Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.534
Filtrar
1.
Int J Mol Sci ; 21(17)2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899231

RESUMO

The coronavirus disease of 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global pandemic with increasing incidence and mortality rates. Recent evidence based on the cytokine profiles of severe COVID-19 cases suggests an overstimulation of macrophages and monocytes associated with reduced T-cell abundance (lymphopenia) in patients infected with SARS-CoV-2. The SARS-CoV-2 open reading frame 3 a (ORF3a) protein was found to bind to the human HMOX1 protein at a high confidence through high-throughput screening experiments. The HMOX1 pathway can inhibit platelet aggregation, and can have anti-thrombotic and anti-inflammatory properties, amongst others, all of which are critical medical conditions observed in COVID-19 patients. Here, we review the potential of modulating the HMOX1-ORF3a nexus to regulate the innate immune response for therapeutic benefits in COVID-19 patients. We also review other potential treatment strategies and suggest novel synthetic and natural compounds that may have the potential for future development in clinic.


Assuntos
Infecções por Coronavirus/metabolismo , Heme Oxigenase-1/metabolismo , Pneumonia Viral/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Animais , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Heme Oxigenase-1/genética , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica
2.
Chem Biol Interact ; 329: 109220, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32763245

RESUMO

The sepsis is considered as serious clinic-pathological condition related with high rate of morbidity and mortality in critical care settings. In the proposed study, the hydrazides derivatives N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (1-2) (NCHDH and NTHDH) were investigated against the LPS-induced sepsis in rodents. The NCHDH and NTHDH markedly improved the physiological sign and symptoms associated with the sepsis such as mortality, temperature, and clinical scoring compared to negative control group, which received only LPS (i.p.). The NCHDH and NTHDH also inhibited the production of the NO and MPO compared to the negative control. Furthermore, the treatment control improved the histological changes markedly of all the vital organs. Additionally, the Masson's trichrome and PAS (Periodic Acid Schiff) staining also showed improvement in the NCHDH and NTHDH treated group in contrast to LPS-induced group. The antioxidants were enhanced by the intervention of the NCHDH and NTHDH and the level of the MDA and POD were attenuated marginally compared to the LPS-induced group. The hematology study showed marked improvement and the reversal of the LPS-induced changes in blood composition compared to the negative control. The synthetic function of the liver and kidney were preserved in the NCHDH and NTHDH treated group compared to the LPS-induced group. The NCHDH and NTHDH markedly enhanced the Nrf2, HO-1 (Heme oxygenase-1), while attenuated the Keap1 and TRPV1 expression level as compared to LPS treated group. Furthermore, the NCHDH and NTHDH treatment showed marked increased in the mRNA expression level of the HSP70/90 proteins compared to the negative control.


Assuntos
Hidrazinas/farmacologia , Insuficiência de Múltiplos Órgãos/etiologia , Sepse/etiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Heme Oxigenase-1/metabolismo , Hidrazinas/química , Hidrazinas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/mortalidade , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Sepse/tratamento farmacológico , Sepse/mortalidade , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
3.
PLoS Pathog ; 16(7): e1008599, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32692767

RESUMO

Heme oxygenase (HO-1) mediates the enzymatic cleavage of heme, a molecule with proinflammatory and prooxidant properties. HO-1 activity deeply impacts host capacity to tolerate infection through reduction of tissue damage or affecting resistance, the ability of the host to control pathogen loads. In this Review, we will discuss the contribution of HO-1 in different and complex protozoan infections, such as malaria, leishmaniasis, Chagas disease, and toxoplasmosis. The complexity of these infections and the pleiotropic effects of HO-1 constitute an interesting area of study and an opportunity for drug development.


