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1.
Zhonghua Gan Zang Bing Za Zhi ; 29(1): 67-71, 2021 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-33541026

RESUMO

Objective: To investigate the protective effect of Colgalt2 gene deletion on acute liver injury induced by acetaminophen (APAP) in mice. Methods: Colgalt2(+/+) wild-type control mice and Colgalt2(-/-) mice (all C57BL/6J strains) were selected as the research subject. APAP solution was injected intraperitoneally to establish a mouse model of acute liver injury. The mouse were divided into four groups: Colgalt2(+/+) wild-type control group, Colgalt2(+/+) wild-type drug group (APAP 500 mg/kg), Colgalt2(-/-) control group, and Colgalt2(-/-) drug group (APAP 500 mg/kg). The survival rate was measured to plot survival curve. Liver function was evaluated by detecting serum ALT and AST levels. Liver histopathological changes were observed by HE staining to evaluate the condition of liver injury. Western blot was used to detect protein c-Jun N-terminal kinase (JNK)-related liver injury. Results: Compared with Colgalt2(+/+) mice, the survival rate was significantly increased after giving APAP to Colgalt2(-/-) mice (86.7% vs. 40%), and liver cell necrosis and inflammatory cell infiltrates of Colgalt2(+/+) mice were milder. Serum ALT, and AST level was significantly decreased [ALT: (5 291.9 ± 1 016.34) U/L vs. (1 616.9 ± 330.65) U/L, P = 0.000; AST: (4 978.0 ± 1 028.43) U/L vs. (1 851.0 ± 437.55) U/L, P = 0.000]. The expression level of JNK was significantly decreased in liver tissue. Conclusion: Colgalt2 gene deletion has a protective effect on acute liver injury induced by acetaminophen (APAP) in mice. Therefore, Colgalt2 may be a potential therapeutic option for acetaminophen-induced hepatotoxicity.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/efeitos adversos , Acetaminofen/metabolismo , Animais , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Deleção de Genes , Glicosiltransferases/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo
2.
Ecotoxicol Environ Saf ; 208: 111725, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396056

RESUMO

Aflatoxin B1 (AFB1) is a potent hepatotoxic and carcinogenic agent. Curcumin possesses potential anti-inflammatory, anti-oxidative and hepatoprotective effects. However, the role of LncRNAs in the protective mechanisms of curcumin against AFB1-induced liver damage is still elusive. Experimental broilers were randomly divided into 1) control group, 2) AFB1 group (1 mg/kg feed), 3) cur + AFB1 group (1 mg/kg AFB1 plus 300 mg/kg curcumin diet) and 4) curcumin group (300 mg/kg curcumin diet). Liver transcriptome analyses and qPCR were performed to identify shifts in genes expression. In addition, histopathological assessment and oxidant status were determined. Dietary AFB1 caused hepatic morphological injury, significantly increased the production of ROS, decreased liver antioxidant enzymes activities and induced inflammation and apoptosis. However, dietary curcumin partially attenuated the abnormal morphological changes, oxidative stress, and apoptosis in liver tissues. Transcriptional profiling results showed that 34 LncRNAs and 717 mRNAs were differentially expressed with AFB1 and curcumin co-treatment in livers of broilers. Analysis of the LncRNA-mRNA network, GO and KEGG enrichment data suggested that oxidative stress, inflammation and apoptosis pathway were crucial in curcumin's alleviating AFB1-induced liver damage. In conclusion, curcumin prevented AFB1-induced oxidative stress, inflammation and apoptosis through LncRNAs. These results provide new insights for unveiling the protective mechanisms of curcumin against AFB1-induced liver damage.


