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1.
Medicine (Baltimore) ; 98(39): e17343, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574875

RESUMO

RATIONALE: Glecaprevir/pibrentasvir, a pan-genotypic and ribavirin-free direct acting antiviral agent regimen, has shown significant efficacy and very few serious complications. However, as the drug metabolizes in the liver, it is not recommended in patients with decompensated liver cirrhosis. Herein, we report the case of a patient with compensated liver cirrhosis who developed severe jaundice after glecaprevir/pibrentasvir medication. PATIENT CONCERNS: A 77-year-old man diagnosed with chronic hepatitis C-related compensated liver cirrhosis visited hospital due to severe jaundice after 12 weeks of glecaprevir/pibrentasvir medication. DIAGNOSES: On the laboratory work-up, the total/direct bilirubin level was markedly elevated to 21.56/11.68 from 1.81 mg/dL; the alanine aminotransferase and aspartate aminotransferase levels were within the normal range. We checked the plasma drug concentration level of glecaprevir, and 18,500 ng/mL was detected, which was more than 15 times higher than the drug concentration level verified in normal healthy adults. INTERVENTIONS: Glecaprevir/pibrentasvir was abruptly stopped and after 6 days, the drug concentration level decreased to 35 ng/mL and the serum total/direct bilirubin decreased to 7.49/4.06 mg/dL. OUTCOMES: Three months after drug cessation, the serum total bilirubin level normalized to 1.21 mg/dL and HCV RNA was not detected. LESSONS: We report what is likely the first known case of severe jaundice after medication with glecaprevir/pibrentasvir in a patient with compensated liver cirrhosis. Clinicians should bear potential hyperbilirubinemia in mind when treating chronic hepatitis C with this regimen and should monitor the patient closely during follow-up laboratory exams, especially in elderly cirrhotic patients.


Assuntos
Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatite C Crônica/tratamento farmacológico , Hiperbilirrubinemia/induzido quimicamente , Cirrose Hepática/induzido quimicamente , Pirrolidinas/efeitos adversos , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Idoso , Doença Hepática Induzida por Substâncias e Drogas/virologia , Combinação de Medicamentos , Humanos , Hiperbilirrubinemia/virologia , Fígado/efeitos dos fármacos , Fígado/virologia , Cirrose Hepática/virologia , Masculino
2.
Zhonghua Gan Zang Bing Za Zhi ; 27(8): 621-627, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594080

RESUMO

Objective: To determine whether the anti-hepatic fibrosis effect of Fuzheng-Huayu formula is related to suppress autophagy in mice. Methods: C57 mice were randomly divided into normal group (N group) and model group. The model group was induced by intraperitoneal injection of carbon tetrachloride to induce liver fibrosis in mice, and the normal group was injected with equal volume of olive oil. After 1 week, the model group was randomly divided into model (M) group, rapamycin (Rapa) group, rapamycin plus chloroquine (Rapa+CQ) group, rapamycin plus salvianolic acid B (Rapa+Sal B) group, rapamycin plus Fuzheng -Huayu formula (Rapa+FZ) group. Each drug group was administered corresponding drugs by gavage on a daily basis, and N group and M group were given the equal amount of drinking water by gavage. After 5 weeks, the mice were sacrificed, and HE and Sirius red staining were used to observe the inflammation and collagen deposition on liver tissue in each group. The hydroxyproline content was determined by alkaline hydrolysis method. Western blotting was used to detect changes in the expression of autophagy in liver tissue and microtubule-associated protein 1 light chain 3II/I (LC3II/I), p62, α-smooth muscle actin (ɑ-SMA) and type I collagen expression. Immunofluorescence staining was used to observe the immunofluorescence localization of ɑ-SMA and LC3B in liver tissues of each group. ). A t-test was used to compare the two independent samples. LSD or Dunnett's T3 test were used to compare the mean of multiple samples. Results: There was no significant difference in N and M groups in terms of body weight. The body weight of the mice in each drug group decreased significantly (F = 14.041, P < 0.001). The liver/spleen /body weight ratios of each drug group and M group were significantly higher than the N group (F = 26.992, 6.589, P < 0.001). The expression of p62 protein in the liver tissue of mice in each drug group was lower than M group, and the difference between Rapa group and Rapa+Sal B group (F = 3.085, P = 0.039, 0.003) was statistically significant, while that of Rapa + Sal B group was lower. Compared with group M, the expression of LC3B II in Rapa group was significantly higher (F = 7.514, P = 0.01). Immunofluorescence staining showed that LC3B and α-SMA CO-stained cells were absent in the liver of mice in N group, and co-stained cells were found in the liver of mice in M group. The co-stained cells in the liver of mice in each drug group were significantly higher than M group, and the co-stained cells in Rapa+FZ group were fewer. Compared with the N group, the collagen deposition of M group and each drug group was significantly increased; the collagen deposition of each drug group was lower than that of the M group. There was no statistically significant difference between each drug group. Compared with N group (77.75 + 48.79), hydroxyproline in liver tissue of mice in M group was significantly increased (293.48 + 84.43) (F = 3.015, P = 0.005), and the content of hydroxyproline in liver tissue of mice in each drug group was lower than M group, but the difference was not statistically significant (F = 0.750, P = 0.573). Compared with the N group, the expressions of α-SMA and type I collagen in the M group were significantly increased (F = 27.718, 18.893, P < 0.01). The expression of α-SMA in Rapa group and Rapa+Sal B group was similar to M group, while Rapa + CQ group and Rapa + FZ group were significantly lower than Rapa group and M group (P < 0.01). The expression of type I collagen in Rapa + CQ group was significantly higher than Rapa group (P = 0.017), while the expression of type I collagen in Rapa + FZ group was significantly lower than M group (P = 0.013). Conclusion: Autophagy of hepatic stellate cells was observed in carbon tetrachloride-induced liver fibrosis model. Rapamycin can promote autophagy in hepatocytes and hepatic stellate cells. Fuzheng-Huayu formula and Salvianolic Acid B might antagonize the effect of rapamycin on autophagy.


