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1.
Adv Biol Regul ; 77: 100741, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773102

RESUMO

Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the mononuclear phagocyte system (MPS) and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.


Assuntos
Antioxidantes/uso terapêutico , Infecções por Coronavirus/epidemiologia , Armadilhas Extracelulares/imunologia , Linfopenia/epidemiologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Acetilcisteína/uso terapêutico , Ácido Ascórbico/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
2.
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
3.
Free Radic Biol Med ; 156: 190-199, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32653511

RESUMO

Studies have shown that infection, excessive coagulation, cytokine storm, leukopenia, lymphopenia, hypoxemia and oxidative stress have also been observed in critically ill Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) patients in addition to the onset symptoms. There are still no approved drugs or vaccines. Dietary supplements could possibly improve the patient's recovery. Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present an anti-inflammatory effect that could ameliorate some patients need for intensive care unit (ICU) admission. EPA and DHA replace arachidonic acid (ARA) in the phospholipid membranes. When oxidized by enzymes, EPA and DHA contribute to the synthesis of less inflammatory eicosanoids and specialized pro-resolving lipid mediators (SPMs), such as resolvins, maresins and protectins. This reduces inflammation. In contrast, some studies have reported that EPA and DHA can make cell membranes more susceptible to non-enzymatic oxidation mediated by reactive oxygen species, leading to the formation of potentially toxic oxidation products and increasing the oxidative stress. Although the inflammatory resolution improved by EPA and DHA could contribute to the recovery of patients infected with SARS-CoV-2, Omega-3 fatty acids supplementation cannot be recommended before randomized and controlled trials are carried out.


Assuntos
Infecções por Coronavirus/dietoterapia , Síndrome da Liberação de Citocina/dietoterapia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Leucopenia/dietoterapia , Pandemias , Pneumonia Viral/dietoterapia , Anti-Inflamatórios não Esteroides/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/dietoterapia , Coagulação Intravascular Disseminada/epidemiologia , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/virologia , Humanos , Hipóxia/dietoterapia , Hipóxia/epidemiologia , Hipóxia/metabolismo , Hipóxia/virologia , Leucopenia/epidemiologia , Leucopenia/metabolismo , Leucopenia/virologia , Estresse Oxidativo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
4.
Life Sci ; 256: 117987, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569778

RESUMO

AIMS: Ischemic stroke is the leading cause of severe disability and death worldwide. As the pathogenesis of stroke has not been clearly elucidated and the ability of current therapeutic drugs on crossing the blood-brain barrier (BBB) is extremely low, there is no effective strategy to treat stroke. We aim at investigating the specific advantages of using plasma exosomes (Pla-Exo) for targeting ischemic brain and exploring its underlying mechanism in neuroprotection. MAIN METHODS: Pla-Exo was obtained by a gradient ultracentrifugation of fresh plasma. The quantification of penetrated Pla-Exo through BBB was investigated in vitro BBB model, furthermore, the effects of Pla-Exo and exosomal HSP70 on cerebral ischemia/reperfusion injury were evaluated. KEY FINDINGS: Pla-Exo enhanced BBB crossing by specific interaction between Pla-Exo inherited heat shock protein 70 (HSP70) and endothelial Toll-like receptor 4 (TLR4). As expected, Pla-Exo increased HSP70 expression in the ischemic region through the transfer of HSP70, and led to HSP70 mediated suppression of ROS, thus alleviating cerebral ischemia/reperfusion (I/R) injury by attenuating the deterioration of BBB and preventing mitochondria damage. SIGNIFICANCE: These findings indicated that Pla-Exo can provide protection against ischemia-reperfusion injury via the regulation of HSP70 and it should be further studied as a potential candidate for protection against ischemic injury.


Assuntos
Isquemia Encefálica/metabolismo , Exossomos/metabolismo , Proteínas de Choque Térmico HSP70/administração & dosagem , Plasma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Isquemia Encefálica/prevenção & controle , Endotélio Vascular/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle
5.
Free Radic Biol Med ; 156: 107-112, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32598985

RESUMO

Ebselen is an organoselenium compound exhibiting hydroperoxide- and peroxynitrite-reducing activity, acting as a glutathione peroxidase and peroxiredoxin enzyme mimetic. Ebselen reacts with a multitude of protein thiols, forming a selenosulfide bond, which results in pleiotropic effects of antiviral, antibacterial and anti-inflammatory nature. The main protease (Mpro) of the corona virus SARS-CoV-2 is a potential drug target, and a screen with over 10,000 compounds identified ebselen as a particularly promising inhibitor of Mpro (Jin, Z. et al. (2020) Nature 582, 289-293). We discuss here the reaction of ebselen with cysteine proteases, the role of ebselen in infections with viruses and with other microorganisms. We also discuss effects of ebselen in lung inflammation. In further research on the inhibition of Mpro in SARS-CoV-2, ebselen can serve as a promising lead compound, if the inhibitory effect is confirmed in intact cells in vivo. Independently of this action, potential beneficial effects of ebselen in COVID-19 are ascribed to a number of targets critical to pathogenesis, such as attenuation of inflammatory oxidants and cytokines.


Assuntos
Antioxidantes/uso terapêutico , Antivirais/uso terapêutico , Azóis/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Compostos Organosselênicos/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/uso terapêutico , Betacoronavirus/enzimologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Modelos Moleculares , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Inibidores de Proteases/uso terapêutico , Ligação Proteica , Estrutura Secundária de Proteína , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
6.
Toxicol Appl Pharmacol ; 401: 115071, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454055

RESUMO

Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of ß-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/ß-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ivermectina/análogos & derivados , Lactonas/farmacologia , Compostos Macrocíclicos/farmacologia , Neoplasias da Próstata/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Ivermectina/química , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lactonas/uso terapêutico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Masculino , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
7.
Toxicol Appl Pharmacol ; 395: 114980, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234516

RESUMO

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1ß (IL-1ß), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor ß (TGF-ß). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.


Assuntos
Anti-Inflamatórios/administração & dosagem , Transtornos da Memória/prevenção & controle , Minociclina/administração & dosagem , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Tolueno/toxicidade , Administração por Inalação , Animais , Expressão Gênica/efeitos dos fármacos , Abuso de Inalantes , Interleucina-1beta/genética , Masculino , Transtornos da Memória/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tolueno/administração & dosagem , Fator de Crescimento Transformador beta/genética
8.
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
9.
Life Sci ; 248: 117471, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112868

RESUMO

AIMS: This study aimed to explore the protective effects and possible mechanisms of baicalein on Aß25-35-induced toxicity. MAIN METHODS: Thioflavin-T (Th-T) dye was used to determine the effects of baicalein on Aß25-35 aggregation in vitro. PC12 cells were stimulated with Aß25-35, then the effects of baicalein on apoptosis, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), mitochondrial respiratory complex I, reactive oxygen species (ROS) and nitric oxide (NO) levels were determined. Moreover, LC-MS metabolomics approach was used to detect metabolic changes induced by baicalein in Aß25-35-injured PC12 cells. KEY FINDINGS: The results showed that baicalein could inhibit the aggregation of Aß25-35 in vitro. Furthermore, pretreatment with baicalein significantly prevented Aß25-35-induced cell apoptosis, as manifested by increasing the levels of MMP, ATP and mitochondrial respiratory complex I, decreasing the contents of ROS and NO. LC-MS metabolomics revealed that baicalein can regulate 5 metabolites, mainly involving two metabolic pathways, arginine and proline metabolism, nicotinate and nicotinamide metabolism. SIGNIFICANCE: Our study revealed that baicalein has a protective effect on Aß25-35-induced neurotoxicity in PC12 cells, which may be related to inhibition of apoptosis and metabolic disorders.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Flavanonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Peptídeos beta-Amiloides/toxicidade , Animais , Arginina/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Niacina/metabolismo , Niacinamida/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Fragmentos de Peptídeos/toxicidade , Prolina/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
10.
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
11.
J Med Chem ; 63(8): 4005-4021, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32207946

RESUMO

Six complexes of formula [Ir(η5:κ1-C5Me4CH2py)(C,N)]PF6, where C5Me4CH2py is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (1), 7,8-benzoquinoline (2), 1-phenylisoquinoline (3), 2-(p-tolyl)pyridine (4), 4-chloro-2-phenylquinoline (5), or 2-(2,4-difluorophenyl)pyridine (6), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η5:κ1-C5Me4CH2pyN) tether-ring structure, as confirmed by the X-ray crystal structures of 1, 2, 4, 5, and 6. Nontether versions of 1 and 2 were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, 1-6, are exceptionally more potent (1-2 orders of magnitude). Additionally, 1-6 disrupt mitochondrial membrane potential (ΔΨm) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.


Assuntos
Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Irídio/química , Antineoplásicos/farmacologia , Proliferação de Células/fisiologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X/métodos , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Irídio/farmacologia , Células MCF-7 , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
12.
Life Sci ; 248: 117452, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088214

RESUMO

AIMS: The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 (SIRT1). MATERIALS AND METHODS: Aging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene (SIRT1) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed. KEY FINDINGS: Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate SIRT1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. SIGNIFICANCE: Tropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via SIRT1 signaling activation.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Sirtuína 1/genética , Tropizetrona/farmacologia , Envelhecimento/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Encéfalo/metabolismo , Encéfalo/patologia , Esquema de Medicação , Galactose/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação , Injeções Intraperitoneais , Injeções Subcutâneas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
13.
Life Sci ; 246: 117403, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035131

RESUMO

Monoclonal antibodies targeting the programmed-death 1 (PD-1) immune checkpoint or its ligand PD-L1 have significantly improved the treatment of cancers but more efficient drugs and combinations are still needed to increase the therapeutic efficacy. As the oxidative state of the immune microenvironment plays a critical role in the antitumor immune response, it is important to evaluate the impact of molecules and drugs used for oxidative stress control on PD-L1 expression and functions. Here we have reviewed the functional relationship between reactive oxygen species (ROS) and PD-L1 expressed on cancer cells, and analyzed the effects of 15 pharmacological ROS modulators - both ROS inducers and attenuators - on PD-L1 expression. The interplay between tumor hypoxia, the HIF-1α/YAP1/NFκB signaling routes and PD-L1 expression has been analyzed and specific non-cytotoxic ROS-associated drugs known to modulate this system are discussed. A complex interplay between ROS effectors and PD-L1 expression is revealed, showing that depending on their targets and mechanisms, ROS effectors can engender an up or down-regulation of PD-L1 expression in cancer cells. An enhanced generation of ROS often promotes PD-L1 expression and, conversely, ROS scavenging generally represses PD-L1. But there are noticeable exceptions with drugs that augment ROS production while reducing PD-L1 expression and vice versa. The variable PD-L1 response to ROS modulation reflects the complexity of ROS biology in the tumor microenvironment. A deeper knowledge of the contribution of ROS to PD-(L)1 immune checkpoint control is warranted.


Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Antígeno B7-H1/metabolismo , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Humanos , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos
14.
Sci Rep ; 10(1): 2744, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066777

RESUMO

Hyperbaric oxygen (HBO) treatment promotes early recovery from muscle injury. Reactive oxygen species (ROS) upregulation is a key mechanism of HBO, which produces high O2 content in tissues through increased dissolution of oxygen at high pressure. Nitric oxide (NO), a type of ROS, generally stabilizes hypoxia-inducible factor (HIF) 1α and stimulates secretion of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) from endothelial cells and macrophages, which then induces angiogenesis. The purpose of the present study was to investigate whether HBO could promote angiogenesis via induction of NO and induce muscle regeneration in contused rat skeletal muscles. The HBO protocol consisted of 2.5 atmospheres absolute (ATA) 100% oxygen for 120 minutes, once a day for 5 consecutive days. We also evaluated the effects of a ROS inhibitor (NAC) or NOS-specific inhibitor (L-NAME) on HBO. HBO significantly increased NO3-, VEGF, and bFGF levels and stabilized HIF1α within 1 day. HBO promoted blood vessel formation at 3-7 days and muscle healing at 5-7 days after contusion. Administration of both NAC and L-NAME before HBO suppressed angiogenesis and muscle regeneration even after HBO. HBO thus promoted angiogenesis and muscle regeneration mainly through generation of NO in the early phase after muscle contusion injury.


Assuntos
Contusões/terapia , Oxigenação Hiperbárica/métodos , Músculo Esquelético/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico/biossíntese , Oxigênio/farmacologia , Acetilcisteína/farmacologia , Indutores da Angiogênese , Animais , Contusões/genética , Contusões/metabolismo , Contusões/patologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/agonistas , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Regeneração/efeitos dos fármacos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Carbohydr Polym ; 234: 115889, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070509

RESUMO

We report a facile method to prepare a novel composite based on Fe-Cu alloy decorated cellulose nanocrystals (Fe-Cu@CNC) via simple oxidation-reduction reaction. Spherical zero-valent iron nanoparticles (NZVI) and sheet-like copper nanoparticles were serially anchored on the CNC surface, and the generated composite exhibited excellent antibacterial activities and highly efficient Pb2+ removal. The composites had high antibacterial ratios of 95.9 %-99.9 %, because superoxide radicals can cause irreversible damage to the bacteria, eventually leading to apoptosis and bacterial death. Meanwhile, the Fe-Cu@CNC composite showed quick Pb2+ ion removal, reaching a 70.76 % removal within 5 min, a total removal of 93.98 % after 1 h, and excellent reusability (retaining removal efficiency of 80.41 % after six cycles). The adsorption kinetics demonstrated that the adsorption behavior can be described by pseudo-second-order kinetic model (R2>0.99). This study offers a new strategy to prepare a promising composite with advanced antibacterial and heavy metal removal properties for wastewater treatment.


Assuntos
Ligas/farmacologia , Antibacterianos/farmacologia , Celulose/farmacologia , Chumbo/isolamento & purificação , Nanopartículas/química , Poluentes Químicos da Água/isolamento & purificação , Ligas/química , Antibacterianos/síntese química , Antibacterianos/química , Celulose/química , Cobre/química , Cobre/farmacologia , Escherichia coli/efeitos dos fármacos , Ferro/química , Ferro/farmacologia , Chumbo/química , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície , Poluentes Químicos da Água/química
17.
J Trauma Acute Care Surg ; 88(5): 677-685, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32039974

RESUMO

INTRODUCTION: Free radicals and reactive oxygen species are related to deteriorating pathological conditions after head trauma because of their secondary effects. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) scavenges free radicals; however, this molecule is also toxic. Here, we have evaluated the neuroprotective effect of antioxidant nanoparticles, which consisted of a novel core-shell type nanoparticle containing 4-amino-TEMPO, that is, redox-active nitroxide radical-containing nanoparticles (RNPs). METHODS: Institute of Cancer Research mice were subjected to a head-impact procedure, randomly divided into four groups and intravenously (3 mg/kg) administered phosphate-buffered saline, TEMPO, micelle (a self-assembling block copolymer micelle without a TEMPO moiety), or RNP through the tail vein immediately thereafter and intraperitoneally at days 1, 3, and 5 after traumatic brain injury (TBI). The RNP distribution was detected by rhodamine labeling. Cognitive behavior was assessed using the neurological severity score and a rotarod test at days 1, 3, and 7 following TBI, and contusion volume was measured at day 7 after TBI. Free radical-scavenging capacity was analyzed by electron paramagnetic resonance on day 1 after TBI, and immunostaining was used to observe mobilization of microglia (Iba-1) and rescued neuronal cells (NeuN). RESULTS: Redox-active nitroxide radical-containing nanoparticle was detected in the microvessels around the injured area in the brain. Cognitive behavior assessment was significantly better, and contusion volume was significantly smaller in the RNP group compared with the other groups. Superoxide anion scavenging capacity was significantly higher in the RNP group, and neuronal loss was significantly suppressed around the injured area at day 7 after TBI. Furthermore, in the RNP group, neurodegenerative microglia production was suppressed at days 3 and 7 after TBI, whereas neuroprotective microglia production was higher at day 7 after TBI. CONCLUSION: The RNP administration after TBI improved cognitive behavior and reduced contusion volume by improving reactive oxygen species scavenging capacity. Therefore, RNP may have a neuroprotective effect after TBI. LEVEL OF EVIDENCE: Therapeutic test.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Depuradores de Radicais Livres/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Espécies Reativas de Oxigênio/antagonistas & inibidores , Administração Intravenosa , Animais , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/patologia , Cognição/efeitos dos fármacos , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/química , Modelos Animais de Doenças , Depuradores de Radicais Livres/química , Humanos , Masculino , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Fármacos Neuroprotetores/química , Óxidos de Nitrogênio/administração & dosagem , Óxidos de Nitrogênio/química
18.
Oxid Med Cell Longev ; 2020: 8285065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998445

RESUMO

White matter injury (WMI) is an important cause of high disability after intracerebral haemorrhage (ICH). It is widely accepted that reactive oxygen species (ROS) contributes to WMI, but there is still no evidence-based treatment. Here, mitoquinone (MitoQ), a newly developed selective mitochondrial ROS scavenger, was used to test its neuroprotective potential. The data showed that MitoQ attenuated motor function deficits and motor-evoked potential (MEP) latency prolongation. Further research found that MitoQ blunted the loss of oligodendrocytes and oligodendrocyte precursor cells, therefore reduced demyelination and axon swelling after ICH. In the in vitro experiments, MitoQ, but not the nonselective antioxidant, almost completely attenuated the iron-induced membrane potential decrease and cell death. Mechanistically, MitoQ blocked the ATP deletion and mitochondrial ROS overproduction. The present study demonstrates that the selective mitochondrial ROS scavenger MitoQ may improve the efficacy of antioxidant treatment of ICH by white matter injury alleviation.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Ubiquinona/análogos & derivados , Substância Branca/metabolismo , Animais , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Camundongos , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/farmacologia , Substância Branca/patologia
19.
Biomater Sci ; 8(5): 1380-1393, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-31916560

RESUMO

To achieve highly systemic therapeutic efficacy, chemotherapy is combined with photothermal therapy for chemo-photothermal synergistic therapy; however, this strategy suffers from high toxicity and unsatisfactory sensitivity for cancer cells. Herein, we developed a pH- and photothermal-responsive zeolitic imidazolate framework (ZIF-8) compound for loading a dual-drug in the tumor site and improving their curative effects. Since autophagy always accompanies tumor progression and metastasis, there is an unmet need for an anticancer treatment related to the regulation of autophagy. Green tea polyphenols, namely, (-)-epigallocatechin-3-gallate (EGCG) and doxorubicin (DOX), both of which exhibit anticancer activity, were dual-loaded via polydopamine (PDA) coating ZIF-8 (EGCG@ZIF-PDA-PEG-DOX, EZPPD for short) through hierarchical self-assembly. PDA could transfer photothermal energy to increase the temperature under near-infrared (NIR) laser irradiation. Due to its pH-response, EZPPD released EGCG and DOX in the tumor microenvironment, wherein the temperature increased with the help of PDA and NIR laser irradiation. The duo of DOX and EGCG induced autophagic flux and accelerated the formation of autophagosomes. In a mouse HeLa tumor model, photothermal-chemotherapy could ablate the tumor with a significant synergistic effect and potentiate the anticancer efficacy. Thus, the results indicate that EZPPD renders the key traits of a clinically promising candidate to address the challenges associated with synergistic chemotherapy and photothermal utilization in antitumor therapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Catequina/análogos & derivados , Doxorrubicina/farmacologia , Indóis/química , Polímeros/química , Neoplasias do Colo do Útero/terapia , Zeolitas/química , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Catequina/síntese química , Catequina/química , Catequina/farmacologia , Doxorrubicina/síntese química , Doxorrubicina/química , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Nus , Fototerapia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
20.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165664, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926265

RESUMO

Neutrophils release neutrophil extracellular traps (NETs) in response to numerous pathogenic microbes as the last suicidal resource (NETosis) in the fight against infection. Apart from the host defense function, NETs play an essential role in the pathogenesis of various autoimmune and inflammatory diseases. Therefore, understanding the molecular mechanisms of NETosis is important for regulating aberrant NET release. The initiation of NETosis after the recognition of pathogens by specific receptors is mediated by an increase in intracellular Ca2+ concentration, therefore, the use of Ca2+ ionophore A23187 can be considered a semi-physiological model of NETosis. Induction of NETosis by various stimuli depends on reactive oxygen species (ROS) produced by NADPH oxidase, however, NETosis induced by Ca2+ ionophores was suggested to be mediated by ROS produced in mitochondria (mtROS). Using the mitochondria-targeted antioxidant SkQ1 and specific inhibitors of NADPH oxidase, we showed that both sources of ROS, mitochondria and NADPH oxidase, are involved in NETosis induced by A23187 in human neutrophils. In support of the critical role of mtROS, SkQ1-sensitive NETosis was demonstrated to be induced by A23187 in neutrophils from patients with chronic granulomatous disease (CGD). We assume that Ca2+-triggered mtROS production contributes to NETosis either directly (CGD neutrophils) or by stimulating NADPH oxidase. The opening of the mitochondrial permeability transition pore (mPTP) in neutrophils treated by A23187 was revealed using the electron transmission microscopy as a swelling of the mitochondrial matrix. Using specific inhibitors, we demonstrated that the mPTP is involved in mtROS production, NETosis, and the oxidative burst induced by A23187.


Assuntos
Armadilhas Extracelulares/metabolismo , Doença Granulomatosa Crônica/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , NADPH Oxidase 2/metabolismo , Neutrófilos/metabolismo , Explosão Respiratória/fisiologia , Adolescente , Calcimicina/farmacologia , Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Células Cultivadas , Criança , Transporte de Elétrons , Depuradores de Radicais Livres/farmacologia , Doença Granulomatosa Crônica/sangue , Voluntários Saudáveis , Humanos , Mutação com Perda de Função , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas de Transporte da Membrana Mitocondrial/ultraestrutura , NADPH Oxidase 2/antagonistas & inibidores , NADPH Oxidase 2/genética , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/ultraestrutura , Oxirredução/efeitos dos fármacos , Plastoquinona/análogos & derivados , Plastoquinona/farmacologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória/efeitos dos fármacos
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