Assuntos
Aflatoxina B1/toxicidade , Curcumina/farmacologia , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Galinhas/metabolismo , Dieta , Inflamação/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia
3.
Ecotoxicol Environ Saf ; 207: 111266, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32919194

RESUMO

Microcystin-LR (MC-LR) is a potent hepatotoxin that can cause liver inflammation and injury. However, the mode of action of related inflammatory factors is not fully understood. PfHMGB1 is an inflammatory factor induced at the mRNA level in the liver of juvenile yellow catfish (Pelteobagrus fulvidraco) that were intraperitoneally injected with 50 µg/kg MC-LR. The PfHMGB1 mRNA level was highest in the liver and muscle among 11 tissues examined. The full-length cDNA sequence of PfHMGB1 was cloned and overexpressed in E. coli, and the purified protein rPfHMGB1 demonstrated DNA binding affinity. Endotoxin-free rPfHMGB1 (6-150 µg/mL) also showed dose-dependent hepatotoxicity and induced inflammatory gene expression of primary hepatocytes. PfHMGB1 antibody (anti-PfHMGB1) in vitro reduced MC-LR (30 and 50 µmol/L)-induced hepatotoxicity, suggesting PfHMGB1 is important in the toxic effects of MC-LR. In vivo study showed that MC-LR upregulated PfHMGB1 protein in the liver. The anti-PfHMGB1 blocked its counterpart and reduced ALT/AST activities after MC-LR exposure. Anti-PfHMGB1 partly neutralized MC-LR-induced hepatocyte disorganization, nucleus shrinkage, mitochondria, and rough endoplasmic reticula destruction. These findings suggest that PfHMGB1 promotes MC-LR-induced liver damage in the yellow catfish. HMGB1 may help protect catfish against widespread microcystin pollution.


Assuntos
Peixes-Gato/fisiologia , Fígado/efeitos dos fármacos , Toxinas Marinhas/toxicidade , Microcistinas/toxicidade , Animais , Peixes-Gato/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , DNA Complementar/metabolismo , Escherichia coli/genética , Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatopatias , Proteínas/metabolismo , RNA Mensageiro/metabolismo
4.
Environ Sci Pollut Res Int ; 27(34): 43028-43043, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32725563

RESUMO

Current research was performed to explore the hepatoprotective potential of Moringa oleifera leaves extract on lead acetate-induced hepatic injury. Twenty-four male Wistar rats were divided equally into 4 groups. The first group was control, while the second, third, and fourth groups were given 200 mg/kg aqueous Moringa extract only, 100 mg/kg lead only, and 100 mg/kg lead plus 200 mg/kg aqueous Moringa leaves extract, respectively, via oral gavage for 4 weeks. Weight gain and feed efficiency ratio were recorded. Serum lipid profiles, liver enzyme activities, and proteins beside hepatic superoxide dismutase activity, reduced glutathione, tumor necrosis factor alpha (TNF-α), and deoxyribonucleic acid fragmentation were assessed. Liver histopathological examination and nuclear factor kappa B (NF-kB) immunohistochemistry were performed. Administration of lead lowered (P < 0.05) weight gain, feed efficiency ratio, and perturbed lipid profile than control. Lead increased liver enzyme activities and TNF-α, while reduced serum proteins and hepatic antioxidant markers compared to control. Lead aggravated hepatic DNA fragmentation beside the presence of histopathological lesions. Co-administration of aqueous Moringa extract with lead significantly alleviated lead-induced adverse effects. The administration of aqueous Moringa extract with its antioxidant significantly restored the lead perturbations through reduction of oxidative stress-induced DNA damage via amelioration of NF-kB and TNF-α which kept hepatocyte integrity and reduced serum hepatic enzyme activities.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Moringa oleifera , Acetatos/metabolismo , Animais , Antioxidantes/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Chumbo/metabolismo , Fígado/metabolismo , Masculino , Estresse Oxidativo , Extratos Vegetais/metabolismo , Folhas de Planta , Ratos , Ratos Wistar
5.
Environ Toxicol ; 35(11): 1251-1259, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32677766

