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1.
Chemosphere ; 262: 127891, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32799150

RESUMO

Fluoride generally exists in the natural environment, and has been reported to induce serious environmental hazard to animals, plants, and even humans via ecological cycle. Silkworm, Bombyx mori, which showed significant growth and reproductivity reduction when exposed to fluoride, has become a model to evaluate the toxicity of fluoride. However, the detailed mechanism underlying fluoride toxicity and corresponding transport proteins remain unclear. In this study, we performed RNA-seq of the larval midgut and fat body with fluoride exposure and normal treatment. Differential analysis showed that there were 4405 differentially expressed genes in fat body and 4430 DEGs in midgut with fluoride stress. By Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we identified several key pathways involved in the fluoride exposure and poisoning. We focused on the oxidative phosphorylation and MAPK signal pathway. QRT-PCR confirmed that oxidative phosphorylation process was remarkably inhibited by fluoride exposure and resulted in the blocking of ATP synthesis. The MAPK signal pathway was stimulated via phosphorylation signal transduction. Moreover, by protein structure analysis combined with the DEGs, we screen 36 potential membrane proteins which might take part in transporting fluoride. Taken together, the results of our study expanded the underlying mechanisms of fluoride poisoning on silkworm larval growth and development, and implied potential fluoride transport proteins in silkworm.


Assuntos
Bombyx/fisiologia , Fluoretos/toxicidade , Substâncias Perigosas/toxicidade , Tecido Adiposo/metabolismo , Animais , Bombyx/metabolismo , Sistema Digestório/metabolismo , Corpo Adiposo/metabolismo , Perfilação da Expressão Gênica/métodos , Inativação Metabólica , Larva/genética , Transcriptoma/fisiologia
2.
Ecotoxicol Environ Saf ; 202: 110906, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800241

RESUMO

The nonsteroidal anti-inflammatory drug diclofenac (DCF) is considered a contaminant of emerging concern. DCF can co-exist with heavy metals in aquatic environments, causing unexpected risks to aquatic organisms. This study aimed to assess the combined effects of DCF and cadmium (Cd) at environmentally relevant concentrations on the bioconcentration and status of oxidative stress and detoxification in Chironomus riparius larvae. The larvae were exposed to DCF (2 and 20 µg L-1) and Cd (5 and 50 µg L-1) alone or in mixtures for 48 h. The combined exposure to DCF and Cd was found to reciprocally facilitate the accumulation of each compound in larvae compared with single exposures. As indicated by the antioxidant enzyme activities, reduced glutathione levels, and malondialdehyde contents, the low concentration of the mixture (2 µg L-1 DCF + 5 µg L-1 Cd) did not alter the oxidative stress status in larvae, while the high concentration of the mixture (20 µg L-1 DCF + 50 µg L-1 Cd) induced stronger oxidative damage to larvae compared with single exposures. The expression levels of eight genes (CuZnSOD, MnSOD, CAT, GSTd3, GSTe1, GSTs4, CYP4G, and CYP9AT2) significantly decreased due to the high concentration of the mixture compared with single exposures in most cases. Overall, the results suggest that the mixture of DCF and Cd might exert greater ecological risks to aquatic insects compared with their individual compounds.


Assuntos
Cádmio/toxicidade , Chironomidae/fisiologia , Diclofenaco/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Cádmio/metabolismo , Chironomidae/efeitos dos fármacos , Diclofenaco/metabolismo , Inativação Metabólica/efeitos dos fármacos , Larva/efeitos dos fármacos , Malondialdeído/metabolismo , Metais Pesados/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Poluentes Químicos da Água/metabolismo
3.
Int J Nanomedicine ; 15: 5005-5016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764932

RESUMO

Background and Aim: With the wide applications of chitosan and gold nanoparticles in drug delivery and many consumer products, there is limited available information about their effects on drug-metabolizing enzymes (DMEs). Changes in DMEs could result in serious drug interactions. Therefore, this study aimed to investigate the effects of exposure to chitosan or gold nanoparticles on hepatic Phase I and II DMEs, liver function and integrity, oxidative damage and liver architecture in male rats. Methods: Animals were divided into three equal groups: a control group, a group treated with chitosan nanoparticles (200 mg/kg, 50±5 nm) and a group treated with gold nanoparticles (4 mg/kg, 15±5 nm). Rats were orally administered their respective doses daily for 10 days. Results: Both chitosan and gold nanoparticles decreased the body weights by more than 10%. Gold nanoparticles reduced the activities of antioxidants (superoxide dismutase and catalase), and reduced glutathione level and elevated the malondialdehyde level in the liver. Gold nanoparticles caused significant reductions in CYP1A1, CYP2E1, quinone oxidoreductase1, and glutathione S-transferase and elevated CYP2D6 and N-acetyl transferase2. Chitosan elevated CYP2E1 and CYP2D6 and reduced UDP-glucuronosyltransferase 1A1. Both nanoparticles disturbed the architecture of the liver, but the deleterious effects after gold nanoparticles treatment were more prominent. Conclusion: Taken together, gold nanoparticles severely perturbed the DMEs and would result in serious interactions with many drugs, herbs, and foods.


Assuntos
Antioxidantes/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inativação Metabólica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas Metálicas/efeitos adversos , Animais , Catalase/genética , Catalase/metabolismo , Quitosana/química , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Interações Medicamentosas , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Glutationa/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Ouro/química , Ouro/farmacocinética , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Nanopartículas Metálicas/química , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
4.
Ecotoxicol Environ Saf ; 205: 111106, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32818877

RESUMO

The uptake and depuration kinetics of diclofenac and carbamazepine alone at an environmentally relevant nominal concentration of 2 µg/L and in combination at a concentration ratio of 1:1 with total concentration of 4 µg/L were evaluated in Carassius carassius after 7 d uptake and depuration. Also, the biochemical effects of both drugs alone at nominal concentrations of 2 and 10 µg/L as well as in combination with total concentrations of 4 and 20 µg/L were investigated in Carassius carassius after 7 d exposure followed by 10 d recovery. In the single treatments, steady-state BCFs measured after the 7 d exposure were 73.05, 49.71, 38.01 and 24.93 L/kg for diclofenac and 9.25, 8.99, 5.29 and 4.11 L/kg for carbamazepine in the liver, brain, gill and muscle of Carassius carassius, respectively. Comparatively lower BCFs were measured in the tissues of Carassius carassius for both drugs in the combined treatments. Acetylcholinesterase activity in the brain was significantly induced by diclofenac while carbamazepine and the mixtures significantly inhibited it during all the exposure days as well as after the 10 d recovery in all treatments. This indicates that Carassius carassius could not recover from the neurotoxic effects caused by carbamazepine unlike the inductive effect caused by diclofenac which was recoverable after 10 days. A significant increase in the activities of 7-ethoxyresorufin O-deethylase and glutathione s-transferase for individual and mixed pharmaceuticals suggest that metabolism and detoxification of both drugs took place in the liver of Carassius carassius. Also, a significant increase in the activities of superoxide dismutase, catalase, glutathione reductase and malondialdehyde contents in the individual and mixture treatments mean that the antioxidant defence system of Carassius carassius was triggered to fight against oxidative stress but lipid peroxidation still occurred. However, Carassius carassius recovered from all these increases (superoxide dismutase, catalase, glutathione reductase and malondialdehyde) after the 10 d recovery, suggesting that oxidative damage is reversible. Our results indicate that both drugs at environmentally relevant concentrations might cause adverse effects in Carassius carassius and other fish species.


Assuntos
Carbamazepina/toxicidade , Carpas/metabolismo , Diclofenaco/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Carbamazepina/metabolismo , Catalase/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Diclofenaco/metabolismo , Glutationa Transferase/metabolismo , Inativação Metabólica , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Malondialdeído/metabolismo , Oxirredução , Superóxido Dismutase/metabolismo , Poluentes Químicos da Água/metabolismo
5.
Chem Biol Interact ; 327: 109162, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32524993

RESUMO

Hundreds of millions of people worldwide are exposed to unacceptable levels of carcinogenic inorganic arsenic. Animal models have shown that selenium and arsenic are mutually protective through the formation and elimination of the seleno-bis(S-glutathionyl) arsinium ion [(GS)2AsSe]-. Consistent with this, human selenium deficiency in arsenic-endemic regions is associated with arsenic-induced disease, leading to the initiation of human selenium supplementation trials. In contrast to the protective effect observed in vivo, in vitro studies have suggested that selenite increases arsenite cellular retention and toxicity. This difference might be explained by the rapid conversion of selenite to selenide in vivo. In the current study, selenite did not protect the human hepatoma (HepG2) cell line against the toxicity of arsenite at equimolar concentrations, however selenide increased the IC50 by 2.3-fold. Cytotoxicity assays of arsenite + selenite and arsenite + selenide at different molar ratios revealed higher overall mutual antagonism of arsenite + selenide toxicity than arsenite + selenite. Despite this protective effect, in comparison to 75Se-selenite, HepG2 cells in suspension were at least 3-fold more efficient at accumulating selenium from reduced 75Se-selenide, and its accumulation was further increased by arsenite. X-ray fluorescence imaging of HepG2 cells also showed that arsenic accumulation, in the presence of selenide, was higher than in the presence of selenite. These results are consistent with a greater intracellular availability of selenide relative to selenite for protection against arsenite, and the formation and retention of a less toxic product, possibly [(GS)2AsSe]-.


Assuntos
Arsenitos/toxicidade , Substâncias Protetoras/farmacologia , Ácido Selenioso/farmacologia , Compostos de Selênio/farmacologia , Arsênico/metabolismo , Arsenitos/metabolismo , Células Hep G2 , Humanos , Inativação Metabólica/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Radioisótopos/metabolismo , Ácido Selenioso/metabolismo , Selênio/metabolismo , Compostos de Selênio/metabolismo , Radioisótopos de Selênio/metabolismo
6.
Medicine (Baltimore) ; 99(23): e20473, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32501994

RESUMO

BACKGROUND: In China, heat-clearing and detoxifying Chinese medicines combined with conventional therapy are commonly applied to treat the mild hand, foot, and mouth disease (HFMD). However, there is lack of solid evidence on the efficacy and safety of such therapies. METHODS: We conducted a pooled analysis with individual patient data from 5 strictly randomized controlled clinical trials to assess the efficacy and safety of this combination therapy for mild HFMD. An intention-to-treat analysis was performed. A 2-stage meta-analysis method was adopted to analyze the pooled effect size. RESULTS: In total, 947 patients were included. Compared with conventional therapy, the combination therapy significantly reduced the progression rate of HFMD from mild to severe (odds ratio [OR] 0.43, 95% confidence interval [CI]: 0.22 to 0.83, P = .01). Meanwhile, the healing time of skin rash and oral ulcer in the combination therapy group was significantly shorter than that of conventional therapy. The overall hazard ratio (HR) of healing time of the skin rash or oral ulcer was 1.22 (95%CI: 1.04 to 1.43; P = .02). However, except Jinlianqingre effervescent tablets, the combination therapy cannot shorten the time to fever resolution (HR 1.12, 95%CI: 0.97 to 1.29, P = .14). Because of the heterogeneity, Jinlianqingre effervescent tablets were analyzed separately and the HRs of the time to fever resolution and the healing time of skin rash or oral ulcer were 3.88 (95%CI: 3.19 to 4.72; P < .0001) and 3.79 (95%CI: 2.81 to 5.11; P < .0001), respectively. There were 30 adverse events reported in total; 2 cases were related to Chinese medicines. CONCLUSION: In conclusion, the heat-clearing and detoxifying Chinese medicines on top of conventional therapy can effectively reduce the progressive rate of mild HFMD and improve healing of skin and oral mucosal lesions. More studies are needed for the time to fever resolution.


Assuntos
Quimioterapia Combinada/normas , Medicamentos de Ervas Chinesas/normas , Febre/tratamento farmacológico , Doença de Mão, Pé e Boca/tratamento farmacológico , Quimioterapia Combinada/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Inativação Metabólica , Razão de Chances
8.
J Insect Sci ; 20(3)2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32484869

RESUMO

Fall armyworm, Spodoptera frugiperda (Smith), has caused significant losses for crop production in China. The fall armyworm is mainly controlled by the chemical insecticides, whereas the frequent application of insecticides would result in the resistance development. Insect cytochrome P450 monooxygenases play an essential part in the detoxification of insecticides. In this study, five P450 genes were selected to determine the role in response to insecticides by RNA interference (RNAi). Developmental expression pattern analysis revealed that S. frugiperda CYP321A8, CYP321A9, and CYP321B1 were highest in second-instar larvae among developmental stages, with 2.04-, 3.39-, and 8.58-fold compared with eggs, whereas CYP337B5 and CYP6AE44 were highest in adult stage, with 16.3- and 10.6-fold in comparison of eggs, respectively. Tissue-specific expression pattern analysis exhibited that CYP321A8, CYP321B1, and CYP6AE44 were highest in the midguts, with 3.56-, 3.33-, and 3.04-fold compared with heads, whereas CYP321A9 and CYP337B5 were highest in wings, with 3.07- and 3.36-fold compared with heads, respectively. RNAi was also conducted to explore detoxification effects of the five P450 genes on chlorantraniliprole. The second-instar larvae became more sensitive to chlorantraniliprole with a higher mortality rate than the control, after silencing CYP321A8, CYP321A9, and CYP321B1, respectively. These findings strongly supported our viewpoint that CYP321A8, CYP321A9, and CYP321B1 may play a critical role in insecticide detoxification. It will provide a basis for further study on regulation of P450 genes and the management of S. frugiperda.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Inativação Gênica , Proteínas de Insetos/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Spodoptera/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Genes de Insetos , Inativação Metabólica , Proteínas de Insetos/metabolismo , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Interferência de RNA , Spodoptera/genética , Spodoptera/crescimento & desenvolvimento
9.
PLoS One ; 15(5): e0230950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365122

RESUMO

A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation.


Assuntos
Biologia Computacional/métodos , Redes e Vias Metabólicas/genética , Preparações Farmacêuticas/metabolismo , Farmacogenética/métodos , Medicina de Precisão/métodos , Software , Bases de Dados Genéticas , Tratamento Farmacológico/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Absorção Gastrointestinal/genética , Estudos de Associação Genética , Humanos , Inativação Metabólica/efeitos dos fármacos , Inativação Metabólica/genética , Armazenamento e Recuperação da Informação/métodos , Redes e Vias Metabólicas/efeitos dos fármacos , Modelos Teóricos
10.
Xenobiotica ; 50(10): 1208-1219, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32352885

RESUMO

Liver enzymes and transporters play an essential role in xenobiotic metabolism, distribution and elimination. Pre-clinical safety assessment relies on studies on animal models, including the (mini)pig. The pig shares many anatomical and physiological characteristics with humans, and there is currently a gap in information about porcine metabolism and disposition pathways and their similarities and differences from human ones.Three different sample preparation methods (filter-aided sample preparation (FASP), enhanced FASP (eFASP) and in-solution sample preparation) were used to prepare porcine liver tissue (two samples) for proteomic analysis. The analysis relied on rapid-separation liquid chromatography coupled to Orbitrap mass spectrometry in data-dependent acquisition mode. MASCOT was used for identification and relative label-free quantification was based on spectral counting.The three sample preparation methods provided complementary results, allowing characterisation of approximately 70 pharmacologically relevant proteins. The main quantified proteins included 16 cytochrome P450 (CYP) enzymes, 5 UGT enzymes, and 11 transporters. In addition, 20 Phase I and 14 Phase II enzymes were also characterised. Inter-operator differences were negligible and the pig liver pies for CYP, UGT and efflux transporter proteins were established. Human homologues of the quantified CYP, UGT and transporter proteins were identified.


Assuntos
Transporte Biológico/fisiologia , Inativação Metabólica/fisiologia , Taxa de Depuração Metabólica/fisiologia , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado , Proteômica , Suínos
11.
Proc Natl Acad Sci U S A ; 117(24): 13248-13255, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32467170

RESUMO

Metal detoxification is essential for bacteria's survival in adverse environments and their pathogenesis in hosts. Understanding the underlying mechanisms is crucial for devising antibacterial treatments. In the Gram-negative bacterium Escherichia coli, membrane-bound sensor CusS and its response regulator CusR together regulate the transcription of the cus operon that plays important roles in cells' resistance to copper/silver, and they belong to the two-component systems (TCSs) that are ubiquitous across various organisms and regulate diverse cellular functions. In vitro protein reconstitution and associated biochemical/physical studies have provided significant insights into the functions and mechanisms of CusS-CusR and related TCSs. Such studies are challenging regarding multidomain membrane proteins like CusS and also lack the physiological environment, particularly the native spatial context of proteins inside a cell. Here, we use stroboscopic single-molecule imaging and tracking to probe the dynamic behaviors of both CusS and CusR in live cells, in combination with protein- or residue-specific genetic manipulations. We find that copper stress leads to a cellular protein concentration increase and a concurrent mobilization of CusS out of clustered states in the membrane. We show that the mobilized CusS has significant interactions with CusR for signal transduction and that CusS's affinity toward CusR switches on upon sensing copper at the interfacial metal-binding sites in CusS's periplasmic sensor domains, prior to ATP binding and autophosphorylation at CusS's cytoplasmic kinase domain(s). The observed CusS mobilization upon stimulation and its surprisingly early interaction with CusR likely ensure an efficient signal transduction by providing proper conformation and avoiding futile cross talks.


Assuntos
Cobre/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Histidina Quinase/metabolismo , Transativadores/metabolismo , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Membrana Celular/metabolismo , Citoplasma/metabolismo , Escherichia coli/genética , Histidina Quinase/química , Histidina Quinase/genética , Inativação Metabólica , Periplasma/metabolismo , Fosforilação , Ligação Proteica , Domínios Proteicos , Transdução de Sinais , Imagem Individual de Molécula
12.
Xenobiotica ; 50(11): 1370-1379, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32401667

RESUMO

We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CLt), distribution volumes in steady state (Vdss) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present study, we examined eight compounds (bosentan, cerivastatin, fluvastatin, pitavastatin, pravastatin, repaglinide, rosuvastatin, valsartan) as typical organic anion transporting polypeptide (OATP) substrates and six compounds metabolized by P450 and non-P450 enzymes to evaluate the predictability of CLt, Vdss and plasma concentration-time profiles after intravenous administration to chimeric mice. The predicted CLt and Vdss of drugs that undergo OATP-mediated uptake and P450/non-P450-mediated metabolism reflected the observed data from humans within a threefold error range. We also examined the possibility of predicting plasma concentration-time profiles of drugs that undergo OATP-mediated uptake using the complex Dedrick plot in chimeric mice. Most profiles could be superimposed with observed profiles from humans within a two- to threefold error range. PK prediction using SSS and the complex Dedrick plot in chimeric mice can be useful for evaluating drugs that undergo both OATP-mediated uptake and P450/non-P450-mediated metabolism.


Assuntos
Fígado/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Humanos , Inativação Metabólica , Taxa de Depuração Metabólica , Camundongos , Farmacocinética
13.
Toxicon ; 181: 57-68, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32353570

RESUMO

This study aimed to identify the bioactive compounds of the ethyl acetate extract of Aspergillus niger SH2-EGY using GC-MS and to evaluate their protective role against aflatoxin B1 (AFB1)-induced oxidative stress, genotoxicity and cytotoxicity in rats. Six groups of male Sprague-Dawley rats were treated orally for 4 weeks included the control group, AFB1-treated group (80 µg/kg b.w); fungal extract (FE)-treated groups at low (140) or high dose (280) mg/kg b.w and the groups treated with AFB1 plus FE at the two tested doses. The GC-MS analysis identified 26 compounds. The major compounds found were 1,2,3,4,6-Penta-trimethylsilyl Glucopyranose, Fmoc-L-3-(2-Naphthyl)-alanine, D-(-)-Fructopyranose, pentakis (trimethylsilyl) ether, bis (2-ethylhexyl) phthalate, trimethylsilyl ether-glucitol, and octadecanamide, N-(2- methylpropyl)-N-nitroso. The in vivo results showed that AFB1 significantly increased serum ALT, AST, creatinine, uric acid, urea, cholesterol, triglycerides, LDL, carcinoembryonic antigen, alpha-fetoprotein, interleukin-6, Malondialdehyde, nitric oxide, Bax, caspase-3 and P53 mRNA expression, chromosomal aberrations and DNA fragmentation. It decreased serum TP, albumin, HDL, Bcl-2 mRNA expression, hepatic and renal TAC, SOD and GPx content and induced histological changes in the liver and kidney. FE prevented these disturbances in a dosage-dependent manner. It could be concluded that A. niger SH2-EGY extract is safe a promising agent for pharmaceutical and food industries.


Assuntos
Aflatoxina B1/toxicidade , Antioxidantes/uso terapêutico , Aspergillus niger , Animais , Fragmentação do DNA/efeitos dos fármacos , Inativação Metabólica/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
Sci Total Environ ; 730: 138314, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32388358

RESUMO

Cancer is considered a complex disease that in many cases results from the interaction between chemical exposures, either from environmental or dietary sources, and genetic polymorphisms of xenobiotic-metabolizing enzymes (XME) or antioxidant enzymatic defenses. This study explored associations and interactions between genetic and environmental risk factors on the risk of prostate cancer (PCa) in 323 subjects that underwent prostate biopsy due to prostate specific antigen (PSA) levels above 4 ng/ml (161 PCa and 162 non-PCa). Eleven genes involved directly or indirectly in xenobiotic detoxification, oxidative stress and estrogen signaling were studied (GSTM1, GPX1 (rs1050450 and rs17650792), NAT2 (rs1801280), TXNRD1 (rs7310505), PRDX3 (rs3740562), CYP17A1 (rs743572), PON1 (rs662), SOD1 (rs10432782), SOD2 (rs4880), CAT (rs1001179), and ESR1 (rs746432)). A structured questionnaire was administered to all individuals to assess environmental and dietary chemical exposures. Medical data was collected by urologists. GPX1 rs17650792 polymorphism was the only one showing a significant inverse association with PCa risk. PRDX3 and GPX1 (rs17650792) genetic polymorphisms were significantly associated with Gleason score and PSA levels, respectively. The intake of nuts and soya products was associated with a reduced risk of PCa, as well as the performance of physical activity. Moreover, a number of gene-environmental interactions were found to increase the risk of PCa, particularly exposure to pesticides and rs1801280 (NAT2) and tobacco smoking and rs1050450 (GPX1). These findings suggest that the association of genetic and environmental risk factors with PCa risk should be assessed jointly for a better understanding of this complex disease.


Assuntos
Neoplasias da Próstata , Antioxidantes , Arilamina N-Acetiltransferase , Arildialquilfosfatase , Biomarcadores , Predisposição Genética para Doença , Humanos , Inativação Metabólica , Masculino , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
15.
Chemosphere ; 255: 126947, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32388261

RESUMO

Gills are considered a key player in organism defenses against environmental pollutants. Since it is the major site of uptake of waterborne chemicals, the modulation of important cellular defenses is expected in this tissue. Chlorothalonil, a fungicide presented in herbicides and antifouling paints, might be responsible for toxicity in marine biota. In this context, mussels were exposed to 0.1 µgL-1 and 10 µgL-1 of chlorothalonil for 24 h and 96 h. Genes from biotransformation and antioxidant defense pathways were investigated. Overall, we report, for the first time, an increase in the transcripts of the AhR-like, SULT1A1-like, CYP1A2-like, GSTO-like, MGST-like and SOD-like genes in the gills of the brown mussel Perna perna. This up-regulation was observed mostly after 96 h of exposure to chlorothalonil. Those results reinforce the important role of gills in xenobiotic metabolism and suggest the involvement of the mentioned genes in the detoxification of the compound. Throughout biotransformation and antioxidant defenses pathway, mussels exposed to chlorothalonil are activating mechanisms of defense against this contaminant.


Assuntos
Fungicidas Industriais/metabolismo , Nitrilos/metabolismo , Perna (Organismo)/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Antioxidantes/metabolismo , Biotransformação , Brânquias/metabolismo , Inativação Metabólica , Alimentos Marinhos , Poluentes Químicos da Água/toxicidade
16.
Arch Insect Biochem Physiol ; 104(2): e21674, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32281173

RESUMO

Insects have evolved resistance to almost all insecticides developed for their control. Multiple mechanisms of resistance, including enhanced metabolism and excretion of insecticides, target-site insensitivity, reduced penetration of insecticides, and avoidance behavior, have been reported. The genes coding for proteins involved in resistance have been identified in numerous insects. The enzymes and transporters required for all three phases of insecticide metabolism and excretion including cytochrome P450 monooxygenases, glutathione S-transferases, UDP-glucuronosyltransferases, carboxylesterases, and ATP-binding cassette transmembrane transporters have been identified. Recent research in multiple insect species identified CNC-bZIP transcription factor superfamily members as regulators of genes coding for enzymes and transporters involved in insecticide metabolic resistance. The information on the pathway including reactive oxygen species, cap "n" collar isoform-C, and its heterodimer partner, muscle aponeurosis fibromatosis transcription factors involved in overexpression of enzymes and transporters involved insecticide resistance will be summarized.


Assuntos
Inativação Metabólica/genética , Proteínas de Insetos/genética , Insetos/efeitos dos fármacos , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Proteína Oncogênica v-maf/genética , Fatores de Transcrição/genética , Animais , Proteínas de Insetos/metabolismo , Insetos/genética , Proteína Oncogênica v-maf/metabolismo , Fatores de Transcrição/metabolismo
17.
Medicine (Baltimore) ; 99(17): e19938, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332675

RESUMO

The pathophysiology of alcohol use disorder (AUD) is not totally clear. The aim of this study was to investigate the serum levels of brain-derived neurotrophic factor (BDNF) and oxidative stress markers in AUD patients during alcohol detoxification. Evaluation of changes in BDNF, glutathione peroxidase (GPX), catalase, superoxide dismutase, thiobarbituric acid reactive substances, 8-hydroxy 2'-deoxyguanosine, PCC and S100B were carried out.14 AUD inpatients and 20 healthy control subjects were recruited for this study. The serum BDNF, S100B and oxidative stress markers were measured with assay kits.Serum levels of catalase, GPX, PCC and 8-hydroxy 2'-deoxyguanosine were significantly higher in the AUD group subjects than in the controls (P < .05). However, BDNF levels were lower in the AUD group than in the controls (P < .05). After alcohol detoxification treatment, the GPX levels in the AUD group dropped (P < .05) and the BDNF levels rose (P < .05).The results suggest that serum BDNF and GPX levels might be state biomarkers for AUD patients undergoing alcohol detoxification.


Assuntos
Alcoolismo/sangue , Alcoolismo/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/análise , Glutationa Peroxidase/análise , Inativação Metabólica/fisiologia , Adulto , Alcoolismo/fisiopatologia , Biomarcadores/análise , Biomarcadores/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Feminino , Glutationa Peroxidase/sangue , Humanos , Inativação Metabólica/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade
18.
Artigo em Inglês | MEDLINE | ID: mdl-32300985

RESUMO

Paracetamol (APAP) is a widely used non-steroidal anti-inflammatory drug and has been frequently detected in aquatic environment. However, limited information is provided about the toxic effects and detoxification mechanism of APAP in aquatic invertebrates. In the present study, the change of life traits of Daphnia magna (e.g., body length, growth rate and reproduction) was investigated under the chronic APAP exposure (0-5000 µg/L) for 21 day, and the effects of APAP on the expression of the detoxification- and reproduction-related genes including HR96, CYP360A8, CYP314, MRP4, P-gp, EcR and Vtg in the acute exposure (up to 96 h) were also determined. Results showed that the molting frequency, days to the first brood and days to the first egg production of D. magna were affected under the 50 µg/L concentration of APAP in the chronic exposure test. In the acute test, the transcriptional expression of HR96 was up-regulated under APAP exposure for 24 and 48 h. Similar performances were also observed in the expression of CYP360A8, CYP314, MRP4 and P-gp. However, with exposure time extended to 96 h, the induction of HR96 decreased or even reversed in some cases. It may indicate that the defense system in Daphnia is activated for a short time of exposure or becomes adaptive after longer term of exposure. APAP exposure also affected reproduction-related genes expression, which was related to the exposure time and concentration of APAP. In summary, APAP significantly affected the expression of genes associated with detoxification metabolism and altered some physiological parameters in D. magna.


Assuntos
Acetaminofen/toxicidade , Daphnia/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Inativação Metabólica , Muda/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Testes de Toxicidade Crônica
19.
Xenobiotica ; 50(10): 1139-1148, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32238093

RESUMO

Elucidating the mechanisms for circadian expression of drug-metabolizing enzymes is essential for a better understanding of dosing time-dependent drug metabolism and pharmacokinetics. CYP2B6 (Cyp2b10 in mice) is an important enzyme responsible for metabolism and detoxification of approximately 10% of drugs. Here, we aimed to investigate a potential role of nuclear receptor co-repressor RIP140 in circadian regulation of Cyp2b10 in mice.We first uncovered diurnal rhythmicity in hepatic RIP140 mRNA and protein with peak values at ZT10 (ZT, zeitgeber time). RIP140 ablation up-regulated Cyp2b10 expression and blunted its rhythm in mice and in AML-12 cells. Consistent with a negative regulatory effect, overexpression of RIP140 inhibited Cyp2b10 promoter activity and reduced cellular Cyp2b10 expression.Furthermore, RIP140 suppressed Car- and Pxr-mediated transactivation of Cyp2b10, and the suppressive effects were attenuated when the RIP140 gene was silenced. Chromatin immunoprecipitation assays revealed that recruitment of RIP140 protein to the Cyp2b10 promoter was circadian time-dependent in wild-type mice. More extensive recruitment was observed at ZT10 than at ZT2 consistent with the rhythmic pattern of RIP140 protein. However, the time-dependency of RIP140 recruitment was lost in RIP140-/- mice.Additionally, we identified a D-box and a RORE cis-element in RIP140 promoter. D-box- and RORE-acting clock components such as Dbp, E4bp4, Rev-erbα/ß and Rorα transcriptionally regulated RIP140, potentially accounting for its rhythmic expression.In conclusion, RIP140 regulates diurnal expression of Cyp2b10 in mouse liver through periodical repression of Car- and Pxr-mediated transactivation. This co-regulator-driven mechanism represents a novel source of diurnal rhythmicity in drug-metabolizing enzymes.


Assuntos
Família 2 do Citocromo P450/metabolismo , Inativação Metabólica/fisiologia , Correpressor 1 de Receptor Nuclear/genética , Animais , Ritmo Circadiano , Sistema Enzimático do Citocromo P-450 , Fígado/metabolismo , Camundongos , Ativação Transcricional
20.
Chemosphere ; 250: 126268, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32234619

RESUMO

The effectiveness of rice waste biochars on heavy metal and metalloid abatement and detoxification was investigated using comprehensive studies based on As and Cd immobilization, bioaccumulation in tubifex, and microbial community changes in contaminated sediment. The remediation effects of biochars produced at different pyrolytic temperatures (400-700 °C) were evaluated. Bioaccumulation of heavy metal and metalloid in the tubifex tissue and change of indigenous microbial community under treatment of different biochars were assessed. Biochars produced at 700 °C exhibited greater effect on decreasing the concentrations of As and Cd in aqueous phase, and TCLP extractable and bioavailable metal(loid) in solid phase of sediment. The concentration of As and Cd in water phase decreased by 26%-89% and 22%-71% under the treatment of straw biochar, and decreased by 13%-92% and 5%-64% under the treatment of rice husk biochar, respectively. As and Cd contents in the tubifex tissue were positively correlated with their concentrations in aqueous phase. High-temperature biochars significantly reduced metal(loid) bioaccumulation in tubifex. The richness and biodiversity of microbial community were both greater in all biochars remediated sediment compared to non-treated sediment. These results indicated that rice waste biochars could effectively inhibit the bio-availability and toxicity of heavy metal and metalloid in sediment, and the higher-temperature biochar exhibited better performance.


Assuntos
Arsênico/química , Cádmio/química , Carvão Vegetal/química , Recuperação e Remediação Ambiental , Disponibilidade Biológica , Inativação Metabólica , Metais Pesados , Oryza , Pirólise , Temperatura , Água
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