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1.
Aquat Toxicol ; 227: 105588, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32861020

RESUMO

The pollution of polybrominated diphenyl ethers (PBDEs) is becoming a pressing environmental problem in aquatic environments, and its threat to aquatic organism has received much attention. In this study, Phaeodactylum tricornutum was treated with 0.8 and 4 mg L-1 2,2',4,4'-tetrabrominated biphenyl ether (BDE-47), the most toxic PBDEs, for 96 h. BDE-47 inhibited cell growth in a time- and concentration-dependent manner. Observation of cell ultrastructure suggested the damage of the chloroplasts morphology. BDE-47 also decreased the chlorophyll content and the oxygen evolution rate, and altered the performance of photosystems. Transcriptomic analysis revealed differential expression of 62 genes related to photosynthesis in BDE-47 treatments (4 mg L-1) and transcription suppression of 58 genes involved in chlorophyll synthesis, antenna proteins, oxygen evolution, electron transport and downstream carbon fixation, implying potential toxicity targets in cells. Additionally, the levels of reactive oxygen species (ROS) and lipid peroxidation increased under BDE-47 stress and were positively correlated with photosynthesis inhibition. Pretreatment with the ROS scavenger N-acetyl-l-cysteine reduced the extent of inhibition, suggesting that ROS was responsible for these effects. Another experiment with the electron transport chain inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethylurea showed that the generation of ROS was partially blocked, primarily indicating that photosynthetic inhibition induced by BDE-47 contributed to ROS overproduction. Thus, BDE-47 inhibited the photosynthesis by down-regulating the gene expression. This change stimulated ROS production, further leading to chloroplast membrane damage to aggravate this inhibition via a feedback loop. These effects of BDE-47 had adverse outcomes on the entire physiological state and the population growth of the microalgae.


Assuntos
Diatomáceas/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Microalgas/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Poluentes Químicos da Água/toxicidade , Acetilcisteína/farmacologia , Clorofila/metabolismo , Diatomáceas/metabolismo , Diatomáceas/ultraestrutura , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Microalgas/metabolismo , Microalgas/ultraestrutura , Modelos Teóricos , Fotossíntese/genética
2.
Toxicol Lett ; 332: 118-129, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659471

RESUMO

Silver-based antimicrobials are widely used topically to treat infections associated with multi-drug resistant (MDR) pathogens. Expanding this topical use to aerosols to treat lung infections requires understanding and preventing silver toxicity in the respiratory tract. A key mechanism resulting in silver-induced toxicity is the production of reactive oxygen species (ROS). In this study, we have verified ROS generation in silver-treated bronchial epithelial cells prompting evaluation of three antioxidants, N-acetyl cysteine (NAC), ascorbic acid, and melatonin, to identify potential prophylactic agents. Among them, NAC was the only candidate that abrogated the ROS generation in response to silver acetate exposure resulting in the rescue of these cells from silver-associated toxicity. Further, this protective effect directly translated to preservation of metabolic activity, as demonstrated by the normal levels of citric acid cycle metabolites in NAC-pretreated silver acetate-exposed cells. Because the citric acid cycle remained functional, silver-exposed cells pre-incubated with NAC demonstrated significantly higher levels of adenosine triphosphate levels compared with NAC-free controls. Moreover, we found that this prodigious capacity of NAC to rescue silver acetate-exposed cells was due not only to its antioxidant activity, but also to its ability to directly bind silver. Despite binding to silver, NAC did not alter the antimicrobial activity of silver acetate.


Assuntos
Acetilcisteína/farmacologia , Antibacterianos/farmacologia , Depuradores de Radicais Livres/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Prata/farmacologia , Prata/toxicidade , Acetatos/farmacologia , Trifosfato de Adenosina/metabolismo , Ácido Ascórbico/farmacologia , Linhagem Celular , Cromatografia Gasosa-Espectrometria de Massas , Glutationa/metabolismo , Humanos , Melatonina/farmacologia , Testes de Sensibilidade Microbiana , Compostos de Prata/farmacologia , Superóxidos/metabolismo
4.
Environ Sci Pollut Res Int ; 27(32): 40563-40572, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32671705

RESUMO

This study evaluated the toxic effects of inorganic mercury (Hg) in pregnant and lactating rats, as well as the possible protective effect of zinc (Zn) and N-acetylcysteine (NAC). Pregnant and lactating rats were pre-treated with ZnCl2 (27 mg/kg) and/or NAC (5 mg/kg) and after 24 h, they were exposed to HgCl2 (10 mg/kg). Animals were sacrificed 24 h after Hg exposure, and biochemical tests and metal determination were performed. Regarding pregnant rats, Hg exposure caused kidney, blood, and placenta δ-aminolevulinic acid dehydratase (δ-ALA-D) activity inhibition, and the pre-treatments showed a tendency of protection. Moreover, all the animals exposed to Hg presented high Hg levels in the kidney, liver, and placenta when compared with control group. Pregnant rats pre-exposed to Zn (Zn-Hg and Zn/NAC-Hg groups) presented an increase in hepatic metallothionein levels. Therefore, lactating rats exposed to Hg presented renal and blood δ-ALA-D inhibition; the pre-treatments showed a tendency to prevent the renal δ-ALA-D inhibition and prevented the blood δ-ALA-D inhibition caused by Hg. Lactating rats exposed to Hg presented high Hg levels in the kidney and liver. These results showed that 10 mg/kg of HgCl2 causes biochemistry alterations in pregnant and lactating rats, and Zn and NAC present promising results against these damages.


Assuntos
Acetilcisteína , Mercúrio , Acetilcisteína/farmacologia , Animais , Feminino , Rim , Lactação , Fígado , Cloreto de Mercúrio/toxicidade , Mercúrio/toxicidade , Sintase do Porfobilinogênio , Gravidez , Ratos , Zinco
5.
Rev Environ Health ; 35(3): 233-238, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32710722

RESUMO

The exposure of methylmercury (MeHg) has become a public health concern because of its neurotoxic effect. Various neurological symptoms were detected in Minamata disease patients, who got intoxicated by MeHg, including paresthesia, ataxia, gait disturbance, sensory disturbances, tremors, visual, and hearing impairments, indicating that MeHg could pass the blood-brain barrier (BBB) and cause impairment of neurons and other brain cells. Previous studies have reported some expected mechanisms of MeHg-induced neurotoxicity including the neuroinflammation pathway. It was characterized by the up-regulation of numerous pro-inflammatory cytokines expression. Therefore, the use of anti-inflammatories such as N-acetyl-l-cysteine (NAC) may act as a preventive compound to protect the brain from MeHg harmful effects. This mini-review will explain detailed information on MeHg-induced pro-inflammatory cytokines activation as well as possible preventive strategies using anti-inflammation NAC to protect brain cells, particularly in in vivo and in vitro studies.


Assuntos
Acetilcisteína/farmacologia , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Inflamação/prevenção & controle , Compostos de Metilmercúrio/efeitos adversos , Animais , Encéfalo , Humanos , Inflamação/induzido quimicamente , Camundongos , Ratos
6.
Environ Toxicol ; 35(11): 1212-1224, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32662599

RESUMO

The antibiotic antimycin A (AMA) is commonly used as an inhibitor for the electron transport chain but its application in anticancer studies is rare. Recently, the repurposing use of AMA in antiproliferation of several cancer cell types has been reported. However, it is rarely investigated in oral cancer cells. The purpose of this study is to investigate the selective antiproliferation ability of AMA treatment on oral cancer cells. Cell viability, flow cytometry, and western blotting were applied to explore its possible anticancer mechanism in terms of both concentration- and exposure time-effects. AMA shows the higher antiproliferation to two oral cancer CAL 27 and Ca9-22 cell lines than normal oral HGF-1 cell lines. Moreover, AMA induces the production of higher reactive oxygen species (ROS) levels and pan-caspase activation in oral cancer CAL 27 and Ca9-22 cells than in normal oral HGF-1 cells, providing the possible mechanism for its selective antiproliferation effect of AMA. In addition to ROS, AMA induces mitochondrial superoxide (MitoSOX) generation and depletes mitochondrial membrane potential (MitoMP). This further supports the AMA-induced oxidative stress changes in oral cancer CAL 27 and Ca9-22 cells. AMA also shows high expressions of annexin V in CAL 27 and Ca9-22 cells and cleaved forms of poly (ADP-ribose) polymerase (PARP), caspase 9, and caspase 3 in CAL 27 cells, supporting the apoptosis-inducing ability of AMA. Furthermore, AMA induces DNA damage (γH2AX and 8-oxo-2'-deoxyguanosine [8-oxodG]) in CAL 27 and Ca9-22 cells. Notably, the AMA-induced selective antiproliferation, oxidative stress, and DNA damage were partly prevented from N-acetylcysteine (NAC) pretreatments. Taken together, AMA selectively kills oral cancer cells in an oxidative stress-dependent mechanism involving apoptosis and DNA damage.


Assuntos
Antimicina A/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Bucais , Acetilcisteína/farmacologia , Antimicina A/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
7.
In Vivo ; 34(3 Suppl): 1567-1588, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-532631

RESUMO

BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever. MATERIALS AND METHODS: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2. RESULTS: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2. CONCLUSION: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.


Assuntos
Acetilcisteína/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Colchicina/uso terapêutico , Cobre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Colchicina/administração & dosagem , Colchicina/farmacologia , Cobre/administração & dosagem , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Inflamação , Óxido Nítrico/administração & dosagem , Óxido Nítrico/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ribonucleosídeos/administração & dosagem , Ribonucleosídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
8.
Pol J Microbiol ; 69(2): 223-229, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32548987

RESUMO

Bovine tuberculosis is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis (MTB) complex. Mycolic acid (MA) is the main lipid component of the cell membrane of MTB. It is non-enzymatically reduced by NAD(P)H and further produces reactive oxygen species (ROS), which can cause oxidative stress in human cells. N-acetylcysteine (NAC) is a synthetic precursor of glutathione (GSH) and exhibits anti-ROS activity. However, the underlying mechanisms of its protective properties remain uncertain. Herein, after pre-incubation of RAW264.7 cells with NAC, the factors associated with apoptosis and autophagy were measured. Mechanistically, NAC could reduce MA-induced expression of pro-apoptotic and pro-autophagy proteins. At the mRNA level, NAC can inhibit AMPK and activate mTOR expression. The results indicate that NAC might regulate autophagy in RAW264.7 cells through the AMPK/mTOR pathway. To further prove the effect of NAC on MA, ICR mice were used to evaluate the lung injury. Hematoxylin-eosin (HE) staining was performed on the lung. The results show that NAC could reduce cell injury induced by MA. In conclusion, our research showed that NAC attenuates apoptosis and autophagy in response to incubation with mycolic acid.Bovine tuberculosis is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis (MTB) complex. Mycolic acid (MA) is the main lipid component of the cell membrane of MTB. It is non-enzymatically reduced by NAD(P)H and further produces reactive oxygen species (ROS), which can cause oxidative stress in human cells. N-acetylcysteine (NAC) is a synthetic precursor of glutathione (GSH) and exhibits anti-ROS activity. However, the underlying mechanisms of its protective properties remain uncertain. Herein, after pre-incubation of RAW264.7 cells with NAC, the factors associated with apoptosis and autophagy were measured. Mechanistically, NAC could reduce MA-induced expression of pro-apoptotic and pro-autophagy proteins. At the mRNA level, NAC can inhibit AMPK and activate mTOR expression. The results indicate that NAC might regulate autophagy in RAW264.7 cells through the AMPK/mTOR pathway. To further prove the effect of NAC on MA, ICR mice were used to evaluate the lung injury. Hematoxylin-eosin (HE) staining was performed on the lung. The results show that NAC could reduce cell injury induced by MA. In conclusion, our research showed that NAC attenuates apoptosis and autophagy in response to incubation with mycolic acid.


Assuntos
Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Mycobacterium tuberculosis/química , Proteínas Quinases Ativadas por AMP/genética , Animais , Apoptose/genética , Autofagia/genética , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Lesão Pulmonar/microbiologia , Camundongos , Ácidos Micólicos/farmacologia , Células RAW 264.7 , Serina-Treonina Quinases TOR/genética
9.
Acta Cir Bras ; 35(4): e202000401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555935

RESUMO

PURPOSE: To evaluate the effect of N-Acetylcysteine (NAC) in newborn rats submitted to hypoxia and reoxygenation (H/R) conditions in an experimental model of necrotizing enterocolitis. METHODS: Eight pregnant rats and their 70 cubs were used (5 groups) and exposed to H/R conditions and received NAC at different times. The animals in the H/R groups were placed in a gas chamber (100% CO2) for 10 minutes and then reoxygenated for 10 minutes (100% O2), twice a day for the first three days of life, with a six-hour span between events. On the third day of life, the animals were anesthetized, laparotomized and the intestines were resected. RESULTS: The H/R and NAC groups showed changes in the intestinal wall in relation to the number, height and width of the villi when compared to the control group (p<0.0001), but with better preservation of structures in the NAC group. There were no differences between groups regarding the number (%) of mitoses. CONCLUSION: The administration of NAC decreased the lesions in the intestinal wall of rats submitted to H/R, therefore suggesting that this drug can be used to prevent the development of necrotizing enterocolitis in newborns.


Assuntos
Acetilcisteína/farmacologia , Enterocolite Necrosante/prevenção & controle , Hipóxia/patologia , Íleo/efeitos dos fármacos , Íleo/patologia , Substâncias Protetoras/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
10.
In Vivo ; 34(3 Suppl): 1567-1588, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503814

RESUMO

BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever. MATERIALS AND METHODS: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2. RESULTS: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2. CONCLUSION: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.


Assuntos
Acetilcisteína/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Colchicina/uso terapêutico , Cobre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Colchicina/administração & dosagem , Colchicina/farmacologia , Cobre/administração & dosagem , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Inflamação , Óxido Nítrico/administração & dosagem , Óxido Nítrico/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ribonucleosídeos/administração & dosagem , Ribonucleosídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
11.
Toxicology ; 440: 152441, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32433928

RESUMO

4-Aminobiphenyl (4-ABP), a well-known human carcinogen, has been shown to cause oxidative DNA damage and induce miR-630 expression in HepG2 cells treated with 18.75 µM-300 µM for 24 h. However, the underlying mechanism regarding the epigenetic regulation of miR-630 on DNA damage repair in liver cells is still not understood and needs to be investigated. In present study, our results showed that miR-630 was upregulated, resulting in mediating a decrease of DNA homologous recombination (HR) repair in L-02, HepG2 or Hep3B cells. Results from a luciferase reporting experiment showed that RAD18 and MCM8 were the potential targets of miR-630 during DNA damage induction. The downregulation of RAD18 or MCM8 by miR-630 was accompanied by inhibition of HR repair. Conversely, inhibiting miR-630 enhanced the expression of RAD18 and MCM8, and rescued HR repair. Additionally, we proved that the transcription factor CREB was related to miR-630 biogenesis in liver cells. Moreover, the levels of CREB, miR-630 expression, and double-strand breaks (DSBs) were attenuated by 5 mM N-acetyl-L-cysteine (NAC) pretreatment, indicating that reactive oxygen species (ROS)-dependent CREB-miR-630 was involved in DSB repair. These findings indicated that the ROS/CREB/-miR-630 axis plays a relevant role in the regulation of RAD18 and MCM8 in HR repair, which may facilitate our understanding of molecular mechanisms regarding the role of miR-630 downregulating DNA damage repair in liver cells.


Assuntos
Compostos de Aminobifenil/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Fígado/metabolismo , MicroRNAs/metabolismo , Proteínas de Manutenção de Minicromossomo/antagonistas & inibidores , Reparo de DNA por Recombinação/efeitos dos fármacos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Acetilcisteína/farmacologia , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Recombinação Homóloga , Humanos , Fígado/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
12.
Life Sci ; 255: 117832, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450164

RESUMO

AIMS: N-Acetylcysteine (NAC) is an effective antidote for the treatment of acetaminophen (APAP) poisoning; however, due to its low stability and bioavailability, repeated dosing of NAC is needed. This study investigated the therapeutic efficacy of NAC by niosomal carriers. MATERIALS AND METHODS: Niosomes were synthesized using surface active agents film hydration method and their physicochemical properties were characterized. In the in vivo study, in addition to control group, male rats were divided in different groups and challenged with an oral dose of APAP (2000 mg/kg); 4 h later, rats were administered normal saline, empty niosome (NIO), NAC (25 mg/kg) and NAC-loaded niosome (NAC-NIO) respectively, and sacrificed 48 h post-APAP overdose. KEY FINDINGS: The particle size and zeta potential of NAC-NIO were 242.3 ± 18.5 nm and -23.9 ± 1.6 mV. The loading and encapsulation efficiency of niosomes were 1.22% ± 0.02% and 26.76% ± 6.02%. APAP administration leads to hepatic damage as evidenced by increases in serum hepatic enzyme levels and tissue levels of nitric oxide and lipid peroxidation as well as decreases in hepatic levels of reduced glutathione, catalase, superoxide dismutase, and glutathione peroxidase. Treatment of rats with NIO-NAC was remarkably more effective than NAC in improving biochemical changes such as serum hepatic aminotransferases. These findings were correlated well to the histopathological experiments. SIGNIFICANCE: Our results suggest that NAC when delivered as a niosomal structure, is potentially more effective than NAC standard, in improving APAP-induced hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Acetilcisteína/administração & dosagem , Analgésicos não Entorpecentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Nanopartículas , Acetaminofen/administração & dosagem , Acetilcisteína/farmacologia , Administração Oral , Analgésicos não Entorpecentes/administração & dosagem , Animais , Antídotos/administração & dosagem , Antídotos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Sistemas de Liberação de Medicamentos , Lipossomos , Masculino , Tamanho da Partícula , Polietilenoglicóis/química , Ratos , Ratos Wistar , Tensoativos/química
13.
J Pharmacol Sci ; 143(3): 133-140, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253104

RESUMO

Endogenous noradrenaline (NA) has multiple bioactive functions and, in the central nervous system (CNS), has been implicated in modulating neuroinflammation via ß-adrenergic receptors (ß-ARs). Microglia, resident macrophages in the CNS, have a central role in the brain immune system and have been reported to be activated by NA. However, intracellular signaling mechanisms of the AR-mediated proinflammatory responses of microglia are not fully understood. Using a rapid and stable in vitro reporter assay system to evaluate IL-1ß production in microglial BV2 cells, we found that NA and the ß-AR agonist isoproterenol upregulated the IL-1ß reporter activity. This effect was suppressed by ß-AR antagonists. We further examined the involvement of EPAC (exchange protein directly activated by cAMP) and TPL2 (tumor progression locus 2, MAP3K8) and found that inhibitors for EPAC and TPL2 reduced AR agonist-induced IL-1ß reporter activity. These inhibitors also suppressed NA-induced endogenous Il1b mRNA expression and IL-1ß protein production. Our results suggest that EPAC and TPL2 are involved in ß-AR-mediated IL-1ß production in microglial cells, and extend our understanding of its intracellular signaling mechanism.


Assuntos
Acetilcisteína/análogos & derivados , Eritromicina/análogos & derivados , Interleucina-1beta/metabolismo , MAP Quinase Quinase Quinases/farmacologia , Microglia/metabolismo , Proteínas Proto-Oncogênicas/farmacologia , Acetilcisteína/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Eritromicina/farmacologia , Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Isoproterenol/farmacologia , MAP Quinase Quinase Quinases/fisiologia , Camundongos , Norepinefrina/farmacologia , Norepinefrina/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Adrenérgicos beta , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
14.
Acta Cir Bras ; 35(2): e202000203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348402

RESUMO

Purpose To evaluate the effect of remote ischemic conditioning associated to N-acetylcysteine (NAC) on testicular ischemia∕reperfusion (I∕R) injury in rats. Methods Twenty-five adult male Wistar rats were randomly distributed into five experimental groups (n=5), as follows: Sham, I∕R, Perconditioning (PER), NAC and PER+NAC. Two-hour ischemia was induced by rotating the left testis 720° to clockwise direction, followed by 4 hours of reperfusion. Perconditioning was performed by three I/R cycles of 10 min each on the left limb, 30 min before reperfusion. N-acetylcysteine (150 mg∕kg) was administered 30 min before reperfusion. Results Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was statistical difference between PER and Sham, and PER+ NAC groups (p<0.05) in plasma. Conclusions The protective effect of perconditioning isolated in the reduction of lipid peroxidation related to oxidative stress was demonstrated. However, when Perconditioning was associated with NAC, there was no protective effect against testicular injury of ischemia and reperfusion.


Assuntos
Acetilcisteína/farmacologia , Depuradores de Radicais Livres/farmacologia , Precondicionamento Isquêmico/métodos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão , Testículo/irrigação sanguínea , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Capacidade de Absorbância de Radicais de Oxigênio , Distribuição Aleatória , Ratos , Ratos Wistar , Testículo/efeitos dos fármacos
15.
Ecotoxicol Environ Saf ; 194: 110415, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32151871

RESUMO

Zinc oxide Nanoparticles (ZnO NPs) are widely used as emerging materials in agricultural and food-related fields, which exists potential safety hazards to public health and environment while bringing an added level of convenience to our original life. It has been proved that ZnO NPs could be taken up by pregnant women and passed through human placental barrier. However, the toxic potential for embryo development remains largely unanswered. In this study, we discovered that ZnO NPs caused the cytotoxicity in vitro. Inhibition of free Zn2+ ions in solution by EDTA or inhibition of Zn2+ ions absorption by CaCl2 could partially eliminate ZnO NPs-mediated cell toxicity, though not redeem completely. This indicated that both nanoparticles and the release of Zn2+ ions were involved in ZnO NPs-mediated cytotoxicity. In addition, we also found that both nanoparticles and Zn2+ ion release triggered reactive oxygen species (ROS) production, which further induced cell toxicity, inflammation and apoptosis, which are mediated by NF-κB signaling cascades and the mitochondria dysfunction, respectively. Eventually, these events lead to the suppressed production and migration of cranial neural crest cells (CNCCs), which subsequently prompts the craniofacial defects in chicken embryos. The application of the antioxidant N-Acetyl-L-cysteine (NAC) rescued the ZnO NPs-induced cell toxicity and malformation of the CNCCs, which further verified our hypothesis. Our results revealed the relevant mechanism of ZnO NPs exposure-inhibited the development of CNCCs, which absolutely contribute to assess the risk of nanoparticles application.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Nanopartículas/toxicidade , Crista Neural/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Óxido de Zinco/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Feminino , Células HEK293 , Humanos , Mitocôndrias/efeitos dos fármacos , NF-kappa B/metabolismo , Nanopartículas/química , Crista Neural/embriologia , Espécies Reativas de Oxigênio/metabolismo , Óxido de Zinco/química
16.
Einstein (Sao Paulo) ; 18: eAO5022, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32215468

RESUMO

OBJECTIVE: To evaluate the effects of oxidative stress on insulin signaling in cardiac tissue of obese mice. METHODS: Thirty Swiss mice were equally divided (n=10) into three groups: Control Group, Obese Group, and Obese Group Treated with N-acetylcysteine. After obesity and insulin resistance were established, the obese mice were treated with N-acetylcysteine at a dose of 50mg/kg daily for 15 days via oral gavage. RESULTS: Higher blood glucose levels and nitrite and carbonyl contents, and lower protein levels of glutathione peroxidase and phosphorylated protein kinase B were observed in the obese group when compared with their respective control. On the other hand, treatment with N-acetylcysteine was effective in reducing blood glucose levels and nitrite and carbonyl contents, and significantly increased protein levels of glutathione peroxidase and phosphorylated protein kinase B compared to the Obese Group. CONCLUSION: Obesity and/or a high-lipid diet may result in oxidative stress and insulin resistance in the heart tissue of obese mice, and the use of N-acetylcysteine as a methodological and therapeutic strategy suggested there is a relation between them.


Assuntos
Acetilcisteína/farmacologia , Dieta Hiperlipídica , Depuradores de Radicais Livres/farmacologia , Resistência à Insulina/fisiologia , Miocárdio/metabolismo , Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Animais , Glicemia/análise , Western Blotting , Peso Corporal , Fluoresceínas/análise , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica , Espécies Reativas de Oxigênio/análise , Valores de Referência , Espectrofotometria
17.
Gene ; 745: 144623, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32222530

RESUMO

Metformin and cisplatin have been widely studied as antitumor agents. However, the effect of metformin combined with cisplatin has not been investigated in colorectal cancer (CRC) cells. This study was aimed to explore the effect of metformin or/and cisplatin on cell viability, apoptosis, and the related signaling pathways in CRC SW480 and SW620 cells. We found that metformin or cisplatin inhibited cell viability of SW480 and SW620 cells in a concentration- and time-dependent manner. Furthermore, metformin combined with cisplatin obviously inhibited cell viability, decreased colony formation, induced apoptosis, mediated cleavage of caspase-9, caspase-3 and PARP, activated mitochondrial membrane potential, downregulated Mcl-1 and Bcl-2 expression, upregulated Bak and Bax expression, and increased reactive oxygen species (ROS) production, compared to the individual agent in SW480 and SW620 cells, which were attenuated by N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, NAC could recover the downregulation of p-PI3K and p-Akt treated with combination of metformin and cisplatin, which subsequently activated the PI3K/Akt signaling pathway. Taken together, our results demonstrated that metformin enhanced the sensitivity of CRC cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Metformina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acetilcisteína/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HCT116 , Humanos , Metformina/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
18.
PLoS One ; 15(3): e0229948, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155190

RESUMO

The integrated stress response (ISR) is one of the most important cytoprotective mechanisms and is integrated by phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Four eIF2α kinases, heme-regulated inhibitor (HRI), double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2 (GCN2), are activated in response to several stress conditions. We previously reported that nanosecond pulsed electric fields (nsPEFs) are a potential therapeutic tool for ISR activation. In this study, we examined which eIF2α kinase is activated by nsPEF treatment. To assess the responsible eIF2α kinase, we used previously established eIF2α kinase quadruple knockout (4KO) and single eIF2α kinase-rescued 4KO mouse embryonic fibroblast (MEF) cells. nsPEFs 70 ns in duration with 30 kV/cm electric fields caused eIF2α phosphorylation in wild-type (WT) MEF cells. On the other hand, nsPEF-induced eIF2α phosphorylation was completely abolished in 4KO MEF cells and was recovered by HRI overexpression. CM-H2DCFDA staining showed that nsPEFs generated reactive oxygen species (ROS), which activated HRI. nsPEF-induced eIF2α phosphorylation was blocked by treatment with the ROS scavenger N-acetyl-L-cysteine (NAC). Our results indicate that the eIF2α kinase HRI is responsible for nsPEF-induced ISR activation and is activated by nsPEF-generated ROS.


Assuntos
Eletricidade/efeitos adversos , Fibroblastos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico/fisiologia , Acetilcisteína/farmacologia , Animais , Linhagem Celular , Técnicas de Inativação de Genes , Camundongos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Espécies Reativas de Oxigênio/antagonistas & inibidores , Estresse Fisiológico/efeitos dos fármacos , eIF-2 Quinase/genética
19.
Int J Nanomedicine ; 15: 1349-1361, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184590

RESUMO

Background: Impaired wound healing might be associated with many issues, especially overactive of reactive oxygen species (ROS), deficiency of blood vessels and immature of epidermis. N-acetylcysteine (NAC), as an antioxidant, could solve these problems by inhibiting overreactive of ROS, promoting revascularization and accelerating re-epithelialization. How to deliver NAC in situ with a controllable releasing speed still remain a challenge. Materials and Methods: In this study, we combined collagen (Col) with N-acetylcysteine to perform the characteristics of sustained release and chemically crosslinked Col/NAC composite with polyamide (PA) nanofibers to enhance the mechanical property of collagen and fabricated this multi-layered scaffold (PA-Col/NAC scaffold). The physical properties of the scaffolds such as surface characteristics, water absorption and tensile modulus were tested. Meanwhile, the ability to promote wound healing in vitro and in vivo were investigated. Results: These scaffolds were porous and performed great water absorption. The PA-Col/NAC scaffold could sustainably release NAC for at least 14 days. After cell implantation, PA-Col/NAC scaffold showed better cell proliferation and cell migration than the other groups. In vivo, PA-Col/NAC scaffolds could promote wound healing best among all the groups. Conclusion: The multi-layered scaffolds could obviously accelerate the process of wound healing and exert better and prolonged effects.


Assuntos
Acetilcisteína/farmacologia , Colágeno/química , Depuradores de Radicais Livres/farmacologia , Nylons/química , Reepitelização/efeitos dos fármacos , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada , Masculino , Nanofibras/química , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
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