RESUMO

Isatidis Folium (IF) has been clinically combined with acetaminophen (APAP), but the rationality of combinational therapy is still ambiguous. In the present study, the protective effect and related mechanism of IF on APAP-induced hepatotoxicity were evaluated. Hepatic histopathology and blood biochemistry investigations clearly demonstrated that IF could restore APAP-induced hepatotoxicity. Liver distribution study indicated that the hepatoprotective effect of IF on APAP is attributed to the reduction of N-acetyl-p-benzoquinone imine (NAPQI) in liver, which is a known hepatotoxic metabolite of APAP. Further study suggested the reduction is not via decreasing the generation of NAPQI through inhibiting the enzyme activities of CYP 1A2, 2E1, and 3A4 but via accelerating the transformation of NAPQI to NAPQI-GSH by promoting GSH and decreasing GSSG contents in liver. Furthermore, IF significantly enhanced the hepatic activities of GSH-associated enzymes in APAP-treated mice. In summary, IF could alleviate APAP-induced hepatotoxicity by reducing the content of NAPQI via enhancing the level of GSH and the followed generation of NAPQI-GSH which might be ascribed to the upregulation of GSH-associated enzymes.


Assuntos
Acetaminofen/toxicidade , Antioxidantes/metabolismo , Extratos Vegetais/farmacologia , Acetaminofen/metabolismo , Animais , Benzoquinonas , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP1A2 , Glutationa/metabolismo , Iminas , Fígado/efeitos dos fármacos , Masculino , Camundongos , Folhas de Planta
6.
Life Sci ; 256: 117908, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512011

RESUMO

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glucosídeos/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Compostos Benzidrílicos/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Descoberta de Drogas , Etanol/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucinas/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , Superóxido Dismutase/metabolismo
7.
FASEB J ; 34(1): 676-690, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914696

RESUMO

Sodium valproate (VPA), an antiepileptic drug, may cause dose- and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations. Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment.


Assuntos
Ácido Butírico/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Anticonvulsivantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Valproico/farmacologia
8.
Oxid Med Cell Longev ; 2020: 4054520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998436

RESUMO

Aronia melanocarpa (AM), which is rich in anthocyanins and procyanidins, has been reported to exert antioxidative and anti-inflammatory effects. This study aimed to systematically analyze the components of AM and explore its effects on alcohol-induced chronic liver injury in mice. A component analysis of AM revealed 17 types of fatty acids, 17 types of amino acids, 8 types of minerals, and 3 types of nucleotides. Chronic alcohol-induced liver injury was established in mice via gradient alcohol feeding over a period of 6 months, with test groups orally receiving AM in the last 6 weeks. AM administration yielded potential hepatoprotective effects by alleviating weight gain and changes in organ indexes, decreasing the ratio of alanine aminotransferase/aspartate aminotransferase, reducing lipid peroxidation, enhancing antioxidant activities, decreasing oxidation-related factor levels, and regulating inflammatory cytokine levels. Histological analyses suggest that AM treatment markedly prevented organ damage in alcohol-exposed mice. Furthermore, AM activated nuclear factor erythroid 2-like 2 (Nrf2) by downregulating the expression of Kelch-like ECH-associated protein 1, resulting in elevated downstream antioxidative enzyme levels. AM activated Nrf2 via modulation of the phosphatidylinositol-3-hydroxykinase/protein kinase B signaling pathway. Altogether, AM prevented alcohol-induced liver injury, potentially by suppressing oxidative stress via the Nrf2 signaling pathway.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Etanol/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo , Photinia/química , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Modelos Animais de Doenças , Etanol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química
9.
Phytomedicine ; 74: 152697, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30392748

RESUMO

BACKGROUND: Phellinus igniarius (L.) Quèl as a potential medicinal mushroom possesses multiple biological activities including hepatoprotection, but the hepatoprotective mechanism is not clear. PURPOSE: To elucidate the hepatoprotective effect and potential target of P. igniarius. METHODS: The male C57BL/6 mice were fed with the Lieber-DeCarli diet containing alcohol or isocaloric maltose dextrin as control diet with or without P. igniarius decoction (PID) in the dosage of 0.65 g/kg and 2.6 g/kg. The levels of serum biomarkers were detected by an automatic biochemistry analyser. The histopathological changes of liver were observed by hematoxylin and eosin (H&E) staining. Ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was applied for investigating the dynamic changes of serum metabolites in chronic ethanol-induced liver injury mice and after treatment with PID. Ingenuity pathway analysis (IPA) was employed to identify the potential target of PID. RESULTS: PID could significantly reduce the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and total bile acid (TBA) in serum and improved hepatic steatosis and inflammation. In terms of metabolism, a total of 36 serum differential metabolites were identified, and PID intervention regulated 24 of them, involving the key metabolic pathways such as the biosynthesis of unsaturated fatty acids, primary bile acid biosynthesis, glycerophospholipid metabolism, fatty acids biosynthesis, ether lipid metabolism and arachidonic acid metabolism. On the mechanism, IPA showed that farnesol X receptor (FXR) was the major potential target for PID, and PID could improve chronic alcohol intake induced by the inhibition of mRNA expression of FXR in the liver and the activation of mRNA expression of FXR in the intestine in mice. CONCLUSION: The present study for the first time systematically illustrated the hepatoprotective effect of P. igniarius and preliminarily explored its potential target FXR. P. igniarius might be exploited as a promising therapeutic option for alcoholic liver injury.


