect on NAFLD, and Ilexhainanoside D (IhD) and ilexsaponin A1 (IsA) were the main triterpenoid saponins extracted from it. PURPOSES: To investigate the hepatoprotective effect of the combination of IhD and IsA (IIC) against NAFLD and discuss the potential mechanisms. METHODS: Male C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD and were treated with IIC (60, 120 or 240â¯mg/kg) for 8 weeks. Growth parameters, abdominal fat content, serum biochemical markers, hepatic lipid accumulation and insulin tolerance were assessed. Quantitative real-time PCR was used to determine the hepatic gene expression of TLR2, TLR4, TNF-α, IL-6, and IL-1ß. Western blot analysis was performed to determine the expression of the epidermal tight junction proteins ZO-1 and occludin. Gut microbiota profiles were established via high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene. RESULTS: IIC significantly reduced the severity of NAFLD induced by HFD in a dose-dependent manner. IIC decreased the ratio of Firmicutes/Bacteroidetes, reduced the relative abundance of Desulfovibrio and increased the relative abundance of Akkermansia. The intestinal barrier was improved as evidenced by the upregulation of the expression of ZO-1 and occludin in the ileum. IIC thus reduced the entry of LPS into the circulation and decreased the hepatic gene expression levels of proinflammatory cytokines. CONCLUSION: This approach demonstrated the positive effects of IIC in a mouse model of NAFLD, indicating that it possibly acts by reducing inflammation and improving the intestinal barrier function.
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Microbioma Gastrointestinal/efectos de los fármacos , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Saponinas/farmacología , Triterpenos/farmacología , Animales , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Microbioma Gastrointestinal/genética , Hepatitis Animal/tratamiento farmacológico , Compuestos Heterocíclicos de Anillo en Puente/administración & dosificación , Intestinos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Sustancias Protectoras/farmacología , ARN Ribosómico 16S , Saponinas/administración & dosificación , Triterpenos/administración & dosificación , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
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.
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Carcinoma Hepatocelular/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis Animal/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Factor de Transcripción ReIA/metabolismo , Animales , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/patología , Dietilnitrosamina/farmacología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Técnicas de Silenciamiento del Gen , Células Hep G2 , Hepatitis B Crónica/virología , Hepatitis Animal/inducido químicamente , Humanos , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Masculino , Medicina Tradicional China/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor de Transcripción ReIA/antagonistas & inhibidores , Factor de Transcripción ReIA/genética , TransfecciónRESUMEN
Supplementation with omega-3 fatty acids or thyroid hormone (T3) exhibit negative effects on inflammatory reactions in experimental animals. The aim of this work was to assess the hypothesis that docosahexaenoic acid (DHA) plus T3 co-administration enhances liver resolvin (Rv) levels as inflammation resolution mediators. Combined DHA (daily doses of 300 mg/kg for 3 consecutive days)-T3 (0.05 mg/kg at the fourth day) administration significantly increased the content of hepatic RvD1 and RvD2, without changes in that of RvE1 and RvE2, an effect that exhibits synergy when compared to the separate DHA and T3 treatments. Under these conditions, liver DHA levels increased by DHA administration were diminished when combined with T3 (p < 0.05), suggesting enhancement in resolvin D biosynthesis in extrahepatic tissues. It is concluded that co-administration of DHA and T3 rises the capacity of the liver for inflammation resolution by augmenting RvD1(2) availability, which represents an important protocol in hepatoprotection in the clinical setting.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Sustancias Protectoras/farmacología , Triyodotironina/farmacología , Animales , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Hepatitis Animal/tratamiento farmacológico , Masculino , Sustancias Protectoras/administración & dosificación , Ratas , Ratas Sprague-Dawley , Triyodotironina/administración & dosificación , Triyodotironina/efectos adversosRESUMEN
Simple metabolites released during physical exercise and fasting like lactate (Lac) and ß-hydroxybutyrate (BHB) have recently been shown to possess anti-inflammatory properties. However, the effects of these metabolites in immune mediated hepatitis are still unknown. Accordingly, we investigated the role of Lac, BHB and their combination on experimentally induced hepatic inflammation. Adult male mice were administered concanavalin A (Con A, 15â¯mg/kg, intravenous) for 12â¯h. In the treatment groups, mice were treated 1â¯h after Con A-intoxication with Lac (500â¯mg/kg, intraperitoneal), BHB (300â¯mg/kg, intraperitoneal) and their combination. The results demonstrated that Lac and BHB, especially when combined together, alleviated Con A-induced hepatocellular injury (ALT, AST and LDH) and necrosis (hematoxylin-eosin and electron microscopy). These beneficial effects correlated with attenuating Con A-induced elevation in hepatic oxidative stress parameters (MDA and NOx). Mechanistically, administration of Lac and BHB led to inhibition of Con A-induced phosphorylation of JNK and AMPK proteins in the liver to the same extent. These effects were concordant with curbing Con A-mediated overexpression of the pro-inflammatory cytokines TNF-α, IL-6 and IL-12 and activation of the transcription factor NF-κB. The marked anti-inflammatory properties of combining Lac and BHB were attributed to their cooperation in repressing immune cells (monocytes and neutrophils) infiltration to the liver. Unlike BHB, Lac administration markedly induced the reparative STAT3 and ERK phosphorylation in the livers of Con A-intoxicated mice at the early time point. In conclusion, the simultaneous use of Lac and BHB might be an auspicious strategy for limiting immune mediated hepatitis.