Assuntos
Autofagia , Medicamentos de Ervas Chinesas/farmacologia , Células Estreladas do Fígado/citologia , Cirrose Hepática/tratamento farmacológico , Animais , Benzofuranos , Tetracloreto de Carbono , Cloroquina , Células Estreladas do Fígado/efeitos dos fármacos , Fígado , Cirrose Hepática/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Sirolimo
3.
Chem Biol Interact ; 309: 108675, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31150632

RESUMO

Liver fibrosis is a progression of chronic liver disease with lacks effective therapies at present. Schisandrin B (Sch B), a bioactive compound extracted from the traditional Chinese medicine Schisandra chinensis, was reported to benefit liver diseases. This study aimed to investigate the therapeutic effects and molecular mechanisms of Sch B against CCl4-induced liver fibrosis in rats. RNA sequencing and transcriptome analysis were performed collaboratively, including analysis of differential gene expression, gene ontology (GO) analysis, pathway analysis and pathway-act-network analysis. The results demonstrated that Sch B effectively alleviated CCl4-induced liver damage and fibrosis in rats, as evidenced by improved liver function and decreased extracellular matrix deposition. Furthermore, 4440 (1878 up-regulated, 2562 down-regulated) genes in the model group versus (vs) normal group, 4243 (2584 up-regulated, 1659 down-regulated) genes in Sch B-treated group vs model group were identified as differentially expressed genes (DEGs). Subsequently, GO analysis revealed that DEGs were mainly enriched in metabolism, oxidation-reduction, endoplasmic reticulum stress and apoptosis-related biological processes. Pathway analysis suggested that Sch B up-regulated cytochrome P450 drug metabolism, PPAR signaling pathways, and down-regulated glutathione metabolism pathways. In addition, the regulatory patterns of Sch B on key genes and pathways were also confirmed. In conclusion, our study demonstrated Sch B alleviated CCl4-induced liver fibrosis by multiple modulatory mechanisms, which provide new clues for further pharmacological study of Sch B.


Assuntos
Lignanas/farmacologia , Cirrose Hepática/patologia , Fígado/metabolismo , Compostos Policíclicos/farmacologia , Transcriptoma , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Perfilação da Expressão Gênica , Lignanas/química , Lignanas/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino , Medicina Tradicional Chinesa , Compostos Policíclicos/química , Compostos Policíclicos/uso terapêutico , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Ratos , Ratos Wistar , Schisandra/química , Schisandra/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos
4.
Acta Cir Bras ; 34(5): e201900504, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166460

RESUMO

PURPOSE: To establish a new rat model, the pathogenesis of which is closer to the clinical occurrence of chronic obstructive jaundice with liver fibrosis. METHODS: 90 SD rats were randomly divided into 3 groups. Group A common bile duct ligation, group B common bile duct injection compont and group C injection saline. The serum of three groups was extracted, and the liver function was detected by ELISA. HE staining, Masson staining and immunohistochemistry were used to detect liver pathology. RESULTS: Group B showed a fluctuant development of jaundice, obstructive degree reached a peak at 2 weeks, and decreased from 3 weeks. HA, LA and PCIII were significantly higher than control group. 3 weeks after surgery, liver tissue fibrosis occurred in group B, and a wide range of fiber spacing was formed at 5 weeks. Immunohistochemistry showed that hepatic stellate cells were more active than the control group. CONCLUSION: Intra-biliary injection of Compont gel is different from the classic obstructive jaundice animal model caused by classic bile duct ligation, which can provide an ideal rat model of chronic obstructive jaundice with liver fibrosis.