Assuntos
Basidiomycota/química , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Substâncias Protetoras/farmacologia , Animais , Ácido Araquidônico/metabolismo , Ácidos e Sais Biliares/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Cromatografia Líquida/métodos , Etanol/toxicidade , Metabolismo dos Lipídeos , Hepatopatias Alcoólicas/patologia , Masculino , Espectrometria de Massas/métodos , Redes e Vias Metabólicas , Metabolômica/métodos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/química
10.
Am J Pathol ; 190(1): 158-175, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733185

RESUMO

Chronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver injury remain unclear. To determine the role of adipose autophagy and mechanistic target of rapamycin (mTOR) in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (KO), adipocyte-specific mTOR KO, adipocyte-specific Raptor KO, and adipocyte-specific tuberous sclerosis complex 1 KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type mice were challenged with chronic-plus-binge alcohol mouse model. Chronic-plus-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in wild-type mice. Adipocyte-specific Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither adipocyte-specific mTOR nor adipocyte-specific tuberous sclerosis complex 1 KO mice exhibited similar detrimental effects. Adipocyte-specific Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 and adiponectin and were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice.


Assuntos
Tecido Adiposo/patologia , Atrofia/patologia , Autofagia , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Etanol/toxicidade , Serina-Treonina Quinases TOR/fisiologia , Animais , Anti-Infecciosos Locais/toxicidade , Atrofia/etiologia , Atrofia/metabolismo , Proteína 5 Relacionada à Autofagia/fisiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Regulatória Associada a mTOR/fisiologia , Transdução de Sinais , Proteína 1 do Complexo Esclerose Tuberosa/fisiologia
11.
Biol Pharm Bull ; 43(1): 145-152, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31666439

RESUMO

Schisandra chinensis is widely used and effective in protecting liver. There are many mechanisms of drug-induced hepatocyte injury, among which endoplasmic reticulum (ER) stress-induced cell injury plays an important role. However, little is known about whether schisandra chinensis can inhibit rifampicin (RFP)-induced hepatocyte injury by affecting ER stress. In our study, firstly, L02 cells were treated with different concentrations of RFP for different time intervals, and the apoptosis, survival rate and endoplasmic reticulum stress gene and protein expressions of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), activating transcription factor (ATF)4, C/EBP-homologus protein (CHOP), ATF6, arginine-rich, mutated in early stage tumors (ARMET), p-inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP-1) were measured. We found that RFP increased apoptosis of L02 cells, decreased cell survival, and increased the gene and protein expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET, p-IRE1 and XBP-1, suggesting that RFP could induce hepatocyte injury, and the degree of injury was positively correlated with the dose and time of RFP. Next, we treated RFP-damaged hepatocytes with schizandrin B. We found that schizandrin B increased cell survival rate in dose-dependent and time-dependent manner, decreased cell apoptosis rate, and reduced protein and gene expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET and XBP-1. These results indicate that schizandrin B alleviates RFP-induced injury in L02 cells by inhibiting ER stress.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Ciclo-Octanos/isolamento & purificação , Ciclo-Octanos/farmacologia , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/genética , Hepatócitos/metabolismo , Humanos , Lignanas/isolamento & purificação , Compostos Policíclicos/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Schisandra/química
12.
J Food Sci ; 84(10): 3027-3036, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31529805

