Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.800
Filtrar
1.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207355

RESUMO

Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression.


Assuntos
Astrócitos/metabolismo , Glicólise , Doenças Neurodegenerativas/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neurodegenerativas/genética , Via de Pentose Fosfato , Acidente Vascular Cerebral/genética
2.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34203049

RESUMO

The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against H2O2-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed in 5xFAD Tg mouse model by administering Bergenin (1, 30 and 60 mg/kg; orally), whereas Bergenin (60 mg/kg) significantly attenuated the memory deficit observed in the Y-maze and Morris water maze (MWM) test. Fourier transform-infrared (FT-IR) spectroscopy displayed restoration of lipids, proteins and their derivatives compared to the 5xFAD Tg mice group. The differential scanning calorimeter (DSC) suggested an absence of amyloid beta (Aß) aggregation in Bergenin-treated mice. The immunohistochemistry (IHC) analysis suggested the neuroprotective effect of Bergenin by increasing Reelin signaling (Reelin/Dab-1) and attenuated Aß (1-42) aggregation in hippocampal regions of mouse brains. Furthermore, IHC and western blot results suggested antioxidant (Keap-1/Nrf-2/HO-1), anti-inflammatory (TLR-4/NF-kB) and anti-apoptotic (Bcl-2/Bax/Caspase-3) effect of Bergenin. Moreover, a decrease in Annexin V/PI-stained hippocampal cells suggested its effect against neurodegeneration. The histopathological changes were reversed significantly by Bergenin. In addition, a remarkable increase in antioxidant level with suppression of pro-inflammatory cytokines, oxidative stress and nitric oxide production were observed in specific regions of the mouse brains.


Assuntos
Benzopiranos/farmacologia , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Benzopiranos/química , Biomarcadores , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Ligação de Hidrogênio , Mediadores da Inflamação/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/diagnóstico , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Resultado do Tratamento
3.
Ecotoxicol Environ Saf ; 221: 112449, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34214916

RESUMO

Dimethoxyethyl phthalate (DMEP) is an environmental endocrine disruptor. However, research into the underlying mechanisms of DMEP mitochondrial toxicity is still in its infancy. We therefore expect to understand whether DMEP induced mitochondrial damage in HepG2 cells and the associated signaling pathways. DMEP (0.125, 0.25, 0.5, 1 and 2 mM) exposure for 48 h induced a notable increment in reactive oxygen species (ROS), malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate transaminase (AST) and 8-hydroxydeoxyguanosine (8-OHdG) in hepG2 cells, resulting in cellular oxidative stress. Low doses of DMEP upregulated nuclear factor E2-related factor 2 (Nrf2) and downstream protein haeme oxygenase-1 (HO-1) levels and high doses down-regulated their levels. Nrf2 levels increased after ROS scavenging by N-acetyl-L-cysteine (NAC), which indicated that the Nrf2 pathway may be affected by oxidative stress. We also found that DMEP decreased ATP content, mitochondrial copy number (mtDNA), translocase of the outer membrane subunit 20 (TOM20) expression, mitochondria-encoded genes CO1, CO2, CO3, ATP6, ATP8 expression, inhibited mitochondrial biogenesis pathway, down-regulated sirtuin 1(SIRT1), PPAR gamma co-activator 1 alpha (PGC-1α), Nuclear respiratory factor 1(Nrf1), Mitochondrial transcription factor A (TFAM) content and activated PINK1/Parkin autophagy pathway. DMEP also activated the mitochondrial apoptotic pathway, causing cytochrome c cytoplasmic translocation and caspase 3 cleavage. What's more, DMEP activated the Nuclear factor-κB (NF-κB) pathway and levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were significantly upregulated, causing an inflammatory response. In summary, DMEP can cause inflammatory response and oxidative stress in HepG2 cells, inhibited the Nrf2 pathway and mitochondrial biogenesis, and induced autophagy and apoptosis. And oxidative stress at least partially affected the Nrf2 pathway and mitochondrial biogenesis SIRT1/PGC-1α pathway.