Assuntos
Heme Oxigenase-1/metabolismo , Infecções por Protozoários/enzimologia , Animais , Humanos , Tolerância Imunológica/fisiologia
4.
Medicine (Baltimore) ; 99(26): e20433, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590729

RESUMO

Bronchopulmonary dysplasia (BPD) is a chronic lung disease common in premature infants and is one of the leading causes of disability and death in newborns. The Keap-1/Nrf2 signaling pathway plays an important role in antioxidant and anti-inflammatory.Ten clean-grade, healthy pregnant Sprague-Dawley rats (purchased from Experimental Animal Center of Peking university, China) naturally gave birth to 55 neonatal rats from which 40 were selected and randomly divided into a hyperoxia group and a control group (N = 20, each). Thirty-two BPD patient samples are from Neonatal Department of the second Hospital of Jilin University from November 30, 2016 to May 1 2019.In present study, we observed that lung tissues of the control group did not undergo obvious pathological changes, whereas in the hyperoxia group, lung tissues had disordered structures. With increased time of hyperoxia exposure, the alveolar wall became attenuated. Under hypoxia conditions, the activity of oxidative stress-related enzymes (CAT, GSH-Px, SOD) in lung samples was significantly lower than that before treatment. The expression level of Keap1 mRNA and protein in the hyperoxia group was slightly lower than that of control group. The expression of Nrf2 and HO-1 mRNA and protein in the hyperoxia group was significantly higher than that of control group. For the infants with BPD, we found that the activity of SOD, GSH-Px, and CAT was significantly different from those of control group.We constructed a premature BPD animal model and found the abnormal of oxidative stress in different groups and the expression levels of Keap1/Nrf2 signaling pathway-related molecules, and we validated the results in premature infants with BPD.


Assuntos
Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Hiperóxia , Hipóxia , Recém-Nascido Prematuro , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Pulmão/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/genética , Gravidez , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Superóxido Dismutase/metabolismo
5.
Life Sci ; 256: 117966, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32535079

RESUMO

AIM: The present study aims to investigate the protective effects of artemisinin (ATZ) on early renal damage in experimental diabetic rats and its probable mechanism. METHODS: Models of diabetic nephropathy (DN) rats was established utilizing streptozotocin (STZ)-injection intraperitoneally (55 mg/kg) method. All rats were subsequently divided into normal control group, model group and ATZ (25, 50, 75 mg/kg) group randomly. Biochemical parameters including body weight, kidney index, blood glucose, 24 h UAER, Scr, BUN, T-SOD, GSH-Px and MDA were comprehensively determined after 8-week consecutive administrations. HE and PAS stainings were performed to observe the histopathological alterations of kidney. Western blot was conducted to detect the expressions of TGF-ß1, Nrf2, HQ-1 and NQO1. KEY FINDINGS: ATZ at three concentrations in ATZ group significantly increased the body weight. Biochemical parameters altered significantly between model group and ATZ group. Moreover, ATZ inhibited TGF-ß1 protein expression and activated the Nrf2 signaling pathway. Pathological histology results revealed the alterations including mesangial cells proliferation, thickness of glomerular capillary basement membrane, extracellular matrix (ECM) and the 24 h UAER. Western blot analysis demonstrated the increase of antioxidant proteins HO-1 and NQO1 and Nrf2-related proteins. SIGNIFICANCE: ATZ could reduce early renal oxidative stress damage in DN rats by inhibiting TGF-ß1 protein expression in kidney tissues as well as activating the Nrf2 signaling pathway and enhancing the expression of antioxidant proteins, thereby exerting the protective effects on DN kidney. The current study is the first report of ATZ on attenuating effects on kidney of DN rats, which could lay solid theoretical foundations on clinical application of ATZ to treat DN.


Assuntos
Artemisininas/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Rim/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Animais , Artemisininas/farmacologia , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Nefropatias Diabéticas/sangue , Heme Oxigenase-1/metabolismo , Rim/efeitos dos fármacos , Masculino , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
6.
PLoS One ; 15(6): e0234872, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559203