RESUMO

This study aimed to investigate the effect of Se (Selenium) treatment on nutritional quality in radish sprouts. The results showed that 15 µM sodium selenite significantly increased phenolics compounds, flavonoids compounds, anthocyanins, and some essential amino acid content, while improving the total antioxidant capacity of radish sprouts. Besides, the Se-enriched radish sprouts significantly alleviated the liver damage caused by carbon tetrachloride (CCl4 ) in mice and improved the antioxidant capacity of the liver in mice, whereas the Se-enriched radish sprouts alleviated the inflammatory reaction and apoptosis caused by CCl4 . These results imply that Se-enriched radish sprouts have a positive impact on mice with CCl4 -induced liver injury, and that in future Se-enriched radish sprouts could be developed into an effective food and health care product for the liver injury prevention. PRACTICAL APPLICATION: Because selenium is an essential trace element in the human body, selenium-enriched sprouts can help eliminate free radicals in the body, relieve aging, and selenium-deficient diseases. They are easy to grow and have low costs. Hence, selenium-enriched sprouts have a great potential of being widely consumed.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Crônica Induzida por Substâncias e Drogas/dietoterapia , Substâncias Protetoras/metabolismo , Raphanus/metabolismo , Selênio/metabolismo , Animais , Antocianinas/análise , Antocianinas/metabolismo , Antioxidantes/análise , Antioxidantes/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Flavonoides/análise , Flavonoides/metabolismo , Humanos , Fígado/metabolismo , Masculino , Fenóis/análise , Fenóis/metabolismo , Substâncias Protetoras/análise , Raphanus/química , Raphanus/crescimento & desenvolvimento , Ratos , Ratos Wistar , Plântula/química , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Sementes/química , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Selênio/análise
13.
Int J Biol Macromol ; 137: 346-357, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31260769

RESUMO

Oxidative stress plays a central role in the incidence of liver injury. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a key protein regulator of antioxidant response elements (ARE)-mediated gene expression. Thus, Nrf2 can be regarded as a plausible therapeutic target during liver injury. ß-Carotene is implicated as one of the important antioxidant with diverse health benefits. The delivery of ß-carotene to the target tissue has been debatable due to its low bioavailability, poor water solubility and instability. Here, a nanocomposite of ß-carotene with reduced graphene oxide (ßC-rGO) has been developed to demonstrate its pronounced effect in regulating Nrf2 to trigger protection against diethylnitrosamine (DEN)-induced hepatic fibrosis in rats. The rGO and ßC-rGO samples were characterised by scanning electron microscopy (SEM), energy dispersive X-ray (EDX), transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy. Progress of disease was monitored through ultrasonography, in vitro liver and serum biochemistry (alanine transaminase, aspartate transaminase, alkaline phosphatase, bilirubin, lipid peroxidation, protein carbonyls, superoxide dismutase, catalase, glutathione-S-transferase, Nrf2, vitamin-A, retinol dehydrogenase), histopathology, confocal and ultrastructural studies. In fibrotic animals liver biochemistry was significantly altered along with massive changes in liver anatomy. ßC-rGO ameliorates experimental fibrogenesis and restores liver functioning due to increased availability of ß-carotene in the liver. It is suggested that ßC-rGO nanocomposite promotes cellular antioxidant status via upregulation of Nrf2 protein factor and invigorate hepatic stellate cells (HSCs) through restoring vitamin-A.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Dietilnitrosamina/efeitos adversos , Grafite , Fator 2 Relacionado a NF-E2/metabolismo , Nanocompostos/química , beta Caroteno/administração & dosagem , Animais , Biomarcadores , Doença Hepática Crônica Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Modelos Animais de Doenças , Grafite/química , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Função Hepática , Masculino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Ratos , Ultrassonografia , beta Caroteno/química
14.
Pharmacol Rep ; 71(4): 746-752, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31220735

