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1.
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
2.
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
3.
Artigo em Chinês | MEDLINE | ID: mdl-32892589

RESUMO

Objective: To investigate the characteristics of inflammatory response in BALB/cA-nu mice induced by oral 1, 2-dichloropropane (1, 2-DCP) , and to provides theoretical reference for further study of subchronic, chronic toxicity and carcinogenic mechanism. Methods: From October 2018, Clean grade healthy BALB/cA-nu mice were randomly divided into 5 groups with 10 mice in each group. And 860, 1150, 1500, 1950, 2535 mg/kg 1, 2-DCP were given by gavage respectively. Meanwhile, blank group and solvent control group (corn oil) were set up. Blood samples were collected from eyeballs and liver and bile tissues were collected for histopathological examination within 24 hours after exposure. The expression of alanine aminotransferase (ALT) , total bilirubin (TBLI) , C-reactive protein (CRP) , interleukin-6 (IL-6) , tumor necrosis factor-α (TNF-α) and tumor necrosis factor-ß (TNF-ß) were detected by enzyme-linked immunosorbent assay. Results: With the increase of the dose of 1, 2-DCP, the number of microbubbles in liver cells and the infiltration of inflammatory cells increased gradually. No pathological changes were found in the gallbladder. Compared with the blank group and solvent control group, the content of serum ALT in each exposure group was increased, the serum levels of IL-6 and TNF-ß in 860, 1150, 1950 and 2350 mg/kg exposure groups were increased, the serum TNF-α and TBLI levels in 1 950, 2535 mg/kg groups were significantly higher (P<0.05) . The levels of ALT, TBLI and TNF-ß in serum of female mice were significantly different (P<0.05) . There were significant differences in ALT, TBLI, CRP, IL-6, TNF-α, TNF-ß in serum of male mice (P<0.05) . Conclusion: Oral 1, 2-DCP may cause acute liver injury in BALB/cA-nu mice and increase the expression of serum inflammatory factors. Moreover, the types of inflammatory factors activated in male mice are more than those in female mice.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Interleucina-6/sangue , Fígado , Propano/análogos & derivados , Alanina Transaminase , Animais , Aspartato Aminotransferases , Biomarcadores/sangue , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Propano/toxicidade , Fator de Necrose Tumoral alfa
4.
J Gastrointestin Liver Dis ; 29(3): 473-475, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32919428
5.
Drug Discov Ther ; 14(3): 135-138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32669522

RESUMO

Drug-induced liver injury (DILI) due to anti-tubercular treatment (ATT) leads to increased morbidity and mortality in patients with tuberculosis (TB). The aim of this study was to find the impact of malnutrition on the development of DILI. This was a prospective cohort study (September 2017 to August 2019) in which all newly diagnosed in-patients with tuberculosis above the age of 18 years were included. Those patients with a body mass index (BMI) of < 18.5 kg/m2 were considered malnourished. The patients were monitored for the development of DILI. Liver function tests were done at the baseline (before initiation of ATT), on the third day and at discharge in all the patients. Chi-square tests and conditional multiple logistic analysis was performed to identify risk factors associated with DILI. Out of the 319 subjects who were enrolled, a total of 138 patents chose to follow up at our hospital. A total of 14 patients (10%) developed DILI. The median time to onset of DILI was found to be ten days. Extra-pulmonary TB, low BMI and high baseline liver enzyme levels had a significant association with the development of DILI (p < 0.05). Low serum albumin had increased odds ratio but wasn't statistically significant. Malnutrition is an important risk factor for TB-DILI.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Desnutrição/diagnóstico , Desnutrição/epidemiologia , Centros de Atenção Terciária/tendências , Adulto , Doença Hepática Induzida por Substâncias e Drogas/sangue , Estudos de Coortes , Feminino , Humanos , Índia/epidemiologia , Masculino , Desnutrição/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Tuberculose/sangue , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia
7.
United European Gastroenterol J ; 8(7): 814-819, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32588791

