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1.
Biomed Khim ; 65(4): 331-338, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31436175

RESUMO

The effect of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers of hepatocytes cytolysis (aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase), parameters reflecting the state of oxidative status (intensity of biochemical luminescence and the content of diene conjugates), and the activity of oxidative metabolism enzymes (aconitate hydratase, glucose-6-phosphate dehydrogenase, NADP-isocitrate dehydrogenase) was studied in rats with CCl4-induced liver injury. The results obtained in the course of the work demonstrated the ability of the test compound to reduce the severity of oxidative stress and liver cells damage, as well as to change the activity of aconitate hydratase and NADP-generating enzymes in the direction of control values. 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline was more effective in normalizing CCl4-induced changes of the analyzed parameters that Carsil used as a reference compound. The tendency to normalize the state of oxidative status and enzyme activity of oxidative metabolism can attributed to hepatoprotective and antioxidant properties of the tested compound.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse Oxidativo , Quinolinas/farmacologia , Animais , Antioxidantes/farmacologia , Radicais Livres , Fígado/enzimologia , Ratos
2.
Toxicol Lett ; 314: 181-186, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31404594

RESUMO

The cytochrome P450 enzyme (CYP) family includes key enzymes for the metabolism of drugs and xenobiotics. Several animal models have been used to determine the metabolite profile of specific drugs. Among these are porcine microsomes prepared from Göttingen minipigs. However, CYP expression profile in microsomes from this pig breed is unknown. In the present study, we determined the mRNA and protein profiles of a comprehensive selection of CYPs in microsomes prepared from male and female Göttingen minipigs. Using RT-PCR, western blotting and mass spectroscopy, we found that the expression levels of CYP1A, CYP2A and CYP2E1 were significantly higher in females than males. Moreover, some of the transcription factors controlling CYP transcription also showed a sex-dependent expression pattern. Conversely, expression of CYP2B, CYP2D and CYP3A was comparable between sexes. The overall CYP expression distribution showed high similarity with what previously been reported in humans. In conclusion, our results suggest that Göttingen minipigs are a reliable model for studying CYPs.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/enzimologia , Animais , Sistema Enzimático do Citocromo P-450/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Isoenzimas , Masculino , Microssomos/enzimologia , Modelos Animais , Fatores Sexuais , Especificidade por Substrato , Suínos , Porco Miniatura
3.
Chem Biol Interact ; 311: 108796, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421116

RESUMO

Lambda-cyhalothrin (LCT) is a broad-spectrum pesticide widely used in agriculture throughout the world. This pesticide is considered a potential contaminant of surface and underground water as well as food, posing a risk to ecosystems and humans. In this sense, we decided to evaluate the activity of enzymes belonging to the purinergic system, which is linked with regulation of extracellular nucleotides and nucleosides, such as adenosine triphosphate (ATP) and adenosine (Ado) molecules involved in the regulation of inflammatory response. However, there are no data concerning the effects of LCT exposure on the purinergic system, where extracellular nucleotides act as signaling molecules. The aim of this study was to evaluate nucleotide hydrolysis by E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase), Ecto-NPP (ecto-nucleotide pyrophosphatase/phosphodiesterase), ecto-5'-nucleotidase and ecto-adenosine deaminase (E-ADA) in platelets and liver of adult rats on days 7, 30, 45 and 60 after daily gavage with 6.2 and 31.1 mg/kg bw of LCT. Gene expression patterns of NTPDases1-3 and 5'-nucleotidase were also determined in those tissues. In parallel, lambda-cyhalothrin metabolites [3-(2-chloro-3,3,3- trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic acid (CFMP), 4-hydroxyphenoxybenzoic acid (4-OH-3-PBA), and 3-phenoxybenzoic acid (3-PBA)] were measured in plasma. Results showed that exposure rats to LCT caused a significant increase in the assessed enzymes activities. Gene expression pattern of ectonucleotidases further revealed a significant increase in E-NTPDase1, E-NTPDase2, and E-NTPDase3 mRNA levels after LCT administration at all times. A dose-dependent increase in LCT metabolite levels was also observed but there no significant variations in levels from weeks to week, suggesting steady-steady equilibrium. Correlation analyses revealed that LCT metabolites in the liver and plasma were positively correlated with the adenine nucleotides hydrolyzing enzyme, E-ADA and E-NPP activities in platelets and liver of rats exposed to lambda-cyhalothin. Our results show that LCT and its metabolites may affect purinergic enzymatic cascade and cause alterations in energy metabolism.


