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1.
Anticancer Res ; 40(10): 5399-5404, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988859

RESUMO

BACKGROUND/AIM: The aim of the present study was to investigate whether idarubicin (IDR) induces oxidative DNA damage in the presence of copper (II). MATERIALS AND METHODS: DNA damage was evaluated by pBR322 plasmid DNA cleavage. The formation of oxidative stress markers [O2 •- and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] was analysed. RESULTS: IDR induced DNA damage and O2 •- and 8-OHdG generation in the presence of copper (II). CONCLUSION: IDR induced oxidative DNA damage in the presence of copper (II). Since it has been reported that the concentration of copper in the serum of cancer patients is higher than that in healthy groups, IDR-induced oxidative DNA damage in the presence of copper (II) may play an important role in anticancer therapeutic strategies.


Assuntos
Antraciclinas/farmacologia , Idarubicina/farmacologia , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antraciclinas/química , Cobre/química , Dano ao DNA/efeitos dos fármacos , Humanos , Idarubicina/química , Neoplasias/genética , Neoplasias/patologia , Espécies Reativas de Oxigênio/química , Superóxido Dismutase/genética
2.
Nat Commun ; 11(1): 4028, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788591

RESUMO

Changes in atmospheric CO2 concentration have played a central role in algal and plant adaptation and evolution. The commercially important red algal genus, Pyropia (Bangiales) appears to have responded to inorganic carbon (Ci) availability by evolving alternating heteromorphic generations that occupy distinct habitats. The leafy gametophyte inhabits the intertidal zone that undergoes frequent emersion, whereas the sporophyte conchocelis bores into mollusk shells. Here, we analyze a high-quality genome assembly of Pyropia yezoensis to elucidate the interplay between Ci availability and life cycle evolution. We find horizontal gene transfers from bacteria and expansion of gene families (e.g. carbonic anhydrase, anti-oxidative related genes), many of which show gametophyte-specific expression or significant up-regulation in gametophyte in response to dehydration. In conchocelis, the release of HCO3- from shell promoted by carbonic anhydrase provides a source of Ci. This hypothesis is supported by the incorporation of 13C isotope by conchocelis when co-cultured with 13C-labeled CaCO3.


Assuntos
Carbono/metabolismo , Genoma , Rodófitas/genética , Rodófitas/metabolismo , Movimentos da Água , Exoesqueleto/química , Animais , Antioxidantes/farmacologia , Composição de Bases/genética , Evolução Biológica , Carbonato de Cálcio/metabolismo , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Núcleo Celular/genética , Dosagem de Genes , Perfilação da Expressão Gênica , Transferência Genética Horizontal/genética , Moluscos , Fotossíntese/efeitos dos fármacos , Ploidias , Rodófitas/efeitos dos fármacos , Superóxido Dismutase/genética , Transcrição Genética/efeitos dos fármacos
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.
PLoS Pathog ; 16(8): e1008856, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32845936

RESUMO

Copper and superoxide are used by the phagocytes to kill bacteria. Copper is a host effector encountered by uropathogenic Escherichia coli (UPEC) during urinary tract infection in a non-human primate model, and in humans. UPEC is exposed to higher levels of copper in the gut prior to entering the urinary tract. Effects of pre-exposure to copper on bacterial killing by superoxide has not been reported. We hypothesized that copper-replete E. coli is more sensitive to killing by superoxide in vitro, and in activated macrophages. We utilized wild-type UPEC strain CFT073, and its isogenic mutants lacking copper efflux systems, superoxide dismutases (SODs), regulators of a superoxide dismutase, and complemented mutants to address this question. Surprisingly, our results reveal that copper protects UPEC against killing by superoxide in vitro. This copper-dependent protection was amplified in the mutants lacking copper efflux systems. Increased levels of copper and manganese were detected in UPEC exposed to sublethal concentration of copper. Copper activated the transcription of sodA in a SoxR- and SoxS-dependent manner resulting in enhanced levels of SodA activity. Importantly, pre-exposure to copper increased the survival of UPEC within RAW264.7 and bone marrow-derived murine macrophages. Loss of SodA, but not SodB or SodC, in UPEC obliterated copper-dependent protection from superoxide in vitro, and from killing within macrophages. Collectively, our results suggest a model in which sublethal levels of copper trigger the activation of SodA and SodC through independent mechanisms that converge to promote the survival of UPEC from killing by superoxide. A major implication of our findings is that bacteria colonizing copper-rich milieus are primed for efficient detoxification of superoxide.


Assuntos
Cobre/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Superóxidos/toxicidade , Infecções Urinárias/tratamento farmacológico , Escherichia coli Uropatogênica/efeitos dos fármacos , Animais , Infecções por Escherichia coli/induzido quimicamente , Infecções por Escherichia coli/microbiologia , Feminino , Regulação Bacteriana da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Superóxido Dismutase/genética , Infecções Urinárias/induzido quimicamente , Infecções Urinárias/microbiologia
5.
Chem Biol Interact ; 329: 109222, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32771325

RESUMO

Extensive application of methylene blue (MB) for therapeutic and diagnostic purposes, and reports for unwanted side effects, demand better understanding of the mechanisms of biological action of this thiazine dye. Because MB is redox-active, its biological activities have been attributed to transfer of electrons, generation of reactive oxygen species, and antioxidant action. Results of this study show that MB is more toxic to a superoxide dismutase-deficient Escherichia coli mutant than to its SOD-proficient parent, which indicates that superoxide anion radical is involved. Incubation of E. coli with MB induced the enzymes fumarase C, SOD, nitroreductase A, and glucose-6-phosphate dehydrogenase, all controlled by the soxRS regulon. Induction of these enzymes was prevented by blocking protein synthesis with chloramphenicol and was not observed when soxRS-negative mutants were incubated with MB. These results show that MB is capable of inducing the soxRS regulon of E. coli, which plays a key role in protecting bacteria against oxidative stress and redox-cycling compounds. Irrespective of the abundance of heme-containing proteins in living cells, which are preferred acceptors of electrons from the reduced form of MB, reduction of oxygen to superoxide radical still takes place. Induction of the soxRS regulon suggests that in humans, beneficial effects of MB could be attributed to activation of redox-sensitive transcription factors like Nrf2 and FoxO. If defense systems are compromised or genes coding for protective proteins are not induced, MB would have deleterious effects.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Azul de Metileno/farmacologia , Regulon/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Cloranfenicol/farmacologia , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Fumarato Hidratase/genética , Fumarato Hidratase/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Transativadores/genética , Fatores de Transcrição/genética
6.
Mem Inst Oswaldo Cruz ; 115: e190469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32638832

RESUMO

BACKGROUND Oxidative stress is responsible for generating DNA lesions and the 8-oxoguanine (8-oxoG) is the most commonly lesion found in DNA damage. When this base is incorporated during DNA replication, it could generate double-strand DNA breaks and cellular death. MutT enzyme hydrolyzes the 8-oxoG from the nucleotide pool, preventing its incorporation during DNA replication. OBJECTIVES To investigate the importance of 8-oxoG in Leishmania infantum and L. braziliensis, in this study we analysed the impact of heterologous expression of Escherichia coli MutT (EcMutT) enzyme in drug-resistance phenotype and defense against oxidative stress. METHODS Comparative analysis of L. braziliensis and L. infantum H2O2 tolerance and cell cycle profile were performed. Lines of L. braziliensis and L. infantum expressing EcMutT were generated and evaluated using susceptibility tests to H2O2 and SbIII, cell cycle analysis, γH2A western blotting, and BrdU native detection assay. FINDINGS Comparative analysis of tolerance to oxidative stress generated by H2O2 showed that L. infantum is more tolerant to exogenous H2O2 than L. braziliensis. In addition, cell cycle analysis showed that L. infantum, after treatment with H2O2, remains in G1 phase, returning to its normal growth rate after 72 h. In contrast, after treatment with H2O2, L. braziliensis parasites continue to move to the next stages of the cell cycle. Expression of the E. coli MutT gene in L. braziliensis and L. infantum does not interfere in parasite growth or in susceptibility to SbIII. Interestingly, we observed that L. braziliensis EcMutT-expressing clones were more tolerant to H2O2 treatment, presented lower activation of γH2A, a biomarker of genotoxic stress, and lower replication stress than its parental non-transfected parasites. In contrast, the EcMutT is not involved in protection against oxidative stress generated by H2O2 in L. infantum. MAIN CONCLUSIONS Our results showed that 8-oxoG clearance in L. braziliensis is important to avoid misincorporation during DNA replication after oxidative stress generated by H2O2.


Assuntos
Antimônio/toxicidade , Proteínas de Escherichia coli/genética , Escherichia coli , Guanina/análogos & derivados , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Pirofosfatases , Superóxido Dismutase/metabolismo , Animais , Antiprotozoários/farmacologia , Proteínas de Escherichia coli/metabolismo , Guanina/farmacologia , Humanos , Peróxido de Hidrogênio/toxicidade , Leishmania braziliensis/enzimologia , Leishmania infantum/enzimologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pirofosfatases/genética , Pirofosfatases/metabolismo , Coelhos , Ratos , Superóxido Dismutase/genética
7.
Nat Rev Immunol ; 20(9): 515-516, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728221

Assuntos
Antioxidantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Pulmão/imunologia , Neutrófilos/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Acetilcisteína/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Quimioterapia Combinada , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Regulação da Expressão Gênica , Glicina/análogos & derivados , Glicina/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/imunologia , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Sulfonamidas/uso terapêutico , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia
8.
J Environ Sci Health B ; 55(9): 803-812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32602772

RESUMO

Organophosphorus pesticides induce gender-specific developmental neurotoxicity after birth, especially in adolescents and adults. However, whether and when the selectivity occurs in fetus remains unclear. In this study, we analyzed chlorpyrifos (CPF)-induced neurotoxicity in the early fetal brains of male and female mice. The gestational dams were administered 0, 1, 3, and 5 mg/(kg.d) CPF during gestational days (GD)7-11, and brains from the fetuses were isolated and analyzed on GD12. Fetal gender was identified by PCR technique based on male-specific Sry gene and Myog control gene. The body weight and head weight, the activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and the content of malondialdehyde (MDA), as well as the oxidative stress-related gene expression were examined. Our results showed that CPF pretreatment induced AChE inhibition in GD12 fetal brain. CPF treatment activated SOD and GPX but not CAT and MDA. For oxidative stress-related gene expression, CPF pretreatment increased mRNA expression of Sod1, Cat, Gpx1, and Gpx2 in the fetal brain on GD12. The statistical analysis did not show gender-selective CPF-induced toxicity. Moreover, our results showed that although the gestational exposure to CPF could elicit abnormalities in the early fetal brain, the toxicity observed was not gender-specific.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Clorpirifos/toxicidade , Inseticidas/toxicidade , Acetilcolinesterase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Inibidores da Colinesterase/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores Sexuais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testes de Toxicidade/métodos
9.
PLoS One ; 15(7): e0236405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702060

RESUMO

Regulatory small RNAs play an essential role in maintaining cell homeostasis in bacteria in response to environmental stresses such as iron starvation. Prokaryotes generally encode a large number of RNA regulators, yet their identification and characterisation is still in its infancy for most bacterial species. Burkholderia cenocepacia is an opportunistic pathogen with high innate antimicrobial resistance, which can cause the often fatal cepacia syndrome in individuals with cystic fibrosis. In this study we characterise a small RNA which is involved in the response to iron starvation, a condition that pathogenic bacteria are likely to encounter in the host. BrrF is a small RNA highly upregulated in Burkholderia cenocepacia under conditions of iron depletion and with a genome context consistent with Fur regulation. Its computationally predicted targets include iron-containing enzymes of the tricarboxylic acid (TCA) cycle such as aconitase and succinate dehydrogenase, as well as iron-containing enzymes responsible for the oxidative stress response, such as superoxide dismutase and catalase. Phenotypic and gene expression analysis of BrrF deletion and overexpression mutants show that the regulation of these genes is BrrF-dependent. Expression of acnA, fumA, sdhA and sdhC was downregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. TCA cycle genes not predicted as target for BrrF were not affected in the same manner by iron depletion. Likewise, expression of sodB and katB was dowregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. BrrF overexpression reduced aconitase and superoxide dismutase activities and increased sensitivity to hydrogen peroxide. All phenotypes and gene expression changes of the BrrF deletion mutant could be complemented by overexpressing BrrF in trans. Overall, BrrF acts as a regulator of central metabolism and oxidative stress response, possibly as an iron-sparing measure to maintain iron homeostasis under conditions of iron starvation.


Assuntos
Proteínas de Bactérias/genética , Burkholderia cenocepacia/genética , Ferro/metabolismo , Pequeno RNA não Traduzido/genética , Aconitato Hidratase/metabolismo , Burkholderia cenocepacia/metabolismo , Catalase/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Ferro/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/genética
10.
Ecotoxicol Environ Saf ; 201: 110861, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544748

RESUMO

Marine biota have been co-challenged with ocean warming and mercury (Hg) pollution over many generations because of human activities; however, the molecular mechanisms to explain their combined effects are not well understood. In this study, a marine planktonic copepod Pseudodiaptomus annandalei was acutely exposed to different temperature (22 and 25 °C) and Hg (0 and 118 µg/L) treatments in a 24-h cross-factored experiment. Hg accumulation and its subcellular fractions were determined in the copepods after exposure. The expression of the genes of superoxide dismutase (SOD), glutathione peroxidase (GPx), metallothionein1 (mt1), heat shock protein 70 (hsp70), hsp90, hexokinase (hk), and pyruvate kinase (pk) was also analyzed. Both the Hg treatment alone and the combined exposure of warmer temperature plus Hg pollution remarkably facilitated Hg bioaccumulation in the exposed copepods. Compared with the Hg treatment alone, the combined exposure increased total Hg accumulation and also the amount of Hg stored in the metal-sensitive fractions (MSF), suggesting elevated Hg toxicity in P. annandalei under a warmer environment, given that the MSF is directly related to metal toxicity. The warmer temperature significantly up-regulated the mRNA levels of mt1, hsp70, hsp90, and hk, indicating the copepods suffered from thermal stress. With exposure to Hg, the mRNA level of SOD increased strikingly but the transcript levels of hsp90, hk, and pk decreased significantly, indicating that Hg induced toxic events (e.g., oxidative damage and energy depletion). Particularly, in contrast to the Hg treatment alone, the combined exposure significantly down-regulated the mRNA levels of SOD and GPx but up-regulated the mRNA levels of mt1, hsp70, hsp90, hk, and pk. Collectively, the results of this study indicate that ocean warming will potentially boost Hg toxicity in the marine copepod P. annandalei, which is information that will increase the accuracy of the projections of marine ecosystem responses to the joint effects of climate change stressors and metal pollution on the future ocean.


Assuntos
Copépodes/efeitos dos fármacos , Temperatura Alta , Mercúrio/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Copépodes/genética , Copépodes/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Hexoquinase/genética , Hexoquinase/metabolismo , Mercúrio/farmacocinética , Metalotioneína/genética , Metalotioneína/metabolismo , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , RNA Mensageiro/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Regulação para Cima , Poluentes Químicos da Água/farmacocinética
11.
Nat Commun ; 11(1): 2738, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483131

RESUMO

Almost half of all enzymes utilize a metal cofactor. However, the features that dictate the metal utilized by metalloenzymes are poorly understood, limiting our ability to manipulate these enzymes for industrial and health-associated applications. The ubiquitous iron/manganese superoxide dismutase (SOD) family exemplifies this deficit, as the specific metal used by any family member cannot be predicted. Biochemical, structural and paramagnetic analysis of two evolutionarily related SODs with different metal specificity produced by the pathogenic bacterium Staphylococcus aureus identifies two positions that control metal specificity. These residues make no direct contacts with the metal-coordinating ligands but control the metal's redox properties, demonstrating that subtle architectural changes can dramatically alter metal utilization. Introducing these mutations into S. aureus alters the ability of the bacterium to resist superoxide stress when metal starved by the host, revealing that small changes in metal-dependent activity can drive the evolution of metalloenzymes with new cofactor specificity.


Assuntos
Proteínas de Bactérias/metabolismo , Ferro/metabolismo , Manganês/metabolismo , Metaloproteínas/metabolismo , Staphylococcus aureus/enzimologia , Superóxido Dismutase/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Domínio Catalítico , Evolução Molecular , Ferro/química , Isoenzimas/classificação , Isoenzimas/genética , Isoenzimas/metabolismo , Manganês/química , Metaloproteínas/química , Metaloproteínas/genética , Mutação , Oxirredução , Filogenia , Homologia de Sequência de Aminoácidos , Staphylococcus aureus/genética , Superóxido Dismutase/química , Superóxido Dismutase/genética , Superóxidos/metabolismo
12.
Environ Toxicol ; 35(10): 1091-1099, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32485069

RESUMO

Various pollutants co-exist in the aquatic environment such as carbamazepine (CBZ) and copper (Cu), which can cause complex effects on inhabiting organisms. The toxic impacts of the single substance have been studied extensively. However, the studies about their combined adverse impacts are not enough. In the present study, zebrafish were exposed to environmental relevant concentrations of CBZ (1, 10, and 100 µg/L), Cu (0.5, 5, and 10 µg/L) and the mixtures (1 µg/L CBZ + 0.5 µg/L Cu, 10 µg/L CBZ + 5 µg/L Cu, 100 µg/L CBZ + 10 µg/L Cu) for 45 days, the effects on nervous and antioxidant systems of zebrafish were investigated. The results demonstrated that, in comparison with single exposure group, the combined presence of CBZ and Cu exacerbated the effect of antioxidant system (the ability of inhibition of hydroxyl radicals (IHR), superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST)) but not nervous system (Acetylcholinesterase [AChE]). The qPCR results supported the changes of corresponding enzymes activities. Hepatic histopathological analysis verified the results of biomarkers. Our work illustrated that the toxicity of mixed pollutants is very complicated, which cannot simply be inferred from the toxicity of single pollutant, and calls for more co-exposure experiments to better understanding of the co-effects of pollutants on aquatic organisms.


Assuntos
Antioxidantes/metabolismo , Carbamazepina/toxicidade , Cobre/toxicidade , Sistema Nervoso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Biomarcadores/metabolismo , Catalase/genética , Catalase/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Sistema Nervoso/enzimologia , Sistema Nervoso/metabolismo , Estresse Oxidativo/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
13.
Ecotoxicol Environ Saf ; 200: 110743, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464441

RESUMO

Gill, as the organ of fish to contact most directly with xenobiotics, suffered more threat. To evaluate the impact of arsenite (AsIII) on the gill of fish, we measured the antioxidative responses (superoxide dismutase (SOD) and catalase (CAT) activities) and oxidative damage (malondialdehyde (MDA) content), histological changes and mRNA transcriptional responses of zebrafish gill, after exposure to AsIII (0, 10, 50, 100, and 150 µg L-1) solutions for 28 days. We found that AsIII increased the activities of CAT by 46%-87%, decreased the activities of SOD and the contents of MDA by 19% and 21%-32%. Furthermore, CuZnSOD and MnSOD mRNA transcription levels were also inhibited, decreasing by 62%-82% and 70%-77%. Besides, ≥ 100 µg L-1 AsIII also caused histological changes (a loss of mucus and desquamation in the surface of the epithelial cells) on zebrafish gill. These results showed that low concentrations of AsIII influenced biochemical and physiological performances of fish gill, which probably aggravates the toxic effect of AsIII on fish.


Assuntos
Arsenitos/toxicidade , Brânquias/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Brânquias/metabolismo , Brânquias/patologia , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
14.
Antioxid Redox Signal ; 33(2): 59-65, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: covidwho-108750

RESUMO

Human lungs single-cell RNA sequencing data from healthy donors (elderly and young; GEO accession no. GSE122960) were analyzed to isolate and specifically study gene expression in alveolar type II cells. Colocalization of angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 enables severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) to enter the cells. Expression levels of these genes in the alveolar type II cells of elderly and young patients were comparable and, therefore, do not seem to be responsible for worse outcomes observed in coronavirus disease 2019 (COVID-19) affected elderly. In cells from the elderly, 263 genes were downregulated and 95 upregulated. Superoxide dismutase 3 (SOD3) was identified as the top-ranked gene that was most downregulated in the elderly. Other redox-active genes that were also downregulated in cells from the elderly included activating transcription factor 4 (ATF4) and metallothionein 2A (M2TA). ATF4 is an endoplasmic reticulum stress sensor that defends lungs via induction of heme oxygenase 1. The study of downstream factors known to be induced by ATF4, according to Ingenuity Pathway Analysis™, identified 24 candidates. Twenty-one of these were significantly downregulated in the cells from the elderly. These downregulated candidates were subjected to enrichment using the Reactome Database identifying that in the elderly, the ability to respond to heme deficiency and the ATF4-dependent ability to respond to endoplasmic reticulum stress is significantly compromised. SOD3-based therapeutic strategies have provided beneficial results in treating lung disorders including fibrosis. The findings of this study propose the hypotheses that lung-specific delivery of SOD3/ATF4-related antioxidants will work in synergy with promising antiviral drugs such as remdesivir to further improve COVID-19 outcomes in the elderly.


Assuntos
Fator 4 Ativador da Transcrição/genética , Infecções por Coronavirus/genética , Pulmão/metabolismo , Pneumonia Viral/genética , Superóxido Dismutase/genética , Adulto , Idoso , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , Antioxidantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Feminino , Regulação da Expressão Gênica/genética , Heme Oxigenase-1/genética , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Metalotioneína/genética , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Serina Endopeptidases/genética
15.
Anticancer Res ; 40(4): 1963-1972, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234885

RESUMO

BACKGROUND/AIM: The menadione/ascorbate (M/A) combination has attracted attention due to the unusual ability of pro-vitamin/vitamin combination to kill cancer cells without affecting the viability of normal cells. The aim of this study was to elucidate the role of M/A in targeting cancerous mitochondria. MATERIALS AND METHODS: Several cancer and normal cell lines of the same origin were used. Cells were treated with different concentrations of M/A for 24 h. The cell viability, mitochondrial superoxide, mitochondrial membrane potential, and succinate were analyzed using conventional analytical tests. RESULTS: M/A exhibited a highly specific suppression on cancer cell growth and viability, without adversely affecting the viability of normal cells at concentrations attainable by oral or parenteral administration in vivo. This effect was accompanied by: (i) an extremely high production of mitochondrial superoxide in cancer cells, but not in normal cells; (ii) a significant dose-dependent depolarization of mitochondrial membrane and depletion of oncometabolite succinate in cancer cells. CONCLUSION: The anticancer effect of M/A is related to the induction of severe mitochondrial oxidative stress in cancer cells only. Thus, M/A has a potential to increase the sensitivity and vulnerability of cancer cells to conventional anticancer therapy and immune system.


Assuntos
Ácido Ascórbico/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Vitamina K 3/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Neoplasias/genética , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxidos/metabolismo
16.
Antioxid Redox Signal ; 33(2): 59-65, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32323565

RESUMO

Human lungs single-cell RNA sequencing data from healthy donors (elderly and young; GEO accession no. GSE122960) were analyzed to isolate and specifically study gene expression in alveolar type II cells. Colocalization of angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 enables severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) to enter the cells. Expression levels of these genes in the alveolar type II cells of elderly and young patients were comparable and, therefore, do not seem to be responsible for worse outcomes observed in coronavirus disease 2019 (COVID-19) affected elderly. In cells from the elderly, 263 genes were downregulated and 95 upregulated. Superoxide dismutase 3 (SOD3) was identified as the top-ranked gene that was most downregulated in the elderly. Other redox-active genes that were also downregulated in cells from the elderly included activating transcription factor 4 (ATF4) and metallothionein 2A (M2TA). ATF4 is an endoplasmic reticulum stress sensor that defends lungs via induction of heme oxygenase 1. The study of downstream factors known to be induced by ATF4, according to Ingenuity Pathway Analysis™, identified 24 candidates. Twenty-one of these were significantly downregulated in the cells from the elderly. These downregulated candidates were subjected to enrichment using the Reactome Database identifying that in the elderly, the ability to respond to heme deficiency and the ATF4-dependent ability to respond to endoplasmic reticulum stress is significantly compromised. SOD3-based therapeutic strategies have provided beneficial results in treating lung disorders including fibrosis. The findings of this study propose the hypotheses that lung-specific delivery of SOD3/ATF4-related antioxidants will work in synergy with promising antiviral drugs such as remdesivir to further improve COVID-19 outcomes in the elderly.


Assuntos
Fator 4 Ativador da Transcrição/genética , Infecções por Coronavirus/genética , Pulmão/metabolismo , Pneumonia Viral/genética , Superóxido Dismutase/genética , Adulto , Idoso , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , Antioxidantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Feminino , Regulação da Expressão Gênica/genética , Heme Oxigenase-1/genética , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Metalotioneína/genética , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Serina Endopeptidases/genética
17.
Food Funct ; 11(4): 3516-3526, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32253400

RESUMO

Chronic obstructive pulmonary disease (COPD) is a chronic, progressive lung disease with few successful treatments, and is strongly associated with cigarette smoking (CS). Since the novel coronavirus has spread worldwide seriously, there is growing concern that patients who have chronic respiratory conditions like COPD can easily be infected and are more prone to having severe illness and even mortality because of lung dysfunction. Loquat leaves have long been used as an important material for both pharmaceutical and functional applications in the treatment of lung disease in Asia, especially in China and Japan. Total flavonoids (TF), the main active components derived from loquat leaves, showed remarkable anti-inflammatory and antioxidant activities. However, their protective activity against CS-induced COPD airway inflammation and oxidative stress and its underlying mechanism still remain not well-understood. The present study uses a CS-induced mouse model to estimate the morphological changes in lung tissue. The results demonstrated that TF suppressed the histological changes in the lungs of CS-challenged mice, as evidenced by reduced generation of pro-inflammatory cytokines including interleukin 6 (IL-6), IL-1ß, tumor necrosis factor α (TNF-α), nitric oxide (NO), and inducible nitric oxide synthase (iNOS) and diminished the protein expression of transient receptor potential vanilloid 1 (TRPV1). Moreover, TF also inhibited phosphorylation of IKK, IκB and NFκB and increased p-Akt. Interestingly, TF could inhibit CS-induced oxidative stress in the lungs of COPD mice. TF treatment significantly inhibited the level of malondialdehyde (MDA) and increased the activity of superoxide dismutase (SOD). In addition, TF markedly downregulated TRPV1 and cytochrome P450 2E1 (CYP2E1) and upregulated the expression of SOD-2, while the p-JNK level was observed to be inhibited in COPD mice. Taken together, our findings showed that the protective effect and putative mechanism of the action of TF resulted in the inhibition of inflammation and oxidative stress through the regulation of TRPV1 and the related signal pathway in lung tissues. It suggested that TF derived from loquat leaves could be considered to be an alternative or a new functional material and used for the treatment of CS-induced COPD.


Assuntos
Fumar Cigarros/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Eriobotrya/química , Flavonoides/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Canais de Cátion TRPV/imunologia , Animais , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Transdução de Sinais/efeitos dos fármacos , Fumaça/efeitos adversos , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia , Canais de Cátion TRPV/genética
18.
Gene ; 742: 144603, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32198126

RESUMO

Adverse environmental conditions, such as salinity, cold, drought, heavy metals, and pathogens affect the yield and quality of Salvia miltiorrhiza, a well-known medicinal plant used for the treatment of cardiovascular and cerebrovascular diseases. Superoxide dismutase (SOD), a key enzyme of antioxidant system in plants, plays a vital role in protecting plants against various biotic and abiotic stresses via scavenging the reactive oxygen species produced by organisms. However, little is known about the SOD gene family in S. miltiorrhiza. In this study, eight SOD genes, including three Cu/Zn-SODs, two Fe-SODs and three Mn-SODs, were identified in the S. miltiorrhiza genome. Their gene structures, promoters, protein features, phylogenetic relationships, and expression profiles were comprehensively investigated. Gene structure analysis implied that most SmSODs have different introns/exons distrbution patterns. Many cis-elements related to different stress responses or plant hormones were found in the promoter of each SmSOD. Expression profile analysis indicated that SmSODs exhibited diverse responses to cold, salt, drought, heavy metal, and plant hormones. Additionally, 31 types of TFs regulating SmSODs were predicted and analyzed. These findings provided valuable information for further researches on the functions and applications of SmSODs in S. miltiorrhiza growth and adaptation to stress.


Assuntos
Regulação da Expressão Gênica de Plantas , Família Multigênica/genética , Proteínas de Plantas/genética , Salvia miltiorrhiza/genética , Superóxido Dismutase/genética , Aclimatação/genética , Secas , Éxons/genética , Perfilação da Expressão Gênica , Íntrons/genética , Filogenia , Melhoramento Vegetal , Proteínas de Plantas/metabolismo , Salinidade , Salvia miltiorrhiza/enzimologia , Estresse Fisiológico/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/metabolismo
19.
Eur J Protistol ; 74: 125689, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193064

RESUMO

The green microalgae Closterium ehrenbergii is an ideal organism for ecotoxicology assessments; however, its toxicogenomics has been insufficiently examined. Here, we identified three iron/manganese superoxide dismutase (SOD) genes (designated as CeFeSOD1, CeFeSOD2, and CeMnSOD) from C. ehrenbergii and examined their expressional patterns for four metals (iron, manganese, copper, and nickel). These genes encoded 362, 224, and 245 amino acids, respectively; signal-peptide analysis showed that they were differentially located in chloroplasts, cytosol, or mitochondria. Real-time PCRs revealed differential expression patterns according to metal and doses. Interestingly, CeSODs displayed no noticeable changes to treatment with their corresponding cofactor metals, iron or manganese, even at high doses. However, they were obviously up-regulated under toxic metal (copper and nickel) exposure, exhibiting approximately 10.8- and 4.4-fold increases, respectively. Copper (0.2 mg/L) dramatically stimulated intracellular reactive oxygen species (ROS) formation, increased SOD activity, and reduced photosynthetic efficiency in C. ehrenbergii. These results suggest that CeFeSODs and CeMnSOD might be involved in protecting cells against damage and oxidative stress caused by non-cofactor metals, such as copper and nickel. These genes were sensitively responsive at levels well below the EC50, showing that they can be used as molecular biomarkers to assess the toxicity of specific metal contaminants.


Assuntos
Closterium , Regulação da Expressão Gênica/efeitos dos fármacos , Metais Pesados/toxicidade , Estresse Fisiológico/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Closterium/efeitos dos fármacos , Closterium/enzimologia , Closterium/genética , Estresse Fisiológico/efeitos dos fármacos
20.
Life Sci ; 248: 117475, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32119963

RESUMO

AIMS: Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. MAIN METHODS: Hepatic fibrosis was induced by CCl4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. KEY FINDINGS: APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. SIGNIFICANCE: APG can ameliorate CCl4-induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product.


Assuntos
Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Bilirrubina/sangue , Tetracloreto de Carbono/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteômica/métodos , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
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