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1.
Toxicol Lett ; 336: 68-79, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33098907

RESUMO

Mushroom toxicity is the main branch of foodborne poisoning, and liver damage caused by amatoxin poisoning accounts for more than 90 % of deaths due to mushroom poisoning. Alpha-amatoxin (α-AMA) has been considered the primary toxin from amatoxin-containing mushrooms, which is responsible for hepatotoxicity and death. However, the mechanism underlying liver failure due to α-AMA remains unclear. This study constructed animal and cell models. In the animal experiments, we investigated liver injury in BALB/c mice at different time points after α-AMA treatment, and explored the process of inflammatory infiltration using immunohistochemistry and western blotting. Then, a metabonomics method based on gas chromatography mass spectrometry (GCMS) was established to study the effect of α-AMA on liver metabonomics. The results showed a significant difference in liver metabolism between the exposed and control mice groups that coincided with pathological and biochemical indicators. Moreover, 20 metabolites and 4 metabolic pathways related to its mechanism of action were identified, which suggested that energy disorders related to mitochondrial dysfunction may be one of the causes of death. The significant changes of trehalose and the fluctuation of LC3-II and sqstm1 p62 protein levels indicated that autophagy was also involved in the damage process, suggesting that autophagy may participate in the clearance process of damaged mitochondria after poisoning. Then, we constructed an α-AMA-induced human normal liver cells (L-02 cells) injury model. The above hypothesis was further verified by detecting cell necrosis, mitochondrial reactive oxygen species (mtROS), mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (Δψ m), and cellular ATP level. Collectively, our results serve as direct evidence of elevated in vivo hepatic mitochondrial metabolism in α-AMA-exposed mice and suggest that mitochondrial dysfunction plays an important role in the early stage of α-AMA induced liver failure.


Assuntos
Amanitinas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Metabolismo Energético , Falência Hepática/metabolismo , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Intoxicação Alimentar por Cogumelos/metabolismo , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Humanos , Fígado/patologia , Falência Hepática/induzido quimicamente , Falência Hepática/patologia , Metabolômica , Camundongos Endogâmicos BALB C , Mitocôndrias Hepáticas/patologia , Intoxicação Alimentar por Cogumelos/etiologia , Intoxicação Alimentar por Cogumelos/patologia , Fatores de Tempo
2.
Ecotoxicol Environ Saf ; 208: 111496, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33099137

RESUMO

Silica nanoparticles (SiNPs) have become one of the most widely studied nanoparticles in nanotechnology for environmental health and safety. Although many studies have devoted to evaluating the hepatotoxicity of SiNPs, it is currently impossible to predict the extent of liver lipid metabolism disorder by identifying changes in metabolites. In the present study, 40 male Sprague-Dawley (SD) rats were randomly divided into control group and 3 groups with different doses (1.8 mg/kg body weight (bw), 5.4 mg/kg bw, 16.2 mg/kg bw), receiving intratracheal instillation of SiNPs. Liver tissue was taken for lipid level analysis, and serum was used for blood biochemical analysis. Then, the metabolites changes of liver tissue in rats were systematically analyzed using 1H nuclear magnetic resonance (1H NMR) techniques in combination with multivariate statistical analysis. SiNPs induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) elevation in treated groups; TG and low-density lipoprotein cholesterol (LDL-C) were significantly higher in SiNPs-treated groups of high-dose, however high-density lipoprotein cholesterol (HDL-C) showed a declining trend in liver tissue. The orthogonal partial least squares discriminant analysis (OPLS-DA) scores plots revealed different metabolic profiles between control and high-dose group (Q2 =0.495, R2Y=0.802, p = 0.037), and a total of 11 differential metabolites. Pathway analysis indicated that SiNPs treatment mainly affected 10 metabolic pathways including purine metabolism, glucose-alanine cycle and metabolism of various amino acids such as glutamate, cysteine and aspartate (impact value>0.1, false discovery rate (FDR)< 0.05). The result indicated that exposure to SiNPs caused liver lipid metabolism disorder in rats, the biochemical criterions related to lipid metabolism changed significantly. The obviously changed metabolomics in SiNPs-treated rats mostly occurred in amino acids, organic acids and nucleosides.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Metaboloma/efeitos dos fármacos , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
3.
Gene ; 764: 145083, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32860902