Assuntos
Plaquetas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nitrilos/farmacologia , Nucleotidases/genética , Nucleosídeos de Purina/metabolismo , Piretrinas/farmacologia , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Animais , Plaquetas/enzimologia , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Hidrólise , Fígado/enzimologia , Fígado/metabolismo , Masculino , Espectrometria de Massas , Nitrilos/sangue , Nitrilos/metabolismo , Nucleotidases/metabolismo , Piretrinas/sangue , Piretrinas/metabolismo , Pirofosfatases/genética , Pirofosfatases/metabolismo , Ratos , Ratos Wistar
4.
J Med Life ; 12(2): 168-172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406519

RESUMO

There is evidence that infection by H. pylori can have a critical proportion in the development of hepatocyte injury and both noncancerous and malignant liver conditions including non-alcoholic fatty liver disease (NAFLD). This is attributed to several mechanisms, the most important one being the toxic products of the bacterium H. pylori and oxidative injury for hepatocytes which promotes hepatic injury. The present research was aimed at determining the association between H. pylori infection and the prevalence of NAFLD in Birjand, Iran. Two groups were included in this cross-sectional study at the outpatient university clinic. One group had NAFLD (65 patients) and the other group was healthy controls without NAFLD (65 subjects). The diagnosis of NAFLD was performed using abdominal ultrasound examination and the absence of taking steatogenic medications or alcohol. Serum anti-H. pylori IgG and fecal H. pylori antigen were tested for diagnosing of H. pylori infection using ELISA method. H. pylori infection diagnosis was made if both tests were positive. None of the subjects in either group had symptoms related to the digestive system including dyspepsia, GERD (gastroesophageal reflux disease), or epigastric pain suspicious of peptic ulcer disease. There were 37 patients (28.5%) in both NAFLD (22 cases, 33.8%) and control (15 cases, 23.1%) groups whose H. pylori tests (both IgG and fecal antigen) were positive. Statistically, no significant difference was observed between the two studied groups regarding H. pylori infection frequency (p = 0.37). Asymptomatic H. pylori infection rate was not significantly different between NAFLD patients and control subjects in Birjand, Iran.


Assuntos
Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/fisiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adulto , Estudos de Casos e Controles , Estudos Transversais , Feminino , Infecções por Helicobacter/sangue , Humanos , Irã (Geográfico)/epidemiologia , Lipídeos/sangue , Fígado/enzimologia , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Transaminases/metabolismo
5.
Exp Parasitol ; 204: 107726, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31299264

RESUMO

The aims of this study were to evaluate if the use of copper oxide wire particles, isolated or in association with closantel, in lambs infected with Haemonchus contortus enhances the anthelmintic efficacy of closantel, as well as to evaluate the effects of treatment in hepatic energy metabolism, inflammatory markers and hematological and biochemical tests. The lambs were randomly divided into five groups (6 animals each), as follows: uninfected animals (Control); animals infected with H. contortus (HC); infected and treated with closantel (HC + CL); infected and treated with copper oxide wire particles (HC + Cu); and infected and treated with closantel plus copper oxide wire particles (HC + CL + Cu). The animals of infected groups were infected orally with H. contortus (5,000 L3 -larvae) and on day 14 post infection (p.i) the treatments were initiated. The egg per gram of feces (EPG), butyrylcholinesterase (BuChE), myeloperoxidase (MPO), adenylate kinase (AK) and pyruvate kinase (PK) activities and hematological and biochemical tests were evaluated. Treatments with copper oxide (isolated and associated) were able to reduce the EPG count on days 28, 35, 42 and 49 p.i when compared to HC group, while closantel was able to reduce EPG only from day 35 p.i. Moreover, treatment with closantel (isolated or associated) was able to prevent the inhibition of hepatic AK and PK activities caused by H. contortus infection, which may contribute to efficient intracellular energetic communication in order to maintain the balance between cellular ATP consumption and production. Butyrylcholinesterase and MPO activities were higher in infected lambs compared to uninfected, while treated groups showed lower enzymatic activity compared to the group HC. The use of all therapeutic protocols was able to reduce the EPG count. Based on these evidences, the use of copper oxide plus closantel may be considered an alternative to treat lambs infected by H. contortus.