RESUMO

The leading cause of death in Pulmonary Arterial Hypertension (PAH) is right ventricular (RV) failure. The tumor suppressor p53 has been associated with left ventricular hypertrophy (LVH) and remodeling but its role in RV hypertrophy (RVH) is unclear. The purpose of this study was to determine whether pharmacological activation of p53 by Quinacrine affects RV remodeling and function in the pulmonary artery banding (PAB) model of compensated RVH in mice. The effects of p53 activation on cellular functions were studied in isolated cardiomyocytes, cardiac fibroblasts and endothelial cells (ECs). The expression of p53 was examined both on human RV tissues from patients with compensated and decompensated RVH and in mouse RV tissues early and late after the PAB. As compared to control human RVs, there was no change in p53 expression in compensated RVH, while a marked upregulation was found in decompensated RVH. Similarly, in comparison to SHAM-operated mice, unaltered RV p53 expression 7 days after PAB, was markedly induced 21 days after the PAB. Quinacrine induced p53 accumulation did not further deteriorate RV function at day 7 after PAB. Quinacrine administration did not increase EC death, neither diminished EC number and capillary density in RV tissues. No major impact on the expression of markers of sarcomere organization, fatty acid and mitochondrial metabolism and respiration was noted in Quinacrine-treated PAB mice. p53 accumulation modulated the expression of Heme Oxygenase 1 (HO-1) and Glucose Transporter (Glut1) in mouse RVs and in adult cardiomyocytes. We conclude that early p53 activation in PAB-induced RVH does not cause substantial detrimental effects on right ventricular remodeling and function.


Assuntos
Hipertrofia Ventricular Direita/metabolismo , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Animais , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ácidos Graxos/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Hipertrofia Ventricular Direita/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Quinacrina/farmacologia , Sarcômeros/metabolismo , Proteína Supressora de Tumor p53/metabolismo
7.
Life Sci ; 256: 117958, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553929

RESUMO

PROPOSE: Understanding the protective effect of exercise against ethanol-induced toxicity through the oxidative stress signaling pathway, apoptosis, and cholesterol metabolism is important to prevent development of cardiovascular diseases. METHODS: Thirty-two male Wistar rats were randomly divided into four equal groups as follow: control, exercise training (ET), ethanol (4 g/kg of body weight/day) and ET + ethanol. The ET and ET + Ethanol groups ran on the treadmill at 65% maximum running speed for 60 min for five sessions per week for eight weeks. The ethanol and ET + Ethanol groups received ethanol for eight weeks. At the end of the study, animals were anesthetized and blood and tissues were sampled to examine the biochemical and molecular evaluation. RESULTS: The results showed that the antioxidant enzymes activity decreased and MDA levels increased in the heart and liver of animals in ethanol group compared to control group. The levels of these oxidative biomarkers improved by ET in ET + Ethanol group compared to ethanol group. It showed that ET could protect the heart and liver against oxidative damage induced by ethanol through up-regulating the expression of the Nrf2/Keap-1/HO-1 pathway. ET could exert a cardioprotective effect on ethanol-induced apoptosis through down-regulating the Bax and the caspase-3 and via up-regulating the Bcl-2 expression in the heart. ET could also improve the impairment of cholesterol metabolism induced by ethanol. CONCLUSION: Exercise can protect against ethanol-induced toxicity through moderating the expression of genes which are involved in oxidative status, apoptosis and cholesterol metabolism.


Assuntos
Apoptose , Etanol/toxicidade , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/patologia , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Condicionamento Físico Animal , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores/sangue , Caspase 3/genética , Caspase 3/metabolismo , Colesterol/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
8.
Life Sci ; 256: 117908, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512011

RESUMO

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glucosídeos/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Compostos Benzidrílicos/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Descoberta de Drogas , Etanol/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucinas/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , Superóxido Dismutase/metabolismo
9.
Life Sci ; 256: 117927, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32526285

RESUMO

AIMS: Ulcerative colitis (UC) has many complications, from colonic damage to colorectal cancer. The mystery of both etiology and effective treatment of UC still challenging process. The role of gut microbiota in UC is still unclear. In the current study we compare the difference in gut microbiota abundance in both UC and normal colon besides the therapeutic effect of Lactobacillus spp. in treating UC versus the standard drug. MATERIALS AND METHODS: The experimental panel included five group of rats; normal control, UC diseased rats, sterilizing rats, ASA treated and Lactobacillus treated. The change in the microbiota abundance was investigated using conventional and real time PCR. In parallel, clinical evaluation of UC and macroscopic examination scoring was also done. Colonic oxidants/antioxidant stress biomarkers; MDA, GSH, catalase, myeloperoxidase activity, and SOD activity were assessed. Colon Nrf2, HO-1 contents and TNF-α was evaluated. KEY FINDINGS: The current study revealed a significant difference in the relative abundance of microbiota where, UC is associated with massive increase of E. coli and Fusobacterium spp., while enormous decrease in Bifidobacteria spp. in contrast with negative control. Both 5-ASA and Lactobacillus show a significant amelioration of all antioxidant enzymes and marked decline of inflammatory and oxidative stress markers. Both Lactobacillus and 5-ASA show significant increase of NrF2 and HO-1 and marked decrease of TNF-α. SIGNIFICANCE: Lactobacillus spp. exerted a beneficial effect on the inflammation, oxidative stress and the symbiosis of gut microbiota that improve structural intestinal defect and promote healing in UC.


Assuntos
Colite Ulcerativa/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Lactobacillus/efeitos dos fármacos , Mesalamina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/farmacologia , Escherichia coli , Fusobacterium , Humanos , Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
10.
J Pharmacol Sci ; 143(3): 209-218, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414692

RESUMO

In the course of our continuous investigation on the bioactive marine-derived fungal metabolites, terrein was isolated from marine-derived fungal strain Penicillium sp. SF-7181. Terrein inhibited the overproduction of pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated BV2 and primary microglial cells. This compound also repressed the LPS-induced production of pro-inflammatory cytokines, interleukin (IL)-1ß and IL-6. These inhibitory effects of terrein were associated with the inactivation of the nuclear factor kappa B (NF-κB) pathway through suppression of the translocation of p65/p50 heterodimer into the nucleus, the phosphorylation and degradation of inhibitor kappa B (IκB)-α and the DNA binding activity of the p65 subunit. In addition, terrein induced the protein expression of heme oxygenase (HO)-1 through the activation of nuclear transcription factor erythroid-2 related factor 2 (Nrf2) in BV2 and primary microglial cells. The anti-inflammatory effect of terrein was blocked by pre-treatment with a selective HO-1 inhibitor, suggesting that its anti-neuroinflammatory effect is mediated by HO-1 induction.


Assuntos
Ciclopentanos/farmacologia , Ciclopentanos/uso terapêutico , Heme Oxigenase-1/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Lipopolissacarídeos/efeitos adversos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios , Linhagem Celular , Células Cultivadas , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Ratos
11.
Am J Chin Med ; 48(4): 967-985, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431178

RESUMO

Inflammation and endoplasmic reticulum (ER) stress have been documented to contribute to the development of atherosclerosis. Ginsenoside Rb2 has been reported to exhibit antidiabetic effects. However, the effects of Rb2 on atherosclerotic responses such as inflammation and ER stress in endothelial cells and monocytes remain unclear. In this study, the expression of inflammation and ER stress markers was determined using a Western blotting method. Concentrations of tumor necrosis factor alpha (TNF[Formula: see text]) and monocyte chemoattractant protein-1 (MCP-1) in culture media were assessed by enzyme-linked immunosorbent assay (ELISA) and apoptosis was evaluated by a cell viability assay and a caspase-3 activity measurement kit. We found that exposure of HUVECs and THP-1 monocytes to Rb2 attenuated inflammation and ER stress, resulting in amelioration of apoptosis and THP-1 cell adhesion to HUVECs under lipopolysaccharide (LPS) condition. Increased AMPK phosphorylation and heme oxygenase (HO)-1 expression, including GPR120 expression were observed in Rb2-treated HUVECs and THP-1 monocytes. Downregulation of both, AMPK phosphorylation and HO-1expression rescued these observed changes. Furthermore, GPR120 siRNA mitigated Rb2-induced AMPK phosphorylation. These results suggest that Rb2 inhibits LPS-mediated apoptosis and THP-1 cell adhesion to HUVECs by GPR120/AMPK/HO-1-associated attenuating inflammation and ER stress. Therefore, Rb2 can be used as a potential therapeutic molecule for treatment of atherosclerosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aterosclerose/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Lipopolissacarídeos/efeitos adversos , Fitoterapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Fosforilação/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Células THP-1 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
12.
Arch Med Res ; 51(5): 388-396, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32409143

