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1.
Life Sci ; 244: 117324, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31958420

RESUMO

AIMS: The aim of the present study was to evaluate the possible antioxidant role of oleic acid (OA) against Cd-induced injuries in the heart and liver tissues of male Wistar rats. MAIN METHODS: Rats were treated with either vehicle (control), or OA (10 mg/kg b.w., fed orally), or Cd (0.44 mg/kg b.w., s.c.), or both (OA + Cd) for 15 days. Following completion of the treatment period, biomarkers of organ damage and oxidative stress including ROS, activities of antioxidant enzymes and their level, activities of Krebs cycle enzymes and respiratory chain enzymes were measured. Levels of interleukins (IL-1ß, IL-6, IL-10), tumor necrosis factor (TNF-α) and nuclear factor kappa B (NFκB) were estimated to evaluate the state of inflammation. In addition, changes in mitochondrial membrane potential and status of cytochrome c (Cyt c) were also studied. KEY FINDINGS: Pre-treatment of rats with OA significantly protected against Cd-induced detrimental changes possibly by decreasing endogenous ROS through regulation of antioxidant defense system, inflammatory responses and activities of metabolic enzymes. Moreover, OA was also found to restore mitochondrial membrane potential possibly by regulating Cyt c leakage thereby increasing mitochondrial viability. SIGNIFICANCE: Our results for the first time demonstrated systematically that OA provided protection against Cd-induced oxidative stress mediated injuries in rat heart and liver tissues through its antioxidant mechanism. The results raise the possibility of using OA singly or in combination with other antioxidants or diet in the treatment of situations arising due to oxidative stress and may have future therapeutic relevance.


Assuntos
Ácido Oleico/metabolismo , Ácido Oleico/farmacologia , Animais , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Cádmio/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Coração/efeitos dos fármacos , Traumatismos Cardíacos/prevenção & controle , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
2.
Arq Gastroenterol ; 56(4): 333-338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721967

RESUMO

BACKGROUND: Indigofera suffruticosa Mill (Fabaceae) is abundant in northeastern Brazil and popularly used in the treatment of infectious and inflammatory processes. Several biological properties, such as anti-inflammatory, anticancer, antitumor, hepatoprotective and low toxicity, are reported for this plant. OBJECTIVE: This study investigated hepatoprotective activity and the antioxidant effect of methanolic extract of I. suffruticosa leaves (MEIS) on Swiss albino mice submitted to experimental models of acetaminophen-induced liver injury. METHODS: MEIS (50 mg/kg; p.o.) was standardized according to the LD50 and its hepatoprotective property on Swiss albino mice evaluated during a 7-day period. On the eighth day, the acetaminophen-induced hepatic injury was performed. Histomorphometric analysis of liver tissue, antioxidant activity and serum levels of alanine aminotransferase (AST), aspartate aminotransferase (ALT) and bilirubin were measured. RESULTS: MEIS (50 mg/kg; p.o.) restored serum enzyme levels and results were close to those of positive control (silymarin) when compared to the negative control. Histopathological and histomorphometric analyzes confirmed MEIS hepatoprotective activity, showing reorganization of structural units of cells, nuclei and sinusoidal capillaries of hepatocytes, reducing the damage on liver tissue and increasing organ regeneration rate. MEIS showed high antioxidant potential at concentrations of 1000 and 500 µg/mL. CONCLUSION: This study suggests that MEIS has hepatoprotective activity and high antioxidant potential.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Indigofera/química , Extratos Vegetais/administração & dosagem , Substâncias Protetoras/administração & dosagem , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Masculino , Camundongos
3.
Sheng Li Xue Bao ; 71(5): 725-731, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646326