Assuntos
Anti-Helmínticos/administração & dosagem , Cobre/administração & dosagem , Hemoncose/veterinária , Inflamação/veterinária , Salicilanilidas/administração & dosagem , Doenças dos Ovinos/tratamento farmacológico , Abomaso/metabolismo , Adenilato Quinase/metabolismo , Administração Oral , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Análise Química do Sangue/veterinária , Butirilcolinesterase/sangue , Cápsulas , Metabolismo Energético/efeitos dos fármacos , Contagem de Eritrócitos/veterinária , Fezes/parasitologia , Hemoncose/complicações , Hemoncose/tratamento farmacológico , Hemoncose/metabolismo , Hematócrito/veterinária , Hemoglobinas/análise , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Contagem de Ovos de Parasitas/veterinária , Peroxidase/sangue , Piruvato Quinase/metabolismo , Distribuição Aleatória , Salicilanilidas/farmacologia , Salicilanilidas/uso terapêutico , Ovinos , Doenças dos Ovinos/metabolismo , Doenças dos Ovinos/prevenção & controle
6.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 477-480, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357769

RESUMO

Cylindromatosis gene is a kind of tumor suppressor genes, whose mutation or deletion will lead to the development of a cylindrical tumor. The deubiquitinating enzyme CYLD protein encoded by it is a member of the deubiquitinating enzyme family. CYLD alters the function of the target molecules by removing the ubiquitin chain linked to the substrate protein K63, and participates in the regulation of signaling pathways, such as NF-κB, JNK and Wnt. This article reviews the recent year's research progress of CYLD, especially its negative regulatory role in the progression of liver-related diseases.


Assuntos
Enzima Desubiquitinante CYLD , Hepatopatias , NF-kappa B , Proteínas Supressoras de Tumor , Enzima Desubiquitinante CYLD/metabolismo , Fígado/enzimologia , Hepatopatias/enzimologia , Pesquisa/tendências , Transdução de Sinais/fisiologia , Ubiquitina/metabolismo
7.
Toxicol Lett ; 313: 188-195, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284022

RESUMO

Brucine is one of the main bioactive and toxic constituents of the herb drug Semen Strychni. Here we aimed to determine dosing time-dependent hepatotoxicity of brucine, and to investigate the role of metabolism in generation of brucine chronotoxicity. Brucine was administered to wild-type or Npas2-/- (a clock disrupted model) mice at different circadian time points for toxicity and pharmacokinetic characterization. The hepatotoxicity was evaluated by plasma alanine aminotransferase and aspartate aminotransferase measurements and histopathological analysis. The role of Cyp3a11 in brucine metabolism was determined by chemical inhibition assays and Cyp3a11-overexpressing HEK293 cells. Hepatic circadian Cyp3a11 mRNA and protein levels were determined by qPCR and Western blotting, respectively. The toxicity of brucine was more severe in the light phase [Zeitgeber time (ZT) 2 and ZT8] than in the dark phase (ZT14 and ZT20). Chemical inhibition and substrate metabolism assays suggested Cyp3a11 as a significant contributor to brucine metabolism. The Cyp3a11 mRNA, protein and activity in the livers of wild-type mice displayed significant circadian fluctuations. Npas2 ablation markedly down-regulated Cyp3a11 mRNA, protein and activity, and abrogated their circadian rhythms. The circadian time differences in brucine pharmacokinetics and liver distribution were lost in Npas2-/- mice, so were the time differences in brucine hepatotoxicity. In conclusion, chronotoxicity of brucine was determined by circadian variations in Cyp3a11 metabolism. The findings have implications in improving brucine (and possibly Semen Strychni) efficacy via dosing time optimization.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Ritmo Circadiano , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Proteínas de Membrana/metabolismo , Fotoperíodo , Estricnina/análogos & derivados , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ritmo Circadiano/genética , Cronoterapia Farmacológica , Células HEK293 , Humanos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Estricnina/administração & dosagem , Estricnina/metabolismo , Estricnina/farmacocinética , Estricnina/toxicidade
8.
Gene ; 712: 143945, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279712

