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1.
Nat Commun ; 11(1): 5666, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168815

RESUMO

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 and glycerol transport, and prevented liver injury in experimental animal models. Using AQP3 knockout mice in a model of liver injury and fibrosis produced by CCl4, we obtained evidence for involvement of AQP3 expression in nuclear factor-κB (NF-κB) cell signaling, hepatic oxidative stress and inflammation in macrophages during liver injury. The activated macrophages caused stellate cell activation, leading to liver injury, by a mechanism involving AQP3-mediated H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.


Assuntos
Anticorpos Monoclonais/farmacologia , Aquaporina 3/antagonistas & inibidores , Aquaporina 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Animais , Aquaporina 3/genética , Células CHO , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Quimiocina CCL4/efeitos adversos , Cricetulus , Modelos Animais de Doenças , Descoberta de Drogas , Glicerol/metabolismo , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Medicina Molecular , NF-kappa B/metabolismo , Estresse Oxidativo , Transdução de Sinais , Transcriptoma
2.
Medicine (Baltimore) ; 99(41): e22259, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031266

RESUMO

Drug-induced liver injury (DILI) is difficult in diagnose, criteria used now are mostly based on history review. We tried to evaluate the value of these criteria and histopathology features in DILI to perform a method diagnosing DILI more definitely.We enrolled 458 consecutive hospitalized DILI patients from January 1, 2012 to December 31, 2018, using Roussel-Uclaf Causality Assessment Method (RUCAM), Maria & Victorino scale (M&V), and Digestive Disease Week-Japan criterion (DDW-J) combined with refined pathological scoring system respectively to perform the evaluation.A total of 458 DILI patients were enrolled, the area under receiver operating characteristics (AUROC) of the 3 clinical diagnostic criteria were 0.730 (95% confidence interval [CI]: 0.667-0.793), 0.793 (95% CI: 0.740-0.847), and 0.764 (95% CI: 0.702-0.826) respectively. Three hundred two DILI patients' liver biopsies were included: steatosis in 204 cases (67.5%), cholestasis in 151 cases (50%), cell apoptosis in 139 cases (46%), eosinophil granulocyte infiltration in 131 cases (43.4%), central and/or portal phlebitis in 103 cases (34.1%), iron deposition in 90 cases (29.8%), and pigmented macrophages in 92 cases (30.5%). The AUROC of refined pathological scale combined with 3 criteria were 0.843 (95% CI: 0.747-0.914), 0.907 (95% CI: 0.822-0.960), and 0.881 (95% CI: 0.790-0.942) respectively. In hepatocellular type, the AUROCs were 0.894 (95% CI: 0.787-0.959), 0.960 (95% CI: 0.857-0.994), and 0.940 (95% CI: 0.847-0.985); in cholestatic type, the AUROCs were 0.750 (95% CI: 0.466-0.931), 0.500 (95% CI: 0.239-0.761), and 0.500 (95% CI: 0.239-0.761); in mixed type, the AUROCs were 0.786 (95% CI: 0.524-0.943), 0.869 (95% CI: 0.619-0.981), and 0.762 (95% CI: 0.498 to -0.930).Combined with pathological scale can significantly improve the accuracy of clinical diagnostic criteria, no matter in alone or combined condition, M&V might be more accurate in diagnosing DILI from suspected patients.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Biomarcadores/sangue , Biópsia por Agulha , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade
3.
Environ Health Prev Med ; 25(1): 53, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917140