RESUMO

BACKGROUND/AIMS: Melamine (ML) is a common food adulterant and contaminant. Moringa oleifera is a well-known medicinal plant with many beneficial biological properties. This study investigated the possible prophylactic and therapeutic activity of an ethanolic extract of M. oleifera (MEE) against ML-induced hepatorenal damage. METHOD: Fifty male Sprague Dawley rats were orally administered distilled water, MEE (800 mg/kg bw), ML (700 mg/kg bw), MEE/ML (prophylactically) or MEE+ML (therapeutically). Hepatic aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphate (ALP) in serum were measured. Serum total bilirubin, direct bilirubin, indirect bilirubin, protein, albumin, and globulin contents were also assayed, and urea and creatinine levels were determined. Moreover, antioxidant enzyme activity of glutathione peroxidase (GPx) and catalase (CAT) in serum levels were quantified. Complementary histological and histochemical evaluation of renal and hepatic tissues was conducted, and expression of oxidative stress (GPx and CAT) and apoptosis-related genes, p53 and Bcl-2, in hepatic tissue were assessed. In parallel, transcriptional expression of inflammation and renal injury-related genes, including kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), and tumor necrosis factor alpha (TNF-α) in the kidney tissue were determined. RESULTS: ML caused significant increases in serum levels of ALT, AST, ALP, total bilirubin, direct bilirubin, indirect bilirubin, urea, and creatinine. Further, ML treated rats showed significant reductions in serum levels of protein, albumin, globulin, GPx, and CAT. Distinct histopathological damage and disturbances in glycogen and DNA content in hepatic and renal tissues of ML treated rats were observed. KIM-1, TIMP-1, and TNF-α gene expression was significantly upregulated in kidney tissue. Also, GPx, CAT, and Bcl-2 genes were significantly downregulated, and p53 was significantly upregulated in liver tissue after ML treatment. MEE significantly counteracted the ML-induced hepatorenal damage primarily for co-exposed rats. CONCLUSION: MEE could be an effective therapeutic supplement for treatment of ML-induced hepato-renal damage, probably via modulating oxidative stress, apoptosis, and inflammation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Moringa oleifera/química , Extratos Vegetais/administração & dosagem , Insuficiência Renal/prevenção & controle , Triazinas/toxicidade , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Moléculas de Adesão Celular/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Modelos Animais de Doenças , Poluentes Ambientais/toxicidade , Etanol/química , Contaminação de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Insuficiência Renal/sangue , Insuficiência Renal/induzido quimicamente , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Triazinas/administração & dosagem
4.
Biomed Pharmacother ; 133: 111064, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378966

RESUMO

COVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early reported symptoms include fever, cough, and respiratory symptoms. There were few reports of digestive symptoms. However, with COVID-19 spreading worldwide, symptoms such as vomiting, diarrhoea, and abdominal pain have gained increasing attention. Research has found that angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, is strongly expressed in the gastrointestinal tract and liver. Whether theoretically or clinically, many studies have suggested a close connection between COVID-19 and the digestive system. In this review, we summarize the digestive symptoms reported in existing research, discuss the impact of SARS-CoV-2 on the gastrointestinal tract and liver, and determine the possible mechanisms and aetiology, such as cytokine storm. In-depth exploration of the relationship between COVID-19 and the digestive system is urgently needed.


Assuntos
/complicações , Gastroenteropatias/etiologia , Hepatopatias/etiologia , Pandemias , /patogenicidade , /metabolismo , Anorexia/etiologia , Antivirais/efeitos adversos , Ductos Biliares/metabolismo , Ductos Biliares/virologia , /imunologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Comorbidade , Síndrome da Liberação de Citocina/etiologia , Efeito Citopatogênico Viral , Gastroenteropatias/epidemiologia , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Humanos , Imunossupressores/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Hepatopatias/epidemiologia , Transplante de Fígado , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/virologia , Complicações Pós-Operatórias , Receptores Virais/metabolismo
5.
Zhongguo Zhong Yao Za Zhi ; 45(20): 5017-5023, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33350277

