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1.
Life Sci ; 254: 117782, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407847

RESUMO

AIMS: This study assessed the prophylactic or therapeutic effects of taurine (TR) and/or hesperidin (HES) on carbon tetrachloride (CCl4) induced acute kidney and testicular injury in rats. MAIN METHODS: Rats were randomly divided into nine experimental groups including control; corn oil; CCl4; HES/CCl4; TR/CCl4; HES + TR/CCl4; CCl4/HES; CCl4/TR; and CCl4/HES + TR groups. CCl4 was intraperitoneally injected with a single dose of 2 ml /kg b.w. HES and TR were orally gavaged twice weekly 100 mg/kg b.w. for four weeks. Kidney function, inflammatory response, sexual hormones, and oxidative stress indicators were assessed. Histomorphological and immune-histochemical studies of the inflammatory marker nuclear factor kappa (NF-κB) in renal and testicular tissues were performed. KEY FINDINGS: The results showed that the TR and/or HES treatment significantly suppressed CCl4 induced rise of urea, uric acid, potassium, and follicle-stimulating hormone levels. However, significant restoration of sodium, testosterone, and luteinizing hormone was apparent in CCl4 exposed rats received HES and/or TR. Also, the HES and/or TR treatment significantly rescues CCl4 induced oxidative stress and inflammation. Moreover, the HES and/or TR dosing significantly repaired the CCl4 evoked altered renal and testicular architecture and suppressed NF-κB immunoexpression. Notably, alleviating CCl4 induced renal and testicular damage was more effective in the prophylactic groups than the therapeutic groups. Also, most of the estimated parameters of the HES + TR group did not significantly vary from those of single TR or HES. SIGNIFICANCE: In conclusion, HES or TR could efficiently guard against CCl4 nephro-and reprotoxic effects, but both bioactive combinations afford only a limited synergistic outcome.


Assuntos
Hesperidina/farmacologia , Inflamação/prevenção & controle , Rim/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Taurina/farmacologia , Testículo/metabolismo , Animais , Tetracloreto de Carbono , Sinergismo Farmacológico , Hormônio Foliculoestimulante/metabolismo , Rim/patologia , Hormônio Luteinizante/metabolismo , Masculino , NF-kappa B/metabolismo , Potássio/metabolismo , Ratos , Sódio/metabolismo , Testículo/patologia , Testosterona/metabolismo , Ureia/metabolismo , Ácido Úrico/metabolismo
2.
Chem Biol Interact ; 325: 109115, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380060

RESUMO

UDP-glucuronosyltransferases (UGTs) are a family of phase II drug metabolizing enzymes that catalyze glucuronidation of numerous endogenous and exogenous substrates. Carbon tetrachloride (CCl4) is widely used to develop liver injuries mimicking human liver diseases. However, effects of CCl4 on the expression and activities of UGTs and the mechanism have not been fully elucidated. The present study aims to elucidate the dysregulation patterns of major UGTs induced by CCl4. Biochemical and histopathological results showed that CCl4 exerted hepatotoxicity in rats. The mRNA levels of UGTs were all significantly reduced in acute liver injury rats. However, mRNA levels of UGT1A1, 1A6, 2B1 and 2B2 were up-regulated while the UGT2B3, 2B6 and 2B12 levels were reduced in chronic CCl4-induced liver fibrosis rats. The protein expression of UGT1A1, 1A6 and 2B were decreased in acute liver injury rats. UGT1A1 and 1A6 proteins were increased, whereas UGT2B protein was reduced in liver fibrosis rats. In addition, CCl4 inhibited the enzyme activities of UGTs in rats. Moreover, the dysregulation of UGTs was accompanied by the decreased mRNA expression of Nrf2, CAR, FXR, PXR, PPAR-α and their corresponding target genes, except for Nrf2, HO-1, AhR and CYP1A1 in liver fibrosis rats. These findings suggest that dysregulation of UGTs under CCl4 exposure is isoform-specific, which could have a complex impact on drug efficacy and endogenous metabolism. Different exposure durations of CCl4 (single vs multiple doses) could have differential effects on rat hepatic UGTs expression.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Glucuronosiltransferase/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição/metabolismo
3.
Zhongguo Zhong Yao Za Zhi ; 45(3): 631-635, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237523

RESUMO

This paper was aimed to observe the interventional effect of Sedum sarmentosum total flavanones on hepatic fibrosis and its possible mechanism through the subcutaneous injection of CCl_4 in rats. Sixty male SD rats were randomly divided into normal control group, model group, low-dose, medium-dose, high-dose S. sarmentosum total flavanones groups(100, 200, 400 mg·kg~(-1)) and silymarin group(200 mg·kg~(-1)). The model of liver fibrosis was established by subcutaneous injection of rats with 40% CCl_4. After the modeling, the drug groups were intragastrically administered with corresponding drugs once a day for consecutively five weeks, while the normal group and the model group were given 0.9% sodium chloride solution during the same period. After the experiment, the general conditions of rats and the pathological changes of liver tissues were observed, and the contents of serum ALT, AST, HA and LN were measured. Besides, the expressions of the protein and relevant mRNA of Smad2/3, Smad4 and α-SMA in rats were detected. Compared with model group, S. sarmentosum total flavanones could significantly increase the rats' body weight, inhibit the increase of liver and spleen index in rats of liver fibrosis, reduce the levels of ALT, AST, HA and LN, and alleviate pathological changes. Meanwhile, compared with the model group, the protein expressions of Smad2/3, Smad4 and α-SMA as well as relevant mRNA expressions in S. sarmentosum total flavanones group were obviously decreased, while Smad7 expression was markedly increased. As a result, S. sarmentosum total flavanones could significantly alleviate CCl_4-induced liver fibrosis, and its anti-hepatic fibrosis mechanism may be related to intervention with Smads pathway, so as to inhibit the activation of HSC.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Flavanonas/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Sedum/química , Proteínas Smad/metabolismo , Animais , Tetracloreto de Carbono , Fígado , Cirrose Hepática/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
4.
Environ Sci Pollut Res Int ; 27(20): 24967-24981, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32342415

RESUMO

Hepatoprotection is a goal for the harmful effect of several hepatotoxic agents. The present study has been executed to assess the useful impacts of Tribulus terrestris (TT) and silymarin (SLM) against carbon tetrachloride (CCL4)-induced hepatotoxicity. Forty-two male rats were partitioned into six groups: group I: received 0.3% CMC-Na in distilled water, group II: TT (500 mg/kg BW, orally), group III: SLM (200 mg/kg, orally) for 14 consecutive days (on days 11 and 12 intraperitoneal corn oil), group IV: CCL4, group V: TT (500 mg/kg BW) plus CCL4, and group VI: SLM (200 mg/kg orally) plus CCL4. The CCL4 was administered (2.0 ml/kg BW) intraperitoneal on days 11 and 12. Sera were collected for assessment of hepatic injury markers and pro-inflammatory cytokines. Additionally, liver tissue oxidative stress, lipid peroxidation, histopathological examination, and immunohistochemical analysis (Bax and bcl-2) were done. CCL4 injection induced significant reductions in hepatic antioxidants while increased hepatic lipid peroxidation as well as serum hepatic injury biomarkers and pro-inflammatory cytokines. The histopathological examination showed necrotic and degenerative changes in the hepatic tissue, while immunohistochemical analysis revealed marked hepatic expression of activated Bax, and bcl-2, following CCL4 injection. TT pretreatment significantly improved all examined parameters and restored the hepatic architecture. The current study illustrated that TT effectively alleviates hepatic oxidative damage, apoptosis, and inflammation, induced by acute CCL4 intoxication. In this manner, TT has promising cytoprotective powers against hepatotoxicity induced by CCL4.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Tribulus , Animais , Antioxidantes , Tetracloreto de Carbono , Inflamação , Peroxidação de Lipídeos , Fígado , Masculino , Estresse Oxidativo , Extratos Vegetais , Ratos
5.
Clin Sci (Lond) ; 134(7): 853-869, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32227122

RESUMO

Angiotensin II (Ang II) has been reported to aggravate hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Alamandine (ALA) protects against fibrosis by counteracting Ang II via the MAS-related G-protein coupled (MrgD) receptor, though the effects of alamandine on hepatic fibrosis remain unknown. Autophagy activated by reactive oxygen species (ROS) is a novel mechanism of hepatic fibrosis. However, whether autophagy is involved in the regulation of Ang II-induced hepatic fibrosis still requires investigation. We explored the effect of alamandine on hepatic fibrosis via regulation of autophagy by redox balance modulation. In vivo, alamandine reduced CCl4-induced hepatic fibrosis, hydrogen peroxide (H2O2) content, protein levels of NOX4 and autophagy impairment. In vitro, Ang II treatment elevated NOX4 protein expression and ROS production along with up-regulation of the angiotensin converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis. These changes resulted in the accumulation of impaired autophagosomes in hepatic stellate cells (HSCs). Treatment with NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine (NAC), and NOX4 small interfering RNA (siRNA) inhibited Ang II-induced autophagy and collagen synthesis. Alamandine shifted the balance of renin-angiotensin system (RAS) toward the angiotensin converting enzyme 2 (ACE2)/alamandine/MrgD axis, and inhibited both Ang II-induced ROS and autophagy activation, leading to attenuation of HSCs migration or collagen synthesis. In summary, alamandine attenuated liver fibrosis by regulating autophagy induced by NOX4-dependent ROS.


Assuntos
Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Células Estreladas do Fígado/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , NADPH Oxidase 4/metabolismo , Oligopeptídeos/farmacologia , Animais , Tetracloreto de Carbono , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colágeno/metabolismo , Células Estreladas do Fígado/enzimologia , Células Estreladas do Fígado/ultraestrutura , Fígado/enzimologia , Fígado/ultraestrutura , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/enzimologia , Cirrose Hepática Experimental/patologia , Masculino , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais
6.
Nat Commun ; 11(1): 1939, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321925

RESUMO

Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.


Assuntos
Acetaminofen/efeitos adversos , Plaquetas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Lectinas Tipo C/imunologia , Neutrófilos/imunologia , Animais , Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Humanos , Lectinas Tipo C/genética , Fígado/efeitos dos fármacos , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
Life Sci ; 253: 117684, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315728

RESUMO

Brain oxidative stress and neuroinflammation have been implicated in various psychiatric disorders. The current study investigated the effect and mechanism of 25-Methoxyhispidol A (25-MHA) against CCl4-induced anxiety and depression. Mice were challenged with CCl4 (1 ml/kg; i.p.) after 30 min of 25-MHA (1, 5 and 10 mg/kg; i.p.) administration. Pretreatment with 25-MHA (10 mg/kg) significantly attenuated the anxiety and depression-like behavior in testing models. The oxidative stress induced by CCl4 was significantly attenuated by pretreatment with 25-MHA. The immunohistochemical (IHC) analysis showed a reduction in kelch-like ECH-associated protein 1 (Keap1) and improvement in expression of nuclear factor erythroid-2-related factor (Nrf-2) and heme oxygenase (HO)-1. In addition, 25-MHA significantly attenuated the CCl4-mediated depletion of antioxidant enzymes in hippocampus (HC) and prefrontal cortex (PFC) region and reduced the expression of toll-like receptor (TLR)-4 and nuclear factor kappa B (NF-κB), along with a decreased production of pro-inflammatory cytokines in HC and PFC region. Pretreatment with 25-MHA also showed an improved expression of neurotrophic factors i.e., brain derived growth factor (BDNF) and vascular endothelial growth factor (VEGF). Furthermore, 25-MHA inhibited malondialdehyde (MDA) and ammonia level in plasma, liver, HC and PFC regions of mice brain. 25-MHA also exhibited anti-apoptotic effect evident from the reduced expression of caspase-3 and decreased hippocampal DNA damage in comet assay. Furthermore, decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and corticosterone level, along with prevention of CCl4-induced alterations in thickness of dentate gyrus and intact hepatic cells morphology, represented by hippocampal and liver histopathology, indicated the neuroprotective effect of 25-MHA.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Tetracloreto de Carbono/toxicidade , Caspase 3/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores/administração & dosagem , Triterpenos/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Life Sci ; 250: 117561, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198052

RESUMO

AIMS: Pyruvate kinase M2 (PKM2), a unique isoform of the pyruvate kinases, not only acts as a crucial metabolic enzyme when it locates in the cytoplasm, but also plays important roles in tumor formation and growth when it accumulates in the nuclei. Our aim was to investigate the potential role of PKM2 in liver regeneration in mice insulted with carbon tetrachloride (CCl4). MATERIAL AND METHODS: The liver regeneration model was established by intraperitoneal injection of CCl4 for 48 h in male BALB/c mice. The expression of PKM2, phospho-STAT3, STAT3, proliferating cell nuclear antigen (PCNA) and Cyclin D1 were evaluated by western blot. The distribution of PKM2 was verified by immunofluorescence staining. The degree of injured region was assessed by hematoxylin and eosin (HE) staining. The proliferation of liver cells was tested by Immunohistochemistry. KEY FINDINGS: The nuclear accumulation of PKM2 increased in the liver treated with CCl4, but treatment with ML-265 significantly suppressed CCl4-induced nuclear accumulation of PKM2. In addition, treatment with ML-265 suppressed the level of cyclin D1 and proliferating cell nuclear antigen (PCNA), reduced the count of Ki67-positive hepatocytes, and expanded the damaged region in histological examination. Meanwhile, treatment with ML-265 suppressed the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 by stattic made the same effects as ML-265. SIGNIFICANCE: These data uncovered the role of nuclear PKM2 in liver regeneration and the pro-proliferation effects of nuclear PKM2 may be through targeting its downstream transcription factor STAT3.


Assuntos
Núcleo Celular/metabolismo , Regeneração Hepática , Piruvato Quinase/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Tetracloreto de Carbono , Proliferação de Células , Citoplasma/metabolismo , Hepatócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo
9.
Zhonghua Gan Zang Bing Za Zhi ; 28(2): 135-140, 2020 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-32164064

RESUMO

Objective: To investigate the mechanism of occurrence and development of zinc-alpha-2-glycoprotein (AZGP1) in the activated hepatic stellate cells (HSCs) and liver fibrosis. Methods: The activated human hepatic stellate cell line LX2 was induced by the stimulation of transforming growth factor - ß1 to construct carbon tetrachloride liver fibrosis mice model. The situation expression of AZGP1 in liver cells and tissues were observed. Plasmid transfection method was used to detect the activation, proliferation, apoptotic functions and changes in related factors of LX2 cells, respectively, after the overexpression and inhibition of AZGP1expression. Univariate analysis of variance was used for multiple group comparison. Results: The results of immunofluorescence staining showed that AZGP1 protein was decreased and α-smooth muscle actin was increased in the activated LX2 cells, and the two were negatively correlated. AZGP1 gene and protein were significantly under-expressed in activated LX2 cells and liver tissues of mice with carbon tetrachloride liver fibrosis. Collagen I, matrix metalloproteinase-2, and α-smooth muscle actin genes and proteins were significantly down-regulated in LX2 cells after over-expression of AZGP1. Cell fluorescence showed that AZGP1-overexpressing cells were activated and α-smooth muscle actin protein was reduced. In addition, the proliferative activity and G1/S-specific cyclin D1 protein of LX2 cells were significantly reduced after overexpression of AZGP1, while cell cycle experiments showed that the proportion of cells overexpressing AZGP1 was significantly increased in the G0/G1 phase, and the proportion of S phase was significantly reduced. AZGP1 had no significant effect on the apoptosis of LX2 cells. Conclusion: AZGP1 can reverse liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells, and thereby overexpression of AZGP1 is expected to become a new target for liver fibrosis treatment.


Assuntos
Tetracloreto de Carbono/toxicidade , Proliferação de Células/efeitos dos fármacos , Glicoproteínas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Actinas , Animais , Glicoproteínas/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática , Metaloproteinase 2 da Matriz , Camundongos , Zinco
10.
Life Sci ; 248: 117475, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32119963

RESUMO

AIMS: Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. MAIN METHODS: Hepatic fibrosis was induced by CCl4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. KEY FINDINGS: APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. SIGNIFICANCE: APG can ameliorate CCl4-induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product.


Assuntos
Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Bilirrubina/sangue , Tetracloreto de Carbono/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteômica/métodos , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Mol Biotechnol ; 62(4): 260-272, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32144553

RESUMO

Pre-existing immune response against adenovirus could diminish transgene expression efficiency when Ad is employed in humans as gene therapy vector. We previously used Ad-hΔuPA (Recombinant adenovirus expressing human urokinase-type plasminogen activator) as antifibrotic gene therapy in cirrhosis models and demonstrated its effectiveness. As a further clinical approach, transient Cyclosporine A (CsA) immunosuppression was induced in cirrhotic animals to determine whether Ad-hΔuPA administration retained efficacy. Adenovirus sensitization was achieved by systemic administration of non-therapeutic Ad-ßGal (Recombinant adenovirus expressing beta-galactosidase) after 4 weeks of intraperitoneal carbon tetrachloride (CCl4) regimen. Cirrhosis induction continued up to 8 weeks. At the end of CCl4 intoxication, immunosuppression was achieved with three CsA doses (40 mg/kg) as follows: 24 h before administration of Ad-hΔuPA, at the moment of Ad-hΔuPA injection and finally, 24 h after Ad-hΔuPA inoculation. At 2 and 72 h after Ad-hΔuPA injection, animals were sacrificed. Liver, spleen, lung, kidney, heart, brain, and testis were analyzed for Ad-biodistribution and transgene expression. In naïve animals, Ad-hΔuPA genomes prevailed in liver and spleen, while Ad-sensitized rats showed Ad genomes also in their kidney and heart. Cirrhosis and Ad preimmunization status notably diminished transgene liver expression compared to healthy livers. CsA immunosuppression in cirrhotic animals has no effect on Ad-hΔuPA biodistribution, but increments survival.


Assuntos
Adenoviridae/genética , Adenoviridae/metabolismo , Cirrose Hepática/terapia , Ativador de Plasminogênio Tipo Uroquinase/genética , Animais , Tetracloreto de Carbono/administração & dosagem , Ciclosporina/uso terapêutico , Terapia Genética , Imunização , Imunossupressores/uso terapêutico , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Ratos , Distribuição Tecidual , Transgenes , Ativador de Plasminogênio Tipo Uroquinase/farmacocinética
12.
Environ Sci Pollut Res Int ; 27(12): 13180-13193, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32016862

RESUMO

Currently, hepatic injury due to environmental pollutants extremely threatens human health and elicits great concern. Hence, there is a high global interest to find natural novel formulation products with potent hepatoprotective activity to combat liver disease. Hence, we evaluated the protective or therapeutic effect of hesperidin (HSP) and taurine (TAU), individually and in combination, on carbon tetrachloride (CCl4)-induced acute hepatic injury in rats. The pre- or posttreatment by HSP and/or TAU significantly depressed CCl4-induced elevation of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, total bilirubin, direct bilirubin, indirect bilirubin, malondialdehyde, globulins (α1, α2, ß, and γ), albumin/globulin ratio, triglycerides, total cholesterol, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, nitric oxide, and myeloperoxidase levels. Also, the pre- or posttreatment by HSP and/or TAU significantly minimized CCl4-induced reduction of superoxide dismutase, catalase, reduced glutathione, and albumin concentrations. Furthermore, the protective or therapeutic administration of HSP and/or TAU markedly restored the CCl4-induced altered hepatic architecture, depleted glycogen, and DNA contents. Notably, alleviating CCl4-induced hepatotoxicity was more prominent in the protective groups than the therapeutic groups. More importantly, most of biochemical and histopathological parameters of HSP+TAU did not significantly differ from those of separate TAU or HSP neither before nor after CCl4 exposure. Conclusively, HSP or TAU could be candidate protective agents against CCl4 hepatotoxic impacts but the combination of both bioactive offers only a limited synergistic effect. Graphical abstract.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hesperidina , Alanina Transaminase , Animais , Antioxidantes , Aspartato Aminotransferases , Tetracloreto de Carbono , Humanos , Fígado , Estresse Oxidativo , Extratos Vegetais , Ratos , Taurina
13.
Sci Total Environ ; 712: 135679, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-31785913

RESUMO

In the transition zone between aquifers and aquitards, DNAPL pools of carbon tetrachloride and chloroform accumulate because of heterogeneity in this zone. Natural attenuation occurs at pools and plumes, indicating that remediation might be possible. The aims of the study were: i) to assess the role of heterogeneity in the natural attenuation of these compounds, ii) determine degradation processes within this zone, and iii) identify dechlorinating microorganisms. For this, groundwater concentrations, redox-sensitive parameters, CSIA isotopic and DGGE molecular techniques were used. The main findings at depth of the transition zone were: (1) the important key control played by heterogeneity on natural attenuation of contaminants. (2) Heterogeneity caused the highly anoxic environment and dominant sulfate-reducing conditions, which accounts for more efficient natural attenuation. (3) Heterogeneity also explains that the transition zone constitutes an ecotone. (4) The bacteria size exclusion is governed by the pore throat threshold and determines the penetration of dechlorinating microorganisms into the finest sediments, which is relevant, since it implies the need to verify whether microorganisms proposed for bioremediation can penetrate these materials. (5) Reductive dechlorination caused the natural attenuation of contaminants in groundwater and porewater of fine sediments. In the case of carbon tetrachloride, it was an abiotic process biogenically mediated by A. suillum, a bacterium capable of penetrating the finest sediments. In the case of chloroform, it was a biotic process performed by a Clostridiales bacterium, which is unable to penetrate the finest materials. (6) Both microorganisms have potential to be biostimulated to dechlorinate contaminants in the source and the plume in the transition zone. These outcomes are particularly relevant given the longevity of DNAPL sources and have considerable environmental implications as many supply wells in industrial areas exploit aquifers contaminated by chlorinated solvents emerging from DNAPL pools accumulated on the low-conductivity layers in transition zones.


Assuntos
Água Subterrânea , Biodegradação Ambiental , Tetracloreto de Carbono , Clorofórmio , Poluentes Químicos da Água , Poços de Água
14.
Chem Biodivers ; 17(1): e1900534, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31730730

RESUMO

Brassica rapa L., also called NIUMA, is used empirically in Tibetan medicine for its antioxidant, anti-inflammatory and antiradiation activities. This study explored the hepatoprotective effects of B. rapa polysaccharides (BRPs) on acute liver injury induced by carbon tetrachloride (CCl4 ) in mice and the underlying mechanisms. Mice were treated with CCl4 after the oral administration of BRPs (55, 110 and 220 mg/kg) or bifendate (100 mg/kg) for 7 days. Blood and liver samples of mice were collected for analysis after 24 h. The ALP, ALT and AST levels and the biological activities of SOD, MDA and GSH-Px were measured. Histopathological changes in the liver were determined through hematoxylin and eosin staining. Moreover, TNF-α, IL-1ß and IL-6 expression levels were detected by commercial reagent kits. Finally, Western blot analysis was used to check the relative expression levels of caspase-3, p-JAK2 and p-STAT3. The BRP pre-treatment significantly decreased the enzymatic activities of ALT, ALP and AST in the serum, markedly increased the activities of SOD and GSH-Px in the liver and reduced the MDA concentration in the liver. BRPs alleviated hepatocyte injury and markedly inhibited the expression of TNF-α, IL-1ß and IL-6, also downregulating the CCl4 -induced hepatic tissue expression of caspase-3. Furthermore, BRPs inhibited the JAK2/STAT3 signaling pathway in a dose-dependent manner in the liver. This study demonstrated that BRPs exert hepatoprotective effect against the CCl4 -induced liver injury via modulating the apoptotic and inflammatory responses and downregulating the JAK2/STAT3 signaling pathway. Therefore, B. rapa could be considered a hepatoprotective medicine.


Assuntos
Apoptose/efeitos dos fármacos , Brassica rapa/química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Citocinas/análise , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/antagonistas & inibidores , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Polissacarídeos/administração & dosagem
15.
Scand J Immunol ; 91(4): e12851, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31733121