RESUMO

Reactive oxygen species, generated in all the aerobic organisms, can cause oxidative stress. Excessive ROS may become a source of carcinogen due to DNA damage, lipid peroxidation, cell injury, and cell death. In order to prevent these adverse effects of ROS, antioxidant enzymes have evolved in aerobic organisms. Catalase is a major antioxidant enzyme that breaks down excessive H2O2 and inhibits apoptotic cell death. Here we molecularly characterized catalase from red-lip mullet. The cDNA sequence of LhCAT consists of an ORF of 1545 bp, which encodes a 527 amino acid peptide (~60 kDa). Based on bioinformatics analysis, LhCAT possesses a domain architecture characteristic of catalases, including a catalase proximal active site signature and a catalase proximal heme-ligand signature. It also has heme and NADPH binding sites homologous to previously described catalases. Pairwise alignment with its homologs revealed that LhCAT shares 95.1% identity with Oplegnathus fasciatus catalase and 97.4% similarity with Sparus aurata catalase. An uprooted phylogenetic tree demonstrated that LhCAT resides in a clade with catalases from other teleosts and exhibits a close relationship with Oplegnathus fasciatus catalase. Among twelve tissue types, we observed the highest LhCAT mRNA expression in the liver, followed by blood. Immune challenge by Lactococcus garvieae, or Poly I:C in the blood or spleen resulted in up-regulation at 24 h post injection. We also tested the antioxidant activity of recombinant LhCAT against hydrogen peroxide and found its optimal concentration to be 12.5 µg/mL. Collectively, these data suggested that LhCAT play an important role in antioxidant defense and immune response of red-lip mullet.


Assuntos
Catalase/metabolismo , Proteínas de Peixes/metabolismo , Smegmamorpha , Adjuvantes Imunológicos , Animais , Antioxidantes/metabolismo , Catalase/genética , DNA Complementar/genética , Proteínas de Peixes/genética , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Heme/química , Peróxido de Hidrogênio/química , Sistema Imunitário , Ligantes , Fígado/enzimologia , Estresse Oxidativo , Filogenia , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Regulação para Cima
9.
Mar Drugs ; 17(6)2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185695

RESUMO

The purpose of this study was to investigate the preventive effects of fucoidan (Fc) and fucoxanthin (Fx) on hyperuricemic rats. Sprague Dawley (SD) rats were randomly assigned to seven groups: a control group, a hyperuricemia (HUA) group, low- and high-dose Fx groups, a Fc group, a combination Fc and Fx group, and a positive control group. Three weeks after the interventions, each group was given potassium oxonate (PO) and hypoxanthine (HX) to induce HUA in all groups except for the control group, and the rats were then sacrificed. Blood and urine were analyzed for biochemical properties, and differences in urine volume were determined. Livers and kidneys were collected to analyze xanthine oxidase (XO) activity and the expression of uric acid (UA) transporter-related proteins (GLUT9, ABCG2, OAT1, URAT1). The results show that HUA was successfully induced by PO/HX after 4 h of administration. The activity of XO was significantly reduced by a combination of Fc and Fx. In the combination group, both ABCG2 and OAT1 increased significantly, whereas GLUT9 and URAT1 decreased significantly. In summary, the combination of Fc and Fx can inhibit the activity of XO in the liver and regulate the expression of proteins related to UA transporter in the kidney to reduce the UA level in serum.


Assuntos
Hiperuricemia/induzido quimicamente , Ácido Oxônico , Polissacarídeos/farmacologia , Xantofilas/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Polissacarídeos/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Xantina Oxidase/metabolismo , Xantofilas/uso terapêutico
10.
Mar Drugs ; 17(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151157

RESUMO

Thioacetamide (TAA) is known to induce lipid accumulation in the liver. In the present study, we investigated the effects of magma seawater (MS) rich in minerals on hepatic lipid metabolism by evaluating lipogenic enzymes regulated by sterol regulatory element-binding proteins (SREBPs). Rats (n = 10 per group) were intraperitoneally injected with TAA (200 mg/kg bw) thrice a week for seven weeks in combination with a respective experimental diet. Rats in the TAA-treated group received either a chow diet (Control group) or a chow diet containing MS (TMS group, 2.05%) or silymarin (TSM group, 0.05%). Rats in the normal group were injected with PBS as a vehicle and received a chow diet. Rats in the TMS group showed significantly lower hepatic lipid concentrations than rats in the control group (p < 0.05). Hepatic protein expression levels of fatty acid synthase, SREBP-1, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and SREBP-2 were significantly downregulated in the TMS group, whereas carnitine palmitoyltransferase 1 levels were upregulated (p < 0.05). Hepatic thiobarbituric acid reactive substances levels were lower in the TMS group, whereas protein levels of glutathione peroxidase and catalase were elevated (p < 0.05). The effects of MS were comparable to those of silymarin. Our results evidently showed that MS inhibits hepatic lipid accumulation by suppressing lipid synthesis, accompanied by lipid oxidation and elevation of antioxidative status.