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Ácido 3-Hidroxibutírico/uso terapéutico , Antiinflamatorios/uso terapéutico , Hepatitis Animal/tratamiento farmacológico , Ácido Láctico/uso terapéutico , Hígado/efectos de los fármacos , Animales , Concanavalina A , Citocinas/metabolismo , Quimioterapia Combinada , Hepatitis Animal/inducido químicamente , Mediadores de Inflamación/metabolismo , Hígado/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Necrosis , Estrés Oxidativo/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, exhibits beneficial effects on metabolic syndrome. Sustained inflammation plays a crucial role in the pathogenesis of metabolic syndrome. Here we explored the effects of PSPC on high-fat diet (HFD)-induced hepatic inflammation and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + PSPC group, and PSPC group. PSPC was administered by daily oral gavage at doses of 700 mg/kg/day for 20 weeks. Nicotinamide riboside (NR) was used to increase NAD⺠levels. Our results showed that PSPC effectively ameliorated obesity and liver injuries in HFD-fed mice. Moreover, PSPC notably blocked hepatic oxidative stress in HFD-treated mice. Furthermore, PSPC dramatically restored NAD⺠level to abate endoplasmic reticulum stress (ER stress) in HFD-treated mouse livers, which was confirmed by NR treatment. Consequently, PSPC remarkably suppressed the nuclear factor-κB (NF-κB) p65 nuclear translocation and nucleotide oligomerization domain protein1/2 (NOD1/2) signaling in HFD-treated mouse livers. Thereby, PSPC markedly diminished the NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation, ultimately lowering the expressions of inflammation-related genes in HFD-treated mouse livers. In summary, PSPC protected against HFD-induced hepatic inflammation by boosting NAD⺠level to inhibit NLRP3 inflammasome activation.
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Antiinflamatorios/farmacología , Hepatitis Animal/tratamiento farmacológico , Hepatitis Animal/metabolismo , Inflamasomas/metabolismo , Ipomoea batatas/química , NAD/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Pigmentos Biológicos/farmacología , Extractos Vegetales/farmacología , Animales , Antocianinas/química , Antocianinas/farmacología , Antiinflamatorios/química , Dieta Alta en Grasa , Estrés del Retículo Endoplásmico , Regulación de la Expresión Génica/efectos de los fármacos , Hepatitis Animal/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones , FN-kappa B/metabolismo , Proteínas Adaptadoras de Señalización NOD/genética , Proteínas Adaptadoras de Señalización NOD/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , Estrés Oxidativo/efectos de los fármacos , Pigmentos Biológicos/química , Extractos Vegetales/química , Transporte de ProteínasRESUMEN
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.
Asunto(s)
Ácido Butírico/uso terapéutico , Infecciones por Escherichia coli/tratamiento farmacológico , Escherichia coli/fisiología , Hepatitis Animal/tratamiento farmacológico , Hepatitis Autoinmune/tratamiento farmacológico , Intestino Delgado/inmunología , Hígado/inmunología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Adyuvante de Freund/inmunología , Humanos , Interleucina-6/metabolismo , Intestino Delgado/microbiología , Intestino Delgado/patología , Hígado/microbiología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas S100/inmunología , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.