RESUMO

BACKGROUND: Pilea umbrosa (Urticaceae) is used by local communities (district Abbotabad) for liver disorders, as anticancer, in rheumatism and in skin disorders. METHODS: Methanol extract of P. umbrosa (PUM) was investigated for the presence of polyphenolic constituents by HPLC-DAD analysis. PUM (150 mg/kg and 300 mg/kg) was administered on alternate days for eight weeks in rats exposed with carbon tetrachloride (CCl4). Serum analysis was performed for liver function tests while in liver tissues level of antioxidant enzymes and biochemical markers were also studied. In addition, semi quantitative estimation of antioxidant genes, endoplasmic reticulum (ER) induced stress markers, pro-inflammatory cytokines and fibrosis related genes were carried out on liver tissues by RT-PCR analysis. Liver tissues were also studied for histopathological injuries. RESULTS: Level of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and glutathione (GSH) decreased (p < 0.05) whereas level of thiobarbituric acid reactive substance (TBARS), H2O2 and nitrite increased in liver tissues of CCl4 treated rat. Likewise increase in the level of serum markers; alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin was observed. Moreover, CCl4 caused many fold increase in expression of ER stress markers; glucose regulated protein (GRP-78), x-box binding protein1-total (XBP-1 t), x-box binding protein1-unspliced (XBP-1 u) and x-box binding protein1-spliced (XBP-1 s). The level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) was aggregated whereas suppressed the level of antioxidant enzymes; γ-glutamylcysteine ligase (GCLC), protein disulfide isomerase (PDI) and nuclear erythroid 2 p45-related factor 2 (Nrf-2). Additionally, level of fibrosis markers; transforming growth factor-ß (TGF-ß), Smad-3 and collagen type 1 (Col1-α) increased with CCl4 induced liver toxicity. Histopathological scrutiny depicted damaged liver cells, neutrophils infiltration and dilated sinusoids in CCl4 intoxicated rats. PUM was enriched with rutin, catechin, caffeic acid and apigenin as evidenced by HPLC analysis. Simultaneous administration of PUM and CCl4 in rats retrieved the normal expression of these markers and prevented hepatic injuries. CONCLUSION: Collectively these results suggest that PUM constituted of strong antioxidant chemicals and could be a potential therapeutic agent for stress related liver disorders.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Urticaceae/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose/genética , Inflamação/genética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
4.
Ecotoxicol Environ Saf ; 205: 111342, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971455

RESUMO

Radix aconiti lateralis (Fuzi) is widely used in China as a traditional Chinese medicine for the treatment of asthenia, pain and inflammation. However, its toxic alkaloids often lead to adverse reactions. Currently, most of the toxicity studies on Fuzi are focused on the heart and nervous system, and more comprehensive toxicity studies are needed. In this study, based on the previous reports of Fuzi hepatotoxicity, serum pharmacochemistry and network toxicology were used to screen the potential toxic components of Heishunpian(HSP), a processed product of Fuzi, and to explore the possible mechanism of HSP-induced hepatotoxicity. The results obtained are expressed based on the toxicological evidence chain (TEC). It was found that 22 potential toxic components screened can affect Th17 cell differentiation, Jak-STAT signaling pathway, glutathione metabolism, and other related pathways by regulating AKT1, IL2, F2, GSR, EGFR and other related targets, which induces oxidative stress, metabolic disorders, cell apoptosis, immune response, and excessive release of inflammatory factors, eventually inducing liver damage in rats. This is the first study on HSP-induced hepatotoxicity based on the TEC concept, providing references for further studies on the toxicity mechanism of Fuzi.


Assuntos
Aconitum/química , Alcaloides/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Medicamentos de Ervas Chinesas/toxicidade , Modelos Biológicos , Alcaloides/sangue , Alcaloides/isolamento & purificação , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , China , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacocinética , Masculino , Medicina Tradicional Chinesa , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
5.
Ecotoxicol Environ Saf ; 203: 110928, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888618