RESUMO

BACKGROUND: Reports of liver injury in patients with novel coronavirus disease 2019 (COVID-19) are emerging from China and the USA. A wide variety of liver function test abnormalities and few cases of severe liver failure have been reported. No data on the hepatic phenotype from Europe are available at current. METHODS: We report a case series of 44 consecutive patients hospitalized for COVID-19 in Germany. RESULTS: At the time of admission, aspartate aminotransferase greater than the upper limit of normal was present in 70%, while alanine aminotransferase was elevated in 15.8%. Markers of cholestatic liver injury were altered only in a minority of patients. During hospitalization, 31% and 22% experienced increasing aspartate aminotransferase and alanine aminotransferase, respectively, when transaminases were normal at admission. Severe liver injury defined by 3×> upper limit of normal was observed in 9.1% over a mean time of 10.5 days. Importantly, patients exhibited cytotoxicity including lactate dehydrogenase and creatinine kinase elevations, but no signs of relevant liver function impairment. CONCLUSION: In summary, in a case series of hospitalized patients in Germany, cytotoxicity in the absence of severe liver dysfunction at admission and only few cases suggestive of severe liver injury during hospital were observed.


Assuntos
Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Infecções por Coronavirus/complicações , Falência Hepática Aguda/epidemiologia , Pneumonia Viral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Humanos , Fígado/efeitos dos fármacos , Fígado/virologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/virologia , Testes de Função Hepática/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Adulto Jovem
8.
Toxicology ; 441: 152493, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32479839

RESUMO

Early diagnosis of liver injuries caused by drugs or occupational exposures is necessary to enable effective treatments and prevent liver failure. Whereas histopathology remains the gold standard for assessing hepatotoxicity in animals, plasma aminotransferase levels are the primary measures for monitoring liver dysfunction in humans. In this study, using Sprague Dawley rats, we investigated whether integrated analyses of transcriptomic and metabolomic data with genome-scale metabolic models (GSMs) could identify early indicators of injury and provide new insights into the mechanisms of hepatotoxicity. We obtained concurrent measurements of gene-expression changes in the liver and kidneys, and expression changes along with metabolic profiles in the plasma and urine, from rats 5 or 10 h after exposing them to one of two classical hepatotoxicants, acetaminophen (2 g/kg) or bromobenzene (0.4 g/kg). Global multivariate analyses revealed that gene-expression changes in the liver and metabolic profiles in the plasma and urine of toxicant-treated animals differed from those of controls, even at time points much earlier than changes detected by conventional markers of liver injury. Furthermore, clustering analysis revealed that both the gene-expression changes in the liver and the metabolic profiles in the plasma induced by the two hepatotoxicants were highly correlated, indicating commonalities in the liver toxicity response. Systematic GSM-based analyses yielded metabolites associated with the mechanisms of toxicity and identified several lipid and amino acid metabolism pathways that were activated by both toxicants and those uniquely activated by each. Our findings suggest that several metabolite alterations, which are strongly associated with the mechanisms of toxicity and occur within injury-specific pathways (e.g., of bile acid and fatty acid metabolism), could be targeted and clinically assessed for their potential as early indicators of liver damage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Acetaminofen/toxicidade , Animais , Biomarcadores/sangue , Biomarcadores/urina , Bromobenzenos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/urina , Perfilação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metabolômica , Ratos Sprague-Dawley
9.
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
10.
Eur J Cancer ; 129: 117-122, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32151941

RESUMO

BACKGROUND: Abiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described. PATIENTS AND METHOD: We identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France. RESULTS: Forty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55-85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4-95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2-14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose. CONCLUSION: Liver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation.