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Linfocitos T CD4-Positivos/efectos de los fármacos , Ácido Clorogénico/uso terapéutico , Hepatitis Animal/tratamiento farmacológico , Macrófagos del Hígado/efectos de los fármacos , Hígado/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Apoptosis/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Adhesión Celular , Concanavalina A/inmunología , Hepatitis Animal/inmunología , Humanos , Interferón gamma/metabolismo , Macrófagos del Hígado/inmunología , Hígado/inmunología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
CONTEXT: Duck virus hepatitis (DVH) caused by duck hepatitis A virus type 1 (DHAV-1) is an acute and lethal disease of young ducklings. However, there is still no effective drug to treat DVH. OBJECTIVE: This study assessed the curative effect on DVH of a flavonoid prescription baicalin-linarin-icariin-notoginsenoside R1 (BLIN) as well as the hepatoprotective and antioxidative effects of BLIN. MATERIALS AND METHODS: MTT method was used to test the anti-DHAV-1 ability of BLIN in vitro. We then treated ducklings by BLIN (3 mg per duckling, once a day for 5 days) to evaluate the in vivo efficacy. To study the hepatoprotective and antioxidative roles of BLIN in its curative effect on DVH, we investigated the hepatic injury evaluation biomarkers and the oxidative stress evaluation indices of the ducklings. RESULTS: On duck embryonic hepatocytes, DHAV-1 inhibitory rate of BLIN at 20 µg/mL was 69.3%. The survival rate of ducklings treated by BLIN was about 35.5%, which was significantly higher than that of virus control (0.0%). After the treatment of BLIN, both the hepatic injury and the oxidative stress of infected ducklings alleviated. At the same time, a significant positive correlation (p < 0.05) existed between the hepatic injury indices and the oxidative stress indices. CONCLUSIONS: BLIN showed a significant curative effect on DVH. The antioxidative and hepatoprotective effects of BLIN made great contributions to the treatment of DVH. Furthermore, BLIN is expected to be exploited as a new drug for the clinical treatment of DVH.
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Antioxidantes/farmacología , Antivirales/farmacología , Patos , Flavonoides/farmacología , Virus de la Hepatitis del Pato/efectos de los fármacos , Hepatitis Animal/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Enfermedades de las Aves de Corral/tratamiento farmacológico , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Células Cultivadas , Combinación de Medicamentos , Ginsenósidos/farmacología , Glicósidos/farmacología , Virus de la Hepatitis del Pato/patogenicidad , Hepatitis Animal/metabolismo , Hepatitis Animal/patología , Hepatitis Animal/virología , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatocitos/virología , Hígado/metabolismo , Hígado/patología , Hígado/virología , Enfermedades de las Aves de Corral/metabolismo , Enfermedades de las Aves de Corral/patología , Enfermedades de las Aves de Corral/virología , Factores de TiempoRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Captopril/uso terapéutico , Hepatitis Animal/tratamiento farmacológico , Hígado/efectos de los fármacos , Peptidil-Dipeptidasa A/metabolismo , Alanina Transaminasa/sangre , Animales , Apoptosis/efectos de los fármacos , Aspartato Aminotransferasas/sangre , Galactosamina/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Hepatitis Animal/inducido químicamente , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolisacáridos/inmunología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Augmenter of liver regeneration (ALR), produced and released by hepatocytes, has cytoprotective and immunoregulatory effects on liver injury, and has been used in many experimental applications. However, little attention has been paid to the effects of ALR on concanavalin A (Con A)-induced hepatitis. The purpose of this paper is to explore the protective effect of ALR on Con A-induced hepatitis and elucidate potential mechanisms. We found that the ALR pretreatment evidently reduced the amount of ALT and AST in serum. In addition, pro-inflammatory cytokines, chemokines and iNOS were suppressed. ALR pretreatment also decreased CD4(+), CD8(+) T cell infiltration in liver. Besides, we observed that ALR pretreatment was capable of suppressing the activation of several signaling pathways in Con A-induced hepatitis. These findings suggest that ALR can obviously weaken Con A-induced hepatitis and ALR has some certain immune regulation function.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Hepatitis Animal/tratamiento farmacológico , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/uso terapéutico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Concanavalina A/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Mediadores de Inflamación/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
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.
Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Hepatitis Animal/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hígado/efectos de los fármacos , Ribonucleótidos/administración & dosificación , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Aminoimidazol Carboxamida/administración & dosificación , Aminoimidazol Carboxamida/farmacología , Animales , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Modelos Animales de Enfermedad , Galactosa/inmunología , Hepatitis Animal/inducido químicamente , Hepatitis Animal/inmunología , Humanos , Lipopolisacáridos/inmunología , Hígado/patología , Masculino , Ratones , Terapia Molecular Dirigida , Óxido Nítrico/metabolismo , Ribonucleótidos/farmacología , Transaminasas/sangre , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Calcitriol/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Hepatitis Animal/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/inmunología , Células Estrelladas Hepáticas/patología , Hepatitis Animal/inmunología , Hepatitis Animal/patología , Factores Inmunológicos/farmacología , Cirrosis Hepática/inmunología , Cirrosis Hepática/patología , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones Noqueados , ARN Mensajero/genética , ARN Mensajero/metabolismo , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Although ursodeoxycholic acid (UDCA) has long been used for patients with chronic cholestatic liver diseases, particularly primary biliary cirrhosis, it may modulate the host immune response. This study investigated the effect of UDCA feeding on experimental hepatitis, endotoxin shock, and bacterial infection in mice. C57BL/6 mice were fed a diet supplemented with or without 0.3% (wt/vol) UDCA for 4 wk. UDCA improved hepatocyte injury and survival in concanavalin-A (Con-A)-induced hepatitis by suppressing IFN-γ production by liver mononuclear cells (MNC), especially NK and NKT cells. UDCA also increased survival after lipopolysaccharide (LPS)-challenge; however, it increased mortality of mice following Escherichia coli infection due to the worsening of infection. UDCA-fed mice showed suppressed serum IL-18 levels and production of IL-18 from liver Kupffer cells, which together with IL-12 potently induce IFN-γ production. However, unlike normal mice, exogenous IL-18 pretreatment did not increase the serum IFN-γ levels after E. coli, LPS, or Con-A challenge in the UDCA-fed mice. Interestingly, however, glucocorticoid receptor (GR) expression was significantly upregulated in the liver MNC of the UDCA-fed mice but not in their whole liver tissue homogenates. Silencing GR in the liver MNC abrogated the suppressive effect of UDCA on LPS- or Con-A-induced IFN-γ production. Furthermore, RU486, a GR antagonist, restored the serum IFN-γ level in UDCA-fed mice after E. coli, LPS, or Con-A challenge. Taken together, these results suggest that IFN-γ-reducing immunomodulatory property of UDCA is mediated by elevated GR in the liver lymphocytes in an IL-12/18-independent manner.
