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1.
Chem Biol Interact ; 317: 108959, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001261

RESUMO

The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5-25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3-5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect.


Assuntos
Amnésia/prevenção & controle , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Quinolinas/farmacologia , Amnésia/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Proteínas de Membrana/genética , Camundongos , Atividade Motora/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Córtex Pré-Frontal/efeitos dos fármacos , Escopolamina/toxicidade , Transdução de Sinais
2.
Am J Pathol ; 190(4): 830-843, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035059

RESUMO

The molecular mechanisms of prostate inflammation are unclear. We hypothesized that heme oxygenase 1 (HMOX1; HO-1), an enzyme responsible for degradation of heme to carbon monoxide, bilirubin, and iron, is an important regulator of inflammation and epithelial responses in the prostate. Injection of non-uropathogenic Escherichia coli (MG1655 strain) or phosphate-buffered saline into the urethra of mice led to increased numbers of CD45+ leukocytes and mitotic markers (phosphorylated histone H3 and phosphorylated ERK1/2) in the prostate glands. Leukocyte infiltration was elevated in the prostates harvested from mice lacking HO-1 in myeloid compartment. Conversely, exogenous carbon monoxide (250 ppm) increased IL-1ß levels and suppressed cell proliferation in the prostates. Carbon monoxide did not affect the number of infiltrating CD45+ cells in the prostates of E. coli- or phosphate-buffered saline-treated mice. Interestingly, immunomodulatory effects of HO-1 and/or carbon monoxide correlated with early induction of the long-chain acyl-CoA synthetase 1 (ACSL1). ACSL1 levels were elevated in response to E. coli treatment, and macrophage-expressed ACSL1 was in part required for controlling of IL-1ß expression and prostate cancer cell colony growth in soft agar. These results suggest that HO-1 and/or carbon monoxide might play a distinctive role in modulating prostate inflammation, cell proliferation, and IL-1ß levels in part via an ACSL1-mediated pathway.


Assuntos
Infecções por Escherichia coli/complicações , Heme Oxigenase-1/metabolismo , Heme/metabolismo , Inflamação/imunologia , Metabolismo dos Lipídeos/imunologia , Proteínas de Membrana/metabolismo , Próstata/imunologia , Animais , Bilirrubina/metabolismo , Monóxido de Carbono/metabolismo , Proliferação de Células , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Heme Oxigenase-1/genética , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Próstata/metabolismo , Próstata/microbiologia , Próstata/patologia , Transdução de Sinais
3.
J Photochem Photobiol B ; 204: 111775, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31935591

RESUMO

Wogonin (5,7-dihydroxy-8-methoxy flavone), an active component isolated from the root of Scutellaria baicalensis Georgi. Neurotoxic effects of γ irradiation have been established in humans and animals. The current study was designed to evaluate whether wogonin could restrain γ irradiation-induced neurotoxicity in rats and to explore the underlying mechanisms. Rats were divided into five groups, 10 rats each. Group 1 was orally administered distilled water and served as control. Group 2 received an oral daily dose of wogonin (30 mg/kg). Rats in group 3 were exposed to a whole-body single dose of γ-irradiation. Animals in group 4 received an oral daily dose of wogonin (30 mg/kg) for 15 days then exposed to a whole-body single dose of γ-irradiation. In group 5, rats were exposed to a whole-body single dose of γ-irradiation then were orally administered a daily dose of wogonin (30 mg/kg) for 15 days. There were significant increases in malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and Interleukin 6 (IL-6) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA and protein expression. Whereas significant decreases in reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) level as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA and protein expression in the irradiated group when compared with the relevant control. The cerebral cortex of irradiated rats showed vacuolization and nuclear pyknosis in the neuronal cells and focal gliosis. Wogonin administration pre- or post-irradiation significantly ameliorated all these previous effects. Wogonin had antioxidant and anti-inflammatory effects and ameliorated the histopathological changes in the brain.


Assuntos
Encéfalo/efeitos dos fármacos , Flavanonas/farmacologia , Raios gama , Fármacos Neuroprotetores/farmacologia , Administração Oral , Animais , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Medicamentos de Ervas Chinesas/farmacologia , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Int J Cancer ; 146(7): 1950-1962, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376303

RESUMO

Heme oxygenase 1 (HO-1) plays a pivotal role in preventing cell damage. Indeed, through the antioxidant, antiapoptotic and anti-inflammatory properties of its metabolic products, it favors cell adaptation against different stressors. However, HO-1 induction has also been related to the gain of resistance to therapy in different types of cancers and its involvement in cancer immune-escape has been hypothesized. We have investigated the role of HO-1 expression in Vemurafenib-treated BRAFV600 melanoma cells in modulating their susceptibility to NK cell-mediated recognition. Different cell lines, isolated in house from melanoma patients, have been exposed to 1-10 µM PLX4032, which efficiently reduced ERK phosphorylation. In three lines, Vemurafenib was able to induce only a limited decrease in cell viability, while HO-1 expression was upregulated. HO-1 silencing/inhibition was able to induce a further significant reduction of Vemurafenib-treated melanoma viability. Moreover, while NK cell degranulation and killing activity were decreased upon interaction with melanoma exposed to Vemurafenib, HO-1 silencing was able to completely restore NK cell ability to degranulate and kill. Furthermore, melanoma cell treatment with Vemurafenib downregulated the expression of ligands of NKp30 and NKG2D activating receptors, and HO-1 silencing/inhibition was able to restore their expression. Our results indicate that HO-1 downregulation can both improve the efficacy of Vemurafenib on melanoma cells and favor melanoma susceptibility to NK cell-mediated recognition and killing.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Inativação Gênica , Heme Oxigenase-1/metabolismo , Humanos , Imunofenotipagem , Células Matadoras Naturais/imunologia , Receptores de Células Matadoras Naturais/metabolismo
5.
Invest Ophthalmol Vis Sci ; 60(15): 5080-5094, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31825462

RESUMO

Purpose: Retinitis pigmentosa (RP) causes progressive photoreceptor degeneration in the retina. The N-methyl-N-nitrosourea (MNU)-administered mouse is used as a chemically induced RP model with rapid progression rate. This study was designed to study heme oxygenase-1 (HO-1) expression in the MNU-administered mice, and to explore the therapeutic effects of cobalt protoporphyrin (CoPP). Methods: The HO-1 expression in the retina of MNU-administered mice was analyzed. CoPP was injected intravenously into the MNU-administered mice. Subsequently, the CoPP-treated mice were subjected to functional and morphologic examinations. Results: HO-1 was involved in the MNU-induced photoreceptor degeneration. CoPP treatment enhanced retinal HO-1 expression in the MNU-administered mice. Electroretinogram (ERG) examination and behavioral tests showed that CoPP treatment improved the retinal responsiveness of MNU-administered mice. Histologic analysis and optical coherence tomography (OCT) examination showed that retinal architecture of the CoPP-treated mice was more intact than that of the MNU+vehicle group. Cone photoreceptors in the MNU-administered mice were rescued efficiently by CoPP treatment. Furthermore, multielectrode array (MEA) recording showed that CoPP treatment mitigated the spontaneous firing response, enhanced the light-induced firing response, and preserved the basic configurations of visual signal pathway in the MNU-administered mice. Mechanism studies suggested that CoPP afforded these therapeutic effects by modulating the apoptosis cascades and alleviating the oxidative stress in degenerative retinas. Conclusions: CoPP alleviated photoreceptor degeneration and rectified the signaling abnormities in MNU-administered mice. CoPP may serve as a potential medication against degenerative retinopathy.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Estresse Oxidativo , Células Fotorreceptoras de Vertebrados/patologia , Protoporfirinas/farmacologia , Degeneração Retiniana/genética , Retinite Pigmentosa/genética , Animais , Apoptose , DNA/genética , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Heme Oxigenase-1/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/metabolismo , Degeneração Retiniana/etiologia , Degeneração Retiniana/prevenção & controle , Retinite Pigmentosa/complicações , Retinite Pigmentosa/tratamento farmacológico , Tomografia de Coerência Óptica
6.
Int J Mol Sci ; 21(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861629

RESUMO

To study the effects of maternal dietary fiber composition during gestation on offspring antioxidant capacity, inflammation, and gut microbiota composition, we randomly assigned 64 gilts to four treatments and administered diets with an insoluble/soluble fiber ratio of 3.89 (R1), 5.59 (R2), 9.12 (R3), and 12.81 (R4). Sow samples (blood and feces at gestation 110) and neonatal samples (blood, liver, and colonic contents) were collected. The results showed that sows and piglets in R1 and R2 had higher antioxidant enzyme activity and lower pro-inflammatory factor levels than those in R3 and R4. Moreover, piglets in R1 and R2 had higher liver mRNA expression of Nrf2 and HO-1 and lower NF-κB than piglets in R4. Interestingly, maternal fiber composition not only affected the production of short-chain fatty acids (SCFAs) in sow feces but also influenced the concentrations of SCFAs in the neonatal colon. Results of high-throughput sequencing showed that piglets as well as sows in R1 and R2 had microbial community structures distinct from those in R3 and R4. Therefore, the composition of dietary fiber in pregnancy diet had an important role in improving antioxidant capacity and decreasing inflammatory response of mothers and their offspring through modulating the composition of gut microbiota.


Assuntos
Animais Recém-Nascidos/fisiologia , Bactérias/classificação , Fibras na Dieta/análise , Heme Oxigenase-1/genética , Fígado/química , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Bactérias/isolamento & purificação , Feminino , Microbioma Gastrointestinal , Sequenciamento de Nucleotídeos em Larga Escala , Fenômenos Fisiológicos da Nutrição Materna , Modelos Animais , Filogenia , Gravidez , Distribuição Aleatória , Análise de Sequência de DNA , Suínos
7.
Zhonghua Zhong Liu Za Zhi ; 41(11): 813-819, 2019 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-31770847

RESUMO

Objective: To investigate the effects of heme oxygenase-1 (HO-1) knockdown on proliferation, invasion and migration of lung adenocarcinoma A549 cells and explore the mechanism. Methods: The expression levels of HO-1 mRNA in human bronchial epithelial cells (HBECs) and human lung cancer cell lines (A549, H1299, H358 and H1993) were detected by real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry (IHC) was used to detect the expression level of HO-1 in human lung adenocarcinoma specimens. The HO-1 short hairpin RNA (shRNA) was transfected into A549 cells by RNA interference technique. HO-1 stably deleted A549 cells were selected (HO-1 shRNA group) and verified by RT-qPCR and western blot. HO-1 shRNA A549 cells and control shRNA A549 cells were treated with the inducer of autophagy Torin1 or its inhibitor Bafilomycin A1 (Baf A1), respectively. The expressions of autophagic markers LC3B and p62 were determined by western blot. The proliferation, invasion and migration abilities of each group of A549 cells were assessed by cell counting, Transwell and wound healing assays, respectively. Results: The expressions of HO-1 mRNA in lung cancer cell lines (A549, H1299, H358 and H1993) were significantly higher than that of HBECs, and HO-1 upregulated in human lung adenocarcinoma. The expression of p62 protein and the ratio of LC3B-Ⅱ/ LC3B-Ⅰ in no treatment group, Torin1 treatment group and Baf A1 treatment group were significantly higher than those of the corresponding control group (P<0.05). After 11 days of culture, the number of cells in HO-1 shRNA group were 41.8%, 30.4% and 14.0% of the corresponding control group, respectively. The number of lower chamber cells in HO-1 shRNA group were (35.7±2.1), (27.0±1.0) and (38.0±1.0)/field, respectively, which were lower than (66.0±9.2), (39.3±1.2) and (43.0±2.6)/field of the corresponding control group, respectively (P<0.05). The migration distances of HO-1 shRNA group were (7.47±0.91) mm, (4.23±0.82) mm and (5.42±0.24) mm, which were lower than (10.07±1.26) mm, (7.14±0.07) mm and (12.04±0.80) mm of the corresponding control groups, respectively (P<0.05). Conclusion: Knockdown of HO-1 inhibits the proliferation, invasion and migration of A549 cells by impeding autophagy.


Assuntos
Adenocarcinoma de Pulmão/patologia , Autofagia , Heme Oxigenase-1/genética , Neoplasias Pulmonares/patologia , Células A549 , Adenocarcinoma de Pulmão/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Invasividade Neoplásica , RNA Interferente Pequeno
8.
J Environ Pathol Toxicol Oncol ; 38(2): 143-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679277

RESUMO

The current study evaluated the cardioprotective activity of genistein in cases of doxorubicin-(Dox) induced cardiac toxicity and a probable mechanism underlying this protection, such as an antioxidant pathway in cardiac tissues. Animals used in this study were categorized into four groups. The first group was treated with sodium carboxymethylcellulose (0.3%; CMC-Na) solution. The second group received Dox (3.0 mg/kg, i.p.) on days 6, 12, 18, and 24. The third and fourth groups received Dox (3 mg/kg, i.p.) on days 6, 12, 18, and 24 and received protective doses of genistein (100 [group 3] and 200 [group 4] mg/kg/day, p.o.) for 30 days. Treatment with genistein significantly improved the altered cardiac function markers and oxidative stress markers. This was coupled with significant improvement in cardiac histopathological features. Genistein enhanced the Nrf2 and HO-1 expression, which showed protection against oxidative insult induced by Dox. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed substantial inhibition of apoptosis by genistein in myocardia. The study showed that genistein has a strong reactive oxygen species scavenging property and potentially (P ≤ .001) decreases the lipid peroxidation as well as inhibits DNA damage in cardiac toxicity induced by Dox. In conclusion, the potential antioxidant effect of genistein may be because of its modulatory effect on Nrf2/HO-1 signalling pathway and by this means exhibits cardioprotective effects from Dox-induced oxidative injury.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Genisteína/farmacologia , Heme Oxigenase-1/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Cardiotoxicidade/etiologia , Heme Oxigenase-1/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar
9.
BMC Complement Altern Med ; 19(1): 310, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718640

RESUMO

BACKGROUND: Heracleum moellendorffii roots (HM-R) have been long treated for inflammatory diseases such as arthritis, backache and fever. However, an anti-inflammatory effect and the specific mechanism of HM-R were not yet clear. In this study, we for the first time explored the anti-inflammatory of HM-R. METHODS: The cytotoxicity of HM-R against RAW264.7 cells was evaluated using MTT assay. The inhibition of NO and PGE2 production by HM-R was evaluated using Griess reagent and Prostaglandin E2 ELISA Kit, respectively. The changes in mRNA or protein level following HM-R treatment were assessed by RT-PCR and Western blot analysis, respectively. RESULTS: HM-R dose-dependently blocked LPS-induced NO and PGE2 production. In addition, HM-R inhibited LPS-induced overexpression of iNOS, COX-2, IL-1ß and IL-6 in RAW264.7 cells. HM-R inhibited LPS-induced NF-κB signaling activation through blocking IκB-α degradation and p65 nuclear accumulation. Furthermore, HM-R inhibited MAPK signaling activation by attenuating the phosphorylation of ERK1/2, p38 and JNK. HM-R increased nuclear accumulation of Nrf2 and HO-1 expression. However, NAC reduced the increased nuclear accumulation of Nrf2 and HO-1 expression by HM-R. In HPLC analysis, falcarinol was detected from HM-R as an anti-inflammatory compound. CONCLUSIONS: These results indicate that HM-R may exert anti-inflammatory activity by inhibiting NF-κB and MAPK signaling, and activating ROS/Nrf2/HO-1 signaling. These findings suggest that HM-R has a potential as a natural material for the development of anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/imunologia , Heracleum/química , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Espécies Reativas de Oxigênio/imunologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Heme Oxigenase-1/genética , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Raízes de Plantas/química , Células RAW 264.7
10.
Molecules ; 24(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31619000

RESUMO

Advanced glycation end-products (AGEs) cause diabetes mellitus (DM) complications and accumulate more highly in periodontal tissues of patients with periodontitis and DM. AGEs aggravate periodontitis with DM by increasing the expression of inflammation-related factors in periodontal tissues. 6-Shogaol, a major compound in ginger, has anti-inflammatory and anti-oxidative activities. However, the influence of shogaol on DM-associated periodontitis is not well known. In this study, the effects of 6-shogaol on AGEs-induced oxidative and anti-oxidative responses, and IL-6 and ICAM-1 expression in human gingival fibroblasts (HGFs) were investigated. When HGFs were cultured with 6-shogaol and AGEs, the activities of reactive oxygen species (ROS) and antioxidant enzymes (heme oxygenase-1 [HO-1] and NAD(P)H quinone dehydrogenase 1 [NQO1]), and IL-6 and ICAM-1 expressions were investigated. RAGE expression and phosphorylation of MAPKs and NF-κB were examined by western blotting. 6-Shogaol significantly inhibited AGEs-induced ROS activity, and increased HO-1 and NQO1 levels compared with the AGEs-treated cells. The AGEs-stimulated expression levels of receptor of AGE (RAGE), IL-6 and ICAM-1 and the phosphorylation of p38, ERK and p65 were attenuated by 6-shogaol. These results suggested that 6-shogaol inhibits AGEs-induced inflammatory responses by regulating oxidative and anti-oxidative activities and may have protective effects on periodontitis with DM.


Assuntos
Catecóis/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Produtos Finais de Glicação Avançada/genética , Molécula 1 de Adesão Intercelular/genética , Interleucina-6/genética , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular , Gengiva/citologia , Produtos Finais de Glicação Avançada/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547324

RESUMO

Oxidative stress is one of the primary factors leading to endothelial dysfunction, a major underlying cause of vascular disorders. This study aims to understand the key signalling pathways regulated by sorghum (Shawaya short black 1 variety; characterised to be very high in its antioxidant activity) under oxidative stress in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pre-treated with non-cytotoxic concentrations of phenolic-rich black sorghum extract (BSE) prior to induction of oxidative stress using hydrogen peroxide (H2O2). Treatment with BSE upregulated the expression of heme oxygenase 1 (HO1) and endothelial nitric oxide synthase (eNOS) and downregulated the levels of NADPH oxidase 4 (NOX4). BSE treatment significantly reduced the expression of pro-inflammatory mediators such as monocyte chemoattractant protein 1 (MCP1) and intracellular adhesion molecule 1 (ICAM1). Results from this study suggest that phenolic-rich BSE may reduce oxidative stress by regulating pro- and antioxidant signalling pathways and the expression of inflammatory mediators linked to endothelial dysfunction under oxidative stress.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sorghum/química , Antioxidantes/metabolismo , Apirase/genética , Heme Oxigenase-1/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/genética , NADPH Oxidase 4/genética , Óxido Nítrico Sintase Tipo III/genética , Estresse Oxidativo/genética , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química
12.
Vet Res ; 50(1): 61, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31506103

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen that causes significant economic losses in the global swine industry. Commercial vaccines provide limited protection against this virus, and no highly effective therapeutic drugs are yet available. In this study, we first screened a library of 386 natural products and found that xanthohumol (Xn), a prenylated flavonoid found in hops, displayed high anti-PRRSV activity by inhibiting PRRSV adsorption onto and internalization into cells. Transcriptome sequencing revealed that Xn treatment stimulates genes associated with the antioxidant response in the nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. Xn causes increased expression of Nrf2, HMOX1, GCLC, GCLM, and NQO1 in Marc-145 cells. The action of Xn against PRRSV proliferation depends on Nrf2 in Marc-145 cells and porcine alveolar macrophages (PAMs). This finding suggests that Xn significantly inhibits PRRSV proliferation and decreases viral-induced oxidative stress by activating the Nrf2-HMOX1 pathway. This information should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV infection.


Assuntos
Flavonoides/administração & dosagem , Humulus/química , Macrófagos Alveolares/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Propiofenonas/administração & dosagem , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Macrófagos Alveolares/virologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Sus scrofa
13.
Int J Mol Sci ; 20(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554302

RESUMO

The Special Issue, "Protective and Detrimental Role of Heme Oxygenase-1", of the International Journal of Molecular Sciences, includes original research papers and reviews, some of which were aimed to understanding the dual role (protective and detrimental) of HO-1 and the signaling pathway involved [...].


Assuntos
Heme Oxigenase-1/metabolismo , Animais , Heme/metabolismo , Heme Oxigenase-1/genética , Humanos , Estresse Oxidativo , Transdução de Sinais
14.
J Agric Food Chem ; 67(36): 10059-10068, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31431007

RESUMO

Torularhodin is a natural product extracted from Sporidiobolus pararoseus and has a similar chemical structure to ß-carotene. The antioxidative effects of torularhodin were investigated using DPPH, ABTS, a cell oxidative damage model in vitro, and a d-galactose-induced liver-injured mouse model in vivo. Cell experiments demonstrated that torularhodin had a powerful effect on oxidative damage caused by H2O2 to AML12 cells. Torularhodin significantly reduced inflammatory cytokines and increased the activity of antioxidant enzymes both in mouse serum and the liver. The inhibition of d-galactose-induced oxidative damage in the liver was correlated with the torularhodin-mediated effects on improving the activity of Nrf2/HO-1, reducing the expression of Bax and NF-κB p65 by western blot analysis. RT-PCR results demonstrated torularhodin upregulated the antioxidative mRNA expression of Nrf2, NQO1, and HO-1 in the liver. In summary, torularhodin significantly scavenged free radicals and prevented oxidative damage in vitro and reduced d-galactose-induced liver oxidation via promotion of the Nrf2/HO-1 pathways in vivo.


Assuntos
Antioxidantes/administração & dosagem , Basidiomycota/química , Carotenoides/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Galactose/efeitos adversos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Biosci Biotechnol Biochem ; 83(12): 2202-2212, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31409200

RESUMO

In this study, we isolated eight phenylethanoid glycosides from Paraboea martinii for the first time, and evaluated the mechanism underlying their neuroprotective effects against H2O2-induced injury in PC12 cells. The MTS method was utilized to screen the phenylethanoid glycosides for protective ability. Next, qRT-PCR and western blotting analysis were used to detect the transcription levels of HO-1 and GCLC, which are regulated by Nrf2. The inhibitor ZnPP was used to analyze the involvement of Nrf2 in HO-1 expression. Analyses showed that caleolarioside B, paraboside B, and paraboside II also upregulated the expression of HO-1, but showed no obvious effect on GCLC. Pretreatment with ZnPP significantly reduced the neuroprotective effects. Thus, phenylethanoid glycosides isolated from P. martinii protected PC12 cells from H2O2-induced damage by upregulating HO-1. The results provided evidence that P. martinii might be a potential therapeutic agent for the treatment of neurodegenerative diseases.


Assuntos
Glicosídeos/farmacologia , Peróxido de Hidrogênio/toxicidade , Fármacos Neuroprotetores/farmacologia , Feocromocitoma/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células PC12 , Ratos , Transcrição Genética/efeitos dos fármacos
16.
J Agric Food Chem ; 67(37): 10342-10351, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31461273

RESUMO

Maltol, a maillard reaction product from ginseng (Panax ginseng C. A. Meyer), has been confirmed to inhibit oxidative stress in several animal models. Its beneficial effect on oxidative stress related brain aging is still unclear. In this study, the mouse model of d-galactose (d-Gal)-induced brain aging was employed to investigate the therapeutic effects and potential mechanisms of maltol. Maltol treatment significantly restored memory impairment in mice as determined by the Morris water maze tests. Long-term d-Gal treatment reduced expression of cholinergic regulators, i.e., the cholineacetyltransferase (ChAT) (0.456 ± 0.10 vs 0.211 ± 0.03 U/mg prot), the acetylcholinesterase (AChE) (36.4 ± 5.21 vs 66.5 ± 9.96 U/g). Maltol treatment prevented the reduction of ChAT and AChE in the hippocampus. Maltol decreased oxidative stress levels by reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production in the brain and by elevating antioxidative enzymes. Furthermore, maltol treatment minimized oxidative stress by increasing the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1). The above results clearly indicate that supplementation of maltol diminishes d-Gal-induced behavioral dysfunction and neurological deficits via activation of the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in brain. Maltol might become a potential drug to slow the brain aging process and stimulate endogenous antioxidant defense capacity. This study provides the novel evidence that maltol may slow age-associated brain aging.


Assuntos
Envelhecimento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Galactose/efeitos adversos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/administração & dosagem , Pironas/administração & dosagem , Envelhecimento/metabolismo , Animais , Heme Oxigenase-1/genética , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Panax/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo
17.
Plant Mol Biol ; 101(1-2): 203-220, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31297725

RESUMO

KEY MESSAGE: Here, a functional characterization of a wheat MSR has been presented: this protein makes a contribution to the plant's tolerance of abiotic stress, acting through its catalytic capacity and its modulation of ROS and ABA pathways. The molecular mechanism and function of certain members of the methionine sulfoxide reductase (MSR) gene family have been defined, however, these analyses have not included the wheat equivalents. The wheat MSR gene TaMSRA4.1 is inducible by salinity and drought stress and in this study, we demonstrate that its activity is restricted to the Met-S-SO enantiomer, and its subcellular localization is in the chloroplast. Furthermore, constitutive expression of TaMSRA4.1 enhanced the salinity and drought tolerance of wheat and Arabidopsis thaliana. In these plants constitutively expressing TaMSRA4.1, the accumulation of reactive oxygen species (ROS) was found to be influenced through the modulation of genes encoding proteins involved in ROS signaling, generation and scavenging, while the level of endogenous abscisic acid (ABA), and the sensitivity of stomatal guard cells to exogenous ABA, was increased. A yeast two-hybrid screen, bimolecular fluorescence complementation and co-immunoprecipitation assays demonstrated that heme oxygenase 1 (HO1) interacted with TaMSRA4.1, and that this interaction depended on a TaHO1 C-terminal domain. In plants subjected to salinity or drought stress, TaMSRA4.1 reversed the oxidation of TaHO1, activating ROS and ABA signaling pathways, but not in the absence of HO1. The aforementioned properties advocate TaMSRA4.1 as a candidate for plant genetic enhancement.


Assuntos
Heme Oxigenase-1/metabolismo , Metionina Sulfóxido Redutases/metabolismo , Transdução de Sinais , Estresse Fisiológico , Triticum/enzimologia , Ácido Abscísico/metabolismo , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/fisiologia , Secas , Perfilação da Expressão Gênica , Heme Oxigenase-1/genética , Metionina Sulfóxido Redutases/genética , Oxirredução , Reguladores de Crescimento de Planta/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Salinidade , Tolerância ao Sal , Plântula/enzimologia , Plântula/genética , Plântula/fisiologia , Triticum/genética , Triticum/fisiologia , Técnicas do Sistema de Duplo-Híbrido
18.
BMC Complement Altern Med ; 19(1): 176, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315617

RESUMO

BACKGROUND: Snake venoms contain various bioactive constituents which possess potential therapeutic effects. The aim of this work was to investigate the effect of the extract from Agkistrodon halys venom on lipopolysaccharide (LPS)-induced myocardial injury. METHODS: Thirty male Sprague-Dawley rats were randomly assigned to three groups (10 rats per group): control group, LPS group and LPS + extract group. Rats in control and the LPS groups were intravenously injected with sterile saline solution, and rats in the LPS + extract group with the extract. After 2 h, rats of the control group were intraperitoneally injected sterile saline solution, and rats in the LPS and the LPS + extract groups were treated with LPS (20 mg per kg body weight). Levels of creatine kinase (CK) and lactate dehydrogenase (LDH) in serum were determined. Anti-inflammation of the extract was analyzed via determination of TNF-α and IL-6 in serum, and expression of TNF-α, IL-6, COX-2 and p-ERK protein in hearts. Heme oxygenase-1 (HO-1) and p-NF-κB protein expression in hearts, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in serum were used to evaluate the anti-oxidative properties of the extract. RESULTS: Extract pretreatment significantly decreased the level of serum CK and LDH, reduced the generation of inflammatory cytokines such as TNF-α and IL-6, and also reduced serum level of MDA in the LPS + extract group compared with the LPS group. In addition, the extract increased SOD activity in serum, HO-1 protein expression in hearts, and decreased TNF-α, IL-6, COX-2, p-NF-κB and p-ERK1/2 protein expression. CONCLUSION: Our results suggested that beneficial effect of this extract might be associated with an improved anti-oxidation and anti-inflammatory effect via downregulation of NF-κB/COX-2 signaling by activating HO-1/CO in hearts.


Assuntos
Agkistrodon/metabolismo , Traumatismos Cardíacos/prevenção & controle , Lipopolissacarídeos/efeitos adversos , Substâncias Protetoras/administração & dosagem , Venenos de Serpentes/administração & dosagem , Animais , Coração/efeitos dos fármacos , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/genética , Traumatismos Cardíacos/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Malondialdeído/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
19.
Mol Med Rep ; 20(2): 1499-1508, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257486

RESUMO

Geniposide, as a type of iridoid glycoside, has antioxidative capacity. However, the mechanism underlying the effect of geniposide in cadmium (Cd)­induced osteoblast injury remains only partly elucidated. In the present study, Cell Counting Kit­8 (CCK­8) was used to determine MC­3T3­E1 cell viability. Flow cytometry was used to determine the rate of apoptosis and levels of reactive oxygen species (ROS). Oxidative stress­related factors were assessed using enzyme­linked immunosorbent method (ELISA). Quantitative real­time polymerase chain reaction (qPCR) and western blotting were used to evaluate apoptosis­ and bone formation­related genes and nuclear factor erythroid 2­related factor (Nrf2) signaling. It was demonstrated that geniposide increased the viability of the Cd­treated MC­3T3­E1 cells. Geniposide decreased apoptosis and ROS accumulation compared to these parameters in the Cd group. Geniposide attenuated oxidative stress­related factors, malondialdehyde and lactate dehydrogenase and increased antioxidant key enzyme superoxidase dismutase (SOD). The expression levels of Bax, Bcl­2 and survivin were modulated by geniposide. Additionally, the mRNA and protein expression of the receptor activator of NF­κB ligand (RANKL) and osterix were significantly increased, while osteoprotegerin was decreased by geniposide treatment compared to the Cd groups. Geniposide also enhanced Nrf2, heme oxygenase­1 (HO­1) and NAD(P)H quinone dehydrogenase 1 (NQO1) expression. The present study identified a potential agent for the treatment of Cd­induced osteoblast injury.


Assuntos
Antioxidantes/farmacologia , Cloreto de Cádmio/antagonistas & inibidores , Iridoides/farmacologia , Fator 2 Relacionado a NF-E2/genética , Oxidantes/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Cloreto de Cádmio/farmacologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Malondialdeído/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Oxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Survivina/genética , Survivina/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
20.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261663

RESUMO

The up-regulation of heme oxygenase-1 (HO-1) is mediated through nicotinamaide adenine dinucleotide phosphate (NADPH) oxidases (Nox) and reactive oxygen species (ROS) generation, which could provide cytoprotection against inflammation. However, the molecular mechanisms of carbon monoxide-releasing molecule (CORM)-2-induced HO-1 expression in human tracheal smooth muscle cells (HTSMCs) remain unknown. Here, we found that pretreatment with CORM-2 attenuated the lipopolysaccharide (LPS)-induced intercellular adhesion molecule (ICAM-1) expression and leukocyte count through the up-regulation of HO-1 in mice, which was revealed by immunohistochemistrical staining, Western blot, real-time PCR, and cell count. The inhibitory effects of HO-1 by CORM-2 were reversed by transfection with HO-1 siRNA. Next, Western blot, real-time PCR, and promoter activity assay were performed to examine the HO-1 induction in HTSMCs. We found that CORM-2 induced HO-1 expression via the activation of protein kinase C (PKC)α and proline-rich tyrosine kinase (Pyk2), which was mediated through Nox-derived ROS generation using pharmacological inhibitors or small interfering ribonucleic acids (siRNAs). CORM-2-induced HO-1 expression was mediated through Nox-(1, 2, 4) or p47phox, which was confirmed by transfection with their own siRNAs. The Nox-derived ROS signals promoted the activities of extracellular signal-regulated kinase 1/2 (ERK1/2). Subsequently, c-Fos and c-Jun-activator protein-1 (AP-1) subunits-were up-regulated by activated ERK1/2, which turned on transcription of the HO-1 gene by regulating the HO-1 promoter. These results suggested that in HTSMCs, CORM-2 activates PKCα/Pyk2-dependent Nox/ROS/ERK1/2/AP-1, leading to HO-1 up-regulation, which suppresses the lipopolysaccharide (LPS)-induced airway inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Heme Oxigenase-1/metabolismo , Compostos Organometálicos/farmacologia , Traqueíte/metabolismo , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Heme Oxigenase-1/genética , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos ICR , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traqueia/citologia , Traqueia/metabolismo , Traqueíte/etiologia
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