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https://www.readbyqxmd.com/read/29328656/design-and-synthesis-of-novel-reactive-oxygen-species-inducers-for-the-treatment-of-pancreatic-ductal-adenocarcinoma
#1
Yuting Kuang, Mario Sechi, Salvatore Nurra, Mats Ljungman, Nouri Neamati
Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29325897/an-improved-cell-permeable-fluorogenic-substrate-as-the-basis-for-a-highly-sensitive-test-for-nad-p-h-quinone-oxidoreductase-1-nqo1-in-living-cells
#2
Simone Cuff, Ruth D Lewis, Edwin Chinje, Mohammed Jaffar, Richard Knox, Ian Weeks
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme upregulated in response to oxidative stress and in some cancers. Its upregulation by compounds has been used as an indicator of their potential anti-cancer properties. In this study we have designed, produced and tested a fluorogenic coumarin conjugate which selectively releases highly fluorescent 4-methylumbelliferone (4-MU) in the presence of NQO1. It was found that measuring 4-MU release rapidly and specifically quantitated NQO1 levels in vitro and in live cells...
January 8, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29319808/intracellular-reduction-of-coenzyme-q-homologues-with-a-short-isoprenoid-side-chain-induces-apoptosis-of-hela-cells
#3
Takayuki Takahashi, Yukitoshi Mine, Tadashi Okamoto
Coenzyme Q (CoQ) is an essential factor of the mitochondrial respiratory chain. CoQ homologues with different lengths of the isoprenoid side chain are widely distributed in nature, but little is known about the relationship between the isoprenoid side chain length and biological function; therefore, we examined the effects of CoQ homologues on HeLa cells. When CoQ homologues with a shorter isoprenoid side chain than CoQ4 were added to HeLa cells, they induced cell death, and the order of cytotoxic intensity was as follows: CoQ0 ≫ CoQ3 ≈ CoQ1 > CoQ2 ≫ CoQ4...
January 8, 2018: Journal of Biochemistry
https://www.readbyqxmd.com/read/29318967/inter-individual-variability-in-activity-of-the-major-drug-metabolizing-enzymes-in-liver-homogenates-of-20-individuals
#4
J Chris Vos, Shalenie P den Braver-Sewradj, Michiel W den Braver, Marc van Dijk, Yongjie Zhang, Stefan J Dekker, Lukas Wijaya, Nico P E Vermeulen, Lysiane Richert, Jan N M Commandeur
BACKGROUND: Inter-individual variability in hepatic drug metabolizing enzyme (DME) activity is a major contributor to heterogeneity in drug clearance and safety. Accurate data on expression levels and activities of DMEs is an important prerequisite for in vitro-in vivo extrapolation and in silico based predictions. Characterization and assessment of inter-correlations of the major DMEs cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) have been extensively documented, but simultaneous quantification including other major DMEs has been lacking...
January 8, 2018: Current Drug Metabolism
https://www.readbyqxmd.com/read/29305270/the-protective-effect-of-diallyl-trisulfide-on-cytopenia-induced-by-benzene-through-modulating-benzene-metabolism
#5
Wenting Han, Shuo Wang, Ming Li, Lulu Jiang, Xujing Wang, Keqin Xie
It has been known that metabolism of benzene is necessary for its toxicity. The purpose of our study is to investigate the effect of diallyl trisulfide (DATS) on attenuating cytopenia in peripheral blood introduced by benzene through regulating benzene metabolism in rats. We established benzene poisoning model with benzene (1.3 g/kg), while the DATS treatment groups were treated with DATS plus benzene (15 or 30 mg/kg) for 28 days, respectively. The results of blood parameters and concentration of metabolites of benzene (t, t-MA and SPMA) determination in urine showed that DATS could effectively attenuate the cytopenia induced by benzene through regulating benzene metabolism...
January 2, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29304479/microrna-140-5p-aggravates-doxorubicin-induced-cardiotoxicity-by-promoting-myocardial-oxidative-stress-via-targeting-nrf2-and-sirt2
#6
Lisha Zhao, Yan Qi, Lina Xu, Xufeng Tao, Xu Han, Lianhong Yin, Jinyong Peng
Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px...
December 29, 2017: Redox Biology
https://www.readbyqxmd.com/read/29298345/redox-modulation-of-nqo1
#7
David Siegel, Donna D Dehn, Samantha S Bokatzian, Kevin Quinn, Donald S Backos, Andrea Di Francesco, Michel Bernier, Nichole Reisdorph, Rafael de Cabo, David Ross
NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates. In cells, NQO1 participates in a number of binding interactions with other proteins and mRNA and these interactions may be influenced by the concentrations of reduced pyridine nucleotides. NAD(P)H can protect NQO1 from proteolytic digestion suggesting that binding of reduced pyridine nucleotides results in a change in NQO1 structure. We have used purified NQO1 to demonstrate the addition of NAD(P)H induces a change in the structure of NQO1; this results in the loss of immunoreactivity to antibodies that bind to the C-terminal domain and to helix 7 of the catalytic core domain...
2018: PloS One
https://www.readbyqxmd.com/read/29291405/enhanced-glycometabolism-as-a-mechanism-of-nqo1-potentiated-growth-of-nsclc-revealed-by-metabolomic-profiling
#8
Xuefang Cheng, Fang Liu, Huiying Liu, Guangji Wang, Haiping Hao
NAD(P)H:quinone oxidoreductase 1 (NQO1), a cytoplasmic 2-electron reductase, has been considered as a potential poor prognostic biomarker and a promising therapeutic target for patients with non-small cell lung cancer (NSCLC) due to its frequent overexpression and significantly increased activity in NSCLC. Previous studies have shown that depleting tumor-NQO1 potentiates anoikis and inhibits growth of NSCLC. However, the underlying mechanisms whereby NQO1 potentiates proliferation have not been fully understood...
December 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29285281/activation-of-nrf2-by-mind4-17-protects-osteoblasts-from-hydrogen-peroxide-induced-oxidative-stress
#9
Shiguang Guo, Hao-Dong Fei, Feng Ji, Feng-Li Chen, Yue Xie, Shou-Guo Wang
MIND4-17 is a recently developed NF-E2-related factor 2 (Nrf2) activator, which uniquely causes Nrf2 disassociation from Keap1. Here, we showed that pretreatment with MIND4-17 significantly inhibited hydrogen peroxide (H2O2)-induced viability reduction of primary osteoblasts and OB-6 osteoblastic cells. Meanwhile, MIND4-17 inhibited both apoptotic and non-apoptotic osteoblast cell death by H2O2. MIND4-17 treatment induced Keap1-Nrf2 disassociation, causing Nrf2 stabilization, accumulation and nuclear translocation in osteoblasts, leading to transcription of several Nrf2-dependent genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), γ-glutamylcysteine synthetase modifier subunit (GCLM) and catalytic subunit (GCLC)...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29282639/estrogen-dependent-nrf2-expression-protects-against-reflux-induced-esophagitis
#10
Yudai Torihata, Kiyotaka Asanuma, Katsunori Iijima, Tetsuhiko Mikami, Shin Hamada, Naoki Asano, Tomoyuki Koike, Akira Imatani, Atsushi Masamune, Tooru Shimosegawa
BACKGROUND: Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress. AIMS: This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide. METHODS: Gastroesophageal reflux was surgically induced in male and female rats...
December 27, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29281794/reduction-and-scavenging-of-chemically-reactive-drug-metabolites-by-nad-p-h-quinone-oxidoreductase-1-and-nrh-quinone-oxidoreductase-2-and-variability-in-hepatic-concentrations
#11
Shalenie P den Braver-Sewradj, Michiel W den Braver, Robin M Toorneman, Stephanie van Leeuwen, Yongjie Zhang, Stefan J Dekker, Nico P E Vermeulen, Jan N M Commandeur, J Chris Vos
Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM...
December 27, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/29274812/cytoprotective-dihydronaphthalenones-from-the-wood-of-catalpa-ovata
#12
Yun-Seo Kil, Yang Kang So, Min Jung Choi, Ah-Reum Han, Chang Hyun Jin, Eun Kyoung Seo
Three previously undescribed dihydronaphthalenones, 7-hydroxycatalponol, (4S)-3,4-dihydro-4-hydroxy-2-[(2R)-2,3-dihydroxy-3-methylbutylidene]naphthalen-1(2H)-one, and (6S)-5,6-dihydro-6-hydroxy-2,2-dimethyl-2H-benzo[h]chromen-4(3H)-one and one phthalide, (±)-3-(5-hydroxy-5-methyl-2-oxohex-3-en-1-yl)isobenzofuran-1(3H)-one, were isolated from the wood of Catalpa ovata G. Don (Bignoniaceae), together with six known compounds. The structures of the previously undescribed compounds were elucidated by interpretation of 1D and 2D NMR data...
December 21, 2017: Phytochemistry
https://www.readbyqxmd.com/read/29260515/-mir-155-bach1-signaling-pathway-in-human-lung-adenocarcinoma-cell-death-induced-by-arsenic-trioxide
#13
Shi-Yan Gu, Hong-Yu Chen, Huang-Mei Dai, Xin-Yang Li, Zun-Zhen Zhang
OBJECTIVE: To explore the changes of micro RNA 155 (miR-155),BTB and CNC homologous protein 1 (BACH1),quinone oxidoreductase 1 (NQO1) and heme-oxygenase-1 (HO-1) in the process of arsenic trioxide-induced cell death,and to clarify the relationship between miR-155 and BACH1,providing experimental basis for the sensitivity of arsenic trioxide (ATO) treatment. METHODS: Human lung adenocarcinoma cell line A549 cells were treated with different concentrations of ATO...
November 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/29248571/the-secondary-fusarium-metabolite-aurofusarin-induces-oxidative-stress-cytotoxicity-and-genotoxicity-in-human-colon-cells
#14
Katharina Jarolim, Konstantin Wolters, Lydia Woelflingseder, Gudrun Pahlke, Julia Beisl, Hannes Puntscher, Dominik Braun, Michael Sulyok, Benedikt Warth, Doris Marko
Aurofusarin (AURO), a dimeric naphthoquinone, is produced by Fusarium fungi. Although frequently found in food and feed, toxicological studies are limited. Hence, the in vitro toxicity of AURO was investigated in the colon adenocarcinoma cell line HT29 and the non-tumorigenic colon cells HCEC-1CT. Cytotoxic effects were found at concentrations ≥1 μM by evaluating mitochondrial activity (WST-1) and cellular proliferation (sulforhodamine B assay). 10 μM of AURO induced a decrease of cells in the S-phase, measured by flow cytometry...
December 14, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29247614/mechanism-implicated-in-the-anti-allodynic-and-anti-hyperalgesic-effects-induced-by-the-activation-of-heme-oxygenase-1-carbon-monoxide-signaling-pathway-in-the-central-nervous-system-of-mice-with-neuropathic-pain
#15
Gabriela Riego, Alejandro Redondo, Sergi Leánez, Olga Pol
The administration of a carbon monoxide-releasing compound (tricarbonyldichlororuthenium(II)dimer, CORM-2) or an heme oxygenase 1 (HO-1) inductor (cobalt protoporphyrin IX, CoPP) exerts potent antinociceptive effects during chronic pain, but their actions in the central nervous system of animals with neuropathic pain have not been evaluated. Our objective is to investigate the effects of these treatments on the oxidative, inflammatory and molecular changes induced by sciatic nerve injury in several brain areas...
December 13, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29247555/the-triterpenoid-corosolic-acid-blocks-transformation-and-epigenetically-reactivates-nrf2-in-tramp-c1-prostate-cells
#16
Jie Yang, Renyi Wu, Wenji Li, Linbo Gao, Yuqing Yang, Ping Li, Ah-Ng Kong
Corosolic acid (CRA) is found in various plants and has been used as a health food supplement worldwide. Although it has been reported that CRA exhibits significant anticancer activity, the effect of this compound on prostate cancer remains unknown. In this study, we investigated the effect of CRA on cellular transformation and the reactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) through epigenetic regulation in TRAMP-C1 prostate cells. Specifically, we found that CRA inhibited anchorage-independent growth of prostate cancer TRAMP-C1 cells but not Nrf2 knockout prostate cancer TRAMP-C1 cells...
December 16, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29247444/effect-of-arsenic-exposure-on-nrf2-keap1-pathway-and-epigenetic-modification
#17
Beata Janasik, Edyta Reszka, Magdalena Stanislawska, Ewa Jablonska, Renata Kuras, Edyta Wieczorek, Beata Malachowska, Wojciech Fendler, Wojciech Wasowicz
Arsenic (As) is a known toxic element and carcinogen. Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidant genes in response to redox stress. To explore associations between As level and NRF2-regulated cytoprotective genes expression, an observational study was conducted in a population of 61 occupationally exposed men with median (Me) age 50 years (interquartile range (IQR) 42-54) and in a control group of 52 men aged 40 (IQR 31-51...
December 15, 2017: Biological Trace Element Research
https://www.readbyqxmd.com/read/29243436/-effect-of-neoflavonoid-latifolin-isolated-from-dalbergia-odorifera-on-acute-myocardial-ischemia-in-rats-and-its-mechanism-of-nrf2-signaling-pathway
#18
Xue-Liang Li, Lan-Ying Chen, Zi-Yi Guan, Yao Luo, Ya-Ru Cui, Rong-Hua Liu, Feng Shao, Ding-Qing Wang
The present study was designed to evaluate the cardioprotective effect of latifolin on pituitrin(Pit) or isoproterenol(ISO)-induced myocardial injury in rats, and further investigate its underlying mechanisms. Rats were administrated sublingually with pituitrin or subcutaneously with isoproterenol to induce acute myocardial ischemia in rats, and lead II electrocardiograph was recorded. In rats with isoproterenol, ELISA assay or colorimetric method was used to detect the content or activity of myocardial injury markers in serum, and the SOD activity and MDA content in myocardium were detected by colorimetric assay; histopathological examination was conducted by HE staining; the frozen section of myocardial tissues was used for DCFH-DA fluorescent staining to detect the content of ROS in myocardium; Western blot was used to detect the protein expression levels of Nrf2, Keap1, HO-1 and NQO1 in myocardium...
October 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29241092/trehalose-protects-against-oxidative-stress-by-regulating-the-keap1-nrf2-and-autophagy-pathways
#19
Yuhei Mizunoe, Masaki Kobayashi, Yuka Sudo, Shukoh Watanabe, Hiromine Yasukawa, Daiki Natori, Ayana Hoshino, Arisa Negishi, Naoyuki Okita, Masaaki Komatsu, Yoshikazu Higami
Dysfunction of autophagy, which regulates cellular homeostasis by degrading organelles and proteins, is associated with pathogenesis of various diseases such as cancer, neurodegeneration and metabolic disease. Trehalose, a naturally occurring nontoxic disaccharide found in plants, insects, microorganisms and invertebrates, but not in mammals, was reported to function as a mechanistic target of the rapamycin (mTOR)-independent inducer of autophagy. In addition, trehalose functions as an antioxidant though its underlying molecular mechanisms remain unclear...
September 20, 2017: Redox Biology
https://www.readbyqxmd.com/read/29225188/rosuvastatin-improves-myocardial-hypertrophy-after-hemodynamic-pressure-overload-via-regulating-the-crosstalk-of-nrf2-are-and-tgf-%C3%AE-smads-pathways-in-rat-heart
#20
Pengbo Wang, Lin Luo, Qiusheng Shen, Gaoyong Shi, Anaz Mohammed, Songshi Ni, Xiang Wu
Left ventricular hypertrophy is more commonly associated with hemodynamic overload imposed by hypertension or volume overload. Transforming growth factor β (TGF-β) is involved in the cardiac hypertrophy and fibrosis of the left ventricle. The fact that TGF-β1 and the nuclear factor erythroid 2-related factor 2 (Nrf2) both become up-regulated upon persistent vessel overload suggests that these two factors may virtually impact on their signaling pathways. In this research, 40 rats were divided into sham group, model group, rosuvastatin low and high dose group...
December 7, 2017: European Journal of Pharmacology
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