Assuntos
Disruptores Endócrinos/toxicidade , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ácidos Ftálicos/toxicidade , Sirtuína 1/metabolismo , Células Hep G2 , Humanos , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
4.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208092

RESUMO

Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C's antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). NXP031 administration alleviates cognitive impairment, microglial activity, and oxidative stress after CCH. NXP031 increased the expression of basal lamina (laminin), endothelial cell (RECA-1, PECAM-1), and pericyte (PDGFRß); these markers maintain the BBB integrity. We found that NXP031 administration activated the Nrf2-ARE pathway and increased the expression of SOD-1 and GSTO1/2. These results suggest that this new aptamer complex, NXP031, could be a therapeutic intervention in CCH-induced VaD.


Assuntos
Encéfalo/patologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Aldeídos/metabolismo , Animais , Barreira Hematoencefálica/patologia , Doença Crônica , Modelos Animais de Doenças , Hipocampo/patologia , Masculino , Microglia/patologia , Microvasos/patologia , Ratos Wistar , Regulação para Cima
5.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(8): 687-692, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34236028

RESUMO

Objective To investigate the effect of N-acetylcysteine (NAC) on the proliferation of fibroblast-like synoviocytes (FLS) treated with low concentration of hydrogen peroxide (H2O2) in rats with adjuvant arthritis (AA) and its mechanism. Methods Twenty SD rats were divided into a normal group and a model group (10 rats in each group). The model group was established by subcutaneous injection of Freund's complete adjuvant into the toe of rats, and the rats were sacrificed 28 days later. The contents of serum malondialdehyde (MDA) were detected by thiobarbituric acid method; the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined by hydroxylamine method and colorimetry respectively; and Nrf2 and Keap1 proteins in ankle synovial tissues of AA rats were detected by immunohistochemistry. AA-FLS were isolated, cultured, and identified by digestion of ankle joint slides of AA rats in vitro. The effects of NAC at different concentrations (final concentration 0, 0.3, 0.9, 3, 10, 30, 90, 180 µmol/L) on the activity of AA-FLS treated with H2O2 at low concentration (5 µmol/L) were detected by CCK-8 assay. The content of mitochondrial reactive oxygen species (ROS) in AA-FLS was detected by MitoSOX fluorescent probe. The effects of NAC (final concentration 0, 3, 10, 30 µmol/L) on Nrf2 and Keap1 protein expressions in AA-FLS treated with H2O2 at low concentration were detected by Western blotting. Results Compared with those in the control group, in AA model, the MDA level increased and SOD and GSH-Px levels decreased in serum, and the Nrf2 protein increased and the Keap1 protein decreased in synovial tissue. Immunocytochemical staining confirmed that the isolated and cultured cells were AA-FLS; NAC inhibited the proliferation of AA-FLS treated with H2O2 in a concentration-dependent manner, and the mitochondrial ROS content and the protein expressions of Nrf2 and Keap1 decreased. Conclusion NAC can inhibit the proliferation of AA-FLS treated with H2O2, which may be related to blocking Nrf2/Keap1 pathway.


Assuntos
Artrite Experimental , Sinoviócitos , Acetilcisteína/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Proliferação de Células , Fibroblastos/metabolismo , Peróxido de Hidrogênio , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Sinoviócitos/metabolismo
6.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202670

RESUMO

Astragalus membranaceus is a famous herb found among medicinal and food plants in East and Southeastern Asia. The Nrf2-ARE assay-guided separation of an extract from Jing liqueur led to the identification of a nontoxic Nrf2 activator, methylnissolin-3-O-ß-d-glucopyranoside (MNG, a component of A. membranaceus). Nrf2 activation by MNG has not been reported before. Using Western Blot, RT-qPCR and imaging, we investigated the cytoprotective effect of MNG against hydrogen peroxide-induced oxidative stress. MNG induced the expression of Nrf2, HO-1 and NQO1, accelerated the translocation of Nrf2 into nuclei, and enhanced the phosphorylation of AKT. The MNG-induced expression of Nrf2, HO-1, and NQO1 were abolished by Nrf2 siRNA, while the MNG-induced expression of Nrf2 and HO-1 was abated and the AKT phosphorylation was blocked by LY294002 (a PI3K inhibitor). MNG reduced intracellular ROS generation. However, the protection of MNG against the H2O2 insult was reversed by Nrf2 siRNA with decreased cell viability. The enhancement of Nrf2 and HO-1 by MNG upon H2O2 injury was reduced by LY294002. These data showed that MNG protected EA.hy926 cells against oxidative damage through the Nrf2/HO-1 and at least partially the PI3K/Akt pathways.