Assuntos
Acetato de Abiraterona/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aspartato Aminotransferases/sangue , Neoplasias Ósseas/secundário , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Incidência , Testes de Função Hepática/estatística & dados numéricos , Neoplasias Hepáticas/secundário , Metástase Linfática/tratamento farmacológico , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/sangue , Remissão Espontânea
13.
Sci Rep ; 10(1): 3657, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32108154

RESUMO

A ketamine/xylazine (K/X) mixture is widely used before and during experiments in rodents. However, the impact of short-term use of K/X mixture and its influences on data interpretation have rarely been discussed. In this study, we administered one shot of a K/X mixture and examined acute hepatic responses using biochemical analysis, histopathological examination, and non-invasive imaging to determine the delay required prior to further assessment of the liver to avoid confounding effects triggered by anaesthesia. After the K/X injection, aspartate aminotransferase (AST) in serum was significantly elevated from 3 to 48 h. Obstructed sinusoidal circulation lasting for 24 or 36 h was revealed by DCE-MRI and drug distribution analysis, respectively. Metabolic alterations were detected at 3 h by NMR analysis and FDG-PET. Moreover, ultrasonography showed that lipid droplet accumulation increased from 1 to 16 h and declined thereafter. Taken together, our findings show that the K/X mixture induces acute hepatotoxicity and metabolic disturbance, and these disturbances cause hemodynamical disorders in the liver. The required time interval for recovery from K/X impact was dependent on the chosen assay. It took at least 16 h for metabolic recovery and 36 h for recovery of sinusoidal circulation. However, the liver was not fully recovered from the injury within 48 h.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Ketamina , Fígado , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Xilazina , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Ketamina/efeitos adversos , Ketamina/farmacologia , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Masculino , Camundongos , Xilazina/efeitos adversos , Xilazina/farmacologia
14.
Am J Case Rep ; 21: e919289, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32086430

RESUMO

BACKGROUND Acetaminophen overdose is the most common cause of acute liver failure. Nevertheless, new biomarker approaches enabling early prediction of the outcome of the acetaminophen overdose are needed. Recently, using next-generation sequencing analysis of serum from human study participants we uncovered injury-specific signatures of circulating microRNAs (miRNAs) that represented underlying molecular mechanisms of toxicity. This case study is first to show the application of miRNA profiling to assess prognosis of acetaminophen poisoning. CASE REPORT The patient was admitted to the hospital following supra therapeutic acetaminophen ingestion. The patient showed elevated levels of biomarkers of hepatocellular injury alanine aminotransferase, aspartate transaminase, and glutamate dehydrogenase. Even though treatment with N-acetyl cysteine was initiated 24 hours post-ingestion, levels of alanine-aminotransferase and aspartate transaminase peaked at about 40 hours post ingestion of acetaminophen. We analyzed global circulating miRNA levels from 24 consecutive serum samples from this study participant covering the period from admission to time of death. CONCLUSIONS The resulting global miRNA profiles were compared with profiles from study participants with non-lethal acetaminophen poisoning and healthy controls. At the admission, the miRNA profiles of both lethal and non-lethal acetaminophen poisoning showed induction of cellular stress and oxidative damage. Later, the miRNA profiles of the lethal poisoning featured fibrosis and coagulation pathways while profiles of non-lethal cases resembled those of healthy study participants. Although additional confirmatory studies are needed, our case study is first to indicate that global miRNA profiles to be used as liquid biopsies have potential to facilitate the assessment of acetaminophen poisoning.


Assuntos
Acetaminofen/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/sangue , Overdose de Drogas/sangue , Biópsia Líquida , MicroRNAs/sangue , Adulto , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Overdose de Drogas/diagnóstico , Evolução Fatal , Feminino , Humanos
15.
Biol Pharm Bull ; 43(4): 619-628, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32009027

RESUMO

Neoagarooligosaccharides (NAOS) are generated by ß-agarases, which cleave the ß-1,4 linkage in agarose. Previously, we reported that NAOS inhibited fat accumulation in the liver and decreased serum cholesterol levels. However, the hepatoprotective effect of NAOS on acute liver injury has not yet been investigated. Thus, we examined whether NAOS could activate nuclear factor (NF)-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) and upregulates its target gene, and has hepatoprotective effect in vivo. In hepatocytes, phosphorylation and subsequent nuclear translocation of Nrf2 are increased by treatment with NAOS, in a manner dependent on p38 and c-Jun N-terminal kinase (JNK). Consistently, NAOS augmented ARE reporter gene activity and the antioxidant protein levels, resulting in increased intracellular glutathione levels. NAOS antagonized tert-butylhydroperoxide-induced reactive oxygen species (ROS) generation. Moreover, NAOS inhibited acetaminophen (APAP)-induced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and significantly decreased hepatocyte degeneration and inflammatory cell infiltration. Moreover, ROS production and glutathione depletion by APAP were reversed by NAOS. APAP-mediated apoptotic signaling pathways were also inhibited in NAOS-treated mice. Upregulalted hepatic expression of genes related to inflammation by APAP were consistently diminished by NAOS. Collectively, our results demonstrate that NAOS exhibited a hepatoprotective effect against APAP-mediated acute liver damage through its antioxidant capacity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Oligossacarídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Acetaminofen , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Masculino , Camundongos Endogâmicos ICR , Oligossacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo
16.
Oxid Med Cell Longev ; 2020: 7504521, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998441