Assuntos
Ductos Biliares/efeitos dos fármacos , Modelos Animais de Doenças , Géis/administração & dosagem , Icterícia Obstrutiva/induzido quimicamente , Cirrose Hepática/induzido quimicamente , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Compostos Azo , Ductos Biliares/patologia , Bilirrubina/análise , Ensaio de Imunoadsorção Enzimática , Amarelo de Eosina-(YS) , Feminino , Imuno-Histoquímica , Injeções , Icterícia Obstrutiva/patologia , Cirrose Hepática/patologia , Verde de Metila , Distribuição Aleatória , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Albumina Sérica/análise , Fatores de Tempo , gama-Glutamiltransferase/sangue
5.
Zhonghua Gan Zang Bing Za Zhi ; 27(4): 267-273, 2019 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-31082337

RESUMO

Objective: To investigate the effect of anluohuaxianwan (ALHXW) using rat model of carbon tetrachloride (CCl(4)) induced liver fibrosis on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Methods: Thirty-six male Wistar rats were randomly assigned into control, model and treatment groups. Rats in the model and treatment groups were injected intraperitoneally with 40% CCl(4) (2 ml/kg), and the control group were given isotonic saline twice a week for six weeks. Meanwhile, the treatment group were gavaged with ALHXW solution daily (concentration 0.15 g/ml, 9.9 ml/kg) for 6 weeks, while the control and model groups were given isotonic saline once a day for 6 weeks. Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured at the end of third and sixth week. At the end of six weeks, liver tissues were harvested for histopathological evaluation and the detection of mRNA and protein expression levels of MMP-2/13 and TIMP-1/2. According to different data, LSD method, parametric (one-way ANOVA) and non-parametric tests (Kruskal-Wallis H-test and Mann-Whitney U test) were used for statistical analysis. Results: Compared with the model group, ALHXW markedly alleviated liver injury in the treatment group, and thereby improved the general state of rats, liver and spleen morphological characteristics, and ALT and AST levels. Histopathological examination demonstrated that the extent of liver fibrosis was improved (2.75 ± 0.75 vs. 3.55 ± 0.69, P = 0.015) in the treatment group as compared with the model group. The mRNA and protein expression levels of MMP-13 in the treatment group were significantly higher than that of the model group (mRNA: 10.50 ± 7.64 vs. 4.40 ± 2.97, P = 0.029. Protein: 1.15 ± 0.09 vs. 0.78 ± 0.21, P = 0.016), whereas the mRNA and protein expression levels of MMP-2, TIMP-1/2 in the treatment group were significantly lower than that of the model group (mRNA: 4.55 ± 3.29 vs. 7.83 ± 4.19, P = 0.048; 1.66 ± 0.73 vs. 3.69 ± 2.78, P = 0.023; 2.25 ± 1.16 vs. 3.41 ± 1.51, P = 0.049; respectively. Protein: 0.44 ± 0.11 vs. 0.65 ± 0.05, P = 0.03; 0.69 ± 0.06 vs. 1.07 ± 0.21, P = 0.016; 0.46 ± 0.09 vs. 0.81 ± 0.13, P = 0.003; respectively). Conclusion: ALHXW exerts anti-liver fibrosis effects mainly by improving liver function, inhibiting the activation of hepatic stellate cells, enhancing the expression of MMP-13, and inhibiting the expression of MMP-2 and TIMP-1/2.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/terapia , Metaloproteinases da Matriz/metabolismo , Medicina Tradicional Chinesa , Animais , Aspartato Aminotransferases/sangue , Tetracloreto de Carbono , Medicamentos de Ervas Chinesas/uso terapêutico , Fígado , Masculino , Ratos , Ratos Wistar
6.
Med Sci Monit ; 25: 2835-2844, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995213

RESUMO

BACKGROUND This study aims to demonstrate the underlying correlation between the resolution of liver fibrosis induced by Gexia-Zhuyu decoction (GZD) treatment and myeloid cell-mediated angiogenesis. MATERIAL AND METHODS A liver fibrosis mouse model induced by carbon tetrachloride (CCl4) intervention was employed in this study. Dynamics of blood liver function parameters were followed. The liver pathology was detected by Sirius Red and Masson staining. Matrix metalloproteinase (MMP) 2/9, tissue inhibitors of metalloproteinase (TIMP)-1/2, and vascular endothelial growth factor (VEGF)-A expression levels were measured. Bone marrow chimera mice were generated by transfer of bone morrow cells from green fluorescent protein (GFP)-knockin mice into irradiated wild-type mice, and were used it to visualize the role of myeloid cells on the fibrosis resolution induced by GZD treatment. RESULTS The result of Sirius Red and Masson staining and the dynamics of blood liver function parameters showed that 5 weeks of GZD treatment attenuated the severity of liver fibrosis with continual CCl4 administration. GZD treatment promoted the expression of MMP2/9 and repressed the heightened level of TIMP-1/2 in the recovery phase. More notably, the increased VEGF-A and augmented endothelial progenitor cells were observed in the liver and blood in mice that received GZD, and contributed to the remodeling of hepatic vascular though the CXCL12/CXCR4 axis. Then, chimera mice with GFP-positive bone marrow cells were used to show angiogenesis driven by GZD-induced myeloid cell motivation. We found that GZD facilitated myeloid cells binding to the vascular CXCR4 and induced the resolution of fibrosis. CONCLUSIONS This study shows that activation of myeloid cells induced by GZD administration accelerates the functional angiogenesis, which benefits the resolution of CCl4-induced liver fibrosis.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática/tratamento farmacológico , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Indutores da Angiogênese/farmacologia , Animais , Células da Medula Óssea/citologia , Tetracloreto de Carbono/farmacologia , Modelos Animais de Doenças , Feminino , Fígado/química , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/metabolismo , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Neovascularização Patológica/metabolismo , Inibidor Tecidual de Metaloproteinase-1/análise , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/análise , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Life Sci ; 225: 20-28, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928408