Assuntos
Astragalus propinquus/química , Citoproteção/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Cromonas , Células Hep G2 , Humanos , Morfolinas , Compostos Fitoquímicos/química
7.
Nat Commun ; 12(1): 3379, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099719

RESUMO

GATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is also involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. Here we show a mechanism utilised by CD4+ T cells to increase mitochondrial mass in response to DNA damage through the actions of GATA3 and AMPK. Activated AMPK increases expression of PPARG coactivator 1 alpha (PPARGC1A or PGC1α protein) at the level of transcription and GATA3 at the level of translation, while DNA damage enhances expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). PGC1α, GATA3 and NRF2 complex together with the ATR to promote mitochondrial biogenesis. These findings extend the pleotropic interactions of GATA3 and highlight the potential for GATA3-targeted cell manipulation for intervention in CD4+ T cell viability and function after DNA damage.


Assuntos
Linfócitos T CD4-Positivos/citologia , Dano ao DNA , Fator de Transcrição GATA3/metabolismo , Mitocôndrias/metabolismo , Biogênese de Organelas , Proteínas Quinases Ativadas por AMP/metabolismo , Adulto , Linfócitos T CD4-Positivos/metabolismo , Sobrevivência Celular/genética , Células Cultivadas , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Cultura Primária de Células
8.
J Agric Food Chem ; 69(26): 7334-7343, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34170670

RESUMO

The clinical usage of doxorubicin (DOX), a potent anthracycline antineoplastic drug, is limited due to its cardiotoxicity. The aim of this study was to assess the possible cardioprotective effects of nerolidol (NERO) in a rat model of DOX-induced chronic cardiotoxicity and the underlying molecular mechanisms. DOX (2.5 mg/kg) was injected intraperitoneally once in a week for 5 weeks to induce chronic cardiotoxicity in male albino Wistar rats. The rats were treated with NERO (50 mg/kg, orally) 6 days a week for a duration of 5 weeks. DOX-injected rats showed a significant decline in cardiac function, elevated levels of serum cardiac marker enzymes, and enhanced oxidative stress markers along with altered PI3K/Akt and Nrf2/Keap1/HO-1 signaling pathways. DOX also triggered the activation of NF-κB/MAPK signaling and increased the levels/expression of proinflammatory cytokines (TNF-α, IL-6, and IL-1ß) and expression of inflammatory mediators (iNOS and COX-2) in the heart. DOX activated NLRP3 inflammasome-mediated pyroptotic cell death along with fibrosis, mitochondrial dysfunction, DNA damage, and apoptosis in the myocardium. Additionally, histological studies, TUNEL staining, and myocardial lesions revealed structural alterations of the myocardium. NERO treatment showed considerable protective effects on the biochemical and molecular parameters studied. The findings demonstrate that NERO protects against DOX-induced chronic cardiotoxicity and the observed cardioprotective effects are attributed to its potent antioxidant and free radical scavenging properties.


Assuntos
Óleos Voláteis , Sesquiterpenos , Animais , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/toxicidade , Apoptose , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Doxorrubicina/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Miocárdio/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óleos Voláteis/farmacologia , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Sesquiterpenos/metabolismo
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(5): 679-686, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34134954