RESUMO

BACKGROUND: Methotrexate (MTX) is used commonly in the treatment of various cancers and inflammatory diseases; nevertheless, the associated hepatotoxicity has limited its clinical application. Crocin (CRO) is described as a natural carotenoid with analgesic, antioxidant, and antiinflammatory properties. This study aimed to determine the effects of CRO on MTX-induced hepatotoxicity. METHODS: For pretreatment, CRO at doses of 25 and 50 mg/kg (po), as well as 20 mg/kg (ip) of MTX, was injected in rats. RESULTS: MTX led to hepatotoxicity, as confirmed by the significant increase in liver markers, histopathological changes, decreased GSH content, and reduced antioxidant enzyme activity (i.e., CAT, SOD, and GPx). It increased TNF-α, IL-1ß, lipid peroxidation, and nitric oxide levels. Nevertheless, by increasing antioxidant defense in hepatic tissues and reducing oxidative stress and proinflammatory mediators, pretreatment with CRO could alleviate hepatotoxicity. CONCLUSION: CRO can inhibit MTX-induced hepatotoxicity through improving antioxidant defense and reducing oxidative stress and inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Antimetabólitos Antineoplásicos/toxicidade , Carotenoides/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Metotrexato/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/sangue , Doença Hepática Crônica Induzida por Substâncias e Drogas/imunologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Relação Dose-Resposta a Droga , Inflamação , Masculino , Estresse Oxidativo/imunologia , Ratos Wistar
15.
Cell Res ; 29(7): 548-561, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31076642

RESUMO

Complement is known to play a role in alcoholic fatty liver disease (AFLD), but the underlying mechanisms are poorly understood, thereby constraining the development of a rational approach for therapeutic intervention in the complement system. C3 deficiency has been shown to impart protective effects against ethanol-induced hepatic steatosis and inflammation. Here we demonstrate a protection effect in wild-type mice by treatment with CR2-Crry, a specific inhibitor of C3 activation. The expression of glycine transfer (t) RNA-derived fragments (Gly-tRFs) is upregulated in ethanol-fed mice and inhibition of Gly-tRFs in vivo decreases chronic ethanol feeding-induced hepatosteatosis without affecting inflammation. The expression of Gly-tRF was downregulated in C3-deficient or CR2-Crry-treated mice, but not in C5-deficient mice; Gly-tRF expression was restored by the C3 activation products C3a or Asp (C3a-des-Arg) via the regulation of CYP2E1. Transcriptome profiling of hepatic tissues showed that Gly-tRF inhibitors upregulate the expression of sirtuin1 (Sirt1) and subsequently affect downstream lipogenesis and ß-oxidation pathways. Mechanistically, Gly-tRF interacts with AGO3 to downregulate Sirt1 expression via sequence complementarity in the 3' UTR. Notably, the expression levels of C3d, CYP2E1 and Gly-tRF are upregulated, whereas Sirt1 is decreased in AFLD patients compared to healthy controls. Collectively, our findings suggest that C3 activation products contribute to hepatosteatosis by regulating the expression of Gly-tRF. Complement inhibition at the C3 activation step and treatment with Gly-tRF inhibitors may be potential and precise therapeutic approaches for AFLD.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Complemento C3/antagonistas & inibidores , Complemento C3/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Fígado/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Animais , Linhagem Celular , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado Gorduroso Alcoólico/tratamento farmacológico , Humanos , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
Mol Pharmacol ; 95(6): 597-605, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30944208