RESUMO

The purpose of this study was to investigate the anti-injury effect and protective mechanism of hydrogen-enriched water in a rat model of acute liver injury induced by aflatoxin B1 (AFB1). Healthy male Sprague-Dawley (SD) rats were randomly divided into control group, model group (AFB1 group) and hydrogen-enriched water treatment group (AFB1+H2 group). The rat model of acute liver injury induced by AFB1 was established by single intragastric administration of AFB1 (2.0 mg/kg), and then the rats were treated with hydrogen-enriched water intragastrically. HE staining was used to observe the pathological changes of liver tissue. Blood samples were taken from vena cava to measure serum liver function indexes. Live tissue was sampled to detect malondialdehyde (MDA) and reduced glutathione (GSH) contents. Western blot was used to detect phosphorylation levels of MAPK signaling pathway proteins (ERK, JNK and p38 MAPK). The results showed that, compared with the AFB1 group, the AFB1+H2 group exhibited increased body weights, alleviated acute liver injury, decreased activities of serum glutamic-pyruvic transaminase and glutamic oxaloacetic transaminase, as well as total bilirubin level in the serum. Meanwhile, hydrogen-enriched water decreased MDA content and increased GSH content in liver tissue. AFB1-increased phosphorylation levels of ERK, JNK and p38 MAPK in liver tissue were down-regulated significantly by hydrogen-enriched water treatment. These results suggest that hydrogen-enriched water can alleviate liver injury induced by AFB1, and its mechanism may be related to the reduction of oxidative stress and the inhibition of MAPK signal transduction pathway activation.


Assuntos
Aflatoxina B1 , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Óxido de Deutério/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
4.
Life Sci ; 236: 116939, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593705

RESUMO

Taxifolin (TAX) reportedly exerts protective and therapeutic effects in liver. Herein, the effects of TAX against acetaminophen (APAP)-induced hepatotoxicity were investigated. Pharmacodynamics, pharmacology and metabolomics analyses of TAX were assessed on C57 mice and L-02 cells. TAX was administered for 7 days, and APAP was given on the last day to establish an acute liver injury model. ALT and AST levels were determined, and liver ROS, MDA, GST, GSH and GPX1 were analysed. The expression and protein abundance of GPX1, GPS-Pi, GCLC and GCLM were assessed by PCR and western blotting, and metabolic changes in cells and serum were investigated by UPLC-Q-Orbitrap-MS. Serum ALT and AST, and liver ROS, MDA, GST, GSH and GPX1 levels confirmed the protective effects of TAX. Besides, we found Only treating with TAX decreased the expression of CYP2E1 in mice liver tissue. TAX reversed the APAP-induced decrease in cell viability in L-02 cells, and reduced cellular ROS levels. Furthermore, TAX reversed the APAP-induced decrease in antioxidant enzymes at both mRNA and protein levels. Metabolomics analysis identified metabolites mainly related to glutathione metabolism (36 in vivo and 23 in vitro). The concentration of glutathione, oxidized glutathione, carnitine, succinic acid, pyroglutamic acid, citrulline, taurine, palmitoleic acid, phytoshingosine-1-P and sphingosine-1-P were close to normal levels after treating with TAX. These results indicate that TAX prevents APAP-induced liver injury by inhibiting APAP metabolic activation mediated by CYP450 enzymes, modulating glutathione metabolism, and expression of related antioxidative signals. These properties could be harnessed to prevent or treat hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glutationa/metabolismo , Metaboloma , Substâncias Protetoras/farmacologia , Quercetina/análogos & derivados , Analgésicos não Entorpecentes/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo
5.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3512-3519, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602916

RESUMO

The aim of this paper was to systematically evaluate the toxicity-reducing effect of Tripterygium-licorice in animal experiments,and also to provide evidence for basic research on the toxicity reduction of Tripterygium wilfordii. The PubMed,EMbase,Web of Science,CBM,CNKI and Wan Fang Databases from their establishment to August 31 th,2018 were searched. Two independent reviewers screened the papers,extracted the data,assessed the risk of bias using SYRCLE assessment tool and conducted Meta-analysis with Rev Man 5. 3 software. A total of 10 papers involving 31 studies were finally included,15 studies of which were used for Meta-analysis. Four studies were included for chronic hepatotoxicity animal model. In experimental group( 34 animals),Tripterygium was administered at dose of 0. 09-0. 1 mg·kg-1·d-1,and glycyrrhizic acid was administered at dose of 90-100 mg·kg-1,both for 2 weeks; in control group( 34 animals),glycyrrhizic acid was replaced with equal volume of normal saline. Eleven studies were included for acute hepatotoxicity animal model. In experimental group( 66 animals),glycyrrhizic acid was administered at dose of 75-480 mg·kg-1 for 7 days,then glycyrrhizic acid was stopped,and Tripterygium began to be administered at dose of 0. 6-1. 0 mg·kg-1 per 24 h or 48 h for a total of 1-2 times; in control group( 66 animals),glycyrrhizic acid was replaced with equal volume of normal saline or corresponding solvent. The results of Meta-analysis showed that in both chronic hepatotoxicity animal model and acute hepatotoxicity animal model,the transaminase levels in the experimental group were lower than those in the control group( P < 0. 05). Subgroup analysis of acute hepatotoxicity animal model showed that the transaminase levels in the experimental group were lower than those in the control group for every subgroup except " glycyrrhizic acid 75 mg·kg-1" subgroup. However,in terms of the mean difference( MD) and confidence interval( CI),there was no significant difference in transaminase decline between each subgroup. Low dose of glycyrrhizic acid( 90-100 mg·kg-1) has a toxicity-reduction effect on chronic hepatotoxicity induced by tripterygium( 0. 09-0. 10 mg·kg-1). Middle and high doses of glycyrrhizic acid( 120-480 mg·kg-1) have a toxicity-reduction effect on acute hepatotoxicity induced by tripterygium( 0. 6-1. 0 mg·kg-1),but with no significant dose-effect relationship.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Medicamentos de Ervas Chinesas/toxicidade , Ácido Glicirrízico/administração & dosagem , Tripterygium/toxicidade , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Glycyrrhiza , Tripterygium/química
6.
Chirurgia (Bucur) ; 114(4): 522-527, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31511139

RESUMO

OBJECTIVE: To highlight the role of albendazole hepatotoxicity in the choice between drainage versus a resection procedure in hepatic hydatidosis. Methods: The charts of four patients were reviewed retrospectively. In three patients, albendazole caused more than 10-fold increases in transaminase levels and was stopped. One patient had concomitant autoimmune hepatitis. Results: In the first case, two large hydatid cysts involving the right and the left hepatic veins were detected. First, left lateral sectionectomy and ligation of the right posterior portal vein branches were performed. Hypertrophy of the remnant liver allowed a safe right posterior sectionectomy two months later. In the second patient, a 9-cm cyst in segments 6 and 7 was treated with pericystectomy. The third patient had a 6-cm centrally located cyst. Pericystectomy, removal of small vesicles from the anterior section bile duct, common bile duct exploration with a T-tube placement were performed. In the patient with auto-immune hepatitis, pericystectomy was chosen for two objectives: 1) to eliminate a cavity prone to recurrence in an immunosuppressed patient 2) to avoid albendazole that may complicate the interpretation of liver function tests. The postoperative period and early follow up of all patients was uneventful. The second and the fourth patients have been followed for 56 and 17 months respectively and no recurrence has been detected. Conclusions: A resection procedure eliminates the cavity and the need for adjuvant albendazole treatment. This is a vital advantage for the small subset of patients with severe albendazole hepatotoxicity.


Assuntos
Albendazol/efeitos adversos , Anticestoides/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Equinococose Hepática/cirurgia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Equinococose Hepática/tratamento farmacológico , Humanos , Estudos Retrospectivos , Resultado do Tratamento
7.
Toxicol Lett ; 316: 85-93, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513885

RESUMO

BACKGROUND: Apoptosis-stimulating protein 2 of p53 (ASPP2) has a variety of biological functions, and is involved in cellular apoptosis, autophagy and inflammatory reaction. However, the role of ASPP2 in acute hepatic injury remains unclear. METHODS: We established an animal model of acute hepatic injury by intraperitoneal injection of CCl4. The expression profile of ASPP2 was measured in wild type (ASPP2+/+) mice with acute hepatic injury induced by CCl4. Hepatic pathological changes and liver function, apoptosis, inflammation and autophagic levels were measured in ASPP2+/+and ASPP2 haploid deletion (ASPP2+/-) mice with acute hepatic injury, respectively. After 3-methyladenine (3-MA) treatment, indicators of hepatic injury were observed in ASPP2+/+and ASPP2+/- mice with CCl4 injection. RESULTS: During the development of acute hepatic injury, ASPP2 expression significantly upregulated at 24 h and 48 h after CCl4 injection. ASPP2 haplotype deletion protected against acute hepatic injury, and this was mainly reflected in decreased ALT and AST levels, less hepatic tissue hemorrhage and necrosis, and reduced cellular inflammation and apoptosis in ASPP2+/- mice compared with ASPP2+/+ mice with acute hepatic injury. ASPP2 haploid deletion activates autophagy in mice with acute hepatic injury, and protects mice from acute hepatic injury via the autophagic signal pathway. CONCLUSION: ASPP2 haplotype deletion protected mice against acute hepatic injury through autophagy activation, which inhibited inflammation and apoptosis in acute hepatic injury.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/metabolismo , Proteínas Supressoras de Tumor/deficiência , Alanina Transaminase/sangue , Animais , Apoptose , Aspartato Aminotransferases/sangue , Autofagia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Haplótipos , Fígado/patologia , Masculino , Camundongos Knockout , Necrose , Fenótipo , Transdução de Sinais , Fatores de Tempo , Proteínas Supressoras de Tumor/genética
8.
Acta Cir Bras ; 34(7): e201900706, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531540