RESUMO

OBJECTIVE: To investigate the antioxidant effect of DJ-1 (Park7) in rats with cerebral ischemia/reperfusion (IR) injury and its potential mechanism. OBJECTIVE: A total of 108 SD rats were randomly divided into sham-operated group, middle cerebral artery occlusion (MCAO) group, Scramble group, DJ-1 siRNA group, negative control (NC) group and DJ-1 overexpression group. Except for those in the sham group, all the rats were subjected to MCAO to establish models of cerebral IR injury. In DJ-1 siRNA and DJ-1 overexpression group, a DJ-1 siRNA and an adeno-associated virus vector carrying DJ-1 gene was injected into the lateral ventricle of the rats, respectively. In each group, neurological scores and brain water content were determined after the operation, and pathological changes of the brain tissue and neuronal injury in the cortical infarction area were assessed using HE and Nissl staining. Oxidative stress in the brain tissues was analyzed by detecting superoxide dismutase (SOD) and malondialdehyde (MDA). The expression levels of DJ-1, Nrf2, Ho-1 and NQO1 in the brain tissue were detected with Western blotting, and the expression and nucleation of Nrf2 was determined by immunofluorescence staining. OBJECTIVE: Compared with those in MCAO group, the neurological scores (P < 0.001) and brain water content (P < 0.001) were significantly increased in DJ-1 siRNA group. Intracerebral injection of DJ-1 siRNA following MCAO obviously aggravated neuron injury in cerebral ischemia region, further reduced SOD activity and increased MDA content (P < 0.001), and significantly lowered the expression levels of Nrf2 and its downstream proteins HO-1 and NQO1 (P < 0.001). Intracerebral injection of the adenoviral vector for DJ-1 (P=0.003) overexpression significantly upregulated the levels of Nrf2 (P=0.006) and its downstream proteins HO-1 (P=0.004) and NQO1 (P=0.014). OBJECTIVE: As an important neuroprotective factor, DJ-1 alleviates oxidative stress induced by cerebral IR injury in rats by activating the Nrf2 pathway.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(5): 729-735, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34134961

RESUMO

OBJECTIVE: To investigate the protective effect of luteolin against cadmium (Cd)-induced injury in human lung epithelial Beas-2B cells. OBJECTIVE: Beas-2B cells were treated with different concentrations of luteolin (0-160 µmol/L) or Cd (0-40 µmol/L) for 24 h, and the cell viability was examined using MTT assay. After treatment with luteolin (0.25, 0.5 and 0.75 µmol/L) with or without Cd (5 µmol/L) for 24 h, the cells were examined for viability, lactate dehydrogenase (LDH) activity and morphological changes of the cell nuclei using Hoechst fluorescent staining. The levels of ROS, SOD, GSH and MDA in the treated cells were detected, and the expression levels of Akt, p-Akt and nuclear factor E2-related factor 2 (Nrf2) proteins were determined using Western blotting. OBJECTIVE: Luteolin within the concentration range of 0-80 µmol/L did not significantly affect the survival rate of Beas-2B cells (P>0.05), but Cd at 5 µmol/L significantly decreased the cell viability (P < 0.05) with an IC50 of 24.6 µmol/L. In Cd-treated cells, treatment with luteolin significantly mitigated the decrease of cell viability, reduced LDH release and cell apoptosis, enhanced SOD activity and GSH content, and inhibited the production of MDA and ROS (all P < 0.05). Luteolin also significantly up-regulated the expression levels of p-Akt and Nrf2 protein in Cd-treated Beas-2B cells (P < 0.05). OBJECTIVE: Luteolin has a significant protective effect against Cd-induced injury in Beas-2B cells, and the effects are probably mediated, at least in part, by promoting the activation of Akt and Nrf2.


Assuntos
Cádmio , Luteolina , Apoptose , Cádmio/toxicidade , Células Epiteliais/metabolismo , Humanos , Pulmão/metabolismo , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo
11.
World J Gastroenterol ; 27(22): 2944-2962, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: covidwho-1268364

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide. In addition to respiratory symptoms, COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the expression of antioxidant proteins, participating in COVID-19-mediated inflammation and liver injury. Here, we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury. Additionally, we describe some mechanisms and treatment strategies.


Assuntos
COVID-19 , Fator 2 Relacionado a NF-E2 , Humanos , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , SARS-CoV-2 , Transdução de Sinais
12.
Life Sci ; 280: 119722, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153300

RESUMO

Although melatonin has been demonstrated to exert a potent antioxidant effect, the ability of melatonin to alleviate blast-induced oxidative stress in the hypothalamic-pituitary-gonadal (HPG) axis remains unclear. This study aimed to elucidate the effects and underlying mechanism of melatonin pretreatment on the HPG axis disrupted by blast injury. Sixty C57BL/6 mice were randomly divided into control, blast, and blast + melatonin groups for behavioral experiments. The elevated maze experiment, open field experiment, and Morris Water Maze experiment were carried out on the 7th, 14th and 28th day after the blast injury. Fifty Sprague Dawley rats were randomly divided into control, blast, blast + melatonin, and blast + melatonin + luzindole groups for hormone assays and molecular and pathological experiments. Blood samples were used for HPG axis hormone detection and ELISA assays, and tissue samples were used to detect oxidative stress, inflammation, apoptosis, and stress-related protein levels. The results showed that melatonin pretreatment alleviated blast-induced behavioral abnormalities in mice and maintained the HPG axis hormone homeostasis in rats. Additionally, melatonin significantly reduced MDA5 expression and increased the expression of Nrf2/HO-1. Moreover, melatonin significantly inhibited NF-κB expression and upregulated IL-10 expression, and it reversed the blast-induced high expression of caspase-3 and Bax and the low expression of Bcl-2. Furthermore, luzindole counteracted melatonin inhibition of NF-κB and upregulated Nrf2/HO-1. Melatonin significantly alleviated blast-induced HPG axis hormone dyshomeostasis, behavioral abnormalities, oxidative stress, inflammation, and apoptosis, which may be achieved by upregulating the Nrf2/HO-1 signaling pathway. Our study suggested that melatonin pretreatment is a potential treatment for blast-induced HPG axis hormonal and behavioral abnormalities.


Assuntos
Antioxidantes/uso terapêutico , Traumatismos por Explosões/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Melatonina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Traumatismos por Explosões/metabolismo , Traumatismos por Explosões/patologia , Heme Oxigenase-1/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Masculino , Melatonina/farmacologia , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia
13.
Molecules ; 26(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073317

RESUMO

Myrciaria dubia (HBK) McVaugh (camu-camu) belongs to the family Myrtaceae. Although camu-camu has received a great deal of attention for its potential pharmacological activities, there is little information on the anti-oxidative stress and anti-inflammatory effects of camu-camu fruit in skin diseases. In the present study, we investigated the preventative effect of 70% ethanol camu-camu fruit extract against high glucose-induced human keratinocytes. High glucose-induced overproduction of reactive oxygen species (ROS) was inhibited by camu-camu fruit treatment. In response to ROS reduction, camu-camu fruit modulated the mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor of activated T cells (NFAT) signaling pathways related to inflammation by downregulating the expression of proinflammatory cytokines and chemokines. Furthermore, camu-camu fruit treatment activated the expression of nuclear factor E2-related factor 2 (Nrf2) and subsequently increased the NAD(P)H:quinone oxidoreductase1 (NQO1) expression to protect keratinocytes against high-glucose-induced oxidative stress. These results indicate that camu-camu fruit is a promising material for preventing oxidative stress and skin inflammation induced by high glucose level.


Assuntos
Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fatores de Transcrição NFATC/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Anti-Inflamatórios/farmacologia , Compostos de Bifenilo/química , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Frutas/metabolismo , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Queratinócitos/citologia , Sistema de Sinalização das MAP Quinases , Myrtaceae , NAD(P)H Desidrogenase (Quinona)/metabolismo , Picratos/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
14.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068193

RESUMO

In this study, we investigate the immunomodulatory effects of a novel antimicrobial peptide, YD1, isolated from Kimchi, in both in vitro and in vivo models. We establish that YD1 exerts its anti-inflammatory effects via up-regulation of the Nrf2 pathway, resulting in the production of HO-1, which suppresses activation of the NF-κB pathway, including the subsequent proinflammatory cytokines IL-1ß, IL-6, and TNF-α. We also found that YD1 robustly suppresses nitric oxide (NO) and prostaglandin E2 (PGE2) production by down-regulating the expression of the upstream genes, iNOS and COX-2, acting as a strong antioxidant. Collectively, YD1 exhibits vigorous anti-inflammatory and antioxidant activity, presenting it as an interesting potential therapeutic agent.


Assuntos
Anti-Inflamatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Inflamação/prevenção & controle , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Animais , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Edema/patologia , Edema/prevenção & controle , Heme Oxigenase-1/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Proteínas de Membrana/genética , Camundongos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
15.
Sci Total Environ ; 783: 146898, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34088152

RESUMO

Di-n-butylphthalate (DBP) has been listed as an environmental priority pollutant in China due to its distinct biotoxicity. Epidemiological studies have shown that exposure to DBP is closely related to a series of congenital and acquired defects in the male reproductive system. The oxidative stress injury caused by DBP plays an important role in these defects. Previous studies have demonstrated that the Keap1/Nrf2 antioxidative pathway plays a protective role in DBP-induced oxidative stress injury. However, the further molecular regulation mechanism of the activation of Nrf2 pathway remains unclear. Here, we demonstrate that DBP caused testicular oxidative stress injury and Nrf2 pathway was activated in response to the injury in vivo and in vitro. Moreover, we validated that reduced level of USP15 attenuates DBP-induced oxidative stress injury through restraining the ubiquitylation and degradation of Nrf2. Notably, USP15 is confirmed as a target of miR-135b-5p and miR-135b-5p mediated inhibition of USP15 is involved in the DBP-induced oxidative stress injury. Collectively, these findings indicated that decreased level of USP15 functions a significant protective effect on the oxidative stress injury of testis caused by DBP via regulating the Keap1/Nrf2 signaling pathway.


Assuntos
Endopeptidases/genética , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Transdução de Sinais , Testículo , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Testículo/metabolismo , Testículo/patologia
16.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064070

RESUMO

C60 fullerene as a potent free radical scavenger and antioxidant could be a beneficial means for neurodegenerative disease prevention or cure. The aim of the study was to define the effects of C60 administration on mitochondrial dysfunction and oxidative stress disorders in a 3-nitropropionic acid (3-NPA)-induced rat model of Huntington's disease. Animals received 3-NPA (30 mg/kg i.p.) once a day for 3 consecutive days. C60 was applied at a dose of 0.5 mg/kg of body weight, i.p. daily over 5 days before (C60 pre-treatment) and after 3-NPA exposure (C60 post-treatment). Oxidative stress biomarkers, the activity of respiratory chain enzymes, the level of antioxidant defense, and pro- and antiapoptotic markers were analyzed in the brain and skeletal muscle mitochondria. The nuclear and cytosol Nrf2 protein expression, protein level of MnSOD, γ-glutamate-cysteine ligase (γ-GCLC), and glutathione-S-transferase (GSTP) as Nrf2 targets were evaluated. Our results indicated that C60 can prevent 3-NPA-induced mitochondrial dysfunction through the restoring of mitochondrial complexes' enzyme activity, ROS scavenging, modulating of pro/antioxidant balance and GSH/GSSG ratio, as well as inhibition of mitochondria-dependent apoptosis through the limitation of p53 mitochondrial translocation and increase in Bcl-2 protein expression. C60 improved mitochondrial protection by strengthening the endogenous glutathione system via glutathione biosynthesis by up-regulating Nrf2 nuclear accumulation as well as GCLC and GSTP protein level.


Assuntos
Fulerenos/fisiologia , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Nitrocompostos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propionatos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
17.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071676

RESUMO

The docking program PLANTS, which is based on ant colony optimization (ACO) algorithm, has many advanced features for molecular docking. Among them are multiple scoring functions, the possibility to model explicit displaceable water molecules, and the inclusion of experimental constraints. Here, we add support of PLANTS to VirtualFlow (VirtualFlow Ants), which adds a valuable method for primary virtual screenings and rescoring procedures. Furthermore, we have added support of ligand libraries in the MOL2 format, as well as on the fly conversion of ligand libraries which are in the PDBQT format to the MOL2 format to endow VirtualFlow Ants with an increased flexibility regarding the ligand libraries. The on the fly conversion is carried out with Open Babel and the program SPORES. We applied VirtualFlow Ants to a test system involving KEAP1 on the Google Cloud up to 128,000 CPUs, and the observed scaling behavior is approximately linear. Furthermore, we have adjusted several central docking parameters of PLANTS (such as the speed parameter or the number of ants) and screened 10 million compounds for each of the 10 resulting docking scenarios. We analyzed their docking scores and average docking times, which are key factors in virtual screenings. The possibility of carrying out ultra-large virtual screening with PLANTS via VirtualFlow Ants opens new avenues in computational drug discovery.


Assuntos
Algoritmos , Inteligência Artificial , Biologia Computacional/métodos , Simulação de Acoplamento Molecular , Proteína 1 Associada a ECH Semelhante a Kelch/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Ligantes , Fator 2 Relacionado a NF-E2/química , Fator 2 Relacionado a NF-E2/metabolismo , Ligação Proteica , Conformação Proteica , Reprodutibilidade dos Testes , Termodinâmica
18.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069882

RESUMO

Geographically, East Asia had the highest liver cancer burden in 2017. Besides this, liver cancer-related deaths were high in Japan, accounting for 3.90% of total deaths. The development of liver cancer is influenced by several factors, and genetic alteration is one of the critical factors among them. Therefore, the detailed mechanism driving the oncogenic transformation of liver cells needs to be elucidated. Recently, many researchers have focused on investigating the liver cancer genome and identified somatic mutations (MTs) of several transcription factors. In this line, next-generation sequencing of the cancer genome identified that oxidative stress-related transcription factor NRF2 (NFE2L2) is mutated in different cancers, including hepatocellular carcinoma (HCC). Here, we demonstrated that NRF2 DLG motif mutations (NRF2 D29A and L30F), found in Japanese liver cancer patients, upregulate the transcriptional activity of NRF2 in HCC cell lines. Moreover, the transcriptional activity of NRF2 mutations is not suppressed by KEAP1, presumably because NRF2 MTs disturb proper NRF2-KEAP1 binding and block KEAP1-mediated degradation of NRF2. Additionally, we showed that both MTs upregulate the transcriptional activity of NRF2 on the MMP9 promoter in Hepa1-6 and Huh7 cells, suggesting that MT derived gain-of-function of NRF2 may be important for liver tumor progression. We also found that ectopic overexpression of oncogenic BRAF WT and V600E increases the transcriptional activity of NRF2 WT on both the 3xARE reporter and MMP9 promoter. Interestingly, NRF2 D29A and L30F MTs with oncogenic BRAF V600E MT synergistically upregulate the transcription activity of NRF2 on the 3xARE reporter and MMP9 promoter in Hepa1-6 and Huh7 cells. In summary, our findings suggest that MTs in NRF2 have pathogenic effects, and that NRF2 MTs together with oncogenic BRAF V600E MT synergistically cause more aberrant transcriptional activity. The high activity of NRF2 MTs in HCC with BRAF MT warrants further exploration of the potential diagnostic, prognostic, and therapeutic utility of this pathway in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Fator 2 Relacionado a NF-E2/genética , Motivos de Aminoácidos/genética , Carcinogênese/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Japão , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metaloproteinase 9 da Matriz/metabolismo , Mutação , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética
19.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070944

RESUMO

Embryogenesis is a complex multi-stage process regulated by various signaling molecules including pineal and extrapineal melatonin (MT). Extrapineal MT is found in the placenta and ovaries, where it carries out local hormonal regulation. MT is necessary for normal development of oocytes, fertilization and subsequent development of human, animal and avian embryos. This review discusses the role of MT as a regulator of preimplantation development of the embryo and its implantation into endometrial tissue, followed by histo-, morpho- and organogenesis. MT possesses pronounced antioxidant properties and helps to protect the embryo from oxidative stress by regulating the expression of the NFE2L2, SOD1, and GPX1 genes. MT activates the expression of the ErbB1, ErbB4, GJA1, POU5F1, and Nanog genes which are necessary for embryo implantation and blastocyst growth. MT induces the expression of vascular endothelial growth factor (VEGF) and its type 1 receptor (VEGF-R1) in the ovaries, activating angiogenesis. Given the increased difficulties in successful fertilization and embryogenesis with age, it is of note that MT slows down ovarian aging by increasing the transcription of sirtuins. MT administration to patients suffering from infertility demonstrates an increase in the effectiveness of in vitro fertilization. Thus, MT may be viewed as a key factor in embryogenesis regulation, including having utility in the management of infertility.


Assuntos
Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Melatonina/uso terapêutico , Ovário/metabolismo , Placenta/metabolismo , Animais , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Infertilidade Feminina/patologia , Infertilidade Feminina/prevenção & controle , Melatonina/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ovário/crescimento & desenvolvimento , Glândula Pineal/crescimento & desenvolvimento , Glândula Pineal/metabolismo , Gravidez , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073079

RESUMO

Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. Since redox imbalance with increased levels of reactive oxygen species (ROS) is involved in the initiation and progression of bladder cancer, this mechanism might be involved when chemoresistance occurs. This review summarizes current understanding regarding the influence of SFN on ROS and ROS-related pathways and appraises a possible role of SFN in bladder cancer treatment.


Assuntos
Anticarcinógenos , Antioxidantes , Carcinoma/tratamento farmacológico , Isotiocianatos , Sulfóxidos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Linhagem Celular Tumoral , Humanos , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sulfóxidos/farmacologia , Sulfóxidos/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...