RESUMO

Keyin Pills is a kind of traditional Chinese medicine for the treatment of psoriasis, but it has been reported that it can cause serious liver injury. In this paper, we used the integrated evidence chain method to retrieve and reevaluate the adverse drug reaction database, CNKI literature and cases of liver injury relating to Keyin Pills in specialist hepatology hospitals. We screened out 23 cases with the causal relationship of the possible grade and above. Among them, 11 cases showed the positive causal relationship only with Keyin Pills, accounting for 47.83%, suggesting that there was objective liver injury caused by Keyin Pills. The incubation period of liver injury caused by Keyin Pills is 1-90 days, and the cumulative dosage span is 20-1 800 g. There were obvious individual diffe-rences. There was no relationship between liver injury as well as dose and course of treatment, suggesting that Keyin Pills could induce immune idiosyncratic liver injury. Furthermore, based on the liver injury model induced by immunological stress, it was confirmed that Keyin Pills could induce acute liver injury in a dose-dependent manner in rats with immunological stress. The toxic dose(14 g·kg~(-1)) of a single dose was 6.7 times of the clinical equivalent dose, and had no significant effect on the biochemical index of liver function and histopathology in normal rats. Decomposition experiments showed that Dictamnus dasycarpus in Keyin Pills is the main medicinal flavor that causes special liver injury, and the other three medicines had neither liver injury nor compatibility attenuation effect. The results suggest that clinical medication shall pay attention to the risk of liver injury caused by Keyin Pills in patients with immunological stress.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Dictamnus , Medicamentos de Ervas Chinesas , Psoríase , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Fígado , Medicina Tradicional Chinesa , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Ratos
6.
Zhonghua Gan Zang Bing Za Zhi ; 28(11): 954-958, 2020 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-33256282

RESUMO

Objective: To investigate the clinical characteristics, incidence trend, underlying diseases, causative drug and prognosis of drug-induced liver injury (DILI), so as to provide basis for its prevention and treatment. Methods: A retrospective study was conducted on 2 820 DILI cases who were admitted to our hospital from January 2002 to December 2015, and their clinical characteristics, incidence trends, underlying related diseases, causative drug, treatment and outcome were analyzed. Results: Among 2 820 DILI cases, the ratio of male to female was 1:1.44, and the age was (44.00±16.32) years old. According to the clinical classification of DILI, there were 2 353 cases (83.43%) of hepatocyte injury, 353 cases (12.51%) of cholestatic type and 114 cases (4.04%) of mixed type. In the three clinical classification of DILI, there was no statistically significant difference in the ratio of male to female (χ(2) = 3.032, P > 0.05). However, the difference in the ratio of male to female between different age groups was statistically significant (χ(2) = 48.367, P < 0.001). Among the patients with liver disease and acute liver disease admitted to our hospital from January 2002 to December 2015, the proportion of DILI and acute DILI showed an overall upward trend. The main underlying related diseases of 2 820 DILI cases were fever (15.14%), skin diseases (11.84%), cardiovascular and cerebrovascular diseases (11.17%). Chinese herbal patent medicines (37.49%), antibiotics (15.85%), antipyretic-analgesics (14.37%), and so on were the main causative drugs involved, and the prognostic differences among the three clinical classifications of DILI in terms of cure, improvement, ineffectiveness, and death were statistically significant (H = 61.300, P < 0.001). Conclusion: In recent years, among the patients with liver disease in our hospital, the proportion of DILI has shown an obvious upward trend, involving a variety of underlying diseases and causative drugs, and thus it needs clinical attention.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Colestase , Adulto , Antibacterianos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Hepatócitos , Humanos , Fígado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
7.
Nihon Yakurigaku Zasshi ; 155(6): 401-405, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132258