RESUMO

PURPOSE: To investigate the protective roles of pyracantha fortune fruit extract (PFE) on acute renal toxicity induced by cadmium chloride (CdCl2) in rats. METHODS: Rats were pretreated with PFE and consecutively injected with CdCl2 (6.5 mg/kg) for 5 days. RESULTS: The concentration of Cd, kidney weight, malondialdehyde (MDA), and nitric oxide (NO) production were remarkably increased in CdCl2 group as well as the levels of plasma uric acid, urea, and creatinine (P < 0.001). However, the body weight and glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione peroxidase (GR) levels were markedly reduced by CdCl2 treatment (P < 0.001). Histological manifestations of renal tissue showed severely adverse changes. Moreover, CdCl2 treatment significantly decreased the B-cell lymphoma-2 (Bcl-2) expression while increased the Bcl-2-Associated X Protein (Bax), tumor necrosis factor-α (TNF-α) expression (P < 0.001). Additionally, the expression of Nrf2/Keap 1 related proteins Keap-1 gained a significant increase (P < 0.001), whereas the Nrf2, HO-1, γ-GCS, GSH-Px and NQO1 expression decreased by CdCl2 treatment (P < 0.05). These rats were pretreated with PFE to improve the changes caused by CdCl2 treatment. CONCLUSION: PFE could protect the kidney against acute renal toxicity induced by CdCl2.


Assuntos
Antioxidantes/farmacologia , Cloreto de Cádmio/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Rim/efeitos dos fármacos , Extratos Vegetais/farmacologia , Pyracantha/química , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Frutas/química , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Rim/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo
9.
Environ Sci Pollut Res Int ; 26(29): 29930-29945, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407268

RESUMO

Cassia fistula L. (Caesalpinioideae) is a highly admirable medicinal plant and is traditionally recommended for the treatment of rheumatism, liver disorders, jaundice, and other inflammatory diseases. This study was designed to investigate the hepatoprotective properties of ethyl acetate fraction from C. fistula leaves in an animal model. Treatment with thioacetamide significantly elevated the level of serum glutamic-oxaloacetic transaminase (1.75-fold), alkaline phosphatase (4.07-fold), and total bilirubin (2.29-fold) as compared to the control. It was found that pretreatment of fraction followed by consecutive 2 days thioacetamide reduced the conversion of thioacetamide carcinogen to its reactive metabolites by phase I enzymes and increased the level of detoxification phase II along with antioxidative enzymes. The histopathological studies revealed the hepatoprotective nature of the fraction in restoring the normal architecture of thioacetamide-intoxicated damaged liver. The fraction showed downregulation in the expression level of p-PI3K, p-Akt, and p-mTOR pointing towards its chemopreventive potential. The HPLC analysis of the fraction had shown the dominance of three phenolic compounds namely, catechin, epicatechin, and chlorogenic acid. The above studies comprising histopathological, immunohistochemical, and hepatic enzymes are strong indicative of the potential protective ability of ethyl acetate fraction phytoconstituents against thioacetamide-induced toxicity. Graphical abstract.


Assuntos
Cassia/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Tioacetamida/toxicidade , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Ratos Wistar
10.
Toxicol Lett ; 316: 183-193, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437515

RESUMO

Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic ß-hydroxybutyrate level (indicator of fatty acid ß-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 µM of IC50), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.


Assuntos
Antipsicóticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Coenzima A Ligases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Fígado Gorduroso/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Olanzapina/toxicidade , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Adulto , Animais , Carnitina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Coenzima A Ligases/genética , Cães , Proteínas de Ligação a Ácido Graxo/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Membro 5 da Família 22 de Carreadores de Soluto/genética , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Regulação para Cima
11.
BMC Complement Altern Med ; 19(1): 228, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438932

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) may increase the sensitivity to liver injury caused by stimulants such as drugs and poisons. The traditional Chinese medicine (TCM) Jiang-Zhi Granule (JZG) has been proven effective for improving liver function, reducing hepatic fat accumulation and inflammation in NAFLD. The purpose of this study is to evaluate the effect of JZG on the susceptibility of NAFLD rats to liver injury and to identify the relevant mechanism. METHODS: Forty wistar rats were randomly divided into five groups, normal group, normal+CCl4 group, high-fat diet (HFD) group, HFD + CCl4 group, and HFD + CCl4 + JZG group. NAFLD were established with HFD for 8 weeks. Then Low-dose CCl4 was given intraperitoneally to induce liver injury in NAFLD rats for 48 h. From the 5th week of HFD, intragastric administration of JZG was simultaneously given to the rats in the HFD + CCl4 + JZG group. At the end of the experiment, liver histological pathology, serum transaminase, lipid in liver and blood, as well as hepatic expression levels of endoplasmic reticulum stress (ERS) related molecules were evaluated. RESULTS: NAFLD rat model was established by eight-week HFD feeding, exhibiting elevated levels of hepatic lipid, blood lipid, serum transaminase and significantly increased expression of ERS related molecules including glucose regulating protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (EIF2α), and nuclear factor-kappa B (NFκB) in liver tissues. After injection of CCl4 in NAFLD rats, elevated serum transaminases, severe inflammation and focal necrosis were observed in liver tissue, but no obvious change was found in the rats of normal group. JZG reduced hepatic inflammation, hepatic necrosis, hepatic lipid, blood transaminases and blood lipids in HFD + CCl4 rats. ERS related molecules were significantly elevated by low-dose CCl4 in NAFLD rats, and were down-regulated by JZG. CONCLUSION: The sensitivity to CCl4-induced liver injury is increased in NAFLD rats, which could be improved by JZG. The pharmacological mechanism may involve the regulation of ERS signaling pathway by JZG.


Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dieta Hiperlipídica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Distribuição Aleatória , Ratos , Ratos Wistar
12.
Molecules ; 24(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373296

RESUMO

The aim of this study was to evaluate the antioxidant and hepatoprotective activity of Croton hypoleucus (EC). The present work reports the first pharmacological, toxicological, and antioxidant studies of EC extract on liver injury. Liver necrosis was induced by thioacetamide (TAA). Five groups were established: Croton Extract (EC), thioacetamide (TAA), Croton extract with thioacetamide (EC + TAA), vitamin E with thioacetamide (VE + TAA) and the positive control and vehicle (CT). For EC and EC + TAA, Wistar rats (n = 8) were intragastrically pre-administered for 4 days with EC (300 mg/kg.day) and on the last day, EC + TAA received a single dose of TAA (400 mg/kg). At 24 h after damage induction, animals were sacrificed. In vitro activity and gene expression of superoxide dismutase (SOD), catalase (Cat), and Nrf2 nuclear factor were measured. The results show that EC has medium antioxidant properties, with an IC50 of 0.63 mg/mL and a ferric-reducing power of 279.8 µM/mg. Additionally, EC reduced hepatic damage markers at 24 h after TAA intoxication; also, it increased SOD and Cat gene expression against TAA by controlling antioxidant defense levels. Our findings demonstrated the hepatoprotective effect of EC by reducing hepatic damage markers and controlling antioxidant defense levels. Further studies are necessary to identify the mechanism of this protection.