Assuntos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado , Minerais/farmacologia , Água do Mar/química , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Tioacetamida/farmacologia , Animais , Dieta , Fígado/química , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Minerais/administração & dosagem , Oxirredutases/genética , Oxirredutases/metabolismo , Ratos , Ratos Sprague-Dawley , Ganho de Peso/efeitos dos fármacos
11.
Aquat Toxicol ; 213: 105219, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31195325

RESUMO

Nrf2 is a crucial transcription factor that regulates the expression of cytoprotective enzymes and controls cellular redox homeostasis. Both arsenic and fluoride are potent toxicants that are known to induce Nrf2. They are reported to coexist in many areas of the world leading to complex mixture effects in exposed organisms. The present study investigated the expression of Nrf2 and related xenobiotic metabolizing enzymes along with other stress markers such as histopathological alterations, catalase activity, reduced glutathione content and lipid peroxidation in zebrafish liver as a function of combined exposure to environmentally relevant concentrations of arsenic (37.87 µgL-1 or 5.05 × 10-7 M) and fluoride (6.8 mg L-1 or 3.57 × 10-4 M) for 60 days. The decrease in the total reduced glutathione level was evident in all treatment conditions. Hyperactivity of catalase along with conspicuous elevation in reactive oxygen species, malondialdehyde content and histo-architectural anomalies signified the presence of oxidative stress in the treatment groups. Nrf2 was seen to be induced at both transcriptional and translational levels in case of both individual and co-exposure. The same pattern was observed in case of its nuclear translocation also. From the results of qRT-PCR it was evident that at each time point co-exposure to arsenic and fluoride seemed to alter the gene expression of Cu/Zn Sod, Mn Sod, Gpx and Nqo1 just like their individual exposure but at a very low magnitude. In conclusion, this study demonstrates for the first time the differential expression and activity of Nrf2 and other stress response genes in the zebrafish liver following individual and combined exposure to arsenic and fluoride.


Assuntos
Arsênico/toxicidade , Fluoretos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Xenobióticos/metabolismo , Peixe-Zebra/metabolismo , Animais , Catalase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
12.
Ecotoxicol Environ Saf ; 181: 130-137, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176247

RESUMO

The pikeperch Sander lucioperca is an economically important freshwater species that is currently threatened by higher summer temperatures caused by global warming. To clarify the physiological state of pikeperch reared under relatively high temperatures and to acquire valuable biomarkers to monitor heat stress in this species, 100 fish were subjected to five different temperature treatments, ranging from 23 °C (control) to 36 °C. The physiological and biochemical indexes of liver and blood were determined, and heat-shock cognate 70 kDa protein (Hsc70) mRNA expression profiles were analyzed. The results showed that the activities of superoxide dismutase, catalase, and glutathione peroxidase in heat-stressed pikeperch first increased and then decreased, exhibiting peaks at 34 °C, 28 °C, and 28 °C, respectively. The level of thiobarbituric acid-reactive substances (TBARS) in all experimental groups was significantly higher than that of the control. The numbers of red blood cells, the packed-cell volume, and the contents of hemoglobin were significantly higher in the 34 °C and 36 °C treatment groups. Under heat stress, the albumin, cholesterol, and triglycerides contents decreased with increasing temperatures. Real-time fluorescence-based quantitative RT-PCR showed that Hsc70 mRNA levels increased in all eight of the tested tissues under heat stress. Expression reached maximum levels at 34 °C in the muscle, heart and gill tissues, and at 36 °C in the other five tissues. These results demonstrate that several physiological and biochemical phenotypes, such as oxidative stress, antioxidant enzymes and molecular chaperones, could be important biomarkers of heat stress in pikeperch, and are potentially valuable to uncover the mechanisms of heat-stress responses in fish.