RESUMO

AIMS: Increasing nicotinamide adenine dinucleotide (NAD+) by Nicotinamide riboside (NR) provides protective benefits in multiple disorders. However, the role of NR on liver fibrosis is unclear. We performed in vivo and in vitro experiments to test the hepatic protective effects of NR against liver fibrosis and the underlying mechanisms. MATERIALS AND METHODS: Mice were injected with CCl4 to establish liver fibrosis model. NR was given by gavage to explore the hepatic protection of NR. LX-2 cells were given a TGF-ß stimulation ±â€¯NR, the activation of LX-2 cells and the acetylation of Smads were analyzed. To further confirm the role of Sirt1 on the protective pathway of NR, we knockdown Sirt1 in LX-2 cells. KEY FINDINGS: We found NR could prevent liver fibrosis and reverse the existing liver fibrosis. NR inhibited the activation of LX-2 cells induced by TGF-ß, activated Sirt1 and deacetylated Smad2/3. Sirt1 knockdown diminished the inhibiting effect of NR on LX-2 cells activation, and increased expressions of acetylated Smads. In conclusion, NR could prevent liver fibrosis via suppressing activation of hepatic stellate cells (HSCs). This protective effect was mediated by regulating the acetylation of Smads signaling pathway. SIGNIFICANCE: NR protected mice against liver fibrosis induced by CCl4. NR suppressed activation of hepatic stellate cells induced by TGF-ß. NR protects liver fibrosis via increasing the activity of Sirt1 and decreasing the expression of P300, resulting in the deacetylation of Smads in stellate cells.


Assuntos
Tetracloreto de Carbono/toxicidade , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Niacinamida/análogos & derivados , Substâncias Protetoras/farmacologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Acetilação , Animais , Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/farmacologia , Sirtuína 1/metabolismo , Fator de Crescimento Transformador beta/metabolismo
8.
Pharmacol Rep ; 71(3): 409-416, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003150

RESUMO

BACKGROUND: Liver fibrosis is a chronic lesion which ultimately results in cirrhosis and possible death. Although the high incidence and lethality, few therapies are effective for liver fibrosis. Fraxetin (7,8-dihydroxy-6-methoxy coumarin), a natural product extracted from cortex fraxini, has exhibited a significant hepatoprotective and anti-fibrotic properties. However, the underlying mechanism of the anti-hepatic fibrotic property remains unknown. METHODS: 48 Male Sprague Dawley rats were divided into four groups at random which were named as normal group, model group, fraxetin 25 mg/kg and 50 mg/kg group. The experimental model of liver fibrosis was founded by carbon tetrachloride (CCl4) rats which were simultaneously treated with fraxetin (25 mg/kg or 50 mg/kg). Normal groups received equal volumes of saline and peanut oil. RESULTS: Results showed that fraxetin ameliorated CCl4 induced liver damage and fibrosis. Furthermore, histopathology examinations revealed that fraxetin improved the morphology and alleviated collagen deposition in fibrotic liver. Fraxetin inhibited inflammation and hepatocytes apoptosis by modulating the NF-κB/IκBα, MAPKs and Bcl-2/Bax signaling pathways. CONCLUSION: Our findings indicate that fraxetin is effective in preventing liver fibrosis through inhibiting inflammation and hepatocytes apoptosis which is associated with regulating NF-κB/IκBα, MAPKs and Bcl-2/Bax signaling pathways in rats.


