RESUMO
Multiple cycles of cisplatin result in a permanent loss of kidney function with severe and life-limited chronic kidney disease (CKD) after successful cisplatin therapy. Recently, studies have showed that the activation of G-protein coupled estrogen receptor (GPER) could protect against kidney disease. This study aimed to test the potential of the G1 compound, a GPER selective agonist, to prevent CKD development after cisplatin therapy. Male C57BL/6 mice were exposed to 2 cycles of 2.5 mg/kg cisplatin in a regimen miming clinical exposure (1 injection daily for 5 days, followed by a 16-day recovery period between cycles). G1 (50 or 100 µg/kg) was administered daily for 6 weeks. G1 dose-dependently improved kidney function biomarkers (serum creatinine, creatinine clearance, and protein excretion) and histopathological changes compared to the cisplatin-treated group. Collagen 3 expression was dose-dependently decreased in G1-treated groups that was parallel to the reduction of fibrosis in Masson's trichrome-stained sections. G1 administration also increased total antioxidant capacity (TAC) and nuclear factor erythroid 2-related factor 2 (Nrf2) and reduced the level of malondialdehyde and the proinflammatory cytokine, tumor necrosis factor-α. In addition, G1 downregulated the expression of inflammasome NLRP3 and nuclear factor kappa B p65 (NF-κB p65) in a dose-dependent manner. In conclusion, these data suggest that G1 could be a new therapeutic tool for CKD prevention post cisplatin therapy. These effects might be mediated through the activation of Nrf2 and the inhibition of NF-κB/NLRP3 signaling.
Assuntos
Cisplatino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G , Insuficiência Renal Crônica , Animais , Cisplatino/farmacologia , Masculino , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Camundongos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Biomarcadores/metabolismo , Receptores de Estrogênio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
Age-related injuries are often connected to alterations in redox homeostasis. The imbalance between free radical oxygen species and endogenous antioxidants defenses could be associated with a growing risk of transient ischemic attack and stroke. In this context, a daily supply of dietary antioxidants could counteract oxidative stress occurring during ischemia/reperfusion injury (I/R), preventing brain damage. Here we investigated the potential antioxidant properties of coffee-derived circulating metabolites and a coffee pulp phytoextract, testing their efficacy as ROS scavengers in an in vitro model of ischemia. Indeed, the coffee fruit is an important source of phenolic compounds, such as chlorogenic acids, present both in the brewed seed and in the discarded pulp. Therefore, rat brain endothelial cells, subjected to oxygen and glucose deprivation (OGD) and recovery (ogR) to mimic reperfusion, were pretreated or not with coffee by-products. The results indicate that, under OGD/ogR, the ROS accumulation was reduced by coffee by-product. Additionally, the coffee extract activated the Nrf2 antioxidant pathway via Erk and Akt kinases phosphorylation, as shown by increased Nrf2 and HO-1 protein levels. The data indicate that the daily intake of coffee by-products as a dietary food supplement represents a potential nutritional strategy to counteract aging.
Assuntos
Antioxidantes/farmacologia , Coffea/química , Fator 2 Relacionado a NF-E2/agonistas , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Traumatismo por Reperfusão/terapia , Animais , Antioxidantes/química , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Linhagem Celular , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Extratos Vegetais/química , Ratos , Traumatismo por Reperfusão/metabolismoRESUMO
Anesthesia and surgery are likely causing cognitive dysfunction in patients, especially the elderly. However, the underlying pathogenic mechanisms largely remain unclear. Accumulating evidence suggest that signaling between Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays an important role in the pathogenesis and treatment of brain dysfunction, while sulforaphane (SFN), a natural compound acting as an Nrf2 agonist, can improve brain function. In the present study, we used 9-month-old mice to perform tibial fracture surgery under isoflurane general anesthesia. Hierarchical cluster analysis of Morris water maze test (MWMT) analysis was performed to classify mice into post-operative cognitive dysfunction (POCD) versus non-POCD phenotypes. Expression levels of Keap1 and Nrf2 were significantly decreased in the medial prefrontal cortex (mPFC), hippocampus and liver, but not in the nucleus accumbens, muscle and gut of POCD mice compared to control and non-POCD mice. Interestingly, both pretreatment and posttreatment with SFN significantly improved the abnormal behaviors of mice in the MWMT, in parallel with the up-regulated levels of Keap1-Nrf2 signaling in the mPFC, hippocampus and liver. In conclusion, these results suggest that decreased Keap1-Nrf2 signaling in the mPFC, hippocampus and liver may contribute to the onset of POCD, and that SFN exerts facilitating effects on POCD symptoms by increasing Keap1-Nrf2 signaling.
Assuntos
Anestesia Geral/efeitos adversos , Hipocampo/efeitos dos fármacos , Isotiocianatos/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Nootrópicos/farmacologia , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Sulfóxidos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/agonistas , Transdução de Sinais/efeitos dos fármacosRESUMO
Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.
Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Esclerose Lateral Amiotrófica/tratamento farmacológico , Ácidos Cumáricos/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/síntese química , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/toxicidade , Idoso , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/toxicidade , Feminino , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/toxicidade , Células HEK293 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/agonistas , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/toxicidade , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
Uropathogenic Escherichia coli (UPEC) cause urinary tract infections (UTIs) by invading urothelial cells. In response, the host mounts an inflammatory response to expel bacteria. Here, we show that the NF-E2-related factor 2 (NRF2) pathway is activated in response to UPEC-triggered reactive oxygen species (ROS) production. We demonstrate the molecular sequence of events wherein NRF2 activation in urothelial cells reduces ROS production, inflammation, and cell death, promotes UPEC expulsion, and reduces the bacterial load. In contrast, loss of NRF2 leads to increased ROS production, bacterial burden, and inflammation, both in vitro and in vivo. NRF2 promotes UPEC expulsion by regulating transcription of the RAB-GTPase RAB27B. Finally, dimethyl fumarate, a US Food and Administration-approved NRF2 inducer, reduces the inflammatory response, increases RAB27B expression, and lowers bacterial burden in urothelial cells and in a mouse UTI model. Our findings elucidate mechanisms underlying the host response to UPEC and provide a potential strategy to combat UTIs.
Assuntos
Infecções por Escherichia coli/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Infecções Urinárias/metabolismo , Escherichia coli Uropatogênica/patogenicidade , Urotélio/metabolismo , Proteínas rab27 de Ligação ao GTP/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Carga Bacteriana , Linhagem Celular Tumoral , Fumarato de Dimetilo/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/microbiologia , Feminino , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Transdução de Sinais , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/genética , Infecções Urinárias/microbiologia , Urotélio/efeitos dos fármacos , Urotélio/microbiologia , Proteínas rab de Ligação ao GTP , Proteínas rab27 de Ligação ao GTP/genéticaRESUMO
Cholestasis is a common manifestation of obstruction of bile flow in various liver diseases. If the bile acid accumulation is not treated in time, it will further lead to hepatocyte damage, liver fibrosis and ultimately to cirrhosis, which seriously affects human life. The pathogenesis of cholestatic liver injury is very complicated, mainly including oxidative stress and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor responsible for upregulating expression of various genes with cytoprotective functions. Nrf2 activation has been proved to inhibit oxidative stress and inflammatory reaction, modulate bile acid homeostasis, and alleviate fibrosis during cholestasis. Therefore, Nrf2 emerges as a potential therapeutic target for cholestatic liver injury. In recent years, natural products with various biological activities including anti-inflammatory, anti-oxidant, anti-tumor and anti-fibrotic effects have received growing attention for being hepatoprotective agents. Natural products like asiatic acid, diosmin, rutin, and so forth have shown significant potential in activating Nrf2 pathway which can lead to attenuate cholestatic liver injury. Therefore, this paper emphasizes the effect of Nrf2 signaling pathway on alleviating cholestasis, and summarizes recent evidence about natural Nrf2 activators with hepatoprotective effect in various models of cholestatic liver injury, thus providing theoretical reference for the development of anti-cholestatic drug.
Assuntos
Produtos Biológicos/farmacologia , Colestase/prevenção & controle , Hepatopatias/prevenção & controle , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Fitoquímicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Produtos Biológicos/uso terapêutico , Colestase/complicações , Humanos , Hepatopatias/etiologia , Compostos Fitoquímicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
The neuropathological hallmark of Parkinson's disease (PD) is the preferential loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies in the dying neurons. Though specific molecular mechanisms for the neurodegeneration remains to be clarified, mitochondrial dysfunction and increased oxidative stress are major players associated with PD pathogenesis and these pathogenic mechanisms can be reproduced in cells and animals by application of various neurotoxins such as MPP+. In this study, we attempted to determine the neuroprotective effects of methylene blue (MB) against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity, and to elucidate its action mechanism. We observed that MB attenuated MPP+-induced apoptotic cell death in SH-SY5Y cells and the mescencephalic dopaminergic neurons. In addition, MB protected the cells against MPP+-induced oxidative stress and mitochondrial dysfunction as evidenced by restoration of mitochondrial complex I activity and ATP levels, and attenuation of oxidative stress. Moreover, we demonstrated that MB induced antioxidant molecules, and activated Nrf2 pathway through AKT activation. These results indicate that MB protects the neurons from MPP+-induced toxicity through activation of antioxidant system, thereby reducing the oxidative stress and mitochondrial impairment, implying the potential use of MB in the treatment of neurodegenerative diseases such as PD.
Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Azul de Metileno/farmacologia , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Herbicidas/toxicidade , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Neuroproteção/fisiologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologiaRESUMO
Excessive consumption of alcohol may induce severe liver damage, in part via oxidative stress and inflammatory responses, which implicates these processes as potential therapeutic approaches. Prior literature has shown that Telmisartan (TEL) may provide protective effects, presumably mediated by its anti-oxidant and anti-inflammatory activities. The purpose of this study was to determine TEL's hepatoprotective effects and to identify its possible curative mechanisms in alcoholic liver disease. A mouse chronic alcohol plus binge feedings model was used in the current study for induction of alcoholic liver disease (ALD). Our results showed that TEL (10 mg/kg/day) has the ability to reduce serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). TEL also increased the activity of superoxide dismutase (SOD) and glutathione (GSH) with concomitant reduction of nitric oxide (NO) malonaldehyde (MDA) in the liver homogenate. Moreover, TEL downregulated nuclear factor kappa B (NF-κB) expression and decreased liver content of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α). These anti-inflammatory and anti-oxidant activities were associated with a significant increase in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), peroxisome proliferator-activated receptors -γ (PPAR-γ), and heme oxygenase-1 (Hmox-1). In conclusion, TEL's hepatoprotective effects against ALD may be attributable to its anti-inflammatory and anti-oxidant activities which may be in part via the modulation of PPAR-γ/ Nrf-2/ NF-κB crosstalk.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Hepatite Alcoólica/tratamento farmacológico , Fator 2 Relacionado a NF-E2/agonistas , PPAR gama/agonistas , Telmisartan/uso terapêutico , Alanina Transaminase/sangue , Alcoolismo/complicações , Fosfatase Alcalina/sangue , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Consumo Excessivo de Bebidas Alcoólicas/complicações , Citocinas/metabolismo , Heme Oxigenase-1/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Substâncias Protetoras/uso terapêutico , Receptor Cross-Talk/efeitos dos fármacosRESUMO
Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other conditions. A library of aspirin derivatives of various scaffolds potentially activating Nrf2 has been tested in Neh2-luc reporter assay which screens for direct Nrf2 protein stabilizers working via disruption of Nrf2-Keap1 interaction. Most aspirin prodrugs had a pro-alkylating or pro-oxidant motif in the structure and, therefore, were toxic at high concentrations. However, among the active compounds, we identified a molecule resembling a well-known Nrf2 displacement activator, bis-1,4-(4-methoxybenzenesulfonamidyl) naphthalene (NMBSA). The direct comparison of the newly identified compound with NMBSA and its improved analog in the reporter assay showed no quenching with N-acetyl cysteine, thus pointing to Nrf2 stabilization mechanism without cysteine alkylation. The potency of the newly identified compound in the reporter assay was much stronger than NMBSA, despite its inhibitory action in the commercial fluorescence polarization assay was observed only in the millimolar range. Molecular docking predicted that mono-deacetylation of the novel prodrug should generate a potent displacement activator. The time-course of reporter activation with the novel prodrug had a pronounced lag-period pointing to a plausible intracellular transformation leading to an active product. Treatment of the novel prodrug with blood plasma or cell lysate demonstrated stepwise deacetylation as judge by liquid chromatography-mass spectrometry (LC-MS). Hence, the esterase-catalyzed hydrolysis of the prodrug liberates only acetyl groups from aspirin moiety and generates a potent Nrf2 activator. The discovered mechanism of prodrug activation makes the newly identified compound a promising lead for future optimization studies.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Pró-Fármacos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Estrutura Terciária de ProteínaRESUMO
BACKGROUND AND AIMS: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. APPROACH AND RESULTS: Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients. CONCLUSIONS: Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.
Assuntos
Regeneração Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Ácido Oleanólico/análogos & derivados , Adulto , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatectomia , Hepatócitos , Humanos , Fígado/fisiologia , Fígado/cirurgia , Regeneração Hepática/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/administração & dosagem , Cultura Primária de CélulasRESUMO
Substituted N-phenyl cinnamamide derivatives were designed and synthesized to confirm activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway by the electronic effect on beta-position of Michael acceptor according to introducing the R1 and R2 group. Compounds were screened using the Nrf2/antioxidant response element (ARE)-driven luciferase reporter assay. Compound 1g showed desirable luciferase activity in HepG2 cells without cell toxicity. mRNA and protein expression of Nrf2/ARE target genes such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase catalytic subunit (GCLC) were upregulated by compound 1g in a concentration-dependent manner. Treatment with 1g resulted in increased endogenous antioxidant glutathione, showing strong correlation with enhanced GCLC expression for synthesis of glutathione. In addition, tert-butyl hydroperoxide (t-BHP)-generated reactive oxygen species were significantly removed by 1g, and the results of a cell survival assay in a t-BHP-induced oxidative cell injury model showed a cytoprotective effect of 1g in a concentration dependent manner. In conclusion, the novel compound 1g can be utilized as an Nrf2/ARE activator in antioxidative therapy.
Assuntos
Cinamatos/farmacologia , Citoproteção/efeitos dos fármacos , Glutationa/biossíntese , Hepatócitos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Elementos de Resposta Antioxidante/genética , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Morte Celular/efeitos dos fármacos , Cinamatos/química , Glutationa/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Luciferases/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Substâncias Protetoras/farmacologia , terc-Butil HidroperóxidoRESUMO
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that governs a highly conserved pathway central to the protection of cells against various oxidative stresses. However, the biological impact of xenobiotic intervention of Nrf2 in physiological and pathophysiological conditions remains debatable. Activation of Nrf2 in cancer cells has been shown to elevate drug resistance and increase cell survival and proliferation, while inhibition of Nrf2 sensitizes cancer cells to drug treatment. On the other hand, activation of Nrf2 in normal healthy cells has been explored as a rather successful strategy for cancer chemoprevention. Selective activation of Nrf2 in off-target cells has recently been investigated as an approach for protecting off-target tissues from untoward drug toxicity. Specifically, induction of antioxidant response element genes via Nrf2 activation in cardiac cells is being explored as a means to limit the well-documented cardiotoxicity accompanied by cancer treatment with commonly prescribed anthracycline drugs. In addition to cancers, Nrf2 has been implicated in many other diseases including Alzheimer's and Parkinson's Diseases, diabetes, and cardiovascular disease. In this review, we discuss the roles of Nrf2 and its downstream target genes in the treatment of various diseases, and its recently explored potential for increasing the benefit: risk ratio of commonly utilized cancer treatments.
Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/prevenção & controle , Fator 2 Relacionado a NF-E2/agonistas , Substâncias Protetoras/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Cardiotoxicidade/etiologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.
Assuntos
Acetofenonas/uso terapêutico , Antioxidantes/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Hidroquinonas/uso terapêutico , Substância Branca/efeitos dos fármacos , Acetofenonas/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Lesões Encefálicas Traumáticas/patologia , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/patologia , Hidroquinonas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/agonistas , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Substância Branca/patologiaRESUMO
Lynch syndrome (LS), is an autosomal dominant disorder predisposing patients to multiple cancers, predominantly colorectal (CRC) and endometrial, and is implicated in 2-4% of all CRC cases. LS is characterized by mutations of four mismatch repair (MMR) genes which code for proteins responsible for recognizing and repairing DNA lesions occurring through multiple mechanisms including oxidative stress (OS). Increased OS can cause DNA mutations and is considered carcinogenic. Due to reduced MMR activity, LS patients have an increased risk of cancer as a result of a decreased ability to recognize and repair DNA lesions caused by OS. Due to its carcinogenic properties, reducing the level of OS may reduce the risk of cancer. Nutritional Nrf2 activators have been shown to reduce the risk of carcinogenesis in the general population through activation of the endogenous antioxidant system. Common nutritional Nrf2 activators include sulforaphane, curcumin, DATS, quercetin, resveratrol, and EGCG. Since LS patients are more susceptible to carcinogenesis caused by OS, it is hypothesized that nutritional Nrf2 activators may have the potential to reduce the risk of cancer in those with LS by modulating OS and inflammation. The purpose of this paper is to review the available evidence in support of this statement.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/genéticaRESUMO
Oxidative stress is constantly involved in the etiopathogenesis of an ever-widening range of neurodegenerative diseases. As a consequence, effective repression of cellular oxidative stress to a redox homeostatic condition is a promising and feasible strategy to treat, or at least retard the progression of, such disorders. Nrf2, a primary orchestrator of cellular antioxidant response machine, is responsible for detoxifying and compensating for deleterious oxidative stress via transcriptional activation of a diverse array of antioxidant biomolecules. In the framework of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we report herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, most of which exhibit robust neuroprotective effect against H2O2-mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds 9b and 9c with marginal cytotoxicity were selected for the follow-up studies. Our results demonstrate that their neuroprotective effects are attributed to the up-regulation of a panel of antioxidant genes and corresponding gene products. Further mechanistic studies indicate that Nrf2 is indispensable for the cellular performances of 9b and 9c, arising from the fact that silence of Nrf2 gene drastically nullifies their protective action. Taken together, 9b and 9c discovered in this work merit further development as neuroprotective candidates for the treatment of oxidative stress-mediated pathological conditions.
Assuntos
Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sulfonas/farmacologia , Compostos de Vinila/farmacologia , Animais , Antioxidantes/síntese química , Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Compostos de Vinila/síntese químicaRESUMO
Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus. High glucose has resulted in oxidative stress and following renal fibrosis as the crucial nodes of this disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating transcription of many antioxidant genes and suppressing synthesis of extracellular matrix. To discover Nrf2 activators targeting DN, we have evaluated polypodiside using cell-based assays. The results showed polypodiside inhibited the high glucose-induced self-limited proliferation of glomerular meangial cells. Activation of Nrf2 and enhanced transcription to antioxidant response elements were observed in the presence of polypodiside. Oxidative stress and accumulation of extracellular matrix induced by high glucose in glomerular meangial cells have been ameliorated by polypodiside. Further investigations revealed the effects of polypodiside on glomerular meangial cells were associated with activation of Nrf2. Co-immunoprecipitation of Nrf2 disclosed polypodiside disrupted the Kelch-like ECH-associated protein-1 (Keap1)-Nrf2 interaction. Molecular docking elucidated polypodiside could enter the Nrf2 binding cavity of Keap1 via interacting with the residues encompassing that cavity. These findings indicate polypodiside is a Keap1-dependent Nrf2 activator affording the catabatic effects against oxidative stress and accumulation of extracellular matrix in glomerular meangial cells under high glucose.
Assuntos
Matriz Extracelular/metabolismo , Glucosídeos/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Estresse Oxidativo/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cumáricos/química , Avaliação Pré-Clínica de Medicamentos , Matriz Extracelular/efeitos dos fármacos , Glucose/farmacologia , Glucosídeos/química , Glucosídeos/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Polypodium/química , Polypodium/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Preeclampsia is a pregnancy-specific syndrome and is one of the major causes of maternal mortality around the world. Cell apoptosis and oxidative stress are involved in development of preeclampsia. Silibinin has been known with anti-inflammatory, anti-oxidative and anti-tumor roles. In this study, hydrogen peroxide (H2O2) administration induced apoptosis in HTR-8/SVneo trophoblast cells, evidenced by decreased level of Bcl-2 and increased levels of Bax and cleaved caspase-3. Western blot and JC-1 staining revealed that H2O2 led to decline of mitochondrial membrane potential (Δψm) and release of cytochrome C from mitochondria to cytoplasm. H2O2 also resulted in reactive oxygen species production and oxidative stress response, evidenced by elevated levels of malondialdehyde, and reduced activity of superoxide dismutase and glutathione peroxidase. Silibinin suppressed H2O2-induced apoptosis, decrease of Δψm and oxidative stress response. In addition, immunofluorescent staining and electrophoretic mobility shift assay demonstrated that H2O2 enhanced expression and nuclear translocation of nuclear factor-erythroid 2-like 2 (Nrf2), and the expression levels of heme oxygenases-1 and quinone oxidoreductase 1 were increased, suggesting the activation of Nrf2 signaling. The activity of Nrf2 signaling was further promoted by silibinin administration. Interestingly, the effect of silibinin on apoptosis and oxidative stress was abolished by interference RNA of Nrf2. In conclusion, we demonstrated that silibinin ameliorated H2O2-induced apoptosis and oxidative stress response by activating Nrf2 signaling in trophoblast cells. These findings may provide novel insights for treatment of preeclampsia.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Peróxido de Hidrogênio/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Silibina/farmacologia , Trofoblastos/efeitos dos fármacos , Apoptose/genética , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Humanos , Peróxido de Hidrogênio/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , 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/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Trofoblastos/metabolismo , Trofoblastos/patologiaRESUMO
Rheumatoid arthritis (RA), autoimmune disease that is categorized via chronic inflammation manifestation, obesity, cardiovascular risk and even enhanced the mortality and affect the 0.3 and 1% of population worldwide. The current experimental study was scrutinize the anti-arthritic effect of ß-sitosterol loaded solid lipid nanoparticles (SLN) against complete Fruend adjuvant (CFA)-induced arthritis via dual pathway. Double emulsion solvent displacement method was used for the preparation of ß-sitosterol solid lipid nanoparticles (SLN). CFA was used to induce arthritis and rats were divided into different groups for 28 days. Biochemical, anti-inflammatory, pro-inflammatory cytokines and inflammatory mediator were estimated, respectively. Receptor activator of nuclear factor kappa-B ligand (RANKL), signal transducer and activator of transcription-3 (STAT3) nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1(HO-1) and Nuclear factor-κB (NF-κB) expression were estimated. ß-sitosterol-SLN significantly (p < .001) reduced the paw edema, arthritic index and increased the body weight. ß-sitosterol-SLN increased the redox status of synovium {reduce the malonaldehyde (MDA) and increase superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT)} level and reduced the cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-2, interleukin-6, interleukin-16, interleukin-17 and increased level of interleukin-10, Transforming growth factor beta (TGF-ß). ß-sitosterol-SLN significantly (p < .001) reduced the level of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), vascular Endothelial Growth Factor (VEGF) and NF-κB. ß-sitosterol-SLN significantly increased the expression of HO-1,Nrf2 and decreased the expression of NF-κB, RANKL, STAT3. In conclusion, ß-sitosterol SLN showed the antiarthritic effect via suppression of NF-kB and activation of HO-1/Nrf-2 pathway.
Assuntos
Artrite Reumatoide/metabolismo , Heme Oxigenase (Desciclizante)/biossíntese , Fator 2 Relacionado a NF-E2/biossíntese , NF-kappa B/biossíntese , Nanopartículas/administração & dosagem , Sitosteroides/administração & dosagem , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Adjuvante de Freund/toxicidade , Hipolipemiantes/administração & dosagem , Masculino , Fator 2 Relacionado a NF-E2/agonistas , NF-kappa B/antagonistas & inibidores , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Neisseria gonorrhoeae (N.g) is Gram-negative bacteria and can lead to endometritis in female. Toll-like receptors regulate immune response in various diseases. However, the roles of TLR2 and TLR4 in. Neisseria gonorrhoeae-induced infection damage in human endometrial epithelia were investigated. METHODS: hEECs were infected with N.g (MOI 10 and 100) and cell viability and apoptosis were measured by CCK8 and flow cytometry assays in both infected groups with the uninfected normal hEECs as negative control. TLR2/TLR4 proteins were measured by ELISA method. Pro-inflammatory markers NLRP3, PGES (PGE2) and TNF-α were assessed by RT-qPCR (mRNA expression) and Elisa (protein concentrations). Transfection assays were performed to up- or down- regulate expression of TLR2 and TLR4 so as to study the functions of TLR2/TLR4 in. N.g-infected hEECs, followed by apoptosis and inflammation assessment. Similarly, we explored the interactions between TLR2/TLR4 and Nrf2/NF-κB/p65 by knocking down TLR2/TLR4 to detect the signaling and further regulating the signaling to evaluate TLR2/ TLR4, apoptosis and inflammation in cells. RESULTS: N.g suppressed cell viabilities and induced cell apoptosis and inflammation. TLR2/TLR4 downregulation inhibited the infection damage. Nrf2 was activated while NF-κB/p65 was depleted as TLR2/ TLR4 was knocked down. Activation of Nrf2 and inhibition of NF-κB resulted in decrease of TLR2/TLR4, which could retard apoptosis and inflammation induced by N.g infection. CONCLUSION: TLR2/TLR4 depletion could alleviate the N.g-infected hEECs via Nrf2/NF-kB signaling, suggesting that TLR2/TLR4 inhibitors might serve as a treatment to reduce N.g infection in human endometrial epithelia.
Assuntos
Endometrite/imunologia , Gonorreia/imunologia , Neisseria gonorrhoeae/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Benzamidas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Di-Hidropiridinas/farmacologia , Dioxinas/farmacologia , Regulação para Baixo , Endometrite/tratamento farmacológico , Endometrite/microbiologia , Endometrite/patologia , Endométrio/citologia , Endométrio/imunologia , Endométrio/metabolismo , Endométrio/patologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Técnicas de Silenciamento de Genes , Gonorreia/tratamento farmacológico , Gonorreia/microbiologia , Gonorreia/patologia , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/metabolismoRESUMO
Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating drug side effects and enhancing cell specificity. Recently, we demonstrated the crucial role of MYC and its downstream effectors in driving osteoclast differentiation. Despite these advances, upstream regulators of MYC have not been well defined. In this study, we identify nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor known to regulate the expression of phase II antioxidant enzymes, as a novel upstream regulator of MYC. NRF2 negatively regulates receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the ERK and p38 signaling-mediated suppression of MYC transcription. Furthermore, the ablation of MYC in osteoclasts reverses the enhanced osteoclast differentiation and activity in NRF2 deficiency in vivo and in vitro in addition to protecting NRF2-deficient mice from pathological bone loss in a murine model of inflammatory arthritis. Our findings indicate that this novel NRF2-MYC axis could be instrumental for the fine-tuning of osteoclast formation and provides additional ways in which osteoclasts could be therapeutically targeted to prevent pathological bone erosion.