Assuntos
Proteínas de Peixes/metabolismo , Proteínas de Choque Térmico HSC70/metabolismo , Resposta ao Choque Térmico , Percas/metabolismo , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Contagem de Eritrócitos , Proteínas de Peixes/genética , Glutationa Peroxidase/metabolismo , Proteínas de Choque Térmico HSC70/genética , Resposta ao Choque Térmico/genética , Hemoglobinas/análise , Fígado/enzimologia , Fígado/metabolismo , Estresse Oxidativo , Percas/genética , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
13.
Environ Pollut ; 251: 502-509, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103010

RESUMO

Benzo[a]pyrene (BaP), a common environmental pollutant, can modulate the immune-associated signal pathway NF-κB, which is one of the critical signal pathways involved in various immune responses. BaP exposure usually generates reactive oxygen species (ROS), but whether ROS are predominantly involved in the modulation mechanism of the NF-κB pathway has not been clearly understood. In this study, an in vivo examination of Oryzias melastigma demonstrated that BaP exposure led to a down-regulation of the NF-κB pathway and increased levels of ROS. Conversely, in vitro results using the medaka liver cell line DIT-29 and a widely applied H2O2 method showed the opposite: up-regulation of the NF-κB pathway. However, the down-regulation of NF-κB upon BaP exposure in vitro was inhibited by the addition of a ROS inhibitor, indicating ROS are involved in the modulation of NF-κB. The discrepancy between in vivo and in vitro results of ROS impacts on NF-κB activation might be related to the concentration and persistence of ROS. Using a modified luminol detection system, BaP was found to generate sustained physiological concentrations of ROS for 24 h, while an H2O2 bolus generated ROS for less than 30 min. Furthermore, a steady-state sub-micromolar H2O2 system (H2O2ss) was developed in parallel as a positive control of ROS, by which H2O2 could be maintained for 24 h. Comparative evaluation using H2O2, H2O2ss and BaP exposures on the medaka cell line with pGL4.32 demonstrated that the persistent physiological concentrations of ROS generated upon BaP exposure or treatment with H2O2ss inhibited the NF-κB pathway, but direct H2O2 exposure had the opposite effect. Moreover, a western-blot assay and EMSA detection further confirmed the modulation of the NF-κB pathway in DIT-29. Taken together, this study shows that BaP exposure inhibits the NF-κB pathway by generating sustained physiological concentrations of ROS.


Assuntos
Benzo(a)pireno/toxicidade , Poluentes Ambientais/toxicidade , NF-kappa B/metabolismo , Oryzias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Linhagem Celular , Regulação para Baixo , Peróxido de Hidrogênio/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Oryzias/imunologia
14.
Environ Pollut ; 251: 13-21, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31071628

RESUMO

Cigarette smoking (CS) and betel quid (BQ) chewing are two known risk factors that have synergistic potential for the enhancing the development of oral squamous cell carcinoma (OSCC) in Taiwan. Most mutagens and carcinogens are metabolically activated by cytochrome P450 (CYP450) to exert their mutagenicity or carcinogenicity. Previous studies have shown that metabolic activation of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), by CYP2A6 activity determines NNK-induced carcinogenesis. In addition, safrole affects cytochrome P450 activity in rodents. However, the effect of BQ safrole on the metabolism of tobacco-specific NNK and its carcinogenicity remains elusive. This study demonstrates that safrole (1 mg/kg/d) induced CYP2A6 activity, reduced urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) levels, and increased NNK-induced DNA damage, including N7-methylguanine, 8-OH-deoxyguanosine and DNA strand breaks in a Syrian golden hamster model. Furthermore, altered NNK metabolism and increased NNK-induced DNA damage were also observed in healthy subjects with CS and BQ chewing histories compared to healthy subjects with CS histories. In conclusion, BQ containing safrole induced tobacco-specific NNK metabolic activation, resulting in higher NNK-induced genotoxicity. This study provides valuable insight into the synergistic mechanisms of CS- and BQ-induced OSCC.