RESUMO

BACKGROUND AND AIMS: Heme oxygenase 1 (HO-1) is mainly regulated by the redox-sensitive transcription factor, namely nuclear factor erythroid 2-related factor 2 (Nrf2). We previously found a physically-made gold nanoparticle (GNP) can affect migration, adhesion, and proliferation of rat aortic vascular smooth muscle cells (VSMCs). This study was sought to investigate whether the GNP can affect HO-1 expression level in VSMCs. METHODS: Cellular fractionation, Western blotting, and immunofluorescence microscopy were used to determine Nrf2 translocation and phosphorylation. SiRNA interference was used to examine role of Nrf2 in GNP-induced HO-1 expression. RESULTS: The GNP concentration- and time-dependently enhanced HO-1 protein and mRNA expression; however, the mRNA induction was declined after 16 h treatment. The GNP treatment caused Nrf2 expression level and phosphorylation. In addition, it induced cytosolic Nrf2 translocation into nucleus. The HO-1 induction was inhibited by a ROS scavenger N-acetylcysteine (NAC), thiol-containing antioxidants (glutathione [GSH] and dithiothreitol [DTT]), JNK and p38 MAPK inhibitors, and nuclear transport inhibitor leptomycin. Meanwhile, the GNP-induced Nrf2 translocation (activation) was also reduced by NAC, JNK and p38 MAPK inhibitors, and nuclear transport inhibitor. Intriguingly, the GNP only enhanced activation of p38 MAPK but not JNK1/2. Finally, introduction of Nrf2 siRNA to cells to knockdown Nrf2 expression significantly inhibited GNP-induced HO-1 protein expression. CONCLUSIONS: This study elucidates the action mechanism that the naked physically-made GNP can enhance HO-1 expression in rat aortic VSMCs by inducing Nrf2 expression and phosphorylation and translocation into nucleus. The Nrf2 activation is mediated through a redox-related reaction and p38 MAPK activation.


Assuntos
Aorta/metabolismo , Ouro/química , Heme Oxigenase-1/metabolismo , Nanopartículas Metálicas/química , Músculo Liso Vascular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Humanos , Ratos
13.
Am J Physiol Renal Physiol ; 318(6): F1531-F1538, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32390514

RESUMO

Renal ischemia-reperfusion injury (I/R) usually occurs in renal transplantation and partial nephrectomy, which could lead to acute kidney injury. However, the effective treatment for renal I/R still remains limited. In the present study, we investigated whether inhibition of chromobox 7 (CBX7) could attenuate renal I/R injury in vivo and in vitro as well as the potential mechanisms. Adult male mice were subjected to right renal ischemia and reperfusion for different periods, both with and without the CBX7 inhibitor UNC3866. In addition, human kidney cells (HK-2) were subjected to a hypoxia/reoxygenation (H/R) process for different periods, both with or without the CBX7 inhibitor or siRNA for CBX7. The results showed that expression of CBX7, glucose regulator protein-78 (GRP78), phosphorylated eukaryotic translation initiation factor-2α (p-eIF2α), and C/EBP homologous protein (CHOP) were increased after extension of I/R and H/R periods. Moreover, overexpression of CBX7 could elevate the expression of CBX7, GRP78, p-eIF2α, and CHOP. However, CBX7 inhibition with either UNC3866 or genetic knockdown led to reduced expression of GRP78, p-eIF2α, and CHOP through nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 activation in I/R and H/R injury. Furthermore, ML385, the Nrf2 inhibitor, could elevate endoplasmic reticulum stress levels, abrogating the protective effects of UNC3866 against renal I/R injury. In conclusion, our results demonstrated that CBX7 inhibition alleviated acute kidney injury by preventing endoplasmic reticulum stress via the Nrf2/HO-1 pathway, indicating that CBX7 inhibitor could be a potential therapeutic target for renal I/R injury.


Assuntos
Lesão Renal Aguda/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Rim/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oligopeptídeos/farmacologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Hipóxia Celular , Linhagem Celular , Heme Oxigenase-1/genética , Humanos , Rim/enzimologia , Rim/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Fator 2 Relacionado a NF-E2/genética , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais
14.
Chemosphere ; 253: 126654, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464761

RESUMO

Heme oxygenase-1(HO-1) is a stress-inducible enzyme that mediates antioxidative and cytoprotective effects to maintain cellular redox homeostasis. In the present study, the full sequence of HO-1 was cloned from golden pompano(Trachinotus ovatus) by RT-PCR and RACE-PCR. The full cDNA sequence of HO-1 was 1349 bp in length which comprised of a 726 bp open reading frame (ORF) preceded by 262 bp 5'-untranslated region (UTR), and followed by a 360 bp 3'UTR, encoding 241 amino acid residues. Phylogenetic analysis revealed that HO-1 showed highest similarity to that of Takifugu rubripes. Tissue distribution analysis showed that the expression level of HO-1 was relatively high in heart, liver and spleen. A trial was conducted to investigate the response of Nrf2/HO-1 signaling pathway to oxidative stress induced by copper. The results showed that mRNA expression of NF-E2-related nuclear factor2 (Nrf2), Kelch-like-ECH-associated protein1 (keap1), superoxide dismutase (SOD), catalase (CAT), HO-1, NAD(P)H quinone oxidoreductase 1 (NQO1) and Glutathione peroxidase (GSH-PX) all significantly increased in copper treated group than that in the control group. This work provides new insight into the molecular mechanism underlying the Nrf2/HO-1 pathway in oxidative response in T. ovatus.


Assuntos
Cobre/farmacologia , Heme Oxigenase-1/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Perciformes/metabolismo , Transdução de Sinais , Animais , Antioxidantes/metabolismo , Heme Oxigenase-1/metabolismo , Oxirredutases/metabolismo , Análise de Sequência de DNA , Distribuição Tecidual
15.
Life Sci ; 255: 117823, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445760

RESUMO

AIMS: Skeletal muscle diseases have become to be the most common complication in patients with type 2 diabetic mellitus (T2DM). However, the effective therapies against skeletal muscle diseases are not yet available. Sulforaphane (SFN) is an organic isothiocyanate found in cruciferous plants. Our aim was to explore whether SFN could attenuate the skeletal muscle diseases in spontaneous type 2 diabetic db/db mice. MATERIALS AND METHODS: The db/m and littermate db/db mice were treated with SFN or dimethyl sulfoxide. The grip strength of mice was measured by a grasping forcing machine. The electron transmission microscopy was used to perform the skeletal muscle. The western blot was used to detect the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signal pathway related proteins, and inflammatory and apoptotic associated proteins. The mRNA levels of anti-inflammatory and anti-oxidative relative genes were detected by RT-QPCR. KEY FINDINGS: We found that SFN could significantly increase the grip strength of the db/db mice. The lean mass and gastrocnemius mass were increased in the db/db mice after administration with SFN. Additionally, the db/db mice restored the skeletal muscle fiber organization after SFN treatment. Mechanistically, SFN could activate the Nrf2/HO-1 signal pathway, and downregulate the expression of inflammatory and apoptotic associated proteins. Furthermore, SFN could also regulate the mRNA levels of anti-inflammatory and anti-oxidative related genes. SIGNIFICANCE: Our results demonstrated that SFN can protect against skeletal muscle diseases in db/db type 2 diabetic mice and provide a potential drug to prevent skeletal muscle dysfunction in T2DM patients.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Isotiocianatos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/prevenção & controle , Animais , Antioxidantes/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Músculo Esquelético/patologia , Doenças Musculares/etiologia , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/metabolismo
16.
Nat Commun ; 11(1): 2332, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393788

RESUMO

Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors.