RESUMO

Drug-induced liver injury (DILI) is the major reason for the discontinuation of new drug development and the withdrawal of drugs from the market. Hence, the evaluation systems which predict the onset of DILI in the pre-clinical stage are needed. To date, many researchers have conducted the mechanism of DILI, but the DILI prediction is poor because of the complexity of DILI. In this regard, based on the information obtained from basic research and clinical case, several pharmaceutical companies have been developed DILI prediction methods with high sensitivity and specificity by combining multiple targets. Another reason for low predictability is derived from the conventional culture method which causes a rapid decrease in hepatocyte function. To overcome these problems, the construction of a high-level in vitro evaluation system has been developed and applied to DILI evaluation. On the other hand, these in vitro evaluation methods require a lot of labor and cost so, in silico prediction methods have also been constructed in recent years. Based on this point, this article reviews the trends in DILI prediction systems in the non-clinical stage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Simulação por Computador , Hepatócitos , Humanos , Fígado
8.
Zhongguo Zhong Yao Za Zhi ; 45(19): 4746-4755, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33164442

RESUMO

To systematically evaluate the efficacy and safety of Chinese medicine in the treatment of drug-induced liver injury(DILI). By searching the randomized controlled trials(RCTs) of the Chinese medicine published in CNKI, WanFang, VIP, PubMed, Web of Science, in a time limit from database establishment to May 1, 2020. The bias risk assessment and Meta-analysis were then conducted for the included studies. Seventeen studies were finally included, all of which were RCTs, including 1 407 patients. The experimental group was treated with Chinese herbal medicine decoction or Chinese patent medicine, involving a total of 11 kinds of drugs, and the control group was treated with conventional Western medicine. Meta-analysis results showed that, in terms of treatment effective rate, Yinlan Yigan Granules, Shuganning, Jiangmeiling Capsules, Baidan Shugan Recipe and Sini Shugan Decoction were all superior to Western medicine treatment. In terms of reducing alanine aminotransferase(ALT), Yinlan Yigan Granules, Shuganning, Hugan Jiedu Recipe, Wuzhi Tablets, Wucao Baogan Recipe and Liuwei Wuling Tablets were superior to Western medicine. In terms of reducing aspartate aminotransferase(AST), Shuganning, Hugan Jiedu Recipe, Wucao Baogan Recipe, Liuwei Wuling Tablets and Sini Shugan Decoction were all superior to Western medicine. In terms of reducing total bilirubin(TBiL), Yinlan Yigan Granules, Shuganning, Jiedu Hugan Yin, Wuzhi Tablets, Wucao Baogan Recipe, Baidan Shugan Recipe and Sini Shugan Decoction were all superior to Western medicine treatment. Combined with network Meta-analysis and probability ranking, it can be seen that, Jiangmeiling Capsules, Shuganning, Sini Shugan Decoction and Baidan Shugan Recipe were most likely to be the best drugs to improve the efficiency and reduce ALT, AST, TBiL, respectively, with certain advantages compared to conventional Western medicine treatment. Of the seventeen studies included, eight studies described safety issues, three of which involved the test group, all of which were minor adverse reactions that disappeared after drug withdrawal or symptomatic treatment. However, due to the low quality of the included studies, more high-quality clinical studies are needed for further verification, thus providing more evidence-based medical evidence for Chinese medicine intervention in DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Medicina Tradicional Chinesa , Metanálise em Rede , Medicamentos sem Prescrição , Resultado do Tratamento
9.
Life Sci ; 263: 118561, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33045213