RESUMO

Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. The sulfotransferase-mediated sulfation of APAP is widely believed to be a protective mechanism to attenuate the hepatotoxicity of APAP. The cholesterol sulfotransferase SULT2B1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to synthesize cholesterol sulfate. SULT2B1b can be transcriptionally and positively regulated by the hepatic nuclear factor 4α (HNF4α). In this study, we uncovered an unexpected role for SULT2B1b in APAP toxicity. Hepatic overexpression of SULT2B1b sensitized mice to APAP-induced liver injury, whereas ablation of the Sult2B1b gene in mice conferred resistance to the APAP hepatotoxicity. Consistent with the notion that Sult2B1b is a transcriptional target of HNF4α, overexpression of HNF4α sensitized mice or primary hepatocytes to APAP-induced hepatotoxicity in a Sult2B1b-dependent manner. We conclude that the HNF4α-SULT2B1b axis has a unique role in APAP-induced acute liver injury, and SULT2B1b induction might be a risk factor for APAP hepatotoxicity.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Overdose de Drogas/complicações , Fator 4 Nuclear de Hepatócito/metabolismo , Sulfotransferases/genética , Animais , Células Cultivadas , Doença Hepática Crônica Induzida por Substâncias e Drogas/genética , Modelos Animais de Doenças , Overdose de Drogas/etiologia , Overdose de Drogas/metabolismo , Feminino , Hepatócitos/citologia , Hepatócitos/metabolismo , Camundongos , Sulfotransferases/metabolismo
17.
Fundam Clin Pharmacol ; 33(5): 535-543, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30903708

RESUMO

This study was designed to observe the compensation between cyclooxygenase-2 pathway and 5-lipoxygenase pathway in chronic aluminum overload-induced liver injury rats. A rat hepatic injury model of chronic aluminum injury was established by the intragastric administration of aluminum gluconate (Al3 + 200 mg/kg per day, 5 days a week for 20 weeks). The COX-2 inhibitor [meloxicam (1 mg/kg)] and 5-LOX inhibitor [caffeic acid (30 mg/kg)] were intragastrically administered 1 h after aluminum administration. The histopathology was detected by hematoxylin-eosin staining. A series of biochemical indicators were measured with biochemistry assay or ELISAs. The expressions of COX-2 and 5-LOX were measured by immunohistochemistry. Our experimental results showed that aluminum overload caused a significant damage to the liver and also significantly increased the expressions of COX-2, 5-LOX and the levels of inflammation and oxidative stress. The administration of meloxicam and caffeic acid significantly protected livers against histopathological injury, significantly decreased plasma ALT, AST, and ALP levels, significantly decreased TNF-α, IL-6, IL-1ß levels, and oxidative stress. However, the administration of caffeic acid did not significantly increase the expression of COX-2 compared with the model group. On the other hand, the administration of meloxicam also did not significantly increase the expression of 5-LOX compared with the model group. Our results indicate that there is no compensation between COX-2 pathway and 5-LOX pathway by inhibiting either COX-2 or 5-LOX in chronic aluminum overload-induced liver injury rat.


Assuntos
Alumínio/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Lipoxigenase/farmacologia , Animais , Ácidos Cafeicos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
Hum Exp Toxicol ; 38(6): 632-645, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30784321

RESUMO

In 2012, alcohol liver disease resulted in 3.3 million-5.9% of global deaths. This study introduced whey protection capacity against chronic alcohol-induced liver injury. Rats were orally administered to 12% ethanol solution in water (ad libitum, average 8.14 g of ethanol/kg body weight (b.w.)/day) alone or combined with whey ( per os, 2 g/kg b.w./day). After 6-week treatment, chronic ethanol consumption induced significant histopathological liver changes: congestion, central vein dilation, hepatic portal vein branch dilation, Kupffer cells hyperplasia, fatty liver changes, and hepatocytes focal necrosis. Ethanol significantly increased liver catalase activity and glutathione reductase protein expression without significant effects on antioxidative enzymes: glutathione peroxidase (GPx), copper-zinc-containing superoxide dismutase (CuZnSOD) and manganese-containing superoxide dismutase (MnSOD). Co-treatment with whey significantly attenuated pathohistological changes induced by ethanol ingestion and increased GSH-Px and nuclear factor kappa B (NF-κB) protein expression. Our results showed positive effects of whey on liver chronically exposed to ethanol, which seem to be associated with NF-κB-GPx signaling.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatopatias Alcoólicas/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Soro do Leite , Consumo de Bebidas Alcoólicas , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Glutationa Peroxidase/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Ratos Wistar
19.
J Ethnopharmacol ; 235: 435-445, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30703498

