Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 207
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028545

RESUMO

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Assuntos
Isotiocianatos/uso terapêutico , Melatonina/análogos & derivados , Fator 2 Relacionado a NF-E2/agonistas , Retinite Pigmentosa/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/química , Isotiocianatos/farmacologia , Masculino , Melatonina/química , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia , Fator de Necrose Tumoral alfa/metabolismo , Acuidade Visual/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Nat Commun ; 10(1): 4878, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653857

RESUMO

Herpesvirus infection initiates a range of perturbations in the host cell, which remain poorly understood at the level of individual cells. Here, we quantify the transcriptome of single human primary fibroblasts during the first hours of lytic infection with HSV-1. By applying a generalizable analysis scheme, we define a precise temporal order of early viral gene expression and propose a set-wise emergence of viral genes. We identify host cell genes and pathways relevant for infection by combining three different computational approaches: gene and pathway overdispersion analysis, prediction of cell-state transition probabilities, as well as future cell states. One transcriptional program, which correlates with increased resistance to infection, implicates the transcription factor NRF2. Consequently, Bardoxolone methyl and Sulforaphane, two known NRF2 agonists, impair virus production, suggesting that NRF2 activation restricts viral infection. Our study provides insights into early stages of HSV-1 infection and serves as a general blueprint for the investigation of heterogeneous cell states in virus infection.


Assuntos
Fibroblastos/metabolismo , Herpes Simples/genética , Herpesvirus Humano 1 , Interações Hospedeiro-Patógeno/genética , Fator 2 Relacionado a NF-E2/genética , Fibroblastos/virologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Cultura Primária de Células , Análise de Sequência de RNA , Análise de Célula Única , Replicação Viral/efeitos dos fármacos
3.
Biol Res ; 52(1): 53, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31542051

RESUMO

BACKGROUND: Oxidative stress is the hallmark of diabetic encephalopathy, which may be caused by hyperglycaemic toxicity. We aimed to discover pharmacologic targets to restore redox homeostasis. We identified the transcription factor Nrf2 as such a target. METHODS: HT22 cells were cultured in 25 or 50 mM D-glucose with various concentrations of sulforaphane (SFN) (from 1.25 to 5.0 µM). Cell viability was tested with the Cell Counting Kit-8 assay. Reactive oxygen species (ROS) production was detected with an inverted fluorescence microscope using the dichlorodihydrofluorescein-diacetate fluorescent probe. The expression of NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1) and nuclear factor-κB (NF-κB) at the mRNA and protein levels was detected by reverse transcription quantitative polymerase chain reaction and western blotting. RESULT: We found that a high glucose concentration (50 mM) increased the generation of ROS, downregulated the expression of Nrf2/HO-1 and upregulated the expression of NF-κB. Moreover, HT22 cell viability significantly decreased after culture in high-glucose medium for 24, 48 and 72 h, whereas the activation of the Nrf2/HO-1 pathway using a pharmacological Nrf2 activator abrogated this high-glucose-induced toxicity. CONCLUSION: This study suggests that the activation of the Nrf2-ARE signalling pathway might be a therapeutic target for the treatment of diabetic encephalopathy.


Assuntos
Glucose/toxicidade , Hipocampo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Neuroproteção , Animais , Western Blotting , Linhagem Celular , Eletroforese em Gel de Campo Pulsado , Imunofluorescência , Hipocampo/citologia , Camundongos , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
4.
Int J Mol Sci ; 20(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416234

RESUMO

Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (n = 11-13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e. Ren, Agt, Ace, and Agtr1a), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat.