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Factores Inmunológicos/farmacología , Hígado/efectos de los fármacos , Linfocitos/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Ácido Ursodesoxicólico/farmacología , Animales , Células Cultivadas , Concanavalina A , Escherichia coli , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/metabolismo , Hepatitis Animal/tratamiento farmacológico , Hepatitis Animal/etiología , Hepatitis Animal/metabolismo , Hepatocitos/metabolismo , Factores Inmunológicos/uso terapéutico , Interleucina-18/sangre , Interleucina-18/genética , Interleucina-18/metabolismo , Macrófagos del Hígado/metabolismo , Lipopolisacáridos/farmacología , Hígado/citología , Hígado/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptores de Glucocorticoides/genética , Choque Séptico/tratamiento farmacológico , Choque Séptico/metabolismo , Transcripción Genética , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
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.
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Colangitis/veterinaria , Colestasis Intrahepática/veterinaria , Infecciones por Clostridium/veterinaria , Enfermedades de los Perros/diagnóstico , Hepatitis Animal/diagnóstico , Animales , Antibacterianos/uso terapéutico , Colangitis/diagnóstico , Colangitis/tratamiento farmacológico , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/tratamiento farmacológico , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Perros , Femenino , Hepatitis Animal/tratamiento farmacológico , Resultado del TratamientoRESUMEN
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.
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Infecciones por Adenoviridae , Amidas/administración & dosificación , Ácidos Dicarboxílicos/administración & dosificación , Hepatitis Animal , Hepatocitos , Imidazoles/administración & dosificación , Hígado , Infecciones por Adenoviridae/tratamiento farmacológico , Adenovirus Humanos/efectos de los fármacos , Adenovirus Humanos/genética , Animales , Caproatos , Cricetinae , Hepatitis Animal/tratamiento farmacológico , Hepatitis Animal/virología , Hepatocitos/efectos de los fármacos , Hepatocitos/ultraestructura , Humanos , Hígado/efectos de los fármacos , Hígado/ultraestructura , Mesocricetus , Microscopía ElectrónicaRESUMEN
Dysregulation of signal transducer and activator of transcription (STAT) signaling is usually associated with intricate immune diseases and rebuilding the balance of STAT1 and STAT3 signaling is being explored as a useful approach for the treatment of these diseases. However, few chemicals have been reported to rebuild the balance of these two signalings for immune hepatitis therapy. In the present study, we found that fusaruside, a new kind of cerebroside isolated from an endophytic fungus Fusarium sp. IFB-121 in Quercus variabilis, significantly ameliorated concanavalin A (Con A)-induced T-cell-mediated fulminant hepatitis in mice, which was closely associated with the improvement of histopathological parameters, inhibition of activation of liver CD4(+) T cells and NKT cells, regulation of balance of Th1/Th2/Th17/Treg cytokines and protection of hepatocyte from apoptosis. Moreover, T-cell proliferation and activation was also notably inhibited by fusaruside in vitro. Furthermore, the protective effect of fusaruside was attributable to a novel regulatory mechanism through down-regulating STAT1 activation and T-bet expression in liver CD4(+) T cells and up-regulating STAT3 activation and Bcl-X(L) expression in hepatocytes. In conclusion, fusaruside exhibited its capability against T-cell-mediated liver injury in vivo, through rebuilding the balance of STAT1 and STAT3 signalings. These results suggest that fusaruside is potentially useful for the treatment of T-cell-mediated human liver disorders.