RESUMO

Acute liver injury is a common pathological basis for a variety of acute liver diseases in the clinic, which can eventually lead to liver fibrosis and even liver failure. In this study, we found that T cell Ig and mucin domain protein 3 (Tim-3) and TLR4 receptors play important roles in CCl4-induced acute liver injury. Tim-3 is a negative regulator that is expressed by T cells and macrophages. Using antibodies against Tim-3 (anti-Tim-3 Ab), we studied the Tim-3 signal in an animal model of acute liver injury and found that a large number of inflammatory factors were upregulated. In vitro experimental data shown that anti-Tim-3 Ab treatment increased interferon-É£ production by concanavalin A (ConA)-stimulated spleen T cells, and we found that the expression level of interleukin (IL)-6 was increased in a macrophage/spleen T cell coculture system, while administration of galectin-9 (Gal-9, a Tim-3 ligand) reduced the IL-6 production. This indicates the importance of the Tim-3/Gal-9 signalling pathway in maintaining hepatic homeostasis. The Tim-3 signalling pathway inhibits TLR4-mediated NF-κB activity, and an anti-Tim-3 Ab does not affect the liver injury in TLR4-deficient mice. Regulation between Tim-3 and TLR4 determines the severity of liver damage. The negative regulation of Tim-3 reflects the protective mechanisms of patients with impaired liver function, and these results provide important information about innate and adaptive responses in the regulation of liver damage. This finding is potentially important for the study of early liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/imunologia
16.
J Dairy Sci ; 103(2): 1884-1893, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837790

RESUMO

Buffalo skim milk retentate was hydrolyzed with papain for 4 h (enzyme:substrate, 1:200), resulting in a retentate hydrolysate (RH) with a degree of hydrolysis of 23%. We then investigated the potential hepatoprotective activity of RH at 250 and 500 mg/kg of body weight per day on carbon tetrachloride (CCl4)-induced oxidative stress in albino rats. Liver biomarkers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase), kidney biomarkers (urea, creatinine), and serum lipid profile (total lipids and triglycerides) were measured, in addition to histopathological status. Injection of CCl4 significantly increased all liver and kidney biomarkers compared with the negative control. In contrast, CCl4 injection significantly reduced hepatic antioxidant enzyme activities; that is, glutathione peroxidase and superoxide dismutase. Oral administration of RH for 28 d effectively maintained a physiologically normal range of liver and kidney biomarkers compared with the positive control. Furthermore, RH administration significantly increased activities of glutathione peroxidase and superoxide dismutase. Histopathological sections of CCl4-stressed rats treated with RH were different from that of the positive control and were similar to those of the negative control, in a concentration-dependent manner. Our results demonstrated the antihepatotoxic activities of buffalo milk RH and demonstrated that the higher RH concentration (500 mg/kg of body weight per day) could maintain the healthy biological status of the CCl4-injected rats.


Assuntos
Antioxidantes/metabolismo , Biomarcadores/metabolismo , Búfalos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Proteínas do Leite/química , Papaína/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Hidrólise , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos
17.
Immunity ; 52(1): 96-108.e9, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31810881

RESUMO

Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl4) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-γ (IFN-γ) and protected mice from CCl4-induced acute liver injury. IFN-γ released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-γ production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-γ production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos/metabolismo , Interferon gama/imunologia , Fígado/citologia , Linfócitos/imunologia , Proteína bcl-X/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Feminino , Subunidade p35 da Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Fígado/lesões , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
J Nat Med ; 74(1): 17-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31280460

RESUMO

To date, there are very few effective drugs for liver fibrosis treatment; therefore, it is urgent to develop novel therapeutic targets and approaches. In the present research, we sought to study the protective effect of sweroside contained in Lonicera japonica or blue honeysuckle berries in a mouse model of liver fibrosis and investigate the underlying mechanism. The mouse model of liver fibrosis in was induced by intraperitoneal injections of 10% CCl4 for 6 weeks (three times/week). At the beginning of the fourth week, sweroside was intragastrically administered once a day and at the end of the treatment, biochemical and histological studies were investigated. The expression of FXR, miR-29a and the downstream targets were analyzed as well. Moreover, the effect of sweroside on cell proliferation was observed in human hepatic stellate cells (HSCs) (LX-2), along with using the siRNA for FXR and miR-29a inhibitor to investigate the underpinning of the anti-fibrotic effect of sweroside. Sweroside successfully protected the liver fibrosis in CCl4-induced mouse model, accompanied by miR-29a induction. Furthermore, sweroside also induced miR-29a in HSCs, resulting in the inhibition of COL1 and TIMP1. Our data also showed that either silencing miR-29a or knockdown of FXR in LX-2 cell abolished the inhibition of COL1 and TIMP1 as well as the inhibition of cell proliferation by sweroside treatment. In conclusion, sweroside exerted its anti-fibrotic effect in vivo and in vitro by up-regulation of miR-29a and repression of COL1 and TIMP1, which was at least in part through FXR.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Glucosídeos Iridoides/uso terapêutico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Proteínas de Ligação a RNA/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Glucosídeos Iridoides/farmacologia , Cirrose Hepática/patologia , Masculino , Camundongos , Transdução de Sinais
19.
Food Chem Toxicol ; 135: 111014, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794804

RESUMO

Chemical liver and kidney injury have become a serious concern to human. Side effects occur when they are treated with medicine. The present study evaluated the preventive effect of Cyclocarya paliurus polysaccharides (CP) on hepatic and renal injury in carbon tetrachloride (CCl4) induced mice. The results showed that CP treatment could effectively prevent H2O2-induced oxidative damage of NCTC-1469 cells. Administrated with CP could ameliorate the body weight loss and organ swelling of mice induced by the 0.2% CCl4. Compared with the model group, CP groups have beneficial effects in decreasing ALT, AST, TBA and CRE levels in serum. In addition, the expression of CYP2E1 in the liver was also significantly decline after continuous administration of CP. Moreover, pre-administration of CP can improve the antioxidant status of liver and kidney (MDA and SOD, GSH-Px). Histopathological studies also supported the improvement of CP on liver and kidney of CCl4-induced mice. These results indicate that CP may be of therapeutic value in ameliorating the hepatic and renal oxidative stress caused by CCl4, through its antioxidant properties.


Assuntos
Tetracloreto de Carbono/toxicidade , Juglandaceae/química , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Linhagem Celular , Citocromo P-450 CYP2E1/metabolismo , Glutationa Peroxidase/metabolismo , Hepatócitos/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Rim/metabolismo , Rim/patologia , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Superóxido Dismutase/metabolismo
20.
Cell Prolif ; 53(1): e12731, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31755616

RESUMO

OBJECTIVES: T-cell immunoglobulin domain and mucin domain-4 (TIM-4) is selectively expressed on antigen-presenting cells (APCs) and modulates various immune responses. However, the role of TIM-4 expressed by Kupffer cells (KCs) in liver fibrosis remains unclear. The present study aimed to explore whether and how TIM-4 expressed by KCs is involved in liver fibrosis. MATERIALS AND METHODS: Mice chronic liver fibrosis models were established and divided into the olive-induced control group, CCL4-induced control group, olive-induced TIM-4 interference group and CCL4-induced TIM-4 interference group. Different techniques were used to monitor the fibrotic effects of TIM-4, including histopathological assays, Western blotting, ELISA and transmission electron microscopy. Additionally, mice liver transplant models were established to determine the fibrotic effects of TIM-4 on fibrosis after liver transplantation (LT). RESULTS: We found that the induction of liver fibrosis by CCL4 was associated with TIM-4 expression in KCs. TIM-4 interference essentially contributed to liver fibrosis resolution. KCs from the TIM-4 interference group had decreased levels of pro-fibrotic markers, reduced TGF-ß1 secretion and inhibited hepatic stellate cell (HSC) differentiation into myofibroblast-like cells. In addition, we used GdCl3 to verify that KCs are the primary source of TGF-ß1 during fibrosis progression. Moreover, KCs from CCL4-induced mice showed increased ROS production, mitophagy activation and TGF-ß1 secretion. However, TIM-4 interference in the KCs inhibited Akt1-mediated ROS production, resulting in the suppression of PINK1, Parkin and LC3-II/I activation and the reduction of TGF-ß1 secretion during liver fibrosis. Additionally, TIM-4 interference potentially attenuated development of fibrosis after LT. CONCLUSIONS: Our findings revealed the underlying mechanisms of TIM-4 interference in KCs to mitigate liver fibrosis.


Assuntos
Intoxicação por Tetracloreto de Carbono/metabolismo , Macrófagos do Fígado/metabolismo , Cirrose Hepática/metabolismo , Proteínas de Membrana/metabolismo , Mitofagia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono/toxicidade , Intoxicação por Tetracloreto de Carbono/patologia , Modelos Animais de Doenças , Macrófagos do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos
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