RESUMO

AIMS: Acetaminophen-induced hepatorenal toxicity varies among sexes with controversial results among species. The aim was to compare the impact of sex and ovarian hormones on hepatorenal toxicity and to elucidate protective effects of estrogen and estrogen receptor (ER) agonists. MAIN METHODS: Under anesthesia, female rats underwent ovariectomy (OVX) or sham-OVX. Starting at postsurgical 40th day, OVX-rats received subcutaneously (each, 1 mg/kg/day) 17ß-estradiol (E2), ERß-agonist (DPN) or ERα-agonist (PPT) for 10 days, while male and sham-OVX rats received vehicle for 10 days. Then, rats received either acetaminophen (3 g/kg) or saline by orogastric gavage and were decapitated at 24th h. Blood samples were obtained to measure serum ALT, AST, BUN, creatinine levels. Liver and kidney samples were obtained for histopathologic examination and for analyzing levels of luminol- and lucigenin-chemiluminescence, glutathione and myeloperoxidase activity. KEY FINDINGS: Compared to their control groups, levels of AST, ALT, BUN, creatinine, hepatic and renal myeloperoxidase activity and chemiluminescence levels were increased, and hepatic glutathione level was decreased in acetaminophen-administered male groups, while ALT and hepatic chemiluminescence levels were not elevated in sham-OVX-rats. Both ER-agonists and E2 reduced BUN, creatinine and reversed all oxidative parameters in renal tissues of OVX-rats. Additionally, ERα-agonist reversed all hepatic injury parameters, while ERß-agonist elevated hepatic glutathione level. SIGNIFICANCE: Acetaminophen toxicity in female rats presented with a more preserved hepatic function, while renal toxicity was not influenced by sex or by the lack of ovarian hormones. Pretreatment with estrogen or ER agonists, via their antioxidant actions, provided protective effects on acetaminophen-induced hepatorenal toxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estrogênios/farmacologia , Nefropatias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores Estrogênicos/química , Analgésicos não Entorpecentes/toxicidade , Animais , Antioxidantes , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estradiol/farmacologia , Feminino , Glutationa , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Nitrilos/farmacologia , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley
11.
Toxicol Appl Pharmacol ; 409: 115301, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33096110

RESUMO

Polychlorinated biphenyl (PCB)126 and perfluorooctane sulfonic acid (PFOS) are halogenated organic pollutants of high concern. Exposure to these chemicals is ubiquitous, and can lead to potential synergistic adverse effects in individuals exposed to both classes of chemicals. The present study was designed to identify interactions between PCB126 and PFOS that might promote acute changes in inflammatory pathways associated with cardiovascular disease and liver injury. Male C57BL/6 mice were exposed to vehicle, PCB126, PFOS, or a mixture of both pollutants. Plasma and liver samples were collected at 48 h after exposure. Changes in the expression of hepatic genes involved in oxidative stress, inflammation, and atherosclerosis were investigated. Plasma and liver samples was analyzed using untargeted lipidomic method. Hepatic mRNA levels for Nqo1, Icam1, and PAI1 were significantly increased in the mixture-exposed mice. Plasma levels of PAI1, a marker of fibrosis and thrombosis, were also significantly elevated in the mixture-exposed group. Liver injury was observed only in the mixture-exposed mice. Lipidomic analysis revealed that co-exposure to the mixture enhanced hepatic lipid accumulation and elevated oxidized phospholipids levels. In summary, this study shows that acute co-exposure to PCB126 and PFOS in mice results in liver injury and increased cardiovascular disease risk.


Assuntos
Ácidos Alcanossulfônicos/efeitos adversos , Biomarcadores/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fluorcarbonetos/efeitos adversos , Bifenilos Policlorados/efeitos adversos , Animais , Poluentes Ambientais/efeitos adversos , Fibrose/induzido quimicamente , Fibrose/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Risco , Trombose/induzido quimicamente , Trombose/metabolismo
12.
Nihon Yakurigaku Zasshi ; 155(5): 323-328, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879174

RESUMO

With the recent progress in drug metabolism and pharmacokinetics studies, the attrition due to pharmacokinetics in clinical trials and post-marketing was reduced to less than 1%. On the other hand, attrition of clinical trials due to adverse effects and toxicity has remained high. In particular, drug-induced liver injury (DILI) is a major cause of discontinuation of clinical trials and withdrawal of drug candidates after marketing. DILI is roughly divided into intrinsic and idiosyncratic. The former is relatively easy to predict its onset in preclinical drug development, but the latter's onset mechanism is still unknown and its onset prediction is difficult. We are investigating to develop an experimental animal model of idiosyncratic DILI (iDILI), clarify the pathogenic mechanism, and apply the obtained biomarker information to the establishment of an in vitro cell-based prediction test system. In this paper, we will introduce various animal models of iDILI, present status of pathogenic mechanism study, and classification of iDILI drugs, and introduce the recent progress of in vitro cell-based prediction test system and new causative factors of iDILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Biomarcadores , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado
13.
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
14.
Ann Agric Environ Med ; 27(3): 368-373, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32955216