RESUMO

Hexavalent chromium [Cr(VI)] is seriously harmful to ecosystems and living organisms due to its strong toxicity. Role of dynamin-related protein 1 (Drp1) and Drp1-associated mitochondrial fragmentation in mitophagy and cytotoxicity after Cr(VI) exposure has not been clarified so far. We confirmed that Cr(VI) caused mitochondrial fission by up-regulating Drp1 expression and enhancing Drp1 mitochondrial translocation. By applying the intracellular Ca2+ antagonist BAPTA-AM and mitochondrial Ca2+ antagonist Ru360, we demonstrated that Cr(VI)-induced excessive mitochondrial fission was in a Ca2+-Drp1 dependent manner. The administration of Drp1 siRNA significantly suppressed the overactivation of mitophagy in Cr(VI)-induced hepatotoxicity. The specific Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) blocked the overactive mitophagy and subsequently ameliorated hepatotoxicity caused by Cr(VI) in vivo. We reached the conclusion that Drp1-dependent mitochondrial fission contributes to Cr(VI)-induced mitophagy and hepatotoxicity, which may provide experimental basis for the study of chromium-associated toxicity, especially for the prevention of health damage in chromium-exposed population.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cromo/toxicidade , Dinaminas/metabolismo , Poluentes Ambientais/toxicidade , Hepatócitos/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ecossistema , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , RNA Interferente Pequeno/metabolismo
6.
Life Sci ; 258: 118172, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738359

RESUMO

The role of gut microbiome in human health and disease is well established. While evidence-based pharmacological studies utilize a variety of chemical-induced metabolic and toxicological disease models that in part recapitulate the natural mode of disease pathogenesis, the mode of actions of these disease models are likely underexplored. Conventionally, the mechanistic principles of these disease models are established as direct tissue toxicity through redox imbalance and pro-inflammatory injury. However, emerging evidences suggest that the mode of action of these chemicals could be largely associated with changes in gut microbial populations, diversity and metabolic functions, affecting pathological changes along the gut-liver and gut-pancreas axis. Especially in these disease models, reversal of disease severity or less sensitivity to induced disease pathogenesis has been observed when germ-free or antibiotic-supplemented microbiota-depleted rodents were treated with disease causing chemicals. Thus, by summarizing evidences from in vivo pharmacological interventions, this review revisits the mode of action of carbon tetrachloride-induced cirrhosis, diethylnitrosamine-induced hepatocellular carcinoma, acetaminophen-induced hepatotoxicity and alloxan- and streptozotocin-induced diabetes through the light of gut microbiota. How changes in gut microbiome affects tissue-level toxicity likely through intestinal-level mechanisms like gastrointestinal inflammation and gut barrier dysfunction has also been discussed. Additionally, this review discusses potential pitfalls of inconsistent experimental models that precludes defining the gut microbial effects in evidence-based pharmacology. Collectively, this review emphasizes the underexplored role of microbial intervention in experimental pharmacology and aims to provide direction towards redefining and establishing microbiome-centric alternative mode of action of chemical-induced metabolic and toxicological disease models in pharmacological research.


Assuntos
Microbioma Gastrointestinal , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dieta , Modelos Animais de Doenças , Humanos , Intestinos/microbiologia , Intestinos/patologia
7.
J Toxicol Sci ; 45(8): 493-502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741899