Assuntos
Tetracloreto de Carbono/farmacologia , Cumarínicos/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
9.
Biomed Environ Sci ; 32(3): 153-161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30987689

RESUMO

OBJECTIVE: This study was designed to evaluate hematological disorders and the orchestrating roles of hepcidin and IL-6 in rat models of thioacetamide (TAA) and carbon tetrachloride (CCl4) hepatotoxicity. METHODS: Rats were intraperitoneally injected with TAA (10 mg/100 g rat weight dissolved in isosaline) or CCl4 (100 µL/100 g rat weight diluted as 1:4 in corn oil) twice weekly for eight consecutive weeks to induce subchronic liver fibrosis. Blood and tissue samples were collected and analyzed. RESULTS: CCl4 but not TAA significantly decreased the RBCs, Hb, PCV, and MCV values with minimal alterations in other erythrocytic indices. Both hepatotoxins showed leukocytosis, granulocytosis, and thrombocytopenia. By the end of the experiment, the erythropoietin level increased in the CCl4 model. The serum iron, UIBC, TIBC, transferrin saturation%, and serum transferrin concentration values significantly decreased, whereas that of ferritin increased in the CCl4 model. TAA increased the iron parameters toward iron overload. RT-PCR analysis revealed increased expression of hepatic hepcidin and IL-6 mRNAs in the CCl4 model and suppressed hepcidin expression without significant effect on IL-6 in the TAA model. CONCLUSION: These data suggest differences driven by hepcidin and IL-6 expression between CCl4 and TAA liver fibrosis models and are of clinical importance for diagnosis and therapeutics of liver diseases.


Assuntos
Hepcidinas/farmacologia , Interleucina-6/farmacologia , Ferro/metabolismo , Cirrose Hepática/terapia , Transferrina/metabolismo , Animais , Análise Química do Sangue , Tetracloreto de Carbono/toxicidade , Injeções Intraperitoneais , Ferro/sangue , Leucocitose/induzido quimicamente , Leucocitose/terapia , Cirrose Hepática/induzido quimicamente , Masculino , Ratos , Tioacetamida/toxicidade , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia
10.
Biomed Pharmacother ; 112: 108701, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30818137

RESUMO

Natural bear bile has been used for liver disease in East Asia for thousands of years. However, its use has restrictions. In the current study, the therapeutic effects and potential mechanisms of cultured bear bile powder (CBBP) against hepatic fibrosis were evaluated in a dimethylnitrosamine (DMN)-induced rat model. CBBP treatment significantly improved DMN-induced hepatic necrosis and inflammatory infiltration. Additionally, CBBP remarkably alleviated the increased hepatic collagen content and expression of alpha-smooth muscle actin. Serum metabolomics revealed that 14 serum metabolites, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were decreased in DMN-treated rats, which was reversed by CBBP. Pathway analyses revealed that the main metabolic pathways affected by CBBP were related to fatty acid biosynthesis and metabolism, and biosynthesis of unsaturated fatty acids. EPA and DHA are ligands of peroxisome proliferator activated receptors (PPARs). CBBP treatment significantly stimulated liver mRNA and protein expression of PPARα and PPARγ. CBBP also markedly increased liver expression of PPARα target genes, which are involved in fatty acid ß-oxidation, and down-regulated IL-6, a downstream inflammatory gene of PPARγ. In conclusion, CBBP has the potential to attenuate liver fibrosis and its mechanism involves the promotion of the liver expression of PPARα and PPARγ. Our results may help in the development of a novel substitute for bear bile and therapeutic strategies for fibrotic liver diseases.


Assuntos
Bile/metabolismo , Citoproteção/efeitos dos fármacos , Dimetilnitrosamina/toxicidade , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Animais , Bile/química , Citoproteção/fisiologia , Relação Dose-Resposta a Droga , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Cirrose Hepática Experimental/prevenção & controle , Distribuição Aleatória , Ratos , Ratos Wistar , Ursidae
11.
Am J Chin Med ; 47(2): 351-367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30871359

RESUMO

Liver fibrosis is a worldwide clinical issue that generally causes hepatic cirrhosis. Lonicerae Japonicae Flos (dried flower buds of Lonicera japonica Thunb) is a traditional heat-clearing and detoxifying herbal medicine in China. This study aims to observe the protection of the water extract of Lonicerae Japonicae Flos (FL) from carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Liver fibrosis was induced in mice by intraperitoneal injection of 2 ml/kg CCl4 twice a week for 4 weeks. FL's attenuation of CCl4-induced liver fibrosis in mice was evidenced by the results of Masson's trichrome and Sirius red staining, liver hydroxyproline content and serum amount of collagen IV. FL reduced hepatic stellate cells (HSCs) activation and reversed the epithelial-mesenchymal transition (EMT) process in mice treated with CCl4. FL also alleviated liver oxidative stress injury and enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant signaling pathway in mice treated with CCl4. Additionally, the main phenolic acids in FL including chlorogenic acid (CGA) and caffeic acid (CA) both reduced HSCs activation in vitro. In summary, FL attenuates CCl4-induced liver fibrosis in mice by inhibiting HSCs activation, reversing EMT and reducing liver oxidative stress injury via inducing Nrf2 activation. CGA may be the main active compound contributing to the antifibrotic activity of FL.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Lonicera/química , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Células Cultivadas , Colágeno Tipo IV/sangue , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Hidroxiprolina/metabolismo , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos
12.
Environ Toxicol Pharmacol ; 68: 109-119, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30884453

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is an environmental pollutant that is widely used in medical and consumer products. An epidemiological study has suggested that a large daily intake of DEHP from phthalate-contaminated food may be a risk factor for liver dysfunction. Long-term exposure to DEHP is associated with liver disease and exacerbates the progression of chronic liver injury. However, the effect of DEHP on hepatic fibrosis is rarely studied. In the present study, we sought to determine the effect of DEHP on carbon tetrachloride (CCl4)-induced liver fibrosis, and to further examine the molecular mechanisms. We found that DEHP exposure remarkably promoted liver inflammation, necrosis and fibrosis, and increased expression of the protein associated with liver inflammation and fibrogenesis, including α-SMA, COL-Ⅰ, COL-Ⅲ, TGF-ß1, P-Smad2, P-Smad3, P-p38 and P-p65. The similar trend was observed in the LX-2 cells. Furthermore, DEHP exposure induced oxidative stress and inflammatory cytokine production. Taken together, DEHP might play a fibrotic role in hepatic fibrosis rats and TGF-ß1-stimulated LX-2 cells in vitro which was related to TGF-ß1/Smad and p38MAPK/NF-κB signal pathway.


Assuntos
Dietilexilftalato/toxicidade , Cirrose Hepática/induzido quimicamente , Plastificantes/toxicidade , Animais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Nutrients ; 11(2)2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781895

RESUMO

The late stages of liver fibrosis are considered to be irreversible. Red quinoa (Chenopodium formosanum Koidz), a traditional food for Taiwanese aborigines, was gradually developed as a novel supplemental food due to high dietary fibre and polyphenolic compounds. Its bran was usually regarded as the agricultural waste, but it contained a high concentration of rutin known as an antioxidant and anti-inflammatory agent. This study is to explore the effect of red quinoa bran extracts on the prevention of carbon tetrachloride (CCl4)-induced liver fibrosis. BALB/c mice were intraperitoneally injected CCl4 to induce liver fibrosis and treated with red quinoa whole seed powder, bran ethanol extracts, bran water extracts, and rutin. In the results, red quinoa powder provided more protection than rutin against CCl4-induced oxidative stress, pro-inflammatory factor expression and fibrosis development. However, the bran ethanol extract with high rutin content provided the most liver protection and anti-fibrosis effect via blocking the tumor necrosis factor alpha (TNF-α)/interleukin 6 (IL-6) pathway and transforming growth factor beta 1 (TGF-ß1) pathway.


Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Chenopodium quinoa , Cirrose Hepática/induzido quimicamente , Extratos Vegetais/farmacologia , Animais , Antioxidantes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Sementes , Substâncias Reativas com Ácido Tiobarbitúrico , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
14.
Biomed Res Int ; 2019: 5756189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30723740

RESUMO

Background: Splenectomy can improve liver function and survival in patients with autoimmune hepatitis (AIH) and liver cirrhosis. We investigated the underlying mechanism in a mouse model of concanavalin A- (ConA-) induced liver fibrosis. Methods: We used ConA to induce immune liver fibrosis in BALB/c mice. Splenectomy was performed alone or with the administration of dexamethasone (DEX). Changes in blood and liver tissues were evaluated. Results: Mice treated with ConA for 7 weeks developed advanced liver fibrosis, while splenectomy suppressed liver fibrosis. Although the populations of macrophages/monocytes and M1 macrophages decreased after splenectomy, the inflammatory factors associated with M2 macrophages increased after splenectomy. Furthermore, the population of circulating CD11b+Ly6Chigh myeloid-derived suppressor cells (MDSCs) increased after splenectomy. After ConA treatment, elevated levels of activated and total NF-kBp65/p50 combined with DNA were observed in hepatic tissues. In contrast, the levels of NF-κB p65/p50 decreased after splenectomy. Conclusions: Splenectomy may promote the polarization of CD11b+Ly6Chigh MDSCs and the differentiation of M2 macrophages while restricting the level of NF-κB p65-p50 heterodimers. These factors may suppress the progression of liver fibrosis.


Assuntos
Cirrose Hepática/metabolismo , Cirrose Hepática/cirurgia , Fígado/metabolismo , Esplenectomia , Animais , Polaridade Celular/genética , Concanavalina A/toxicidade , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/fisiopatologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Células Supressoras Mieloides/metabolismo , Baço/fisiopatologia , Baço/cirurgia , Fator de Transcrição RelA/genética
15.
J Biochem Mol Toxicol ; 33(5): e22287, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30719803

RESUMO

Activated factor X has a central role in the coagulation activation and also contributes to chronic inflammation and tissue fibrosis. In this study, rivaroxaban, a direct factor X inhibitor, attenuates liver fibrosis induced by carbon tetrachloride (CCl4 ). Male rats were randomly allocated into three groups: a control group, CCl 4 fibrotic group, and CCl 4 +rivaroxaban (5 mg/kg) group. Liver fibrosis was induced by subcutaneous injection of CCl 4 twice a week for 6 weeks. Rivaroxaban significantly restored the biochemical parameter including inflammatory and fibrosis markers with histopathological evidence using routine and Masson trichrome staining. It reduced also the expression of tissue factor, fibrin, transforming growth factor and α-smooth muscle actin in the liver tissues. This concludes that rivaroxaban attenuates liver injury caused by CCl 4 , at least in part by inhibiting coagulation and proinflammatory activation. In conclusion, rivaroxaban may be used for the management of liver fibrosis.