RESUMO

INTRODUCTION: Chlorpyrifos (CPF) is a organophosphate insecticide widely used in agriculture with attendant adverse health outcomes. Chronic exposure to CPF induces oxidative stress and elicits harmful effects, including hepatic dysfunction. Molecular hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. OBJECTIVE: The aim of this study was to determine whether the intake of hydrogen-rich water (HRW) could protect rats from hepatotoxicity caused by sub-chronic exposure to CPF. MATERIAL AND METHODS: Rats were treated with hydrogen-rich water by oral intake for 8 weeks. Biochemical indicators of liver function, SOD and CAT activity, GSH and MDA levels were determined by the spectrophotometric method. Liver cell damage induced by CPF was evaluated by histopathological and electron microscopy analysis. PCR array analysis was performed to investigated the effects of molecular hydrogen on the regulation of oxidative stress related genes. RESULTS: Both the hepatic function tests and histopathological analysis showed that the liver damage induced by CPF could be ameliorated by HRW intake. HRW intake also attenuated CPF induced oxidative stress, as evidenced by restored SOD activities and MDA levels. The results of PCR Array identified 12 oxidative stress-related genes differentially expressed after CPF exposure, 8 of chich, including the mitochondrial Sod2 gene, were significantly attenuated by HRW intake. The electron microscopy results indicated that the mitochondrial damage caused by CPF was alleviated after HRW treatment. CONCLUSIONS: The results obtained suggest that HRW intake can protect rats from CPF induced hepatotoxicity, and the oxidative stress signaling and the mitochondrial pathway may be involved in the protection of molecular hydrogen.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Clorpirifos/toxicidade , Hidrogênio/farmacologia , Inseticidas/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Relação Dose-Resposta a Droga , Masculino , Estresse Oxidativo/genética , Ratos , Ratos Wistar
15.
J Gastrointestin Liver Dis ; 29(3): 473-475, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32919428
16.
Life Sci ; 260: 118426, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937159

RESUMO

AIMS: Tobacco smoking is a major health problem associated with lung and liver damage. Lung and liver damage secondary to tobacco smoking is mediated through nicotine-induced oxidative stress. Therefore, we hypothesized that antioxidant treatment with tiron may improve nicotine-induced lung and liver damage. MATERIALS AND METHODS: Rats were divided into six groups, a control, nicotine (10 mg/kg/day, i.p.; for 8 weeks) and tiron (100 or 200 mg/kg/day, i.p.; for 8 weeks) with or without nicotine administration. KEY FINDINGS: Tiron improved survival rate and attenuated lung and liver damage as reflected by decreased total and differential cell counts, lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid (BALF) and decreased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in serum; also histopathological examination confirmed the protective effect of tiron in lung and liver tissues of nicotine treated rats. Tiron attenuated dyslipidemia, which is associated with nicotine. These ameliorative effects of tiron may be mainly due to its antioxidant effect as proved by a significant decrease in malondialdehyde (MDA) content, reactive oxygen species (ROS) and total nitrite/nitrate (NOx) levels, and increase in reduced glutathione (GSH) level, catalase (CAT) and superoxide dismutase (SOD) activities. This is likely related to suppression of protein levels of NADPH oxidase enzyme (NOX1), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α); and up-regulation of protein levels of nuclear factor erythroid-2 (Nrf2). SIGNIFICANCE: This makes tiron (synthetic analogue of vitamin E) good candidate for future use to minimize nicotine's hazards among smokers.


Assuntos
Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Lesão Pulmonar/prevenção & controle , Nicotina/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Peso Corporal/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Contagem de Células , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Enzimas/sangue , L-Lactato Desidrogenase/metabolismo , Lipídeos/sangue , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/mortalidade , Lesão Pulmonar/patologia , Masculino , NADPH Oxidase 1/sangue , NADPH Oxidase 1/metabolismo , NF-kappa B/sangue , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley
17.
J Oleo Sci ; 69(9): 1107-1115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879198

RESUMO

Medicinal plants and their secondary metabolites have long been a rich source of biologically active compounds that can prevent many diseases. In this context, we investigated the antioxidant activities of the essential oil of Lavandula officinalis and tested its potency against hepatic and renal toxicity induced by hydrogen peroxide in adult male mice based on measurements of biochemical parameters, oxidative stress, and tissue damage in both organs. We proved a remarkable antioxidant power of this plant (in vitro) by correcting the harmful effects of the prooxidant (in vivo). It can be concluded that lavender is an aromatic plant capable of reducing the stress caused by reactive oxygen species.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Antioxidantes , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Peróxido de Hidrogênio/toxicidade , Lavandula/química , Óleos Voláteis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Folhas de Planta/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Técnicas In Vitro , Masculino , Camundongos , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
18.
Bull Cancer ; 107(10): 1056-1068, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-32951849

RESUMO

Pharmacological immune checkpoint inhibitors (ICI) restore the anti-tumor properties of T-lymphocytes, but unfortunately can engender auto-immune-like disorders. Those, frequent and of variable severity, sometimes target the liver parenchyma. Liver toxicity of ICI firstly leads to alteration of liver function tests (ALFT) with a risk of clinical decompensation. The appearance of ALFT should lead the clinician to exclude a non-immunological injury or a tumoral invasion of the liver parenchyma. In case of high grade ALFT, liver biopsy is necessary for diagnosis purpose. In ICI-induced hepatoxicity, histology examination shows most frequently a lobular acute hepatitis associated with lymphocytic infiltrates, but with different features than those encountered in primary auto-immune hepatitis. The management of ICI-related ALFT depends of their severity. Discontinuation of ICI is recommended for ALFT≥grade 2, and corticosteroid therapy for ALFT≥grade 3, or grade 2 without any improvement after ICI discontinuation. Addition of mycophenolate may be indicated whether corticosteroid inefficiency. Reintroduction of ICI is inadvisable for the most severe toxicities. The management of ALFT occurring on underlying chronic hepatopathy has not got consensual guidelines so far, but they should take account of the basal grade of ALFT and their worsening level under ICI therapy. The situation becomes more complex with associations between ICI and anti-angiogenic agents or cytotoxic chemotherapies where each of the drugs can be hepatotoxic. Thus, liver biopsy is primordial to figure out the mechanism of liver toxicity.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Humanos , Incidência
19.
Isr Med Assoc J ; 9(22): 481-485, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32954693

RESUMO

BACKGROUND: Acetaminophen is the most common drug involved in pediatric poisonings, both intentionally and accidentally, and is the leading cause of acute liver failure among all age groups. OBJECTIVES: To define the characteristics of patients admitted to a pediatric emergency department (ED) where serum acetaminophen concentrations were measured, and to determine which variables are associated with significant risk of acetaminophen toxicity. METHODS: Acetaminophen serum concentrations were measured, in a retrospective case series, of patients younger than 18 years who had been admitted to the ED at Shamir Medical Center between 1 January 2008 and 31 December 2015. RESULTS: During the study period 180,174 children were admitted to the ED. Acetaminophen serum concentrations were measured in 209 (0.12%) patients. Mean age was 12.4 ± 5.9 years. Elevated liver enzymes were found in 12 patients, 5 of whom had documented acute liver injury. All five were older than 11years.Two cases of acute liver injury were attributable to acetaminophen ingestion. In both cases the cause was intentional overdose. Univariate analysis showed a significant (P < 0.05) correlation between detectable acetaminophen blood level and a positive history of drug or acetaminophen ingestion, and suicide attempt. Not all children with non-severe acetaminophen poisoning had been diagnosed during the study period. A positive history of acetaminophen ingestion was associated with a 28-fold higher risk for detectable acetaminophen blood level. CONCLUSIONS: In the absence of a positive history of acetaminophen ingestion and in young children with accidental intoxication, the risk of hepatotoxicity is relatively low.


Assuntos
Acetaminofen/envenenamento , Analgésicos não Entorpecentes/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Overdose de Drogas/epidemiologia , Serviço Hospitalar de Emergência , Acetaminofen/sangue , Adolescente , Analgésicos não Entorpecentes/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Israel , Masculino , Estudos Retrospectivos , Tentativa de Suicídio/estatística & dados numéricos
20.
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
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