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Objective: To assess the nuclear factor-erythroid 2-related factor-2 (Nrf2) modulatory effect of caffeic acid and protocatechuic acid and determine the anti-tumor activity of these phenolic compounds against Ehrlich ascites carcinoma growth in mice. Methods: Antioxidant activity of protocatechuic acid and caffeic acid was assessed using ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH). Nrf2 activation potential of phenolic compounds was tested by quantitative realtime polymerase chain reaction, and luciferase complementation reporter assays. In vivo efficacy was tested using the Ehrlich ascites carcinoma model. Results: FRAP and DPPH radical scavenging assays showed that caffeic acid and protocatechuic acid were more potent compared with cinnamic acid and benzoic acid. Luciferase complementation reporter assays identified caffeic acid and protocatechuic acid as the activators of Nrf2. Both caffeic acid and protocatechuic acid upregulated the expression of Nrf2 target genes heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM) and the activity of NAD(P)H:quinone oxidoreductase 1 (NQO1) when tested on HCT-116 cells using a cell-based assay system at 9 h. In addition, intraperitoneal administration of caffeic acid and protocatechuic acid to Ehrlich ascites carcinoma bearing mice suppressed tumor growth and angiogenesis. Conclusions: Caffeic acid and protocatechuic acid can modulate Nrf2 and inhibit Ehrlich ascites carcinoma cells.
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The present study aimed to explore the effect of nuclear factor erythroid 2 related factor 2(Nrf2)/heme oxygenase-1(HO-1) signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis(UC). After the UC model was induced by 3% dextran sodium sulfate(DSS), experimental animals were randomly divided into control group, model group, salazosulfapyridine(SASP) group, and low-and high-dose Sishen Pills groups. Drug intervention(ig) was performed for seven consecutive days during modeling. On the 7 th day, the mice were euthanized. The body weight and colon length were recorded, and the histopathological changes of the colon were observed by HE staining. Serum interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and reactive oxygen species(ROS) were detected by ELISA. The protein and mRNA expression of Nrf2, HO-1, and NADPH quinine oxidoreductase-1(NQO-1) was determined by Western blot and reverse transcription-polymerase chain reaction(RT-PCR). Compared with the normal group, the model group exhibited reduced body weight, colon length, and T-AOC, increased IL-6, TNF-α, MDA, and ROS, and diminished protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. Compared with the model group, the SASP group and high-dose Sishen Pills group showed elevated body weight, colon length, and T-AOC, lowered IL-6, TNF-α, MDA, and ROS levels, and increased protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. As assessed by HE staining, Sishen Pills could improve the pathological changes of the colon. The findings suggested that Sishen Pills could protect the colon against UC induced by 3% DSS. The specific mechanism of action may be related to the anti-inflammatory and anti-oxidative stress effects by the activation of the Nrf2/HO-1 signaling pathway.
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Animals , Mice , Colitis, Ulcerative/genetics , Dextran Sulfate , Heme Oxygenase-1/metabolism , NF-E2-Related Factor 2/metabolism , Signal TransductionABSTRACT
Objective:To explore the mechanism of Banxia Xiexintang （BXXX） in preventing and treating chronic atrophic gastritis （CAG） through Kelch-like ECH-associated protein 1 （Keap1）/nuclear factor erythroid 2-related factor 2 （Nrf2）/antioxidant response element （ARE） signaling pathway. Method:SD rats were divided into a normal group （<italic>n</italic>=12） and an experimental group for CAG model induction. The model rats were then randomly divided into a model group， a vatacoenayme （VG） group （60 mg·kg<sup>-1</sup>）， and high- （280 mg·kg<sup>-1</sup>）， medium- （140 mg·kg<sup>-1</sup>）， and low-dose （70 mg·kg<sup>-1</sup>） BXXX groups. The doses in the BXXX groups were equivalent to 28， 14， and 7 g·kg<sup>-1</sup> crude drugs. The rats in the normal group and the model group received distilled water at an equal volume， and those in the VG group and the BXXX groups were treated correspondingly by gavage. After 12 weeks of treatment， hematoxylin-eosin （HE） staining was carried out to observe pathological changes in the gastric mucosa of CAG rats. Western blot and real-time fluorescence-based quantitative PCR was used to detect the protein and mRNA expression levels of Nrf2， glutathione S-transferase （GST）， and NAD （P）H：quinone oxidoreductase 1 （NQO1） in the gastric mucosa of CAG rats. Result:Compared with the normal group， the model group showed increased protein and mRNA expression levels of Nrf2， NQO1， and GST in the gastric mucosa of the rats （<italic>P</italic><0.05）， atrophic gastric mucosa， and even intestinal metaplasia. The protein and mRNA expression levels of Nrf2， NQO1， and GST in the VG group and the high- and medium-dose BXXX groups were lower than those in the model group （<italic>P</italic><0.05）， and gastric mucosa atrophy and intestinal metaplasia were significantly improved， especially in the high-dose BXXX group. However， the effect in the low-dose BXXX group was not significant. Conclusion:BXXX can blunt the transcriptional activity of Nrf2， shut down Nrf2 signaling pathway， and reduce the expression levels of NQO1 and GST to achieve normal oxidation-anti-oxidation balance， which may be one of its action mechanisms in the treatment of CAG.
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OBJECTIVE: To investigate the anti-oxidant mechanism of andrographolide on HaCaT cells via Nrf2/ARE signal pathway. METHODS: The effect of andrographolide on the viability of HaCaT cells and the effect of H2O2-induced cell viability were measured by CCK-8. HaCaT cells were pretreated with andrographolide of different concentration for 24 h. The protein and mRNA expression levels of Nrf2, HO-1, AKR1C1 and NQO1 in HaCaT cells were detected by Western blot and RT-qPCR, respectively. The expression of Nrf2 protein in the nucleus was analyzed by nuclear cytoplasmic separation and immunofluorescence. RESULTS: Andrographolide had no significant effect on cell viability and dose-dependently decreased H2O2-induced cell death, the difference was statistically significant. Andrographolide significantly enhanced the expression of protein and mRNA of antioxidant enzymes Nrf2, HO-1, AKR1C1, NQO1, increased the distribution of Nrf2 in the nucleus, and up-regulated the expression of ARE. Besides, andrographolide upregulated the phosphorylation level of the upstream protein kinase AMPKα (p-AMPKα). CONCLUSION: Andrographolide could decrease H2O2-induced cell death, and its mechanism may be through the activation of Nrf2/ARE signaling pathway, thereby regulating the expression levels of HO-1, AKR1C1, and NQO1.
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Objective: To investigate the reproductive protective effect of Duzhong Butiansu Capsule (DBC) by using cyclophosphamide induced spermatogenic disorder model, and explore its mechanism. Methods: The model of spermatogenic disorder was established by intraperitoneal injection of cyclophosphamide (60 mg/kg) for 5 d. Drug intervention at high and low doses (1.388 g/kg and 0.694 g/kg) was given for 4 weeks from the 8th day. The body weight and organ index of each group were measured. The pathological structure of testis was detected by HE staining. ELISA method was used to detect the levels of T, FSH, LH, MDA, SOD, GSH-Px. Western blotting and immunohistochemistry were used to analyze the expression of Nrf2/ARE signaling pathway related factors Nrf2, HO-1, NQO1, HDAC2, and p-PKC in testicular tissue. Results: Compared with the model group, DBC significantly reduced the weight of mice, increased the index of testis, epididymis and kidney, improved the pathological morphology of testis, increased the number of spermatozoa, increased the motility of sperm, decreased the rate of abnormal sperm, increased the level of T and decreasd the level of LH and FSH, increased the content of MDA, decreased the content of SOD and GSH-Px, increased the expression of Nrf2, HO-1, NQO1, HDAC2, and p-PKC protein, and increased the area of positive expression of Nrf2, HO-1 protein (P < 0.05 or P < 0.01). Conclusion: DBC can obviously improve the spermatogenic disorder induced by cyclophosphamide, and the mechanism may be related to the regulation of Nrf2/ARE signal pathway associated with oxidative stress.
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Objective: To investigate the expression of NAD (P) H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) in T-cell lymphoma (TCL), and investigate the correlation between these two indicators and other clinicopathological parameters in TCL. Methods: Clinical data of 61 patients with TCL who were initially diagnosed in Gansu Provincial Hospital were analyzed retrospectively. Immunohistochemical examination was performed to detect NQO1 and HO-1 expression levels in 61 TCL tissues (TCL group) and 20 lymph node reactive hyperplasia tissues (control group). Results: Positive expression rates of NQO1 and HO-1 were significantly higher in TCL tissues than in lymph node reactive hyperplasia tissues (P<0.05). NQO1 expression was closely related with Ann-Arbor clinical stage and B symptoms (P<0.05); HO-1 expression was correlated with clinical stage, bone marrow invasion, and B symptoms (P<0.05). NQO1 and HO-1 expression levels were not related to age, sex, lactate dehydrogenase level, and pathological type (P>0.05); there was a correlation between NQO1 and HO-1 expression (r=0.264; P=0.040). Conclusions: NQO1 and HO-1 are highly expressed in TCL and may interact and contribute to the occurrence and development of TCL.
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OBJECTIVE Glioblastomas(GBM)are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutics are urgently needed. Here, we reported 2-methoxy-6-acetyl-7-methyljuglone (MAM)-induced cell death in U87 and U251 glioma cancer cells. METHODS Cells were cultured and treated with MAM, the cell viability was determined by MTT assay and LDH assay. Intracellular reactive oxygen species (ROS) generation was observed by DCF fluorescence. The protein expression was determined by Western blotting. RESULTS MAM induced glioma cancer cell death without caspase activation. The cell death induced by MAM was attenuated by the pharmacological or genetic blockage of necroptosis signaling,including RIP1 inhibitor necrostatin-1s (Nec-1s)and siRNA-mediated gene silencing of RIP1 and RIP3,but was unaffected by caspase inhibitor z-vad-fmk or necrosis inhibitor 2-(1H-Indol-3-yl)-3-pentylamino-maleimide (IM54). MAM treated U87 and U251 glioma cancer cells induced RIP1/RIP3 complex formation, ROS level increased, ATP concentration decreased and loss of plasma membrane integrity, further confirmed this process was necroptosis.The essential role of ROS was confirmed by the protective effect of ROS scavenger NAC. Interestingly, MAM induced necroptosis both triggered by RIP1/RIP3 complex and ROS generation. Moreover, MAM induced necroptosis through cytosolic calcium (Ca2 +) accumulation and sustained c-Jun N-terminal kinase (JNK) activation. Both calcium chelator BAPTA-AM and JNK inhibitor SP600125 could attenuate cell death. Further, we found there exists a feedback loop between RIP1 and JNK activation.Finally,MAM induced necroptosis was inhibited by dicoumarol(a NQO1 inhibitor). Dicoumarol exposed glioma cancer cells were resistant to RIP1/RIP3 complex formation and ROS generation. MAM induced necroptosis was independent of MLKL. CONCLUSION MAM induced non-canonical necroptosis through the NQO1-dependent ROS and RIP1/RIP3 pathway.This study also provided new insights into the molecular regulation of necroptosis in human glioma cancer cells and a promising approach for GBM treatment.
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Objective To investigate the difference of iNOS and NQO1 in breast cancer with different mo-lecular subtypes and the correlation between clinical parameters,and to explore the clinical treatment of breast can-cer. Methods The data on 100 patients with breast cancer who had undergone modified radical mastectomy was retrospectively reviewed.Expressions of iNOS and NQO1 were detected by immunohistochemistry.Numeration data was processed using χ2test or Fisher′s exact test.Spearman correlation was applied to analyze different clinical mo-lecular pathological features.Results NQO1 expression was correlated with TNM staging and lymph node metasta-sis(χ2=6.603,4.938,P<0.05),and the expression rate of NQO1 in overexpressing of HER-2 was higher than that in type luminal A(χ2=8.341,P < 0.008). Expression of iNOS was related to expression of Ki-67,stage of TNM and lymph node metastasis(χ2=5.243,8.157,and 5.929,P<0.05),the expression rate of iNOS in lumi-nal A was significantly lower than that in type luminal B(χ2=7.990,P<0.008).Conclusions The expression of NQO1 and iNOS may be involved the process of oxidative stress associated with breast cancer,and it plays an im-portant role in the development of breast cancer. Different molecular level of oxidative stress between the types of breast cancer may be different,whose molecular mechanism needs to be further studied.
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A diet rich in tocotrienols has been shown to be beneficial for health. However, its detailed mechanism of action is still not fully understood. NAD(P)H:quinone oxidoreductase 1 (NQO1) is important in cellular defence due to its ability to detoxify reactive quinones and quinoneimines to their less toxic hydroquinones forms. The objective of this study is to investigate the effects of different doses of palm oil-derived tocotrienol rich fraction (palm TRF) supplementation on NQO1 gene and protein expression in mice livers. Western blot and qPCR assays were used to detect NQO1 expression levels. It was found that palm TRF significantly induced NQO1 expression at all doses given. In conclusion, palm TRF treatment increased NQO1 gene and protein expression in mice liver dose dependently, with the highest expression seen in mice treated with 1000 mg/kg palm TRF, followed by 500 and 200 mg/kg respectively.
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Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD(+), repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.
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Humans , Abietanes , Pharmacology , Apoptosis , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Genetics , Cell Line, Tumor , Cytokines , Genetics , Metabolism , Enzyme Inhibitors , Pharmacology , NAD , Metabolism , NAD(P)H Dehydrogenase (Quinone) , Genetics , Metabolism , Naphthoquinones , Pharmacology , Nicotinamide Phosphoribosyltransferase , Genetics , MetabolismABSTRACT
Objective To investigate the clinicopathological significance of upregulated NQO 1 protein expression in uterine cervix carcinoma ( UCC) .Methods Immunohistochemical staining was performed on paraf-fin-embedded UCC specimens from 123 patients.Disease-free survival(DFS)and overall survival(OS)rates for all cervical UCC patients were calculated using the Kaplan -Meier method ,and univariate or multivariate analyses were performed using the Cox proportional hazards regression model .Results The NQO1 protein showed a main-ly cytoplasmic staining pattern in cervical cancer cells ,and the strongly positive rate of NQO 1 was significantly higher in UCC.High-level NQO1 was closely associated with poor differentiation ,late-stage,lymph node metas-tasis and high-risk for HPV infection.Additionally,high-level NQO1 was associated with lower DFS and OS rates .Furthermore ,Cox analysis revealed that NQO 1 expression emerged as a significant independent hazard factor for DFS rate in patients with UCC .Conclusion NQO1 overexpression might be an independent biomarker for prognostic evaluation of UCCs .
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BACKGROUND: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD+ by various quinones and thereby elevates the intracellular NAD⁺ levels. In this study, we examined the effect of increase in cellular NAD⁺ levels on bleomycin-induced lung fibrosis in mice. METHODS: C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with β-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor β1 (TGF-β1) and β-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). RESULTS: β-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-β1, α-smooth muscle actin accumulation. In addition, β-lapachone showed a protective role in TGF-β1–induced ECM expression and EMT in A549 cells. CONCLUSION: Our results suggest that β-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-β1–induced EMT in vitro, by elevating the NAD+/NADH ratio through NQO1 activation.
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Animals , Mice , Actins , Bleomycin , Bronchoalveolar Lavage Fluid , Cytokines , Epithelial-Mesenchymal Transition , Extracellular Matrix , Fibrosis , Idiopathic Pulmonary Fibrosis , In Vitro Techniques , Inflammation , Lung Diseases , Lung Diseases, Interstitial , Lung , NAD , Pneumonia , Pulmonary Fibrosis , Quinones , Transforming Growth Factor beta1 , Transforming Growth FactorsABSTRACT
Objective: To study the effect and mechanism of thymoquinone in the growth inhibition of ovarian cancer. Methods: After ovarian cancer cells SKOV3 were treated with thymoquinone, cell growth was observed by the CCK-8 assay and apoptosis was evaluated by ELISA. ROS in SKOV3 cells was detected by fluorescent probe. The expression of Keap1 protein, nuclear Nrf2 protein, P-Akt protein, Akt protein, NQO1 protein, and GCLC protein in SKOV3 cells was analyzed by Western blotting assay. NQO1 and GCLC mRNA were analyzed by RT-PCR. SKOV3 cells were injected into nude mice to establish engrafted tumor model. Immunohistochemistry was used to detect the positive expression of NQO1, GCLC, and Nrf2 in the ovarian tumors. Results: Compared with the control group, thymoquinone significantly inhibited the proliferation of SKOV3 cells and increased the apoptosis (P < 0.05, 0.01). Thymoquinone could lessen the expression of nuclear Nrf2 protein and P-Akt protein (P < 0.05), but significantly increase the expression of Keap1 protein (P < 0.001). Protein and mRNA expression of NQO1 and GCLC in SKOV3 cells treaded by thymoquinone, were lower than those in the control group (P < 0.05, 0.01). The positive expression of NQO1, GCLC, and Nrf2 was also decreased in ovarian tumors after treatment of thymoquinone (P < 0.05, 0.01). Conclusion: Thymoquinone could inhibit the proliferation of ovarian cancer cells by inhibiting the expression of nuclear Nrf2, increasing the generation of ROS in ovarian cancer cells to promote apoptosis.
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The role of genetic polymorphisms of NAD(P)H:quinone oxidoreductase 1 (NQO1), which is known to be related to carcinogen metabolism and oxidative status, was evaluated for lung cancer development. The genotypes of two NQO1 polymorphisms, namely, IVS1-27C>G and Ex6+40C>T, were determined in 616 lung cancer cases and 616 lung cancer-free controls and haplotypes composed of the two polymorphisms were estimated. In the evaluation of the effect of the NQO1 genotypes or diplotypes, we did not find any significant association with lung cancer risk after adjusting for body mass index and smoking status. However, when we evaluated the effect of the NQO1 diplotypes for lung cancer risk in combination with smoking, smokers without the C-T/C-T diplotype showed a significantly increased risk of lung cancer compared with nonsmokers without the C-T/C-T diplotype (adjusted OR, 2.2; 95% CI, 1.67-3.02), and smokers with the C-T/C-T diplotype showed the highest OR of lung cancer (adjusted OR, 2.7; 95% CI, 1.78-4.21). Moreover, a trend test showed an additive interaction between smoking and the NQO1 C-T/C-T diplotype (P(trend) < 0.01). The additive effect of smoking and the NQO1 C-T/C-T diplotype was more apparent in squamous cell carcinoma, although this effect was statistically significant in all lung cancer cell types (all cell types, P(trend) < 0.05). This result suggests that haplotypes of the NQO1 gene play an important role in the development of lung cancer by interaction with smoking.
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Aged , Female , Humans , Male , Middle Aged , Carcinoma, Non-Small-Cell Lung/epidemiology , Genetic Predisposition to Disease , Haplotypes/genetics , Lung Neoplasms/epidemiology , NAD(P)H Dehydrogenase (Quinone)/genetics , Polymorphism, Single Nucleotide/genetics , Risk , Small Cell Lung Carcinoma/epidemiology , Smoking/adverse effectsABSTRACT
Purpose To investigate the distribution of polymorphisms of quinone oxidoreductase 1 (NQO1) C609T gene in breast cancer patients, and to analyze the relationship with breast cancer molecular subtype. Methods Genotyping of C609T rs1800566 lo-cus of NQO1 gene in peripheral blood of 248 cases of female breast cancer were detected using high-throughput TaqMan MGB real-time fluorescence quantitative PCR technology, while the detection of ER, PR, HER-2 and Ki-67 in cancerous tissues were used with immu-nohistochemical staining and FISH gene amplification. Results Among 248 cases of breast cancer patients, CC genotype accounted for 27. 42% (68/248), CT genotype accounted for 49. 60% (123/248), TT genotype accounted for 22. 98% (57/248), which con-sistent with Hardy-Weinberg equilibrium law genetic (P>0. 05). 5 cases of HER-2 (++) who did not undergo FISH testing were re-moved, all the rest were done with FISH detection. Luminal A type accounted for 15. 2% (37/243), Luminal B type accounted for 51. 4% (125/243), HER-2 overexpression type accounted for 19. 8% (48/243), basal cell type accounted for 13. 6% (33/243). Compared with patients carrying the CC genotype, ER and PR positive rates in breast cancer patients carrying CT and TT genotype was significantly higher (P0. 05). There was no statistically difference on distribution of C609T polymorphism of NQO1 gene among different molecular sub-types of breast cancer (P>0. 05). Conclusions Here is no relationship between C609T polymorphism of NQO1 gene and breast cancer molecular subtype, miss rate of NQO1 ( CT+TT) in basal cell carcinoma is lower, and its gene polymorphism may provide the reasonable explanation to the heterogeneity of breast cancer molecular subtype.
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NAD(P)H:quinone-oxidoreductase-1 (NQO1) is a cytosolic enzyme that catalyses two- or four-electron reduction of many endogenous and environmental quinones using flavin adenine dinucleotide (FAD) as a cofactor. It is a cytosolic enzyme exists as a homodimer and is biochemically distinguished by its prominent ability to use either NADH or NADPH as reducing cofactors and by its suppression by the anticoagulant dicumarol. This enzyme generally considered as a detoxification enzyme due to of its ability to diminish reactive quinones and quinoneimines to its less reactive and less toxic hydroquinones forms. NQO1 is a substantially inducible enzyme that is controlled by the Nrf2-Keap1/ARE pathway. Evidence for the significance of the antioxidant functions of NQO1 in suppression of oxidative stress is provided by manifestations that induction of NQO1 levels or their reduction are associated with reduced and raised susceptibilities to oxidative stress, respectively. The gene coding for NQO1 has two common polymorphisms at nucleotide position 609(C-T) and 465 (C-T) of the human cDNA. C465T causes reduction in enzyme activity, whereas the C609T results in complete loss of enzymatic activity due to protein instability.In this review, we discuss the protective functions of NQO1 and present its possible transcriptional pathways regulating its induction by Nrf2-Keap1/ARE pathway.
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Aims: Breast cancer is the most common cancer in women worldwide, being exposure to estrogens the acknowledged main risk factor. CYP17, CYP19 and NQO1 are enzymes involved in the estrogen metabolism, so their polymorphisms may be involved in breast carcinogenesis. The aim of this study was to determine the magnitude of the association between CYP17 MspA1, CYP19 Arg264Cys, and NQO1 C609T polymorphisms and breast cancer in young women. Methods: This is a hospital-based case-control study carried out in Rio de Janeiro. Cases were 270 women with age range 18-35 years and a histopathological diagnosis of breast cancer between 1999-2009. Controls were 270 women without cancer at the same age range. Results: An association between CYP17 MspA1 or CYP19 Arg264Cys polymorphisms and breast cancer were not observed (OR = 1.02, 95% CI 0.72-1.44 for CYP17 genotypes TC/CC and OR = 0.85, 95% CI 0.48-1.49 for CYP19 genotypes CT/TT). However, a statistically significant increased risk estimate was identified in women who had at least one NQO1 polymorphic allele (T), OR= 1.96, 95% CI 1.13-3.40 following adjustment for selected confounders. Conclusion: This study suggests that the NQO1 609T polymorphism may be a risk factor for breast carcinogenesis in women less than 36 years in Brazil.
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Purpose To investigate the prognostic significance of NQO1 protein expression in colorectal carcinoma ( CRC) patients. Methods 192 cases of primary CRC, 28 of colonic dysplasia, and 44 of adjacent non-tumor tissues were selected for immunohisto-chemical staining of NQO1 protein. Correlation between NQO1 overexpression and clinicopathologic characteristics, and the survival rates were calculated by the statistical methods. Results The strongly positive rate of NQO1 protein in CRC was significantly higher than that in gastric dysplasia and adjacent non-tumor tissues (P<0. 01, respectively). NQO1 high-expression rate was positively cor-related with differentiation, serosal invasion, lymph node metastasis, and clinical stage (P <0. 05, respectively). Survival curve showed that the disease-free survival and 5-year survival rates of the patients with high NQO1 expression were obviously shorter than those of patients with low NQO1 expression (P<0. 001, respectively). Further analysis showed that, high expression of NQO1 predic-ted the lower disease-free survival and 5-year survival rates in late-stage patients (P<0. 01, respectively). Importantly, NQO1 was an independent risk factor for the prognosis of CRC using Cox proportional hazards regression model ( HR: 1. 398,95%CI: 1. 011 ~1. 934, P=0. 043). Conclusions Detection of NQO1 protein expression in CRC has an important clinical significance, and it is ex-pected to become a new biomarker for CRC.
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Parkinson's disease (PD) is a progressive neurodegenerative movement disorder associated with a selective loss of the dopamine(DA)rgic neurons in the substantia nigra pars compacta and the degeneration of projecting nerve fibers in the striatum. Because there is currently no therapy that delays the neurodegenerative process, modification of the disease course by neuroprotective therapy is an important unmet clinical need. Toward this end, understanding cellular mechanisms that render the nigral neurons particularly vulnerable have been a subject of intensive research. Increasing evidence suggests that oxidative stress plays a major role. The metabolism of DA itself contributes to oxidative stress, resulting in modification of intracellular macromolecules whose functions are important for cell survival. Mitochondrial dysfunction and the consequent increase in reactive oxygen species also trigger a sequence of events that leads to cell demise. In addition, activated microglia produce nitric oxide and superoxide during neuroinflammatory responses, and this is aggravated by the molecules released by damaged DAergic neurons such as alpha-synuclein, neuromelanin and matrix metalloproteinase-3. Ways to reduce oxidative stress therefore can provide a therapeutic strategy. NAD(P)H:quinone reductase (NQO1) and other antioxidant enzymes, whose gene expression are commonly under the regulation of the transcription factor Nrf2, can serve as target proteins utilized toward development of disease-modifying therapy for PD.
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alpha-Synuclein , Cell Survival , Dopamine , Gene Expression , Melanins , Microglia , Movement Disorders , Nerve Fibers , Neurons , Nitric Oxide , Oxidative Stress , Oxidoreductases , Parkinson Disease , Proteins , Reactive Oxygen Species , Substantia Nigra , Superoxides , Transcription FactorsABSTRACT
Beta-lapachone (beta-Lap; 3,4-dihydro-2, 2-dimethyl-2H-naphthol[1, 2-b]pyran-5,6-dione) is a novel anti-cancer drug under phase I/II clinical trials. beta-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human cancer cells in vitro and in vivo. The mechanisms underlying the beta-Lap toxicity against cancer cells has been controversial. The most recent view is that beta-Lap, which is a quinone compound, undergoes two-electron reduction to hydroquinone form utilizing NAD(P)H or NADH as electron source. This two-electron reduction of beta-Lap is mediated by NAD(P)H:quinone oxidoreductase (NQO1), which is known to mediate the reduction of many quinone compounds. The hydroquinone forms of beta-Lap then spontaneously oxidizes back to the original oxidized beta-Lap, creating futile cycling between the oxidized and reduced forms of beta-Lap. It is proposed that the futile recycling between oxidized and reduced forms of beta-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced beta-Lap is converted first to one-electron reduced beta-Lap, i.e., semiquinone beta-Lap (SQ).- causing production of reactive oxygen species (ROS), which then causes apoptotic cell death. The second mechanism is that severe depletion of NAD(P)H and NADH as a result of futile cycling between the quinone and hydroquinone forms of beta-Lap causes severe disturbance in cellular metabolism leading to apoptosis and necrosis. The relative importance of the aforementioned two mechanisms, i.e., generation of ROS or depletion of NAD(P)H/NADH, may vary depending on cell type and environment. Importantly, the NQO1 level in cancer cells has been found to be higher than that in normal cells indicating that beta-Lap may be preferentially toxic to cancer cells relative to non-cancer cells. The cellular level of NQO1 has been found to be significantly increased by divergent physical and chemical stresses including ionizing radiation. Recent reports clearly demonstrated that beta-Lap and ionizing radiation kill cancer cells in a synergistic manner. Indications are that irradiation of cancer cells causes long-lasting elevation of NQO1, thereby sensitizing the cells to beta-Lap. In addition, beta-Lap has been shown to inhibit the repair of sublethal radiation damage. Treating experimental tumors growing in the legs of mice with irradiation and intraperitoneal injection of beta-Lap suppressed the growth of the tumors in a manner more than additive. Collectively, beta-Lap is a potentially useful anti-cancer drug, particularly in combination with radiotherapy.