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla chinensis (Bunge) Regel is a valuable traditional Chinese medicine (TCM) which is widely used for the treatment of schistosomiasis, inflammatory, bacterial infections. In recent years, P chinensis has been reported to exhibit antitumor activities. However, the mechanisms underlying its toxic effects remain largely unresolved. This paper is designed to investigate the damage of long-term oral P. chinensis saponins (PRS) and to explore its potential damage mechanisms by serum metabonomics approach. MATERIALS AND METHODS: The serum samples from control and PRS treated rats were analyzed by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) in positive ionization mode and negative ionization mode. Liver function index of ALT, AST and ALP, blood biochemistry and biomarkers were examined to identify specific changes of injury. Acquired data were subjected to principal component analysis (PCA) for differentiating the control and PRS treated groups. Then, serum metabolic profiling was analyzed and pathway analysis performed on the biomarkers reversed after PRS treated and further integration of metabolic networks. RESULTS: The results suggested that serum liver function indexes of ALT had significantly changed and stage increased. AST, ALP detection content show volatility changes. Changes in the 15 biomarkers found in the serum, such as acetaminophen glucuronide, 9 E, 11 E-linoleic acid, chenodeoxycholic acid, monoacylglycerides, sphingomyelin (SM), 7-ketodeoxycholic acid and 12-keto-deoxycholic acid, which were closely related to changes in liver injury. It could be seen clearly that with the change of the dosing time, the biomarkers in the serum have undergone obvious, regular and progressive changes through the score plot and corresponding loading plot. The underlying regulations of PRS-perturbed metabolic pathways were discussed according to the identified metabolites. CONCLUSION: The present study proves the potential of UPLC-QTOF-MS based metabonomics in mapping metabolic response. Long-term oral administration of P. chinensis saponins can cause chronic liver injury, and its safety needs further attention. It is of great significance in safeguarding human health to explore the damage mechanism of Pulsatilla chinensis saponins on liver by serum metabolomics.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Metabolômica/métodos , Pulsatilla/química , Saponinas/toxicidade , Administração Oral , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Testes de Função Hepática , Masculino , Espectrometria de Massas/métodos , Ratos , Ratos Sprague-Dawley , Saponinas/administração & dosagem , Saponinas/isolamento & purificação , Fatores de Tempo
20.
Naunyn Schmiedebergs Arch Pharmacol ; 392(5): 623-631, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30693382

RESUMO

Methotrexate (MTX) is a widely used drug for treatment of many malignant, rheumatic, and autoimmune diseases. However, hepatotoxicity remains one of the most serious side effects of MTX. The extrinsic coagulation pathway is activated after tissue injury through the release of tissue factor (TF) which activates a cascade of clotting factors including prothrombin and fibrinogen. Liver sinusoidal endothelial cells express endothelial nitric oxide synthase (eNOS) as a source for nitric oxide (NO) that serves as vasodilator and antithrombotic factor. In the current study, we tested the possible role of coagulation system activation in MTX-induced hepatotoxicity. Our results showed that single-dose administration of MTX significantly altered rat liver functions with concurrent turbulence in redox status. Immunofluorescence staining showed accumulation of fibrin in the periportal hepatocytes and downregulation of eNOS expression in hepatic endothelial and sinusoidal cells following MTX treatment. Moreover, MTX administration increased the expression of inducible nitric oxide synthase (iNOS) and NOSTRIN (eNOS traffic inducer) in the hepatic sinusoids. On the other hand, pre-treatment with enoxaparin rescued against MTX-induced liver injury with subsequent amelioration of liver redox status. Furthermore, it significantly prevented the effect of MTX on the expression of fibrin, iNOS, eNOS, and NOSTRIN. We concluded that liver tissue aggregation of the coagulation product, fibrin, may play a crucial role in the pathogenesis of MTX-induced liver injury.


Assuntos
Anticoagulantes , Antirreumáticos/efeitos adversos , Doença Hepática Crônica Induzida por Substâncias e Drogas , Enoxaparina , Fibrina/metabolismo , Imunossupressores/efeitos adversos , Metotrexato/efeitos adversos , Substâncias Protetoras , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Proteínas de Ligação a DNA/metabolismo , Enoxaparina/farmacologia , Enoxaparina/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos Sprague-Dawley
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