Assuntos
Nitrosaminas/urina , Safrol/toxicidade , Uso de Tabaco/urina , Tabaco/metabolismo , Ativação Metabólica/efeitos dos fármacos , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/metabolismo , Cricetinae , Citocromo P-450 CYP2A6/metabolismo , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/metabolismo , Taiwan , Tabaco/toxicidade
15.
Food Chem Toxicol ; 130: 32-43, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082462

RESUMO

Crocus sativus L., a perennial plant grown mainly around the Mediterranean and Iran, has many medicinal properties including anti-inflammatory, anti-depressive and cancer preventing properties. Aqueous herbal extracts may affect the activity of Phase I and II enzymes involved in xenobiotic metabolism. The present study was designed to determine whether C. sativus infusion alters the activity of CYP1A2, CYP2A6, XO and NAT2 enzymes in humans. Thirty-four healthy volunteers consumed infusion prepared from C. sativus stigmata for six days. Enzyme phenotyping was assessed in saliva and urine using caffeine metabolite ratios as follows: CYP1A2: 17X/137Χ (saliva) and CYP1A2: (AFMU+1U+1X)/17U, CYP2A6: 17U/(17U + 17X), XO: 1U/(1U+1X) and NAT2: AFMU/(AFMU+1U+1X) (urine). Following C. sativus intake, CYP1A2 index was reduced by ∼13.7% in saliva (before: 0.51 ±â€¯0.22, after: 0.44 ±â€¯0.14; p = 0.002) and ∼6.0% in urine (before: 3.81 ±â€¯1.20, after: 3.58 ±â€¯0.92; p = 0.054). CYP1A2 index was significantly reduced only in males (saliva, before: 0.65 ±â€¯0.22, after: 0.51 ±â€¯0.16; p = 0.0001; urine, before: 4.53 ±â€¯1.19, after: 4.03 ±â€¯0.87; p = 0.017) suggesting sexual dimorphism in CYP1A2 inhibition. There was no effect of C. sativus intake on CYP2A6, XO or NAT2 indices. Short-term consumption of C. sativus infusion is unlikely to result in significant herb-drug interactions involving the enzymes studied, with the exception of potential herb-CYP1A2 substrate interaction in males.


Assuntos
Crocus/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , Adulto , Carotenoides/química , Feminino , Voluntários Saudáveis , Interações Ervas-Drogas , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083300

RESUMO

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.


Assuntos
Ascite Quilosa/induzido quimicamente , Ascite Quilosa/enzimologia , Metilcolantreno/toxicidade , Poli(ADP-Ribose) Polimerases/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Compostos Azo/farmacologia , Ascite Quilosa/patologia , Citocinas/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Knockout , Poli(ADP-Ribose) Polimerases/genética , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Análise de Sobrevida
17.
Res Vet Sci ; 124: 399-405, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31078787

RESUMO

Sodium dehydroacetate (Na-DHA), an antibiotic agent that combats growth of bacteria, fungi, and yeast, is used as a preservative in animal feed, food, and cosmetics. We previously reported that Na-DHA induces coagulation anomalies in Wistar rats, but the anticoagulant mechanism of Na-DHA remains to be established. Here we report that Na-DHA prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) in male and female Wistar rats. In addition, Na-DHA decreased vitamin K (VK) levels and increased the levels of protein induced by vitamin K absence/antagonist-II (PIVKA-II) in rat serum. Moreover, we found that treatment with VK not only reversed Na-DHA-decreased serum VK and -increased PIVKA-II levels, but also attenuated Na-DHA-prolonged PT and APTT, suggesting that Na-DHA-decreased serum VK level contributes to the anticoagulation due to Na-DHA. Further we found that Na-DHA inhibited vitamin K epoxide reductase complex subunit 1 (VKORC1), a key enzyme in VK recycling, in the liver tissue of Wistar rats, as evidenced by reduced mRNA and protein levels of VKORC1 following Na-DHA treatment. Taken together, our data indicate that Na-DHA inhibits liver VKORC1, resulting in a decrease of serum VK levels, leading to abnormal coagulation in rats.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fígado/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Pironas/farmacologia , Vitamina K/administração & dosagem , Animais , Feminino , Fígado/enzimologia , Masculino , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Ratos , Ratos Wistar , Vitamina K Epóxido Redutases
18.
Environ Toxicol ; 34(9): 1025-1033, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31087429