Assuntos
Dexametasona/administração & dosagem , Dieta Hiperlipídica , Fumarato de Dimetilo/administração & dosagem , Hipertensão/etiologia , Hipertensão/prevenção & controle , Exposição Materna , Fator 2 Relacionado a NF-E2/agonistas , Efeitos Tardios da Exposição Pré-Natal , Animais , Biomarcadores , Feminino , Expressão Gênica , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Recém-Nascido , Masculino , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Fosforilação , Gravidez , Ratos
5.
Oxid Med Cell Longev ; 2019: 9372182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396308

RESUMO

The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers the first line of homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic approach for several chronic diseases that are underlined by oxidative stress and inflammation, such as neurodegenerative, cardiovascular, and metabolic diseases. A particular case is cancer, where NRF2 confers a survival advantage to constituted tumors, and therefore, NRF2 inhibition is desired. This review describes the electrophilic and nonelectrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which at this time provide proof of concept for blocking NRF2 activity in cancer therapy.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Ensaios Clínicos como Assunto , Curcumina/química , Curcumina/uso terapêutico , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Oxidativo , Triterpenos/química , Triterpenos/uso terapêutico
6.
Food Chem Toxicol ; 133: 110758, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31412289

RESUMO

Various phytochemicals have been reported to protect against oxidative stress. However, the mechanism underlying has not been systematically evaluated, which limited their application in disease treatment. Nuclear factor erythroid 2-related factor 2 (Nrf2), a central transcription factor in oxidative stress response related to numerous diseases, is activated after dissociating from the cytoskeleton-anchored Kelch-like ECH-associated protein 1 (Keap1). The Keap1-Nrf2 protein-protein interaction has become an important drug target. This study was designed to clarify whether antioxidantive phytochemicals inhibit the Keap1-Nrf2 protein-protein interaction and activate the Nrf2-ARE signaling pathway efficiently. Molecular docking and 3D-QSAR were applied to evaluate the interaction effects between 178 antioxidant phytochemicals and the Nrf2 binding site in Keap1. The Nrf2 activation effect was tested on a H2O2-induced oxidative-injured cell model. Results showed that the 178 phytochemicals could be divided into high-, medium-, and low-total-score groups depending on their binding affinity with Keap1, and the high-total-score group consisted of 24 compounds with abundant oxygen or glycosides. Meanwhile, these compounds could bind with key amino acids in the structure of the Keap1-Nrf2 interface. Compounds from high-total-score group show effective activation effects on Nrf2. In conclusion, phytochemicals showed high binding affinity with Keap1 are promising new Nrf2 activators.


Assuntos
Antioxidantes/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/agonistas , Compostos Fitoquímicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Antioxidantes/toxicidade , Sítios de Ligação , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Células PC12 , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/toxicidade , Relação Quantitativa Estrutura-Atividade , Ratos
7.
Ren Fail ; 41(1): 750-761, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31441362

RESUMO

Diabetic patients are more susceptible to renal ischemia/reperfusion (I/R) injury (RI/RI) and have a poor prognosis, but the underlying mechanism remains unclear. The present study aimed to examine whether diabetes could worsen acute kidney injury induced by I/R in rats and clarify its mechanism. Control and streptozotocin-induced diabetic rats were subjected to 45 min renal pedicle occlusion followed by 24 h reperfusion. Tert-butylhydroquinone (TBHQ, 16.7 mg/kg) was administrated intraperitoneally 3 times at intervals of 8 h before ischemia. Serum and kidneys were harvested after reperfusion to evaluate renal function and histological injury. Enzyme-linked immunosorbent assays were used to test pro-inflammatory cytokines. Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assays were used to detect apoptotic cells, and western blotting was performed to determine the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3, as well as oxidative stress and inflammation-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB). Compared with control animals, diabetic rats undergoing I/R exhibited more severe tubular damage and renal dysfunction. Diabetes exacerbated oxidative stress, the inflammatory response, and apoptosis after renal I/R by enhancing TLR4/NF-κB signaling and blocking the Nrf2/HO-1 pathway. RI/RI in diabetic rats was attenuated by pretreatment with TBHQ (a Nrf2 agonist), which exerted anti-inflammatory and anti-apoptotic properties by inhibiting NF-κB signaling. These findings indicate that hyperglycemia exacerbates RI/RI by intensifying oxidative stress, inflammation, and apoptosis. Antioxidant pretreatment may alleviate RI/RI in diabetic patients.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/patologia , Inflamação/patologia , Rim/patologia , Traumatismo por Reperfusão/patologia , Animais , Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/prevenção & controle , Humanos , Hidroquinonas/administração & dosagem , Inflamação/etiologia , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/toxicidade
8.
Redox Biol ; 26: 101271, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31302408