Assuntos
Intoxicação por Tetracloreto de Carbono/metabolismo , Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Cirrose Hepática/metabolismo , Rivaroxabana/farmacologia , Animais , Tetracloreto de Carbono/toxicidade , Intoxicação por Tetracloreto de Carbono/patologia , Intoxicação por Tetracloreto de Carbono/prevenção & controle , Fator Xa/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Masculino , Ratos , Ratos Wistar
16.
Transplant Proc ; 51(1): 90-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30655144

RESUMO

Herein we report a case of liver dysfunction caused by consumption of vitamin A supplements leading to liver transplantation. The patient was a 48-year-old male with a medical history of congenital ichthyosiform erythroderma in treatment with vitamin A until 12 years of age, at which point he discontinued the supplements because he had developed ascites. Liver cirrhosis was diagnosed as secondary to hypervitaminosis A on the basis of histologic examination of liver biopsy and the absence of other potential causes of chronic liver disease. Despite interruption of administration of vitamin A, the patient continued to deteriorate over the years, with development of portal hypertension signs. His medical conditions were aggravated with the development of hepatic insufficiency manifested by refractory ascites, renal insufficiency, and severe encephalopathy and he underwent orthotopic liver transplantation, followed by disappearance of all signs of portal hypertension. This case highlights the need to take a careful history of consumption of vitamin A when evaluating a patient with liver failure.


Assuntos
Suplementos Nutricionais/envenenamento , Hipervitaminose A/complicações , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/cirurgia , Transplante de Fígado , Humanos , Hipertensão Portal/induzido quimicamente , Eritrodermia Ictiosiforme Congênita/complicações , Fígado/patologia , Masculino , Pessoa de Meia-Idade
17.
Hum Cell ; 32(2): 125-140, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30637566

RESUMO

Liver transplantation is the most effective treatment for treating liver cirrhosis. However, a limited number of donors, graft rejection, and other complications can undermine transplant success. It is considered that cell transplantation is an alternative approach of liver transplantation. We previously developed a protocol for hepatic differentiation of cluster of differentiation 117+ stem cells isolated from human exfoliated deciduous tooth pulp (SHEDs) under hydrogen sulfide exposure. These cells showed excellent hepatic function. Here, we investigated whether hepatocyte-like cell transplantation is effective for treating carbon tetrachloride (CCl4)-induced liver cirrhosis. SHEDs were hepatically differentiated, which was confirmed via immunological analyses and albumin concentration determination in the medium. Rats were intraperitoneally injected with CCl4 for and the differentiated cells were injected into rat spleen. Histopathological and immunohistochemical analyses were performed. Liver functions were serologically and pathologically determined. Quantitative real-time-polymerase chain reaction was implemented to clarify the treatment procedure of liver cirrhosis. In vitro-differentiated hepatocyte-like cells were positive for all examined hepatic markers. SHED-derived hepatocyte transplantation eliminated liver fibrosis and restored liver structure in rats. Liver immunohistochemical analyses showed the presence of human-specific hepatic markers, i.e., a large amount of human hepatic cells were very active in the liver and spleen. Serological tests revealed significant liver function recovery in the transplantation group. Expression of genes promoting fibrosis increased after cirrhosis induction but was suppressed after transplantation. Our results suggest that xenotransplantation of hepatocyte-like cells of human origin can treat cirrhosis. Moreover, cell-based therapy of chronic liver conditions may be an effective option.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Diferenciação Celular , Polpa Dentária/citologia , Hepatócitos/transplante , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/terapia , Células-Tronco/fisiologia , Animais , Humanos , Masculino , Ratos Endogâmicos F344 , Baço , Transplante Heterólogo
18.
J Agric Food Chem ; 67(5): 1392-1401, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30644744

RESUMO

Our previous study has confirmed that maltol can attenuate alcohol-induced acute hepatic damage and prevent oxidative stress in mice. Therefore, maltol might have the capacity to improve thioacetamide (TAA)-induced liver fibrosis. The purpose of this work was to explore the antifibrotic efficacy and underlying mechanisms of maltol for TAA-treated mice. Progressive liver fibrosis was established with a dose-escalating protocol in which the mice received TAA intraperitoneal three times a week for a total duration of 9 weeks. The injection doses of TAA were 50 mg/kg for the first week, 100 mg/kg for the second and third weeks, and 150 mg/kg for the rest of the injections. Maltol with doses of 50 and 100 mg/kg was given by gavage after 4 weeks of intraperitoneal injection of TAA, respectively, once daily for 5 weeks. Results indicated that TAA intraperitoneal injection significantly increased serum activities of alanine aminotransferase (ALT) (52.93 ± 13.21 U/L vs 10.22 ± 3.36 U/L) and aspartate aminotransferase (AST) (67.58 ± 25.84 U/L vs 39.34 ± 3.89 U/L); these elevations were significantly diminished by pretreatment with maltol. Additionally, maltol ameliorated TAA-induced oxidative stress with attenuation in MDA ( p < 0.05 or p < 0.01) content; evident elevation in the GSH levels, GSH/GSSG ratio ( p < 0.05 or p < 0.01), and superoxide dismutase (SOD) ( p < 0.01); and restored liver histology accompanied by a decrease of α-smooth muscle actin (α-SMA) expression. Furthermore, maltol significantly suppressed the transforming growth factor-ß1 (TGF-ß1) expression and the PI3K/Akt pathway. This study suggested that maltol alleviated experimental liver fibrosis by suppressing the activation of HSCs and inducing apoptosis of activated HSCs through TGF-ß1-mediated PI3K/Akt signaling pathway. These findings further clearly suggested that maltol is a potent therapeutic candidate for the alleviation of liver fibrosis.


Assuntos
Cirrose Hepática/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pironas/administração & dosagem , Fator de Crescimento Transformador beta1/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Tioacetamida/efeitos adversos , Fator de Crescimento Transformador beta1/genética
19.
Biomed Pharmacother ; 109: 892-901, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551543

RESUMO

The present study was conducted to investigate the potential protective effects of coenzyme Q 10 (CoQ10) administration on methotrexate induced lung and liver fibrosis in rat model, and to explore our hypothesis regarding its possible mechanism of action through reactivation of autophagy pathway. Methotrexate induced fibrosis was achieved by intraperitoneal injections twice a week for 4 weeks. A combined treatment of CoQ10 and methotrexate were used. Blood samples for biochemical analysis, lung and livers tissue for biochemical and histopathological analysis, were investigated. Concomitant treatment of CoQ10 & methotrexate caused improvement in histological picture of the lung and liver tissues, liver function and oxidative stress biomarkers, modulation of autophagy genes [mammalian target of rapamycin (m-TOR), Microtubule-associated proteins 1 A/1B light chain 3 (MAP1LC3B), and Sequestosome 1 ubiquitin-binding protein p62 (p62/SQSTM1)] with simultaneous reduction in High Mobility Group Protein B1 (HMGB1). Based on our results we postulated that CoQ10 up regulates autophagy pathway that could explain its protective properties against lung and liver fibrosis caused by methotrexate treatment in current study rat model.


Assuntos
Autofagia/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Metotrexato/toxicidade , Ubiquinona/análogos & derivados , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Autofagia/fisiologia , Inibidores Enzimáticos/toxicidade , Cirrose Hepática/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
20.
J Biochem ; 165(4): 361-367, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535384

RESUMO

As is known, hepatic stellate cells (HSCs) activation contributes to liver cirrhosis. This study aims to find out the acting mechanisms of miR-454 inhibiting the activation and proliferation of hepatic stellate cells. The expression of Col1A1, α-smooth muscle actin (α-SMA) and Wnt10a were determined by western blot, and the miR-454 level was determined by quantitative real-time PCR in this study. We took two objects as experiment subjects, one was liver cirrhosis rats, and the other was transforming growth factor (TGF)-ß1-stimulated HSC-T6 cells. After activated with TGF-ß1 and transfected with microRNA-454 mimic, separately or successively, the changes on the Col1A1 and α-SMA expression, HSC proliferation, miR-454 level and Wnt10a expression were examined in HSC-T6 cells, respectively. Interaction between miR-454 and Wnt10a was evaluated with dual luciferase reporter assay. MiR-454 expression was down-regulated in tissues of liver cirrhosis rats. TGF-ß1 caused the down-regulation of the miR-454 in HSC-T6 cells. MiR-454 inhibited the activation and proliferation of HSC-T6 cells. Wnt10a had a targeting relationship with miR-454. TGF-ß1 promoted HSC-T6 activation and proliferation via down-regulating miR-454 expression, which further up-regulated Wnt10a expression. MiR-454 mimic inhibited cirrhosis progression in liver cirrhosis rats. MiR-454 can inhibit the activation and proliferation of HSCs via suppressing the expression of Wnt10a, to restrain liver cirrhosis.


Assuntos
Proliferação de Células , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , MicroRNAs/metabolismo , Proteínas Wnt/metabolismo , Animais , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Ratos , Fator de Crescimento Transformador beta1/metabolismo
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