RESUMO

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Concanavalina A/efeitos adversos , Serotonina/sangue , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/farmacologia , Citocinas/sangue , Citocinas/genética , Masculino , Malondialdeído/sangue , Camundongos , Camundongos Knockout , Óxido Nítrico/sangue , Óxido Nítrico/genética , Peroxidase/sangue , Peroxidase/genética , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/genética , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
17.
Am J Gastroenterol ; 115(2): 251-261, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31789632

RESUMO

INTRODUCTION: We conducted this study to characterize the incidence, clinical features, treatment, and outcomes of immune checkpoint inhibitor (ICI) hepatotoxicity. METHODS: Patients who received ICIs (with either single-agent or combination regimens) from January 1, 2010, to March 31, 2018, were identified. Hepatotoxicity was defined as alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN), in the absence of an alternate cause, and categorized as grade 3 (ALT 5-20× ULN) or grade 4 (ALT >20× ULN), according to Common Terminology Criteria for Adverse Events 4.03. RESULTS: Among 5,762 patients, 100 (2%) developed hepatotoxicity, occurring in a higher proportion of recipients of combination therapy (9.2%) compared with monotherapy (up to 1.7%, P < 0.001). ICIs were discontinued permanently in 69 and temporarily in 31 patients. Sixty-seven patients received steroids, 10 of whom (14%) had recurrent hepatotoxicity after the steroid taper. Thirty-one patients resumed ICIs after ALT improvement, 8 of whom (26%) developed recurrent hepatotoxicity. Characteristics of liver injury, response to steroids, and outcomes were similar between 38 individuals with and 62 without possible pre-existing liver disease. The severity and outcome of hepatotoxicity due to combination therapy were not significantly different from monotherapy. There were 36 deaths. Two had liver failure at the time of death, both with progression of liver metastases and grade 3 hepatotoxicity. DISCUSSION: Clinically significant ICI-related hepatotoxicity was uncommon but led to permanent ICI discontinuation in the majority. ICIs were restarted in a sizable proportion of patients, most of whom did not experience recurrent hepatotoxicity.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Dor Abdominal/etiologia , Corticosteroides/uso terapêutico , Idoso , Alanina Transaminase/sangue , Consumo de Bebidas Alcoólicas , Ascite/etiologia , Aspartato Aminotransferases/sangue , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/terapia , Colite/induzido quimicamente , Desprescrições , Feminino , Febre/etiologia , Humanos , Icterícia/etiologia , Neoplasias Hepáticas/secundário , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Recidiva , Estudos Retrospectivos , Índice de Gravidade de Doença , Neoplasias Cutâneas/patologia
18.
J Ethnopharmacol ; 248: 112323, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31639487

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenoside compound K (CK), a product produced by the intestinal bacteria-mediated breakdown of ginsenoside, exhibits a wide array of pharmacological activities against diverse targets. However, few of preclinical safety evaluation of CK is reported. AIMS OF THE STUDY: The present study therefore sought to assess the toxicity of oral CK in Beagle dogs over a 26-week period. MATERIAL AND METHODS: All dogs received 4, 12, or 36 mg/kg oral CK doses for 26 weeks with regular monitoring, followed by a 4-week recovery period. Animals were monitored through measurements of temperature, weight, food intake, blood chemistry and hematological findings, electrocardiogram (ECG) measurements, urinalysis, gross necropsy and organ weight and tissue histopathology. RESULTS: Animals in the 36 mg/kg group exhibited an apparent reduction in body weight over the study period, in addition to the presence of focal liver necrosis and increased plasma enzyme levels (alanine aminotransferase, ALT; alkaline phosphatase, ALP) consistent with hepatotoxicity, although there was some evidence suggesting this toxicity was reversible. Animals in the 4 and 12 mg/kg groups did not exhibit any apparent toxicity for any measured parameters. CONCLUSION: These results thus indicate that the no observed adverse effect level (NOAEL) in dogs is 12 mg/kg.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ginsenosídeos/toxicidade , Fígado/efeitos dos fármacos , Administração Oral , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cães , Relação Dose-Resposta a Droga , Feminino , Ginsenosídeos/administração & dosagem , Fígado/metabolismo , Fígado/patologia , Masculino , Necrose , Nível de Efeito Adverso não Observado , Medição de Risco , Fatores de Tempo , Perda de Peso/efeitos dos fármacos
19.
Artif Cells Nanomed Biotechnol ; 47(1): 3929-3937, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571510

RESUMO

Immune hepatic injury is a liver disease closely related to an immune imbalance of T cells and macrophages. Our previous series of studies have demonstrated that taraxasterol isolated from Taraxacum possesses great anti-inflammatory and immunomodulatory effects in vivo and in vitro. In this study, we explored the preventive effects of taraxasterol and its underlying mechanisms on concanavalin A (Con A)-induced acute hepatic injury in mice. It was found that treatment with taraxasterol significantly decreased the Con A-induced increase of liver index, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and hepatic malondialdehyde (MDA) levels, and increased the Con A-induced decrease of hepatic glutathione (GSH) and superoxide dismutase (SOD) production. Taraxasterol also significantly inhibited the release of pro-inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, interferon-γ (IFN-γ) and IL-4. In addition, treatment with taraxasterol alleviated the hepatic histopathological injury and apoptosis induced by Con A. Furthermore, taraxasterol dramatically down-regulated the expressions of T toll-like receptor (TLR2), TLR4 and nuclear factor-κappaB (NF-κB) p65, and decreased the expression ratio of Bax/Bc1-2 in hepatic tissues. These findings suggest that taraxasterol prevents Con A-induced acute hepatic injury in mice by inhibiting TLRs/NF-κB inflammatory signalling pathway and promoting Bax/Bc1-2 anti-apoptotic signalling pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Concanavalina A/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Esteróis/farmacologia , Taraxacum/química , Triterpenos/farmacologia , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/sangue , Citoproteção/efeitos dos fármacos , Glutationa/biossíntese , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Superóxido Dismutase/biossíntese , Receptores Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
20.
Regul Toxicol Pharmacol ; 108: 104478, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539568

RESUMO

Worldwide, drug-induced liver injury (DILI) is a major cause of hepatic failure. It is also the leading cause of withdrawal, cautionary labeling, and restricted usage of licensed drugs; therefore, European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) warn that the existing methods of assessing DILI are insufficient and that some of the translational biomarkers of hepatotoxicity must be relooked. Magnetic resonance imaging (MRI) seems to be a proper tool in elucidating the effects of DILI in both preclinical and clinical studies, providing excellent visualization of the morphology of the liver parenchyma. Therefore, herein, we propose preclinical MRI assessment of liver injury in experimental paracetamol-treated rats. Quantitative MRI clearly provides evidence of adverse effects in the liver tissue caused by a single overdose of paracetamol (1 g kg-1 and 1.5 g kg-1 b.w.). The results of the MRI were confirmed by the histopathological examination (H&E) of the rat liver specimen, however the adverse effects were not disclosed due to standard aminotransferase assays (ALT/AST) in rat blood serum. The results of our analysis demonstrate the successful application of MRI in the examination of paracetamol-induced hepatotoxicity in rats; it has a potential to serve as the early diagnostic tool for the prediction of DILI in preclinical evaluation.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Imagem por Ressonância Magnética , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/patologia , Ratos Wistar
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