RESUMO

Gefitinib (GEF) is the first selective tyrosine kinase inhibitor of epidermal growth factor receptor. It is associated with the occurrence of clinical drug-induced liver injury. Although GEF is metabolized to chemically reactive metabolites by cytochrome P450 3A and 1A enzymes and then conjugated to glutathione (GSH), whether these reactive metabolites contribute to GEF-induced toxicity remains unknown. In this study, we investigated whether GSH depletion can sensitize mice to liver injury caused by GEF. Male C57BL/6J mice were intraperitoneally pretreated with L-buthionine (S,R)-sulfoximine (BSO) at 700 mg/kg to inhibit GSH synthesis and then orally administered GEF at 500 mg/kg every 24 hr for 4 consecutive days. The coadministration of BSO and GEF increased plasma alanine aminotransferase (ALT) levels to approximately 700 U/L and 1600 U/L at 72 and 96 hr after the first administration, respectively, whereas the increase in plasma ALT levels in mice receiving GEF at 500 mg/kg alone was limited, suggesting that GSH plays a protective role in GEF-induced liver injury. Histological examination showed nuclear karyorrhexis and sporadic single hepatocyte death in the livers of BSO+GEF coadministered mice. In these mice, the hepatic expression levels of heme oxygenase 1 (Hmox1) and metallothionein 2 (Mt2) mRNA, caspase 3/7 enzymatic activity, and the amounts of 2-thiobarbiuric acid reactive substances were significantly increased, suggesting the presence of oxidative stress, which may be associated with hepatocellular death. Together, these results show that oxidative stress as well as the reactive metabolites of GEF are involved in GEF-induced liver injury in GSH-depleted mice.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Gefitinibe/efeitos adversos , Gefitinibe/toxicidade , Glutationa/deficiência , Glutationa/metabolismo , Fígado/metabolismo , Fígado/patologia , Estresse Oxidativo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/toxicidade , Animais , Butionina Sulfoximina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP3A/fisiologia , Progressão da Doença , Gefitinibe/metabolismo , Glutationa/fisiologia , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/metabolismo
8.
Toxicol Lett ; 333: 192-201, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805337

RESUMO

To gain insights into the benefits of ascorbic acid (AsA) in hepatoprotection, we examined the status of Akr1a-/- (KO) mice, which biosynthesize AsA at about 10% the rate as Akr1a+/+ (WT) mice, in terms of their response to an N-nitrosodiethylamine (NDEA)-induced hepatic injury. The intraperitoneal injection of NDEA (35 mg/kg) started at 4 weeks of age and was performed at weekly intervals thereafter. While the fatality rate was substantial in the KO mice, AsA supplementation (1.5 mg/ml in the drinking water) greatly extended their life-spans. Only two out of 54 KO mice survived to 28 weeks, and both contained approximately an order of magnitude greater number of tumor nodules compared to WT mice or KO mice with AsA supplementation. Histological and biochemical examinations at 20 weeks indicated that AsA potently protected against the hepatotoxic action of NDEA. Interestingly, the AsA levels in the liver were higher in the AsA-supplemented KO mouse groups that had received the NDEA treatment compared to the corresponding control group. While the protein levels of Cyp2e1, an enzyme that plays a major role in the bioactivation of NDEA, had declined to a similar extent among the experimental groups, p-nitrophenol-oxidizing activity was sustained at high levels in the KO mouse livers but AsA supplementation suppressed this activity. These findings confirm that AsA is a potent micronutrient that copes with hepatic injury and cancer development caused by exposure to NDEA in the livers of Akr1a-knockout mice.


Assuntos
Aldeído Redutase/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Carcinogênese/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dietilnitrosamina/toxicidade , Fígado/efeitos dos fármacos , Aldeído Redutase/genética , Animais , Antioxidantes/metabolismo , Biomarcadores/sangue , Carcinogênese/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sobrevida
9.
Toxicol Lett ; 333: 290-302, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835833

RESUMO

Triptolide, a major active component of Triptergium wilfordii Hook. f, is used in the treatment of autoimmune disease. However, triptolide is associated with severe adverse reactions, especially hepatotoxicity, which limits its clinical application. To examine the underlying mechanism of triptolide-induced liver injury, a combination of dose- and time-dependent toxic effects, RNA-seq and metabolomics were employed. Triptolide-induced toxicity occurred in a dose- and time-dependent manners and was characterized by apoptosis and not necroptosis. Transcriptomics profiles of the dose-dependent response to triptolide suggested that PI3K/AKT, MAPK, TNFα and p53 signaling pathways were the vital steps in triptolide-induced hepatocyte apoptosis. Metabolomics further revealed that glycerophospholipid, fatty acid, leukotriene, purine and pyrimidine metabolism were the major metabolic alterations after triptolide exposure. Finally, acylcarnitines were identified as potential biomarkers for the early detection of triptolide-induced liver injury.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas , Diterpenos/toxicidade , Metaboloma/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Fenantrenos/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Apoptose/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Relação Dose-Resposta a Droga , Compostos de Epóxi/toxicidade , Perfilação da Expressão Gênica , Metaboloma/genética , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necroptose/genética
10.
Chem Biol Interact ; 330: 109230, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32828744

RESUMO

Although physiological levels of iron are essential for numerous biological processes, excess iron causes critical tissue injury. Under iron overload conditions, non-chelated iron generates reactive oxygen species that mediate iron-induced tissue injury with subsequent induction of apoptosis, necrosis, and inflammatory responses. Because liver is a central player in iron metabolism and storage, it is vulnerable to iron-induced tissue injury. Taxifolin is naturally occurring compound that has shown potent antioxidant and potential iron chelation competency. The aim of the current study was to investigate the potential protective effects of taxifolin against iron-induced hepatocellular injury and to elucidate the underlining mechanisms using rats as a mammalian model. The results of the current work indicated that taxifolin inhibited iron-induced apoptosis and enhanced hepatocellular survival as demonstrated by decreased activity of caspase-3 and activation of the pro-survival signaling PI3K/AKT, respectively. Western blotting analysis revealed that taxifolin enhanced liver regeneration as indicated by increased PCNA protein abundance. Taxifolin mitigated the iron-induced histopathological aberration and reduced serum activity of liver enzymes (ALT and AST), highlighting enhanced liver cell integrity. Mechanistically, taxifolin modulated the redox-sensitive MAPK signaling (p38/c-Fos) and improved redox status of the liver tissues as indicated by decreased lipid peroxidation and protein oxidation along with enhanced total antioxidant capacity. Interestingly, it decreased liver iron content and down-regulated the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. Collectively, these data highlight, for the first time, the ameliorating effects of taxifolin against iron overload-induced hepatocellular injury that is potentially mediated through anti-inflammatory, antioxidant, and potential iron chelation activities.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Sobrecarga de Ferro/complicações , Regeneração Hepática/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quercetina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Ratos
11.
Toxicol Lett ; 332: 222-234, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32679240

RESUMO

The relative toxicity of three legacy and six emerging brominated flame retardants* was studied in the male Harlan Sprague Dawley rat. The hepatocellular and thyroid toxicity of each flame retardant was evaluated following five-day exposure to each of the nine flame retardants (oral gavage in corn oil) at 0.1-1000 µmol/kg body weight per day. Histopathology and transcriptomic analysis were performed on the left liver lobe. Centrilobular hypertrophy of hepatocytes and increases in liver weight were seen following exposure to two legacy (PBDE-47, HBCD) and to one emerging flame retardant (HCDBCO). Total thyroxine (TT4) concentrations were reduced to the greatest extent after PBDE-47 exposure. The PBDE-47, decaBDE, and HBCD liver transcriptomes were characterized by upregulation of liver disease-related and/or metabolic transcripts. Fewer liver disease or metabolic transcript changes were detected for the other flame retardants studied (TBB, TBPH, TBBPA-DBPE, BTBPE, DBDPE, or HCDBCO). PBDE-47 exhibited the most disruption of hepatocellular toxic endpoints, with the Nrf2 antioxidant pathway transcripts upregulated to the greatest extent, although some activation of this pathway also occurred after decaBDE, HBCD, TBB, and HCBCO exposure. These studies provide information that can be used for prioritizing the need for more in-depth brominated flame retardant toxicity studies.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Retardadores de Chama/toxicidade , Hidrocarbonetos Bromados/toxicidade , Fígado/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Tamanho Celular/efeitos dos fármacos , Monitoramento Ambiental , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Doenças da Glândula Tireoide/induzido quimicamente , Doenças da Glândula Tireoide/patologia , Tiroxina/metabolismo , Toxicogenética
12.
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
13.
Leg Med (Tokyo) ; 47: 101740, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32634765

RESUMO

Hepatotoxicity from paracetamol/acetaminophen has occasionally been reported at lower than expected doses. As herbal preparations may interact with pharmaceutical drugs the following in vitro study was undertaken to determine whether the toxic effects of paracetamol on liver cell growth in culture would be exacerbated by the addition of psoralen, a furanocoumarin compound that is present in Psoralea corylifolia, a common Chinese herb. The following study utilising a liver carcinoma cell line (HepG2) showed that Psoralea corylifolia was significantly toxic from 0.3 mg/ml to 5 mg/ml (p < 0.05), whereas paracetamol was not toxic below 50 mM (p = 0.0026). Interactions between previously non-toxic levels of 0.1 mg/ml of Psoralea corylifolia and increasing concentrations of paracetamol (0-50 mM), however, were observed, with a significant increase in toxicity compared to paracetamol alone (30% cell death vs. 72% cell death with Psoralea corylifolia). A significant synergistic interaction was observed at 40 mM paracetamol with 0.1 mg/ml of Psoralea (p = 0.038). This study has, therefore, shown significantly increased hepatotoxicity in cell cultures exposed to paracetamol when herbal compounds containing furanocoumarins were added. Fulminant acute liver failure occurring after the ingestion of low doses of paracetamol may not, therefore, always be due to an occult idiosyncratic response to paracetamol, but instead possibly to the combined effects of paracetamol and herbal preparations. Given the widespread use of both paracetamol and herbal preparations this possibility should be considered in cases of unexplained hepatic necrosis and liver failure that present for medicolegal investigation.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ficusina/toxicidade , Fígado/patologia , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sinergismo Farmacológico , Ficusina/isolamento & purificação , Células Hep G2 , Humanos , Falência Hepática/induzido quimicamente , Necrose/induzido quimicamente , Psoralea/química
14.
Toxicol Lett ; 333: 22-32, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721574

RESUMO

HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-ß-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1ß secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismo , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Retroalimentação Fisiológica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Tetrazóis/farmacologia , Tioacetamida/toxicidade
15.
Toxicol Lett ; 333: 49-61, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32726682

RESUMO

Hepatotoxicity induced by Mylabris has been reported in both clinical and animal experiments. Cantharidin (CTD), the main active compound of Mylabris was responsible for the hepatotoxicity, which aroused widespread concern. However, the mechanism of CTD hepatotoxicity remained unclear. In this study, LO2 cells were exposed to two doses of CTD (6.25 and 25 µM) for 12 h, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured. The metabolites in LO2 cells were profiled by LC-MS. Partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis were used for screening potential biomarkers. The MetPA software was used for clustering and pathway analysis. Network pharmacology was used to predict the genes acted with potential biomarkers. Compared with the control group, the levels of ALT, AST, and LDH was significantly increased after CTD treatment. A total of 46 potential biomarkers for hepatotoxicity induced by CTD were identified. And downregulated potential biomarkers reflected the inhibitory effects of CTD toxicity on metabolism of LO2. Moreover, CTD-induced liver toxicity of LO2 cells is mainly related to three pathways: cysteine and methionine metabolism; glutathione metabolism; and glycine, serine, and threonine metabolism. Furtherly, the mRNA expression of CES2, DNMT1, NOS1, NOS3, S1PR2, and CES1 screened by network pharmacology were regulated by CTD. These studies provide valuable mechanistic insights into CTD-associated hepatotoxicity that will aid in the development of therapeutic prevention and treatment options for this liver disease.


Assuntos
Cantaridina/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Hepatócitos/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Estresse Oxidativo/efeitos dos fármacos , Biomarcadores/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cromatografia Líquida/métodos , Relação Dose-Resposta a Droga , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Espectrometria de Massas/métodos , Metabolômica/instrumentação
16.
Chemosphere ; 257: 127111, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32485513

RESUMO

Microcystin-leucine arginine (MC-LR) is a potent liver toxin produced by freshwater cyanobacteria, also known as blue-green algae. While harmful algal blooms are increasing in frequency and severity worldwide, there is still no established method for the diagnosis and assessment of MC-LR induced liver damage. The guidelines for MC-LR safe exposure limits have been previously established based on healthy animal studies, however we have previously demonstrated that pre-existing non-alcoholic fatty liver disease (NAFLD) increases susceptiblity to the hepatotoxic effects of MC-LR. In this study, we sought to investigate the suitability of clinically used biomarkers of liver injury, specifically alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as potential diagnostic tools for liver damage induced by chronic low dose administration of MC-LR in the setting of pre-existing NAFLD. In our Leprdb/J mouse model of NAFLD, we found that while MC-LR induced significant histopathologic damage in the setting of NAFLD, gene expression of ALT and ALP failed to increase with MC-LR exposure. Serum ALT and ALP also failed to increase with MC-LR exposure, except for a moderate increase in ALP with the highest dose of MC-LR used (100 µg/kg). In HepG2 human liver epithelial cells, we observed that increasing MC-LR exposure levels do not lead to an increase in ALT or ALP gene expression, intracellular enzyme activity, or extracellular activity, despite a significant increase in MC-LR induced cytotoxicity. These findings demonstrate that ALT and ALP may be unsuitable as diagnostic biomarkers for MC-LR induced liver damage.


Assuntos
Fígado/metabolismo , Microcistinas/toxicidade , Alanina Transaminase/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cianobactérias , Expressão Gênica , Proliferação Nociva de Algas , Humanos , Camundongos , Hepatopatia Gordurosa não Alcoólica
17.
J Vis Exp ; (159)2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32538903

RESUMO

Drug-induced autoimmune hepatitis (DIH) is the most common hepatic drug-induced hypersensitization process observed in approximately 9 to 12% of patients with autoimmune hepatitis. The overwhelming majority of patients with DIH are women. The underlying mechanisms of these sex differences in prevalence are unclear because of the paucity of animal models that mimic human disease. Even so, underlying mechanisms are widely believed to be associated with human leukocyte antigen haplotypes and sex hormones. In contrast, using a DIH mouse model, we have uncovered that IL-4 initiated CD4+ T cells directed against an epitope of cytochrome P450 2E1 induces influx of neutrophils, macrophages and mast cells into the livers of female BALB/c mice. Using this model, we have also shown that IL-33-induced FoxP3+regulatory T cells confer protection against DIH in female and male mice. This DIH model is induced by immunizing mice with an epitope of CYP2E1 that has been covalently altered with a drug metabolite that has been associated with DIH. This epitope is recognized by patients with DIH. Our method induces robust and reproducible hepatitis and autoantibodies that can be utilized to study the pathogenesis of DIH. While in vivo studies can cause undue pain and distress in mice when done improperly, the advantage of an in vivo model is the ability to evaluate the pathogenesis of disease in a large number of mice. Additionally, biological effects of the altered liver proteins can be studied using invasive procedures. The addition of in vitro studies to the experimental design allows rapid repetition and mechanistic analysis at a cellular level. Thus, we will demonstrate our model protocol and how it can be utilized to study in vivo and in vitro mechanisms of DIH.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Hepatite Autoimune/etiologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatite Autoimune/patologia , Camundongos , Camundongos Endogâmicos BALB C
18.
J Ayub Med Coll Abbottabad ; 32(1): 28-32, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468750

RESUMO

BACKGROUND: Autonomic nervous system modulates acetaminophen induced hepatotoxicity. The purpose of the study was to determine the hepatoprotective effect of α1 antagonist (prazosin) and ß2 agonist (salbutamol) on acetaminophen induced hepatotoxicity in mice. METHODS: This experimental study was conducted at Post Graduate Medical Institute, Lahore in which 50 adult mice were divided in to five groups. With the exception of normal control, hepatotoxicity was induced in all other study groups by giving single intraperitoneal injection of acetaminophen 300 mg/ kg. First and second groups served as normal and toxic control were given distilled water 6 ml/ kg while third, fourth and fifth experimental groups were given N-acetylcysteine (300 mg/ kg), prazosin (0.18 mg/ kg) and salbutamol (0.35 mg/kg) intraperitoneally at 2,4 and 8 hours after acetaminophen injection. Serum liver enzymes were analysed at 0 and 72 hours while histopathological finding were assessed at the end of study by using SPSS-20. RESULTS: All the groups treated with toxic dose of acetaminophen showed significant increase in serum ALT, i.e., B (Toxic control 3372%), C (NAC treated 282%), D (Prazosin treated 582%), E(Salbutamol treated 3297%) and AST levels, i.e., B (Toxic control 2750% ), C (NAC treated 230% ), D (Prazosin treated 280%), E (Salbutamol treated 828%) with p-value ˂0.001. When this increase was compared between groups, the lowest increase in serum ALT and AST levels was observed in Nacetylcysteine and prazosin group with no significant difference. Similarly, experimental animals receiving prazosin and N-acetylcysteine had the lowest inflammation, degeneration and necrosis scores than the toxic control group in histopathological analysis of the liver with p-value <0.001. CONCLUSIONS: The hepatoprotective effect of prazosin is comparable to N- acetylcysteine against acetaminophen induced hepatotoxicity in mice.


Assuntos
Acetaminofen/efeitos adversos , Acetilcisteína/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Depuradores de Radicais Livres/uso terapêutico , Prazosina/uso terapêutico , Albuterol/uso terapêutico , Analgésicos não Entorpecentes/efeitos adversos , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Feminino , Fígado/patologia , Masculino , Camundongos , Necrose
19.
PLoS One ; 15(5): e0229753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407333

RESUMO

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.


Assuntos
Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Glutamato Desidrogenase/sangue , Distrofia Muscular de Duchenne/sangue , Acetaminofen/efeitos adversos , Adolescente , Adulto , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/complicações , Doença Hepática Induzida por Substâncias e Drogas/patologia , Criança , Pré-Escolar , Creatina Quinase/sangue , Modelos Animais de Doenças , Diagnóstico Precoce , Feminino , Humanos , Hipóxia/sangue , Hipóxia/complicações , Fígado/lesões , Fígado/patologia , Masculino , Camundongos , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/patologia , Rabdomiólise/sangue , Rabdomiólise/complicações , Rabdomiólise/patologia
20.
Life Sci ; 254: 117760, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418889

RESUMO

AIM: The present study focused on the possible underlying protective mechanisms of UDCA against GNT-induced hepatic injury. METHODS: For achieving this goal, adult male rats were allocated into 4 groups: normal control (received vehicle), GNT (100 mg/kg, i.p. for 8 days), UDCA (60 mg/kg, P.O. for 15 days), and GNT + UDCA (received UDCA for 15 days and GNT started from the 7th day and lasted for 8 days). RESULTS: The results revealed that UDCA significantly improved GNT-induced hepatic injury, oxidative stress, apoptosis, and inflammatory response. Interestingly, UDCA inhibited apoptosis by marked down-regulation of the Bax gene, Caspase-3, and cleaved Caspase-3 protein expressions while the level of Bcl-xL gene significantly increased. Moreover, UDCA strongly inhibited the inflammatory response through the down-regulation of both NF-κB-p65 and TNF-α accompanied by IL-10 elevation. Furthermore, the obtained results ended with the restored of mitochondria function that confirmed by electron microscopy. Histological analysis showed that UDCA remarkably ameliorated the histopathological changes induced by GNT. SIGNIFICANCE: UDCA may be a promising agent that can be used to prevent hepatotoxicity observed in GNT treatment. This effect could be attributed to, at least in part, the ability of UDCA to modulate NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS signaling pathways.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Gentamicinas/antagonistas & inibidores , Gentamicinas/toxicidade , Hepatócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Interações Medicamentosas , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
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