RESUMO

Hepatocellular carcinoma is considered one of the most prevalent and lethal malignancies worldwide. Chemotherapy with cytotoxic agents showed a low response rate with possible toxic effects. Recently, some emphases have been placed on the anticancer properties of bovine whey protein and its components, especially lactoferrin. The present study aimed to evaluate and compare the antihepatocarcinogenic activity of bovine whey protein concentrate (WPC, 300 and 600 mg/kg body weight) and lactoferrin (30 and 60 mg/kg body weight), orally and daily for 14 weeks, in the mice model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. The results showed that both WPC and lactoferrin (in a dose-dependent manner) alleviated significantly (P < .001) the elevation in serum markers of liver carcinoma and inflammation in the DEN-treated mice. Also, they exhibited a great amelioration in the livers' histological structure of the DEN-treated mice by 37.0% to 66.7%. In addition, they decreased significantly (P < .001) the hepatic DNA fragmentation in the DEN-treated mice by 23.1% to 32.7%. Only, the high doses of WPC and lactoferrin completely modulated the decrease in the activity of liver enzymic antioxidant defense system (catalase, glutathione peroxidase, and superoxide dismutase) and improved significantly (P < .01-.001) the concentration of hepatic reduced glutathione of the DEN-treated mice. Moreover, the high doses of WPC and lactoferrin reduced significantly (P < .05-.001) the elevation in the concentrations of hepatic active caspases 3, 8, and 9 of the DEN-treated mice. In conclusion, both WPC and lactoferrin were effective in inhibiting the hepatocarcinogenic activity of DEN in mice model through their ability to alleviate the hepatic inflammation and apoptosis.


Assuntos
Anticarcinógenos/uso terapêutico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Fígado/efeitos dos fármacos , Proteínas do Soro do Leite/uso terapêutico , Animais , Anticarcinógenos/administração & dosagem , Antioxidantes/metabolismo , Bovinos , Dietilnitrosamina/administração & dosagem , Relação Dose-Resposta a Droga , Lactoferrina/administração & dosagem , Lactoferrina/uso terapêutico , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Masculino , Camundongos , Proteínas do Soro do Leite/administração & dosagem
19.
Yakugaku Zasshi ; 139(5): 837-844, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31061351

RESUMO

The hydrolysis activity and expression level of carboxylesterase (CES) in skin were compared with liver and intestine in the same individual of beagle dog and cynomolgus monkey, and their aging effects were studied. CES1 isozymes were mainly present in skin of both animals. The dermal hydrolysis activity was about 10 and 40% of hepatic activity in beagle dog and cynomolgus monkey, respectively. In beagle dog, the hydrolysis activity and the expression level of CES isozyme in liver and skin were nearly the same between 2- and 11-year-old individuals. On the other hand, the dermal hydrolase activity was lower in young individual than in old, in contrast to slight increase of hepatic and intestinal activity in old cynomolgus monkey. These differences by aging in cynomolgus monkey were related to the expression of CES1 proteins and their mRNA. Furthermore, mRNA level of human CES was investigated using total RNA of two individuals (63 and 85 years old). The two individuals showed approximately 2-fold higher expression of hCE2 than hCE1 in human skin.


Assuntos
Envelhecimento/metabolismo , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Hidrolases/genética , Hidrolases/metabolismo , Intestinos/enzimologia , Fígado/enzimologia , Pele/enzimologia , Idoso de 80 Anos ou mais , Animais , Cães , Feminino , Expressão Gênica , Humanos , Hidrólise , Isoenzimas/genética , Isoenzimas/metabolismo , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
J Vet Med Sci ; 81(7): 980-982, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31118351

RESUMO

Knowledge of genetic polymorphisms of metabolizing enzymes of medical drugs and xenobiotics including cytochrome P450 (CYP) is very limited in cats. We investigated polymorphisms in CYP1A2, one of the major CYP isoforms in the feline liver. Wild-type and three non-synonymous polymorphic variants, but no synonymous variant, were identified in feline CYP1A2 in 50 alleles of domestic cats in Japan. Metabolic parameters, Km and Vmax, of ethoxyresorufin hydroxylation by CYP1A2 were shown to range within two times for identified non-synonymous variants by using a heterologous coexpression system. The results confirmed the polymorphic nature of CYP1A2 as a basis for effective application of medicines and prevention of adverse reactions in the treatment of domestic cats as well as for hereditary disorders.


Assuntos
Gatos/genética , Gatos/metabolismo , Citocromo P-450 CYP1A2/genética , Variação Genética , Animais , Cumarínicos/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Feminino , Hidroxilação , Fígado/enzimologia , Masculino , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Sequência de DNA
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