Assuntos
Antioxidantes , Doença Hepática Induzida por Substâncias e Drogas , Croton/química , Extratos Vegetais , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Modelos Animais de Doenças , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Necrose , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Tioacetamida/toxicidade
13.
Biomed Res Int ; 2019: 4516730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396529

RESUMO

Background and Objectives: Environmental pollution with the different Aluminum (Al) containing compounds has been increased. Liver and kidney are two vital organs targeted by Al accumulation. The aim of this study was to assess the possible protective and curative effects of Lepidium sativum Linn (LS) against Al-induced impairment of liver and kidney in albino rat and to explore the mechanism behind this effect. Materials and Methods: This experimental animal-based study included fifty albino rats divided into five groups, the control, LS-treated (20 mg/kg), AlCl3-treated (10 mg/kg), AlCl3 then LS, and AlCl3 plus LS-treated, simultaneously for 8 weeks. At the end of the experiment, hepatic and renal functions as well as the biomarkers of antioxidants activities were assessed in the serum. Both liver and kidney were dissected out and histopathologically examined. Results: This study showed that administration of AlCl3 caused a significant (p<0.05) reduction in rats body weight. It significantly increased serum AST, ALT, ALP, bilirubin, urea, and creatinine levels and decreased total protein and albumin. AlCl3 significantly reduced enzymatic (catalase), nonenzymatic (reduced glutathione), and ferric reducing antioxidant power (FRAP) in the serum. Histopathologically, it induced necrosis and degeneration of hepatocytes, glomeruli, and renal tubules. Administration of LS after or along with AlCl3 significantly restored the serum biomarkers of liver and kidney functions to their near-normal levels and had the ability to overcome Al-induced oxidative stress and preserved, to some extent, the normal hepatic and renal structure. The coadministration of LS had a superior effect in alleviating Al-induced changes. Conclusion: Exposure to AlCl3 induced a set of functional and structural changes in the liver and kidney of rats evident through both biochemical and histopathological assessment. The antioxidant activity of LS seeds mediated a protective and curative effect of LS against such changes. Further study through a rigorous clinical trial to prove LS activity on human is recommended.


Assuntos
Cloreto de Alumínio/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Nefropatias , Lepidium sativum/química , Extratos Vegetais/farmacologia , Alumínio/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/prevenção & controle , Extratos Vegetais/química , Ratos
14.
Environ Sci Pollut Res Int ; 26(30): 31215-31224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31463753

RESUMO

In the present study, in vivo antioxidant properties of the n-butanol extract obtained from aerial parts of Perralderia coronopifolia were investigated in term of its hepatoprotective effect of female Wistar albino rats (n, 36; average age, 48 ± 5 days; weighing 150 ± 18 g) against PCP (pentachlorphenol)-induced toxicity. PCP (20 mg/kg b.w.) and plant extract (50 mg/kg b.w.) were administered daily by gavages for 2 weeks. Vitamin E (100 mg/kg b.w.) was given intraperitoneally as a positive control. Lipid peroxidation (LPO) levels, reduced glutathione (GSH) levels, and glutathione peroxidase (GPx) activities were evaluated in liver homogenates. While, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, and triglyceride parameters were analyzed in serums. The liver fragments were observed using light microscopy. Experimental results exhibited that PCP-treated group has a significant increase in the liver lipid peroxidation (LPO) levels of animals while decreased in plant extract-treated group. In addition, PCP caused significant decreases in glutathione peroxidase (GPx) activities and reduced glutathione (GSH) levels. Moreover, PCP induced hepatotoxicity by increasing serum transaminase enzymes, cholesterol, and triglyceride levels. While, these levels were restored to control value in animals treated with plant extract. The regularized levels of LPO, GSH, cholesterol, triglyceride, transaminase enzymes, and GPx activities revealed the antioxidant properties of the extract plant as well as of the vitamin E. The histological study showed the hepatoprotective effect of our extracts against PCP-induced acute intoxication, protecting the hepatic architecture and decreasing the functional and structural alterations of the liver. The plant extract had high antioxidant potential and completely prevented the toxic effect of PCP on the above of liver and serum parameters.


Assuntos
Asteraceae/química , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Pentaclorofenol/toxicidade , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , 1-Butanol/química , Alanina Transaminase/sangue , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Extratos Vegetais/química , Substâncias Protetoras/química , Ratos Wistar
15.
Ecotoxicol Environ Saf ; 183: 109467, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31374384

RESUMO

Mancozeb (MZ) is a widely used ethylene-bis-dithiocarbamate fungicide in agriculture causing hepatoxic and genotoxic effects in rats. Curcumin (CUR) has various pharmacological effects including antioxidant and anti-inflammatory properties. This study investigated the efficacy of CUR in mitigating MZ-induced hepatotoxicity and genotoxicity in rats. Twenty-four male rats were divided into four equal groups; group I (control) was given carboxymethyl cellulose, group II was orally administered CUR (100 mg/kg b.wt), group III was gavaged with MZ (750 mg/kg b.wt), and group IV was co-treated with MZ and CUR at the same doses daily for 10 weeks. As a result, the concurrent treatment with CUR and MZ minimized the increased levels of liver function markers in serum, lipid peroxidation, pro-inflammatory mediators and DNA damage parameters in liver. In addition, CUR administration improved the depleted markers of hepatic antioxidant status in MZ-treated rats. Moreover, CUR protected the liver against the histological alterations elicited by MZ exposure and also, reduced the immunopositive reactivity of pro-apoptotic p53 in cytoplasm of hepatocytes. The present findings suggest that CUR exerts a significant protective effect against MZ-induced hepatotoxicity and genotoxicity.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/farmacologia , Dano ao DNA , Hepatócitos/efeitos dos fármacos , Maneb/toxicidade , Zineb/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Dano ao DNA/efeitos dos fármacos , Hepatócitos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/genética , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos
16.
World J Gastroenterol ; 25(26): 3291-3298, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31341356

RESUMO

Solid organ transplantation (SOT) is the best treatment option for end-stage organ disease. Newer immunosuppressive agents have reduced the incidence of graft rejection but have increased the risk of infection, particularly due to the reactivation of latent infections due to opportunistic agents such as Mycobacterium tuberculosis. Active tuberculosis (TB) after SOT is a significant cause of morbidity and mortality. Most cases of posttransplant TB are secondary to reactivation of latent tuberculosis infection (LTBI) due to the effects of long-term immunosuppressive therapy. Risk minimization strategies have been developed to diagnose LTBI and initiate treatment prior to transplantation. Isoniazid with vitamin B6 supplementation is the treatment of choice. However, liver transplantation (LT) candidates and recipients have an increased risk of isoniazid-induced liver toxicity, leading to lower treatment completion rates than in other SOT populations. Fluoroquinolones (FQs) exhibit good in vitro antimycobacterial activity and a lower risk of drug-induced liver injury than isoniazid. In the present review, we highlight the disease burden posed by posttransplant TB and summarize the emerging clinical evidence supporting the use of FQs for the treatment of LTBI in LT recipients and candidates.


Assuntos
Antituberculosos/administração & dosagem , Fluoroquinolonas/administração & dosagem , Tuberculose Latente/tratamento farmacológico , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Aloenxertos , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Incidência , Isoniazida/efeitos adversos , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Fígado , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/microbiologia , Fatores de Risco , Resultado do Tratamento
17.
Pak J Pharm Sci ; 32(3): 1033-1042, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278717

RESUMO

Ketoconazole is a first orally available anti-fungal drug which has been reported as a potent inhibitor of human cytochrome P-450. The present study was designed to examine the heptoprotective effect of ketoconazole in both in vitro and in vivo liver injury models. Hepatocyte injury was induced by 8mM CCl4 while hepatic fibrosis model was established by injecting 1 ml/kg CCl4 followed by treatment with ketoconazole. Effect of ketoconazole treatment on injured hepatocytes was determined by lactate dehydrogenase release and trypan blue assay. Analysis of ketoconazole treatment and prevention on liver fibrosis was assessed by sirius red staining, masson trichome staining, PCR and liver function tests for bilirubin and alanine transaminase (ALAT).A significant reduction (P<0.05) in LDH release and reduced number of dead cells was observed in hepatocytes treated with ketoconazole. Sirus red and masson trichome stainings showed reduced levels of collagen in both treated and preventive groups and down regulation of alpha smooth muscle actin was observed with up-regulations of MMP-2, CK-8 and CK-18. Hepatic functional assessment demonstrated reduced serum levels of bilirubin and ALAT. Treatment of fibrotic liver with ketoconazole improves hepatic microenvironment and enhanced reduction of liver injury after fibrosis. Cytochrome P-450 inhibitors seems a favored therapeutic option in attenuation of liver fibrosis.


Assuntos
Hepatócitos/efeitos dos fármacos , Cetoconazol/farmacologia , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Actinas/genética , Animais , Tetracloreto de Carbono/toxicidade , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , L-Lactato Desidrogenase/metabolismo , Fígado/fisiologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Metaloproteinase 2 da Matriz/genética , Camundongos Endogâmicos C57BL
18.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261843

RESUMO

The antioxidant effect of salidroside has been proven, but its role in liver injury is poorly understood. In this study, we aimed to evaluate the protective effects and mechanism of salidroside on liver injury induced by carbon tetrachloride (CCl4) in vivo. Mice were pretreated with salidroside (60 mg/kg, intraperitoneally injected, i.p.) once per day for 14 consecutive days and then administered with CCl4 (15.95 g/kg, i.p.) for 24 h to produce a liver injury model. Salidroside attenuated hepatic transaminase elevation in serum and ameliorated liver steatosis and necrosis, thereby suggesting its protective effect on the liver. Salidroside antagonized CCl4-induced toxicity by equilibrating antioxidation system, thereby inhibiting reactive oxygen species accumulation, and restoring mitochondrial structure and function. Salidroside exerts antioxidant and liver-protective effects by selectively inhibiting the activation of genes, including growth arrest and DNA -damage-inducible 45 α (Gadd45a), mitogen-activated protein kinase 7 (Mapk7), and related RAS viral oncogene homolog 2 (Rras2), which induce oxidative stress in the mitogen-activated protein kinase pathway. These results revealed that salidroside can protect the liver from CCl4-induced injury by resisting oxidative stress and protecting mitochondrial function.


Assuntos
Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glucosídeos/uso terapêutico , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo , Fenóis/uso terapêutico , Animais , Antioxidantes/farmacologia , Tetracloreto de Carbono/toxicidade , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glucosídeos/farmacologia , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Fenóis/farmacologia
19.
Am J Health Syst Pharm ; 76(10): 654-666, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31361856

RESUMO

PURPOSE: Using information from institutional electronic health records, we aimed to develop dynamic predictive models to identify patients at high risk of acute kidney injury (AKI) among those who received a nephrotoxic medication during their hospital stay. METHODS: Candidate predictors were measured for each of the first 5 hospital days where a patient received a nephrotoxic medication (risk model days) to predict an AKI, using logistic regression with reduced backward variables elimination in 100 bootstrap samples. An AKI event was defined as an increase of serum creatinine ≥ 200% of a baseline SCr within 5 days after a risk model day. Final models were internally validated by replication in 100 bootstrap samples and a risk score for each patient was calculated from the validated model. As performance measures, the area under the receiver operation characteristic curves (AUC) and the number of AKI events among patients who had high risk scores were estimated. RESULTS: The study population included 62,561 admissions followed by 1,212 AKI events (1.9 events/100 admissions). We constructed 5 risk models corresponding to the first 5 hospital days where patients were exposed to at least one nephrotoxic medication. Validated AUCs of the 5 models ranged from 0.78 to 0.81. Depending on risk model day, admissions ranked in the 90th percentile of the risk score captured between 43% to 49% of all AKI events. CONCLUSION: A dynamic prediction model was built successfully for inpatient AKI with excellent discriminative validity and good calibration, allowing clinicians to focus on a select high-risk population that captures the majority of AKI events.


Assuntos
Algoritmos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Técnicas de Apoio para a Decisão , Pacientes Internados , Modelos Teóricos , Idoso , Área Sob a Curva , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estudos de Coortes , Registros Eletrônicos de Saúde , Feminino , Florida/epidemiologia , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Serviço de Farmácia Hospitalar , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco
20.
Gastroenterology ; 157(5): 1352-1367.e13, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31362006

RESUMO

BACKGROUND & AIMS: Activation of TGFB (transforming growth factor ß) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteínas da Matriz Extracelular/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/prevenção & controle , Fígado/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/genética , Células Estreladas do Fígado/patologia , Hepatite Alcoólica/metabolismo , Hepatite Alcoólica/patologia , Hepatite Viral Humana/metabolismo , Hepatite Viral Humana/patologia , Humanos , Fígado/patologia , Cirrose Hepática Alcoólica/metabolismo , Cirrose Hepática Alcoólica/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
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