Assuntos
Ácido Ascórbico/farmacologia , Dieta , Jejum/fisiologia , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Heme Oxigenase-1/metabolismo , Humanos , Ferro/metabolismo , Camundongos Endogâmicos BALB C , Oxaliplatina/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Transferrina/metabolismo
17.
Life Sci ; 254: 117781, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407842

RESUMO

AIMS: Previous evidence has demonstrated that oxidative stress is related to the pathogenesis of missed abortion (MA), but the specific mechanism remains obscure. The adaptor protein APPL1 is one of the differential proteins in chorionic trophoblasts. Thus, this study aimed to assess the potential influence of APPL1 on oxidative stress responses as well the possible molecular mechanisms involving in MA. MAIN METHODS: In the present study, the chorionic trophoblasts and the HTR-8/SVneo cell line were researched in vitro. Small interfering RNA (siRNA) was used to suppress the expression of APPL1. The fluorescent probes DHE and DCFH-DA were used to assess the intracellular reactive oxidative species (ROS). The activity of superoxide dismutase (SOD) was determined. Apoptosis was detected by TUNEL and flow cytometry. Cell viability was determined using Cell Counting Kit-8. Protein expression was detected by immunohistochemistry, western blotting, and reverse transcription-quantitative PCR. KEY FINDINGS: The application of oxidant in normal chorionic trophoblasts induced cell death and overproduction of ROS, which was consistent with MA. In addition, knockdown of APPL1 in HTR-8/SVneo cells resulted in increased ROS and apoptosis, which could be rescued by pretreatment with antioxidants. Mechanistically, we report that overproduction of ROS in trophoblasts and disturbed SOD, APPL1 and Nrf2/HO-1 antioxidant responses constitute important contributors to apoptosis. SIGNIFICANCE: Our results suggest that APPL1 has antioxidant properties that suppress oxidative stress and apoptosis via the Nrf2/HO-1 pathway. Moreover, antioxidant N-acetylcysteine (NAC) effectively restored the impaired antioxidative defense system elicited by excess ROS, as a potential therapeutic reagent for MA.


Assuntos
Aborto Retido/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/fisiologia , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Técnicas de Silenciamento de Genes , Humanos , Gravidez , RNA Interferente Pequeno/farmacologia , Superóxido Dismutase/metabolismo , Trofoblastos/metabolismo
18.
Med Sci Monit ; 26: e921905, 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32245940

RESUMO

BACKGROUND Type 2 diabetes mellitus (T2DM) and its comorbidities, including obesity, hypertension, and hyperlipidemia, are commonly associated with non-alcoholic fatty liver disease (NAFLD). Ganoderma lucidum polysaccharide (GDLP) is one of the central bioactive components in Ganoderma lucidum with anti-inflammatory, antioxidant, and hepatoprotective properties. However, the effect and mechanisms of GDLP in hepatic steatosis remain largely unknown. In the present study, we aimed to investigate the function of GDLP in hepatic steatosis and the underlying mechanism. MATERIAL AND METHODS In this study, male db/db mice were received with a high-fat diet (HFD) to investigate the effect of GDLP in T2DM-induced hepatic steatosis. The biological characteristics of the hepatic steatosis were evaluated through the detection of clinical indicators, including biochemical parameters, histopathology, and related cytokine levels. Additionally, the protein expression levels of Nrf2 (nuclear factor E2 (erythroid-derived 2)-related factor-2) signaling pathway were investigated by using western blotting and immunohistochemical staining. RESULTS The levels of food/water intake, body weight, fasting blood glucose, plasma lipids, urinary biomarkers, hepatic lipid accumulation, and tumor necrosis factor (TNF)-alpha were observably decreased in GDLP-treated db/db mice. Additionally, administration of GDLP increased the expression of various antioxidases, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), whereas it reduced the level of malonaldehyde (MDA). Furthermore, GDLP was significantly promoted protein expression level of Nrf2 and its downstream target gene HO-1 (heme oxygenase-1) while decreased TNF-alpha expression. CONCLUSIONS These results indicate that GDLP against T2DM-induced hepatic steatosis, oxidative stress, and inflammation by improving the Nrf2/HO-1 signaling pathway in db/db mice, suggesting the GDLP may serve as an effective strategy for in fatty liver treatment.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Reishi/química , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Camundongos , Polissacarídeos
19.
BMC Complement Med Ther ; 20(1): 101, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228565

RESUMO

BACKGROUND: Particulate matter (PM) can cause various negative acute and chronic diseases of the respiratory system, including the upper airways. Curcumin has been reported to have anti-inflammatory and anti-oxidative effects; therefore, we investigated the effects of curcumin on nasal fibroblasts exposed to urban PM (UPM). METHODS: Samples of inferior turbinate tissue were obtained from six patients. Flow cytometry was used to assess the levels of reactive oxygen species (ROS) following the treatment of nasal fibroblasts with UPM and/or curcumin. We evaluated the effects of UPM and/or curcumin on the expression of phosphorylated ERK, Nrf2, HO-1, and SOD2 in fibroblasts by Western blotting. RESULTS: When UPM was applied to nasal fibroblasts, ROS production was significantly increased in a dose-dependent manner. UPM-exposed fibroblasts caused the activation of ERK to increase HO-1 expression and decrease SOD2 expression. Treatment with curcumin reduced the UPM-mediated increase in ROS; this decrease in ROS occurred in a dose-dependent manner. The UPM-induced activation of ERK was inhibited by curcumin. Nrf2 production was also promoted to increase the expression of HO-1 and SOD2 by curcumin. CONCLUSION: Curcumin reduced ROS production caused by UPM in human nasal fibroblasts in a dose-dependent manner, suggesting that curcumin has anti-oxidative effects and may be useful in the treatment of nasal diseases caused by UPM, such as allergic and chronic rhinitis.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Curcumina/farmacologia , Fibroblastos/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Material Particulado/efeitos adversos , Células Cultivadas , Humanos , Mucosa Nasal/citologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
20.
BMC Complement Med Ther ; 20(1): 126, 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32336289

RESUMO

BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. Diosgenin is a natural steroidal saponin with a variety of beneficial effects, including antidiabetic effects, and is a raw material for the synthesis of carrier hormones. In our study, we aimed to assess the antioxidant effects of diosgenin in diabetic mice. METHODS: Male C57 mice were fed a high-fat diet for 8 weeks and intraperitoneally injected with streptozotocin (STZ) at a dose of 100 mg/kg for 2 consecutive days. Eligible mice were divided into the normal control group (CON), diabetic group (DM), low-dose diosgenin (50 mg/kg) group (DIO50) and high-dose diosgenin (100 mg/kg) group (DIO100). Treatment was started 6 weeks after the induction of diabetes by STZ and continued for 8 weeks. Blood sugar and body weight were monitored dynamically. The behavioural effects of diosgenin were detected by a hot tail immersion test and paw tactile responses. HE staining was used to evaluate edema and degeneration of the sciatic nerve. The levels of SOD, MDA and GPx were tested according to the instructions of the respective kits. The levels of Nrf2, HO-1 and NQO1 were detected by immunofluorescence and Western blotting. Statistical analysis was performed using SPSS, and P < 0.05 was considered statistically significant. RESULTS: Diosgenin decreased the blood glucose levels and increased the body weight of diabetic mice. There was a significant increase in the tail withdrawal latency of diabetic animals, and mechanical hyperalgesia was significantly alleviated after diosgenin treatment. Histopathological micrographs of HE-stained sciatic nerves showed improvement after diosgenin treatment. Diosgenin attenuated the level of MDA but increased the activities of SOD and GPx. Diosgenin increased the expression of Nrf2, HO-1 and NQO1. CONCLUSIONS: Our results demonstrate that diosgenin can ameliorate behavioural and morphological changes in DPN by reducing oxidative stress. The Nrf2/HO-1 signalling pathway was involved in its neuroprotective effects.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Diosgenina/farmacologia , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica , Modelos Animais de Doenças , Masculino , Camundongos , Estreptozocina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA