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1.
Artigo em Inglês | MEDLINE | ID: mdl-35805773

RESUMO

Arsenic is widely present in nature and is a common environmental poison that seriously damages human health. Chronic exposure to arsenic is a major environmental poisoning factor that promotes cell proliferation and leads to malignant transformation. However, its molecular mechanism remains unclear. In this study, we found that arsenite can promote the transformation of immortalized human keratinocyte cells (HaCaT) from the G0/G1 phase to S phase and demonstrated malignant phenotypes. This phenomenon is accompanied by obviously elevated levels of NRF2, NQO1, Cyclin E, and Cyclin-dependent kinase 2 (CDK2). Silencing the NRF2 expression with small interfering RNA (siRNA) in arsenite-transformed (T-HaCaT) cells was shown to reverse the malignant phenotype. Furthermore, the siRNA silencing of NQO1 significantly decreased the levels of the cyclin E-CDK2 complex, inhibiting the G0/G1 to S phase cell cycle progression and transformation to the T-HaCaT phenotypes. Thus, we hypothesized that the NRF2/NQO1 pathway played a key role in the arsenite-induced malignancy of HaCaT cells. By increasing the expression of Cyclin E-CDK2, the NRF2/NQO1 pathway can affect cell cycle progression and cell proliferation. A new common health effect mechanism of arsenic carcinogenesis has been identified; thus, it would contribute to the development of novel treatments to prevent and treat skin cancer caused by arsenic.


Assuntos
Arsênio , Arsenitos , Arsênio/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Ciclina E/farmacologia , Humanos , Queratinócitos , NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD(P)H Desidrogenase (Quinona)/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA Interferente Pequeno/metabolismo
2.
Nutrients ; 14(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35893874

RESUMO

The compound ß-lapachone, a naturally derived naphthoquinone, has been utilized as a potent medicinal nutrient to improve health. Over the last twelve years, numerous reports have demonstrated distinct associations of ß-lapachone and NAD(P)H: quinone oxidoreductase 1 (NQO1) protein in the amelioration of various diseases. Comprehensive research of NQO1 bioactivity has clearly confirmed the tumoricidal effects of ß-lapachone action through NAD+-keresis, in which severe DNA damage from reactive oxygen species (ROS) production triggers a poly-ADP-ribose polymerase-I (PARP1) hyperactivation cascade, culminating in NAD+/ATP depletion. Here, we report a novel combination strategy with aminooxyacetic acid (AOA), an aspartate aminotransferase inhibitor that blocks the malate-aspartate shuttle (MAS) and synergistically enhances the efficacy of ß-lapachone metabolic perturbation in NQO1+ breast cancer. We evaluated metabolic turnover in MDA-MB-231 NQO1+, MDA-MB-231 NQO1-, MDA-MB-468, and T47D cancer cells by measuring the isotopic labeling of metabolites from a [U-13C]glucose tracer. We show that ß-lapachone treatment significantly hampers lactate secretion by ~85% in NQO1+ cells. Our data demonstrate that combinatorial treatment decreases citrate, glutamate, and succinate enrichment by ~14%, ~50%, and ~65%, respectively. Differences in citrate, glutamate, and succinate fractional enrichments indicate synergistic effects on central metabolism based on the coefficient of drug interaction. Metabolic modeling suggests that increased glutamine anaplerosis is protective in the case of MAS inhibition.


Assuntos
Ácido Amino-Oxiacético , Neoplasias da Mama , Naftoquinonas , Ácido Amino-Oxiacético/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Citratos , Feminino , Glutamatos/metabolismo , Humanos , NAD/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Succinatos/metabolismo
3.
PLoS One ; 17(7): e0272090, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35905076

RESUMO

NAD(P)H quinone oxidoreductase 1 (NQO1) is a flavoprotein that catalyzes two-electron reduction of quinone to hydroquinone by using nicotinamide adenine dinucleotide (NADPH), and functions as a scavenger for reactive oxygen species (ROS). The function of NQO1 in the immune response is not well known. In the present study, we demonstrated that Nqo1-deficient T cells exhibited reduced induction of T helper 17 cells (Th17) in vitro during Th17(23)- and Th17(ß)- skewing conditions. Nqo1-deficient mice showed ameliorated symptoms in a Th17-dependent autoimmune Experimental autoimmune encephalomyelitis (EAE) model. Impaired Th17-differentiation was caused by overproduction of the immunosuppressive cytokine, IL-10. Increased IL-10 production in Nqo1-deficient Th17 cells was associated with elevated intracellular Reactive oxygen species (ROS) levels. Furthermore, overproduction of IL-10 in Th17 (ß) cells was responsible for the ROS-dependent increase of c-avian musculoaponeurotic fibrosarcoma (c-maf) expression, despite the lack of dependency of c-maf in Th17(23) cells. Taken together, the results reveal a novel role of NQO1 in promoting Th17 development through the suppression of ROS mediated IL-10 production.


Assuntos
NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD , Células Th17 , Animais , Antioxidantes , Interleucina-10 , Camundongos , NAD(P)H Desidrogenase (Quinona)/genética , NADH NADPH Oxirredutases , Quinonas , Espécies Reativas de Oxigênio/metabolismo , Células Th17/metabolismo
4.
Zhongguo Zhong Yao Za Zhi ; 47(10): 2698-2704, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35718489

RESUMO

This study aimed to explore the effect of artesunate(ARS) on bone destruction in rheumatoid arthritis(RA) based on the aryl hydrocarbon receptor(AhR)/AhR nucleart ranslocator(ARNT)/NAD(P)H quinone dehydrogenase 1(NQO1) signaling pathway. Macrophage-colony stimulating factor(M-CSF) and receptor activator of nuclear factor-κB(RANKL) were used to induce the differentiation of primary bone marrow-derived mouse macrophages into osteoclasts. After intervention with ARS(0.2, 0.4, and 0.8 µmol·L~(-1)), the formation and differentiation of osteoclasts were observed by tartrate-resistant acid phosphatase(TRAP) and F-actin staining. The protein expression levels of AhR and NQO1 were detected by Western blot, and their distribution in osteoclasts was observed by immunofluorescence localization. Simultaneously, the collagen induced arthritis(CIA) rat model was established using type Ⅱ bovine collagen emulsion and then treated with ARS(7.5, 15, and 30 mg·kg~(-1)) by gavage for 30 days. Following the observation of spinal cord and bone destruction in CIA rats by Masson staining, the expression of AhR and ARNT in rat knee joint tissue was measured by immunohistochemistry and the NQO1 protein expression in the knee joint tissue by Western blot. The results showed that a large number of TRAP-positive cells were present in RANKL-induced rats. Compared with the RANKL-induced group, ARS(0.2, 0.4, and 0.8 µmol·L~(-1)) inhibited the number of TRAP-positive cells in a dose-dependent manner. F-actin staining results showed that the inhibition of F-actin formation was enhanced with the increase in ARS dose. As revealed by Western blot and immunofluorescence assay, ARS significantly promoted the expression of AhR and its transfer to the nucleus, thereby activating the protein expression of downstream ARNT and antioxidant enzyme NQO1. At the same time, the CIA rat model was successfully established. Masson staining revealed serious joint destruction in the model group, manifested by the failed staining of surface cartilage, disordered arrangement of collagen fibers, and unclear boundaries of cartilage and bone. The positive drug and ARS at different doses all improved cartilage and bone destruction to varying degrees, with the best efficacy detected in the high-dose ARS group. According to immunohistochemistry, ARS promoted AhR and ARNT protein expression in knee cartilage and bone of CIA rats and also NQO1 protein expression in rat knee and ankle joint tissues. In conclusion, ARS inhibited osteoclast differentiation by activating the AhR/ARNT/NQO1 signaling pathway, thus alleviating RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Actinas/metabolismo , Animais , Artesunato/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Translocador Nuclear Receptor Aril Hidrocarboneto/farmacologia , Bovinos , Colágeno Tipo II/metabolismo , Camundongos , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Osteoclastos , Ratos , Transdução de Sinais
5.
Phytomedicine ; 104: 154255, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35738116

RESUMO

BACKGROUND: Diabetic cardiomyopathy (DC) is one of the major lethal complications in patients with diabetes mellitus (DM); however, no specific strategy for preventing or treating DC has been identified. PURPOSE: This study aimed to investigate the effects of ß-lapachone (Lap), a natural compound that increases antioxidant activity in various tissues, on DC and explore the underlying mechanisms. STUDY DESIGN AND METHODS: As an in vivo model, C57BL/6 mice were fed with the high-fat diet (HF) for 10 weeks to induce type 2 DM. Mice were fed Lap with the HF or after 5 weeks of HF treatment to investigate the protective effects of Lap against DC. RESULTS: In the two in vivo models, Lap decreased heart weight, increased heart function, reduced oxidative stress, and elevated mitochondrial content under the HF. In the in vitro model, palmitic acid (PA) was used to mimic the effects of an HF on the differentiated-cardiomyoblast cell line H9c2. The results demonstrated that Lap reduced PA-induced ROS production by increasing the expression of antioxidant regulators and enzymes, inhibiting inflammation, increasing mitochondrial activity, and thus reducing cell damage. Via the use of specific inhibitors and siRNA, the protective effects of Lap were determined to be mediated mainly by NQO1, Sirt1 and mitochondrial activity. CONCLUSION: Heart damage in DM is usually caused by excessive oxidative stress. This study showed that Lap can protect the heart from DC by upregulating antioxidant ability and mitochondrial activity in cardiomyocytes. Lap has the potential to serve as a novel therapeutic agent for both the prevention and treatment of DC.


Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Naftoquinonas , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/farmacologia , Estresse Oxidativo
6.
J Med Chem ; 65(11): 7746-7769, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35640078

RESUMO

Targeting NAD+ metabolism has emerged as an effective anticancer strategy. Inspired by the synergistic antitumor effect between NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates increasing the NAD consumption and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors hampering the NAD synthesis, first-in-class small molecules simultaneously targeting NQO1 and NAMPT were identified through structure-based design. In particular, compound 10d is an excellent NQO1 substrate that is processed faster than TSA by NQO1 and exhibited a slightly decreased NAMPT inhibitory potency than that of FK866. It can selectively inhibit the proliferation of NQO1-overexpressing A549 cells and taxol-resistant A549/taxol cells and also induce cell apoptosis and inhibit cell migration in an NQO1- and NAMPT-dependent manner in A549/taxol cells. Significantly, compound 10d demonstrated excellent in vivo antitumor efficacy in the A549/taxol xenograft models with no significant toxicity. This proof-of-concept study affirms the feasibility of discovering small molecules that target NQO1 and NAMPT simultaneously, and it also provides a novel, effective, and selective anticancer strategy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamento farmacológico , NAD/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , NADH NADPH Oxirredutases , Nicotinamida Fosforribosiltransferase/metabolismo , Paclitaxel , Quinonas
7.
J Control Release ; 347: 632-648, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35618186

RESUMO

Currently, clinical intravesical instillation chemotherapy has been greatly compromised by the toxicological and physiological factors. New formulations that can specifically and efficiently kill bladder cancer cells are in urgent need to overcome the low residence efficiency and dose limiting toxicity of current ones. The combination of mucoadhesive nanocarriers and cancer cell selective prodrugs can to great extent address these limitations. However, the insignificant endogenous stimulus difference between cancer cells and normal cells in most cases and the high local drug concentration make it essential to develop new drugs with broader selectivity-window. Herein, based on the statistically different NQO1 expression between cancerous and normal bladder tissues, the reactive oxygen species (ROS) activatable epirubicin prodrug and highly potent NQO1 substrate, KP372-1, was co-delivered using a GSH-responsive mucoadhesive nanocarrier. After endocytosis, epirubicin could be promptly activated by the NQO1-dependent ROS production caused by KP372-1, thus specifically inhibiting the proliferation of bladder cancer cells. Since KP372-1 is much more potent than some commonly used NQO1 substrates, for example, ß-lapachone, the cascade drug activation could occur under much lower drug concentration, thus greatly lowering the toxicity in normal cells and broadening the selectivity-window during intravesical bladder cancer chemotherapy.


Assuntos
Nanopartículas , Pró-Fármacos , Neoplasias da Bexiga Urinária , Administração Intravesical , Epirubicina/farmacologia , Humanos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico
8.
Future Med Chem ; 14(5): 363-383, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35102756

RESUMO

NAD(P)H:quinine oxidoreductase (NQO1) is a class of flavoprotein enzymes commonly expressed in eukaryotic cells. It actively participates in the metabolism of various quinones and their in vivo bioactivation through electron reduction reactions. The expression level of NQO1 is highly upregulated in many solid tumor cells compared with that in normal cells. NQO1 has been considered a candidate molecular target because of its overexpression and bioactivity in different tumors. NQO1-responsive prodrugs and nanocarriers have recently been identified as effective objectives for achieving controlled drug release, reducing adverse reactions and improving clinical efficacy. This review systematically introduces the research advances in applying NQO1-responsive prodrugs and nanocarriers to cancer treatment. It also discusses the existing problems and the developmental prospects of these two antitumor drug delivery systems.


Assuntos
Portadores de Fármacos/química , NAD(P)H Desidrogenase (Quinona)/metabolismo , Nanopartículas/química , Pró-Fármacos/química , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico , Quinonas/química , Quinonas/metabolismo , Quinonas/uso terapêutico
9.
Virol J ; 19(1): 23, 2022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-35101046

RESUMO

BACKGROUND: Nuclear factor E2-related factor 2 (Nrf2) is an important transcription factor which plays a pivotal role in detoxifying reactive oxygen species (ROS) and has been more recently shown to regulate inflammatory and antiviral responses. However, the role of Nrf2 in Herpes Simplex Virus type 1 (HSV-1) infection is still unclear. In this study, the interaction between the Nrf2 and HSV-1 replication was investigated. METHODS: The levels of oxidative stress was monitored by using 8-hydroxy-2'-deoxyguanosine (8-OHdG) ELISA kits, and the dynamic changes of Nrf2-antioxidant response element (Nrf2-ARE) pathway were detected by Western Blot. The effect of Nrf2-ARE pathway on the regulation of HSV-1 proliferation was analyzed by Western Blot, Real-Time PCR and TCID50 assay. RESULTS: HSV-1 infection induced oxidative stress. Nrf2 was activated, accompanied by the increase of its down-stream antioxidant enzyme heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1) in the early stage of HSV-1 infection. The proliferation of HSV-1 was inhibited by overexpression of Nrf2 or treatment with its activator tert-Butylhydroquinone (tBHQ). On the contrary, silencing of Nrf2 promotes virus replication. HO-1 is involved in the regulation of IFN response, leading to efficient anti-HSV-1 effects. CONCLUSION: Our observations indicate that the Nrf2-ARE pathway activates a passive defensive response in the early stage of HSV-1 infection. Targeting the Nrf2 pathway demonstrates the potential for combating HSV-1 infection.


Assuntos
Herpesvirus Humano 1 , Fator 2 Relacionado a NF-E2 , Antioxidantes , Herpesvirus Humano 1/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Estresse Oxidativo , Regulação para Cima
10.
Toxicol In Vitro ; 79: 105276, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34875353

RESUMO

Aloe-emodin (AE) is a natural hydroxyanthraquinone derivative that was found in many medicinal plants and ethnic medicines. AE showed a wide array of pharmacological activities including anticancer, antifungal, laxative, antiviral, and antibacterial effects. However, increasing number of published studies have shown that AE may have some hepatotoxicity effects but the mechanism is not fully understood. Studies have shown that the liver injury induced by some free hydroxyanthraquinone compounds is associated with the inhibition of some metabolic enzymes. In this study, the CYP3A4 and CYP3A1 were found to be the main metabolic enzymes of AE in human and rat liver microsomes respectively. And AE was metabolized by liver microsomes to produce hydroxyl metabolites and rhein. When CYP3A4 was knocked down in L02 and HepaRG cells, the cytotoxicity of AE was increased significantly. Furthermore, AE increased the rates of apoptosis of L02 and HepaRG cells, accompanied by Ca2+ elevation, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) overproduction. The mRNA expression of heme oxygenase-1 in L02 and HepaRG cells increased significantly in the high-dose of AE (40 µmol/L) group, and the mRNA expression of quinone oxidoreductase-1 was activated by AE in all concentrations. Taken together, the inhibition of CYP3A4 enhances the hepatocyte injury of AE. AE can induce mitochondrial injury and the imbalance of oxidative stress of hepatocytes, which results in hepatocyte apoptosis.


Assuntos
Antraquinonas/toxicidade , Citocromo P-450 CYP3A/genética , Hepatócitos/efeitos dos fármacos , Animais , Linhagem Celular , Citocromo P-450 CYP3A/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
11.
J Nutr Biochem ; 101: 108929, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34954079

RESUMO

The toxic effects of excess dietary iron within the colonic lumen are well documented, particularly in the context of Inflammatory Bowel Disease (IBD) and Colorectal Cancer (CRC). Proposed mechanisms that underpin iron-associated intestinal disease include: (1) the pro-inflammatory and ROS-promoting nature of iron, (2) gene-expression alterations, and (3) intestinal microbial dysbiosis. However, to date no studies have examined the effect of iron on the colonic epigenome. Here we demonstrate that chronic iron exposure of colonocytes leads to significant hypomethylation of the epigenome. Bioinformatic analysis highlights a significant epigenetic effect on NRF2 (nuclear factor erythroid 2-related factor 2) pathway targets (including NAD(P)H Quinone Dehydrogenase 1 [NQO1] and Glutathione peroxidase 2 [GPX2]); this demethylating effect was validated and subsequent gene and protein expression quantified. These epigenetic modifications were not observed upon the diminishment of cellular lipid peroxidation with endogenous glutathione and the subsequent removal of iron. Additionally, the induction of TET1 expression was found post-iron treatment, highlighting the possibility of an oxidative-stress induction of TET1 and subsequent hypomethylation of NRF2 targets. In addition, a strong time dependence on the establishment of iron-orchestrated hypomethylation was found which was concurrent with the increase in the intracellular labile iron pool (LIP) and lipid peroxidation levels. These epigenetic changes were further validated in murine intestinal mucosa in models administered a chronic iron diet, providing evidence for the likelihood of dietary-iron mediated epigenetic alterations in vivo. Furthermore, significant correlations were found between NQO1 and GPX2 demethylation and human intestinal tissue iron-status, thus suggesting that these iron-mediated epigenetic modifications are likely in iron-replete enterocytes. Together, these data describe a novel mechanism by which excess dietary iron is able to alter the intestinal phenotype, which could have implications in iron-mediated intestinal disease and the regulation of ferroptosis.


Assuntos
Enterócitos/metabolismo , Epigênese Genética , Glutationa Peroxidase/genética , Mucosa Intestinal/metabolismo , Ferro na Dieta , Ferro/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , Animais , Células CACO-2 , Colo/metabolismo , Metilação de DNA , Epigenoma , Ferritinas/genética , Ferritinas/metabolismo , Compostos Ferrosos/farmacologia , Glutationa Peroxidase/metabolismo , Humanos , Camundongos , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Oxirredutases/genética , Oxirredutases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo
12.
ACS Appl Mater Interfaces ; 13(50): 59708-59719, 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34879654

RESUMO

Responsive drug delivery systems possess great potential in disease diagnosis and treatment. Herein, we develop an activatable prodrug and fluorescence imaging material by engineering the endogenous NAD(P)H:quinone oxidoreductase-1 (NQO1) responsive linker. The as-prepared nanomaterials possess the NQO1-switched drug release and fluorescence enablement, which realizes the tumor-specific chemotherapy and imaging in living mice. The enzyme-sensitive prodrug nanoparticles exhibit selectively potent anticancer performance to NQO1-positive cancer and ignorable off-target toxicity. This work provides an alternative strategy for constructing smart prodrug nanoplatforms with precision, selectivity, and practicability for advanced cancer imaging and therapy.


Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Medicina de Precisão , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Teste de Materiais , Camundongos , Estrutura Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Imagem Óptica , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química
13.
Int J Mol Sci ; 22(23)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34884772

RESUMO

Royal jelly (RJ) is secreted by honeybees and has been used as an apitherapy to obtain healthy skin since ancient times. However, the mechanism of the protective effects of RJ against skin aging and skin diseases caused by skin stress and its components have not been clarified. In this study, we attempted to understand the effect of RJ on epidermal function and observed that NAD(P)H quinone dehydrogenase 1 (NQO1) is significantly induced by RJ in keratinocytes. The expression of NQO1 was also increased in the 3D epidermal skin model. NQO1 is involved in antioxidation and detoxification metabolism, and we found that RJ protects against the epidermal stress caused by UVB and menadione through the upregulation of NQO1. We identified 10-hydroxy-2-decenoic acid (10H2DA), a major fatty acid in RJ, as an active compound in this reaction as it induced the expression of NQO1 and protected the skin against oxidative stress. We demonstrated that the protective effect of RJ against epidermal stress is mediated through the upregulation of NQO1 by 10H2DA.


Assuntos
Antioxidantes/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos/farmacologia , NAD(P)H Desidrogenase (Quinona)/biossíntese , Animais , Abelhas , Células Cultivadas , Epiderme/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/análise , Humanos , Queratinócitos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pele/patologia , Regulação para Cima
15.
Drug Deliv ; 28(1): 2361-2372, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34747277

RESUMO

Although podophyllotoxin (POD) demonstrates high efficiency to inhibit various cancers, its clinic application is limited to poor bioavailability. Nanoparticles derived from homodimeric prodrugs with high drug loading potential are emerging as promising nanomedicines. However, complete intracellular drug release remains a major hindrance to the use of homodimeric prodrugs-based nanomedicine. We sought to develop a reactive oxygen species (ROS) responsive POD dimeric prodrug by incorporating vitamin K3 (VK3) and Pluronic F127 to synthesize a spheroid nanoparticle (PTV-NPs). PTV-NPs with high POD content could release drugs under the ROS enrichment microenvironment in cancer cells. The released VK3 could produce abundant ROS selectively in tumor cells catalyzed by the overexpressed NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme. In turn, the resultant high ROS concentration promoted the conversion of POD dimeric prodrug to POD monomer, thereby achieving the selective killing of cancer cells with weak system toxicity. In vitro and in vivo studies consistently confirmed that PTV-NPs exhibit high drug loading potential and upstanding bioavailability. They are also effectively internalized by tumor cells, induce abundant intracellular ROS generation, and have high tumor-specific cytotoxicity. This ROS-responsive dimeric prodrug nanoplatform characterized by selective self-amplification drug release may hold promise in the field of antitumor drug delivery.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias/patologia , Podofilotoxina/administração & dosagem , Podofilotoxina/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NAD(P)H Desidrogenase (Quinona)/metabolismo , NADP/metabolismo , Nanopartículas/química , Podofilotoxina/farmacocinética , Poloxâmero/química , Polímeros/química , Pró-Fármacos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/fisiologia , Vitamina K 3/química , Ensaios Antitumorais Modelo de Xenoenxerto
16.
BMC Cancer ; 21(1): 1234, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789190

RESUMO

BACKGROUND: ß-lapachone (ß-lap), the NQO1 bioactivatable drug, is thought to be a promising anticancer agent. However, the toxic side effects of ß-lap limit the drug use, highlighting the need for a thorough understanding of ß-lap's mechanism of action. ß-lap undergoes NQO1-dependent futile redox cycling, generating massive ROS and oxidative DNA lesions, leading to cell death. Thus, base excision repair (BER) pathway is an important resistance factor. XRCC1, a scaffolding component, plays a critical role in BER. METHODS: We knocked down XRCC1 expression by using pLVX-shXRCC1 in the MiaPaCa2 cells and BxPC3 cells and evaluated ß-lap-induced DNA lesions by γH2AX foci formation and alkaline comet assay. The cell death induced by XRCC1 knockdown + ß-lap treatment was analysed by relative survival, flow cytometry and Western blotting analysis. RESULTS: We found that knockdown of XRCC1 significantly increased ß-lap-induced DNA double-strand breaks, comet tail lengths and cell death in PDA cells. Furthermore, we observed combining XRCC1 knockdown with ß-lap treatment switched programmed necrosis with ß-lap monotherapy to caspase-dependent apoptosis. CONCLUSIONS: These results indicate that XRCC1 is involved in the repair of ß-lap-induced DNA damage, and XRCC1 loss amplifies sensitivity to ß-lap, suggesting targeting key components in BER pathways may have the potential to expand use and efficacy of ß-lap for gene-based therapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Quebras de DNA de Cadeia Dupla , Naftoquinonas/farmacologia , Neoplasias Pancreáticas/terapia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/deficiência , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Sobrevivência Celular , Ensaio Cometa , Reparo do DNA , DNA de Neoplasias/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular , Histonas/metabolismo , Humanos , Pontos de Checagem da Fase M do Ciclo Celular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/efeitos adversos , Naftoquinonas/metabolismo , Necroptose/efeitos dos fármacos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poli(ADP-Ribose) Polimerase-1/biossíntese , Pontos de Checagem da Fase S do Ciclo Celular
17.
Int J Mol Sci ; 22(21)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34769515

RESUMO

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation of NADH to NAD+, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD+ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD+ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD+ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis.


Assuntos
Neoplasias da Mama/complicações , Armadilhas Extracelulares/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD/metabolismo , Naftoquinonas/farmacologia , Trombofilia/tratamento farmacológico , Tromboplastina/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Sirtuína 1/metabolismo , Trombofilia/etiologia , Trombofilia/prevenção & controle , Tromboplastina/antagonistas & inibidores , Trombose/tratamento farmacológico , Trombose/etiologia , Trombose/prevenção & controle
18.
Oxid Med Cell Longev ; 2021: 5544600, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691356

RESUMO

Supplemental oxygen administration is frequently used in premature infants and adults with pulmonary insufficiency. NADPH quinone oxidoreductase (NQO1) protects cells from oxidative injury by decreasing reactive oxygen species (ROS). In this investigation, we tested the hypothesis that overexpression of NQO1 in BEAS-2B cells will mitigate cell injury and oxidative DNA damage caused by hyperoxia and that A-1221C single nucleotide polymorphism (SNP) in the NQO1 promoter would display altered susceptibility to hyperoxia-mediated toxicity. Using stable transfected BEAS-2B cells, we demonstrated that hyperoxia decreased cell viability in control cells (Ctr), but this effect was differentially mitigated in cells overexpressing NQO1 under the regulation of the CMV viral promoter, the wild-type NQO1 promoter (NQO1-NQO1), or the NQO1 promoter carrying the SNP. Interestingly, hyperoxia decreased the formation of bulky oxidative DNA adducts or 8-hydroxy-2'-deoxyguanosine (8-OHdG) in Ctr cells. qPCR studies showed that mRNA levels of CYP1A1 and NQO1 were inversely related to DNA adduct formation, suggesting the protective role of these enzymes against oxidative DNA injury. In SiRNA experiments entailing the NQO1-NQO1 promoter, hyperoxia caused decreased cell viability, and this effect was potentiated in cells treated with CYP1A1 siRNA. We also found that hyperoxia caused a marked induction of DNA repair genes DDB2 and XPC in Ctr cells, supporting the idea that hyperoxia in part caused attenuation of bulky oxidative DNA lesions by enhancing nucleotide excision repair (NER) pathways. In summary, our data support a protective role for human NQO1 against oxygen-mediated toxicity and oxidative DNA lesions in human pulmonary cells, and protection against toxicity was partially lost in SNP cells. Moreover, we also demonstrate a novel protective role for CYP1A1 in the attenuation of oxidative cells and DNA injury. Future studies on the mechanisms of attenuation of oxidative injury by NQO1 should help in developing novel approaches for the prevention/treatment of ARDS in humans.


Assuntos
Pulmão/metabolismo , Pulmão/fisiopatologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo , Humanos , Pulmão/patologia
19.
Oxid Med Cell Longev ; 2021: 2637577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630847

RESUMO

Studies have shown that the peroxidation caused by oxygen free radicals is an important reason of vascular endothelial dysfunction and multiple diseases. In this study, active peptides (F2ds) were isolated from the fermentation product of rice dregs and its antioxidant effects were approved. Human umbilical vein endothelial cells (HUVECs) stimulated by H2O2 were used to evaluate the antioxidation effect and its molecular mechanism in the oxidative stress model. F2d protected H2O2-induced damage in HUVECs in a dosage-dependent manner. F2d can reduce the expression of Keap1, promote the expression of Nrf2, and activate the downstream target HO-1, NQO1, etc. It means F2d can modulate the Nrf2 signaling pathway. Using Nrf2 inhibitor ML385 to block the Nrf2 activation, the protective function of F2d is partially lost in the damage model. Our results indicated that F2d isolated from rice exerts antioxidant effects via the Nrf2 signaling pathway in H2O2-induced damage, and the work will benefit to develop functional foods.


Assuntos
Antioxidantes/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oryza/química , Peptídeos/farmacologia , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Aspergillus niger , Sobrevivência Celular/efeitos dos fármacos , Fermentação , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oryza/microbiologia , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo
20.
Oxid Med Cell Longev ; 2021: 5147069, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630849

RESUMO

Intestinal ischemia-reperfusion (I/R) may induce cell/tissue injuries, leading to multiple organ failure. Based on our preexperiments, we proposed that sesamin could protect against and ameliorate intestinal I/R injuries and related disorders with involvement of activating Nrf2 signaling pathway. This proposal was evaluated using SD intestinal I/R injury rats in vivo and hypoxia/reoxygenation- (H/R-) injured rat small intestinal crypt epithelial cell line (IEC-6 cells) in vitro. Sesamin significantly alleviated I/R-induced intestinal histopathological injuries and significantly reduced serum biochemical indicators ALT and AST, alleviating I/R-induced intestinal injury in rats. Sesamin also significantly reversed I/R-increased TNF-α, IL-6, IL-1ß, and MPO activity in serum and MDA in tissues and I/R-decreased GSH in tissues and SOD in both tissues and IEC-6 cells, indicating its anti-inflammatory and antioxidative stress effects. Further, sesamin significantly decreased TUNEL-positive cells, downregulated the increased Bax and caspase-3 protein expression, upregulated the decreased protein expression of Bcl-2 in I/R-injured intestinal tissues, and significantly reversed H/R-reduced IEC-6 cell viability as well as reduced the number of apoptotic cells among H/R-injured IEC-6 cell, showing antiapoptotic effects. Activation of Nrf2 is known to ameliorate tissue/cell injuries. Consistent with sesamin-induced ameliorations of both intestinal I/R injuries and H/R injuries, transfection of Nrf2 cDNA significantly upregulated the expression of Nrf2, HO-1, and NQO1, respectively. On the contrary, either Nrf2 inhibitor (ML385) or Nrf2 siRNA transfection significantly decreased the expression of these proteins. Our results suggest that activation of the Nrf2/HO-1/NQO1 signaling pathway is involved in sesamin-induced anti-inflammatory, antioxidative, and antiapoptotic effects in protection against and amelioration of intestinal I/R injuries.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Dioxóis/administração & dosagem , Heme Oxigenase (Desciclizante)/metabolismo , Enteropatias/tratamento farmacológico , Enteropatias/metabolismo , Lignanas/administração & dosagem , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Sesamum/química , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Intestinal/citologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética , Transfecção , Resultado do Tratamento
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