RESUMO

Oxidative stress contributes to endothelial dysfunction, a key step in cardiovascular disease development. Ageing-related vascular dysfunction involves defective antioxidant response. Nuclear factor erythroid 2-like-2 (Nrf2), orchestrates cellular response to oxidative stress. We evaluated the impact of Nrf2-activation on endothelium-dependent and H2O2-mediated vasodilations in: aorta (RA), mesenteric artery (RMA), coronary artery (RCA) and corpus cavernosum (RCC) from ageing rats and in human penile arteries (HPRA) and corpus cavernosum (HCC) from erectile dysfunction (ED) patients. Relaxant responses were evaluated in organ chambers and wire myographs. Nrf2 content and heme oxygenase-1 (HO-1) were determined by ELISA. Superoxide and Nrf2 were detected by immunofluorescence. Pharmacological activation of Nrf2 with sulforaphane (SFN) improved NO- and endothelium-derived hyperpolarizing factor-mediated endothelium-dependent vasodilation and H2O2-induced relaxation in vascular beds from aging rats. SFN-induced effects were associated with increased Nrf2 (RMA, RCA) and reduced superoxide detection in RCA. Improvement of vascular function was confirmed in HPRA and HCC from ED patients and mimicked by another Nrf2 activator, oltipraz. Nrf2 increase and superoxide reduction together with HO-1 increase by Nrf2 activation was evidenced in HCC from ED patients. PDE5 inhibitor-induced relaxations of HPRA and HCC from ED patients were enhanced by SFN. Nrf2 short-term pharmacological activation attenuates age-related impairment of endothelium-dependent and reactive oxygen species (ROS)-induced vasodilation in different rat and human vascular territories by upregulation of Nrf2-related signaling and decreased oxidative stress. In ED patients target tissues, Nrf2 potentiates the functional effect of ED conventional pharmacological therapy suggesting potential therapeutic implication.


Assuntos
Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Fator 2 Relacionado a NF-E2/metabolismo , Fatores Etários , Animais , Circulação Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Suscetibilidade a Doenças , Endotélio/metabolismo , Feminino , Hemodinâmica , Humanos , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Masculino , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/agonistas , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos , Vasodilatação
9.
Inflammation ; 42(5): 1843-1856, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256292

RESUMO

Ozone is a strong oxidant in air pollution that exacerbates respiratory disorders and is a major risk factor for acute asthma exacerbation. Ozone can induce reactive oxygen species (ROS) and airway neutrophilic inflammation. In addition, γδT17 cells contribute to IL-17A production upon ozone challenge, resulting in neutrophilic inflammation. It is known, however, that Nrf2 can ameliorate oxidative stress. We therefore investigated whether RTA-408, an Nrf2 activator, can attenuate airway inflammation and inhibit ROS production and whether this effect involves γδT17 cells. Balb/c mice were sensitized/challenged with ovalbumin (OVA) and followed by ozone exposure. We investigated the effect of Nrf2 activator RTA-408 on airway hyperresponsiveness, neutrophilic airway inflammation, cytokine/chemokine production, and OVA-specific IgE level in a mouse model of O3 induced asthma exacerbation. Furthermore, malondialdehyde (MDA) and glutathione (GSH) levels in lung and intracellular ROS were measured. IL-17+ γδT cell percentage by flow cytometer was determined. Nrf2 protein expression by western blot was also examined. We observed that RTA-408 attenuated ROS release during ozone-induced asthma exacerbation and suppressed neutrophil lung infiltration. RTA-408 decreased pro-inflammatory cytokine production and reduced the percentage of IL-17+ γδT cells. Thus, our results suggest that RTA-408 does attenuate airway inflammation in a murine model of ozone-induced asthma exacerbation.


Assuntos
Asma/prevenção & controle , Interleucina-17/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Ozônio/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Triterpenos/farmacologia , Animais , Asma/induzido quimicamente , Linhagem Celular , Inflamação/tratamento farmacológico , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Substâncias Protetoras/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/patologia
10.
Mol Med Rep ; 20(2): 1017-1024, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173182

RESUMO

Puerarin is the major bioactive ingredient isolated from the dry root of Pueraria lobata, a plant used in traditional Chinese medicine. Puerarin has been used to treat diabetes and cataracts in China; however, its underlying mechanism of action remains unclear. The aim of the present study was to investigate the effectiveness and mechanism of puerarin in preventing cataracts in diabetic rats. Diabetes was induced by streptozocin (STZ) administration and rats were intraperitoneally injected with puerarin (25, 50 and 100 mg/kg). Blood glucose levels and cataract development were examined in the different experimental groups. In addition, the expression levels of markers associated with oxidative stress, including nuclear factor erythroid 2 like 2 (Nrf2) and heme oxygenase­1 (HO­1), were analyzed. The present results suggested that treatment with puerarin at 25, 50 and 100 mg/kg significantly reduced blood glucose levels and the incidence of cataract in STZ­induced diabetic rats. Additionally, puerarin treatment reduced oxidative stress, restoring the levels of malondialdehyde and glutathione, and the activity of glutathione peroxidase. Furthermore, puerarin administration decreased the expression levels of retinal vascular endothelial growth factor and interleukin­1ß and increased the mRNA expression levels of Nrf2 and HO­1, thus inhibiting oxidative stress. The present findings suggested that puerarin had hypoglycemic effects and that it prevented cataract development and progression in diabetic rats by reducing oxidative stress through the Nrf2/HO­1 signaling pathway.


Assuntos
Catarata/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Heme Oxigenase (Desciclizante)/genética , Hipoglicemiantes/farmacologia , Isoflavonas/farmacologia , Fator 2 Relacionado a NF-E2/genética , Pueraria/química , Animais , Glicemia/metabolismo , Catarata/induzido quimicamente , Catarata/genética , Catarata/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Medicamentos de Ervas Chinesas/química , Regulação da Expressão Gênica , Glutationa/agonistas , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hipoglicemiantes/isolamento & purificação , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Isoflavonas/isolamento & purificação , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Transdução de Sinais , Estreptozocina , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Biofactors ; 45(4): 563-574, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31131946

RESUMO

Isoflavones are one group of the major flavonoids and possess multiple biological activities due to their antioxidant properties. However, a clear antioxidant mechanism of dietary isoflavones is still remained to be answered. In this study, the effects of isoflavones on the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway and the underlying molecular mechanisms were investigated. Results showed that isoflavones are potential Nrf2-ARE activators while their activities were structure dependent. Biochanin A (BCA), an O-methylated isoflavone with low direct antioxidant activity, can effectively protect HepG2 cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage via activation of the Nrf2 signaling, and thereby the induction of downstream cytoprotective enzymes including NAD(P)H quinone oxidoreductase-1, heme oxygenasae-1, and glutamate-cysteine ligase catalytic subunit. A molecular docking study revealed that BCA could directly bind into the pocket of Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a cytoplasmic suppressor of Nrf2, to facilitate Nrf2 activation. The upstream mitogen-activated protein kinase (MAPK) pathways were also involved in the activation of Nrf2 signaling. These findings indicate that the protective actions of dietary isoflavones against oxidative damage may be at least partly due to their ability to enhance the intracellular antioxidant response system by modulating the Nrf2-ARE signaling pathway.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Genisteína/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Fator 2 Relacionado a NF-E2/genética , Espécies Reativas de Oxigênio/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADH NADPH Oxirredutases/genética , NADH NADPH Oxirredutases/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Oxidantes/antagonistas & inibidores , Oxidantes/farmacologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , terc-Butil Hidroperóxido/antagonistas & inibidores , terc-Butil Hidroperóxido/farmacologia
12.
Nutrients ; 11(4)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30987009

RESUMO

Certain antioxidative flavonoids are known to activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates cellular antioxidants and detoxifying response and is reportedly highly activated in many types of cancers. Few studies on the potential undesired effects of flavonoid intake during chemotherapy have been conducted, yet Nrf2 activators could favor cancer cell survival by attenuating chemotherapeutic efficiency. This study aimed to examine if luteolin, an Nrf2 activator, hinders chemotherapeutic activity of oxaliplatin, a potent anticancer agent for colorectal cancer, in HCT116 cells. Luteolin treatment strongly increased the transcriptional activity of the antioxidant response element in HCT116 cells and induced the protein expression of heme oxygenase-1, which were indicative of its Nrf2-inducing potential. Intriguingly, 25 µM luteolin reduced cell viability through apoptotic induction, which was intensified in p53-expressing cells while 1 µM oxaliplatin caused cell cycle arrest at G0/G1-phase via the p53/p21-dependent mechanism. Moreover, luteolin treatment was found to reduce oxaliplatin-treated p53-null cell viability and colony counts further, thereby demonstrating an additional effect of luteolin in the killing of human colorectal tumor HCT116 cells not expressing functional p53 protein. The findings suggest that luteolin can induce p53-mediated apoptosis regardless of oxaliplatin treatment and may eliminate oxaliplatin-resistant p53-null colorectal cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Luteolina/farmacologia , Oxaliplatina/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Elementos de Resposta Antioxidante/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células HCT116 , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Mol Med Rep ; 19(5): 4001-4010, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896808

RESUMO

The present study aimed to investigate the function of micro (mi)RNA­153 against isoflurane­induced neurotoxicity and its mechanism. In isoflurane­induced mice, miRNA­153 expression was downregulated compared with in the control group. Downregulation of miRNA­153 induced neurocyte apoptosis, reduced cell growth and promoted oxidative stress in an in vitro model. Overexpression of miRNA­153 reduced oxidative stress, promoted cell growth and inhibited neurocyte apoptosis within an in vitro model. Downregulation of miRNA­153 suppressed nuclear erythroid­2 related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which was induced via the overexpression of miRNA­153 in vitro. The Nrf2 agonist, dimethyl fumarate (2.5 µM), induced the Nrf2/ARE signaling pathway and reduced oxidative stress to induce neurocyte apoptosis in vitro following treatment with anti­miRNA­153. The results of the present study suggested the function of miRNA­153 against neurotoxicity via Nrf2/ARE­mediated cytoprotection.


Assuntos
Elementos de Resposta Antioxidante/genética , Isoflurano/toxicidade , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/agonistas , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Biotechnol Appl Biochem ; 66(3): 465-471, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30892727

RESUMO

Nerve damage is the main pathogenesis of neurodegenerative diseases. Recently, in search for a promising therapeutic target that could stop neurodegenerative diseases progression, the antioxidant signaling pathway regulated by transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has attracted new hopes. Icariin (ICA) exhibited a battery of pharmacological properties, including antioxidation, anti-aging, and anti-inflammation activities. Recent studies indicate ICA conferred neuroprotection against brain ischemic injury and neurodegenerative diseases. However, the mechanisms underlying ICA-mediated neuroprotection remain unelucidated. This study aimed at analyzing whether ICA evoked neuroprotection against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells and the mechanisms of action. ICA protected against 6-OHDA-induced neuronal damage, accompanied by the inhibition of cell apoptosis through the marked decreases in the Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 cleavage. In addition, the activation of Nrf2 signaling pathway was responsible for ICA-mediated neuroprotection. First, ICA relieved reactive oxygen species accumulation and increased superoxide dismutase generation via the activation of Nrf2 signaling. Second, Nrf2 knockdown by siRNA reversed ICA-mediated neuroprotection. Together, these results suggested ICA-mediated neuroprotection might be attributable to the activation of Nrf2 pathway via antioxidative signaling pathways.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Flavonoides/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Células PC12 , RNA Interferente Pequeno/antagonistas & inibidores , RNA Interferente Pequeno/metabolismo , Ratos , Relação Estrutura-Atividade
15.
Basic Clin Pharmacol Toxicol ; 125(3): 259-270, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30861618

RESUMO

The Keap1-Nrf2-ARE system serves as a premier defence mechanism to curb oxidative stress, which remains as one of the major causes of ageing and pathogenesis in various diseases. Nrf2 is the principal master regulator of the cellular defence system, and its activation remains the prospective therapeutic approach against chronic diseases. One of the recent strategies is to disrupt Keap1-Nrf2 protein-protein interaction (PPI) that alters the docking of Keap1 with Nrf2 by compounds occupying a position in the Keap1 blocking the interface with Nrf2. In this study, we made an attempt to identify the compounds with anticancer, antioxidant and anti-inflammatory properties to disrupt Keap1a/b-Nrf2 PPI through in silico molecular docking in zebrafish. The phylogenetic analysis of Keap1 proteins revealed the existence of orthologous Keap1-Nrf2-ARE system in lower vertebrates that includes zebrafish. The DGR domains of zebrafish Keap1a and Keap1b were modelled with Modeller 9.19 using Keap1 of Mus musculus (PDB ID:5CGJ) as template. Based on the docking calculations, top hit compounds were identified to disrupt both Keap1a and Keap1b interaction with Nrf2 which include quercetin 3,4'-diglucoside, flavin adenine dinucleotide disodium salt hydrate, salvianolic acid A, tunicamycin and esculin. The LC50 of esculin in 3 dpf zebrafish larvae is 5 mmol/L, and the qRT-PCR results showed that esculin significantly increased the transcription of Nrf2 target genes-Gstpi, Nqo1, Hmox1a and Prdx1 in 3 dpf zebrafish larvae. These potential hits could serve as safer Nrf2 activators due to their non-covalent disruption of Keap1-Nrf2 PPI and be developed into efficacious preventive/therapeutic agents for various diseases.


Assuntos
Antioxidantes/farmacologia , Descoberta de Drogas , Fator 2 Relacionado a NF-E2/agonistas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas de Peixe-Zebra/agonistas , Animais , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Embrião não Mamífero , Esculina/farmacologia , Dose Letal Mediana , Ligantes , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Filogenia , Ligação Proteica/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas/genética , Transcrição Genética/efeitos dos fármacos , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
Mol Vis ; 25: 47-59, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820141

RESUMO

Purpose: Oxidative stress is implicated in the etiology of diabetes and its debilitating complications, such as diabetic retinopathy (DR). Various flavonoids have been reported to be useful in reducing DR progression. Myricetin derivatives (F2) isolated from leaf extract of Syzygium malaccense have the potential to serve as functional food as reported previously. The present study was performed with the aim of determining the antioxidant potential and protective effect of myricetin derivatives (F2) isolated from leaf extract of S. malaccense against glucose oxidase (GO)-induced hydrogen peroxide (H2O2) production that causes oxidative stress in ARPE-19 (RPE) cells. Methods: Antioxidant properties were assessed through various radical (DPPH, ABTS, and nitric oxide) scavenging assays and determination of total phenolic content and ferric reducing antioxidant power level. ARPE-19 cells were preincubated with samples before the addition of GO (to generate H2O2). Cell viability, change in intracellular reactive oxygen species (ROS), H2O2 levels in cell culture supernatant, and gene expression were assessed. Results: F2 showed higher antioxidant levels than the extract when assessed for radical scavenging activities and ferric reducing antioxidant power. F2 protected the ARPE-19 cells against GO-H2O2-induced oxidative stress by reducing the production of H2O2 and intracellular reactive oxygen species. This was achieved by the activation of nuclear factor erythroid 2-related factor 2 (Nrf2/NFE2L2) and superoxide dismutase (SOD2), as well as downregulation of nitric oxide producer (NOS2) at the transcriptional level. Conclusions: The results showed that myricetin derivatives from S. malaccense have the capacity to exert considerable exogenous antioxidant activities and stimulate endogenous antioxidant activities. Therefore, these derivatives have excellent potential to be developed as therapeutic agents for managing DR.


Assuntos
Antioxidantes/farmacologia , Células Epiteliais/efeitos dos fármacos , Flavonoides/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Syzygium/química , Antioxidantes/isolamento & purificação , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Flavonoides/isolamento & purificação , Regulação da Expressão Gênica , Glucose Oxidase/antagonistas & inibidores , Glucose Oxidase/química , Glucose Oxidase/farmacologia , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Ácidos Sulfônicos/antagonistas & inibidores , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
17.
Neurochem Int ; 126: 96-108, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30880045

RESUMO

Post stroke recanalization has been associated with increased risk of oxidative stress. Stimulating endogenous antioxidant pathway by activation of nuclear factor erythroid-2-related factor-2 (Nrf2) plays a key role in neuronal defense against inflammation and oxidative stress in penumbra. Here, we explored whether monomethyl fumarate (MMF) could produce neuro-protection after ischemia/reperfusion (I/R) injury via Nrf2/HO1 activation. In male SD rats, middle cerebral artery was occluded for 90 min and confirmed using Laser Doppler flowmeter. MMF (10, 20 and 40 mg/kg) was administered in two divided doses at 30 min post ischemia and 5-10 min after reperfusion. After 24 h, effect on neurobehavioral parameters, infarct damage by TTC staining and MRI, oxidative stress and inflammatory cytokines were assessed. Expression studies of nuclear Nrf2 and cytoplasmic HO1 were performed in peri-infarct cortex and striatum; followed by dual immunofluorescence study to check the specific cell type. I/R induced neurobehavioral deficits and infarct damage were significantly (p < 0.05) attenuated by MMF (20 and 40 mg/kg). MMF, 20 mg/kg, significantly normalized I/R induced altered redox status and increased levels of TNF-α, IL-1ß in the ipsilateral cortex. MRI data showed significantly reduced infarct in cortex but not in striatum after MMF treatment. Expression of nuclear Nrf2 and cytoplasmic HO1 were significantly (p < 0.05) increased in peri-infarct cortex after treatment with MMF. Additionally, dual immunofluorescence showed increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex after MMF treatment. Our results show the neuro-protective potential of MMF probably by restricting the progression of damage from striatum to cortex through activation of Nrf2/HO1 pathway in peri-infarct cortex.


Assuntos
Fumaratos/uso terapêutico , Heme Oxigenase (Desciclizante)/biossíntese , Infarto da Artéria Cerebral Média/metabolismo , Maleatos/uso terapêutico , Fator 2 Relacionado a NF-E2/biossíntese , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Animais , Fumaratos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Masculino , Maleatos/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
18.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717178

RESUMO

Cadmium (Cd) is harmful for humans and animals, especially for the reproductive system. However, the mechanism of its toxicity has not been elucidated, and how to alleviate its toxicity is very important. This study aimed to explore the role and mechanism of action of sulforaphane (SFN) in protecting mouse Leydigs (TM3) cells from cadmium (Cd)-induced damage. The half-maximal inhibitory concentration (IC50) of Cd and the safe doses of SFN were determined using a methyl thiazolyl tetrazolium (MTT) assay. The testosterone secretion from TM3 cells was measured using the enzyme-linked immunosorbent assay. The intracellular oxidative stress was evaluated using corresponding kits. The cell apoptosis was detected using flow cytometry. The mRNA expression of genes associated with NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling was detected using reverse transcription⁻polymerase chain reaction, including Nrf2, heme oxygenase I (HO-1), glutathione peroxidase (GSH-Px), NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), and γ-glutamylcysteine synthetase (γ-GCS). The protein expression of Nrf2, GSH-Px, HO-1, γ-GCS, and NQO1 was detected using Western blot analysis. The results showed that the IC50 of Cd to TM3 cells was 51.4 µmol/L. SFN reduced the release of lactate dehydrogenase from Cd-exposed cells. Cd + SFN 2.5 treatment significantly elevated testosterone concentration compared with the Cd group (p < 0.05). SFN significantly increased total superoxide dismutase (T-SOD) and GSH-Px activity and GSH content in Cd-treated cells (p < 0.05; p < 0.01), inhibited the production of malondialdehyde or reactive oxygen species caused by Cd (p < 0.05; p < 0.01), and reduced the apoptotic rate of Cd-induced TM3 cells (p < 0.01). SFN upregulated the mRNA expression of Nrf2, GSH-Px, HO-1, NQO1, and γ-GCS in Cd-treated cells, indicating the protective effect of SFN against Cd-induced oxidative stress or cell apoptosis by activating the Nrf2/ARE signaling pathway.


Assuntos
Antioxidantes/farmacologia , Cloreto de Cádmio/antagonistas & inibidores , Isotiocianatos/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Cloreto de Cádmio/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/metabolismo , Masculino , 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/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testosterona/biossíntese
19.
J Neuroinflammation ; 16(1): 24, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30709405

RESUMO

BACKGROUND: Previous studies had showed that Apelin 13 could protect against apoptosis induced by ischemic/reperfusion (I/R). However, the mechanisms whereby Apelin 13 protected brain I/R remained to be elucidated. The present study was designed to determine whether Apelin 13 provided protection through AMPK/GSK-3ß/Nrf2 pathway. METHODS: In vivo, the I/R model was induced and Apelin 13 was given intracerebroventricularly 15 min before reperfusion. The neurobehavioral scores, infarction volumes, and some cytokines in the brain were measured. For in vitro study, PC12 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were used. Protein levels were investigated by western blotting. RESULTS: The results showed that Apelin 13 treatment significantly reduced infarct size, improved neurological outcomes, decreased brain edema, and inhibited cell apoptosis, oxidative stress, and neuroinflammation after I/R. Apelin 13 significantly increased the expression of Nrf2 and the phosphorylation levels of AMPK and GSK-3ß. Furthermore, in cultured PC12 cells, the same protective effects were also observed. Silencing Nrf2 gene with its siRNA abolished the Apelin 13's prevention of I/R-induced PC12 cell injury, oxidative stress, and inflammation. Inhibition of AMPK by its siRNA decreased the level of Apelin 13-induced Nrf2 expression and diminished the protective effects of Apelin 13. The interplay relationship between GSK-3ß and Nrf2 was also verified with relative overexpression. Using selective inhibitors, we further identified the upstream of AMPK/GSK-3ß/Nrf2 is AR/Gα/PLC/IP3/CaMKK. CONCLUSIONS: In conclusion, the previous results showed that Apelin 13 protected against I/R-induced ROS-mediated inflammation and oxidative stress through activating the AMPK/GSK-3ß pathway by AR/Gα/PLC/IP3/CaMKK signaling, and further upregulated the expression of Nrf2-regulated antioxidant enzymes.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/prevenção & controle , Injeções Intraventriculares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Masculino , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
Ann Clin Transl Neurol ; 6(1): 15-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30656180

RESUMO

Objective: Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF-kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose-ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435). Methods: Sixty-nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5-300 mg/day. Results: Omaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P < 0.0001) and by 4.4 points versus placebo (P = 0.01) at the 160 mg/day. Interpretation: Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.


Assuntos
Ataxia de Friedreich/tratamento farmacológico , Fator 2 Relacionado a NF-E2/agonistas , NF-kappa B/antagonistas & inibidores , Triterpenos/farmacologia , Adolescente , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA