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Keap1

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https://www.readbyqxmd.com/read/29330291/keap1-inhibits-metastatic-properties-of-nsclc-cells-by-stabilizing-architectures-of-f-actin-and-focal-adhesions
#1
Bo Wu, Shu Yang, Haimei Sun, Tingyi Sun, Fengqing Ji, Yurong Wang, Lie Xu, Deshan Zhou
Low expression of the tumor suppressor, Kelch-like ECH-associated protein 1 (KEAP1) in non-small cell lung cancer (NSCLC) often results in higher malignant biological behavior and poor prognosis; however, the underlying mechanism remains unclear. The present study demonstrates that overexpression of Keap1 significantly suppresses migration and invasion of three different lung cancer cells (A549, H460, and H1299). Highly-expressed Keap1, compared to the control, promotes formation of multiple stress fibers with larger mature focal adhesion complexes in the cytoplasm where only fine focal adhesions were observed in the membrane under control conditions...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29323338/ulinastatin-attenuates-lps-induced-inflammation-in-mouse-macrophage-raw264-7-cells-by-inhibiting-the-jnk-nf-%C3%AE%C2%BAb-signaling-pathway-and-activating-the-pi3k-akt-nrf2-pathway
#2
Si-Tong Li, Qi Dai, Shu-Xian Zhang, Ya-Jun Liu, Qiu-Qiong Yu, Fei Tan, Shu-Hong Lu, Quan Wang, Jian-Wen Chen, He-Qing Huang, Pei-Qing Liu, Min Li
Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions, which is widely used for the treatment of various diseases, such as pancreatitis and sepsis. Although the therapeutic effects of UTI are reported to be associated with a variety of mechanisms, the signaling pathways mediating the anti-inflammatory action of UTI remain to be elucidated. In the present study we carried out a systematic study on the anti-inflammatory and anti-oxidative mechanisms of UTI and their relationships in LPS-treated RAW264...
January 11, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29316436/oncogenic-kras-regulates-amino-acid-homeostasis-and-asparagine-biosynthesis-via-atf4-and-alters-sensitivity-to-l-asparaginase
#3
Dana M Gwinn, Alex G Lee, Marcela Briones-Martin-Del-Campo, Crystal S Conn, David R Simpson, Anna I Scott, Anthony Le, Tina M Cowan, Davide Ruggero, E Alejandro Sweet-Cordero
KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation...
January 8, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29306329/gene-expression-signature-regulated-by-the-keap1-nrf2-cul3-axis-is-associated-with-a-poor-prognosis-in-head-and-neck-squamous-cell-cancer
#4
Akhileshwar Namani, Md Matiur Rahaman, Ming Chen, Xiuwen Tang
BACKGROUND: NRF2 is the key regulator of oxidative stress in normal cells and aberrant expression of the NRF2 pathway due to genetic alterations in the KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2 like 2)-CUL3 (cullin 3) axis leads to tumorigenesis and drug resistance in many cancers including head and neck squamous cell cancer (HNSCC). The main goal of this study was to identify specific genes regulated by the KEAP1-NRF2-CUL3 axis in HNSCC patients, to assess the prognostic value of this gene signature in different cohorts, and to reveal potential biomarkers...
January 6, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29305174/inhibition-of-autophagy-reverses-alcohol-induced-hepatic-stellate-cells-activation-through-activation-of-nrf2-keap1-are-signaling-pathway
#5
Zheng-Yuan Xie, Zhi-Hua Xiao, Fen-Fen Wang
BACKGROUND: Numerous documents have indicated a critical role of autophagy in alcoholic liver fibrosis (ALF), but few papers have reported its function in hepatic stellate cells (HSCs) activation. The current study aimed to investigate the regulation effect of autophagy in HSCs activation, in further to explore the underlying mechanism involved. METHODS: HSC-T6 cells were treated with ethanol, 3-MA (autophagy inhibitor) or rapamycin (autophagy inducer), and cells were also transfected with si-Nrf2 or si-Keap1...
January 2, 2018: Biochimie
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/29300356/synergistic-promotion-on-tyrosinase-inhibition-by-antioxidants
#7
Yan Wang, Mi-Mi Hao, Ying Sun, Li-Feng Wang, Hao Wang, Yan-Jun Zhang, Hong-Yan Li, Peng-Wei Zhuang, Zhen Yang
When exposed to ultraviolet radiation, the human skin produces profuse reactive oxygen species (ROS), which in turn activate a variety of biological responses. Mounting ROS levels activate tyrosinase by mobilizing α-melanocyte-stimulating hormone in the epidermis and finally stimulates the melanocytes to produce melanin. Meanwhile, the Keap1-Nrf2/ARE pathway, which removes ROS, is activated at increased ROS levels, and antioxidant compounds facilitates the dissociation of Nrf2. In this study, we explored the possible suppressing effects of antioxidant compounds and tyrosine inhibitors on melanin formation and the promotory effects of these compounds on ROS scavenging...
January 4, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29285281/activation-of-nrf2-by-mind4-17-protects-osteoblasts-from-hydrogen-peroxide-induced-oxidative-stress
#8
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/29285219/microrna-200a-activates-nrf2-signaling-to-protect-osteoblasts-from-dexamethasone
#9
Sai Zhao, Li Mao, Shou-Guo Wang, Feng-Li Chen, Feng Ji, Hao-Dong Fei
Treatment with dexamethasone in human osteoblasts leads to oxidative stress and cell injures. NF-E2-related factor 2 (Nrf2) is a key anti-oxidant signaling. We want to induce Nrf2 activation via microRNA-mediated silencing its suppressor Keap1. Our results show that microRNA-200a ("miR-200a") expression depleted Keap1, causing Nrf2 protein stabilization in OB-6 osteoblastic cells. Reversely, the miR-200a anti-sense led to Keap1 upregulation and Nrf2 degradation. miR-200a expression activated Nrf2 signaling, which inhibited dexamethasone-induced reactive oxygen species production and OB-6 cell death/apoptosis...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29274776/nrf2-p62-autophagy-pathway-and-its-response-to-oxidative-stress-in-hepatocellular-carcinoma
#10
REVIEW
Bartolini Desirée, Dallaglio Katiuscia, Torquato Pierangelo, Piroddi Marta, Francesco Galli
Deregulation of autophagy is proposed to play a key pathogenic role in hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the third leading cause of cancer death. Autophagy is an evolutionarily conserved catabolic process activated to degrade and recycle cell's components. Under stress conditions, such as oxidative stress and nutrient deprivation, autophagy is an essential survival pathway that operates in harmony with other stress response pathways. These include the redox-sensitive transcription complex Nrf2-Keap1 that controls groups of genes with roles in detoxification and antioxidant processes, intermediary metabolism, and cell cycle regulation...
November 29, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/29274336/the-long-non-coding-rna-malat1-activates-nrf2-signaling-to-protect-human-umbilical-vein-endothelial-cells-from-hydrogen-peroxide
#11
Rong Zeng, Rui Zhang, Xitao Song, Leng Ni, Zhichao Lai, Changwei Liu, Wei Ye
The potential effect of the long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) against hydrogen peroxide (H2O2)-induced oxidative injury in endothelial cells was tested. We show that forced-expression of MALAT1 using a lentiviral vector ("LV-MALAT1") significantly attenuated H2O2-induced death and apoptosis of human umbilical vein endothelial cells (HUVECs). Conversely, knocking down of MALAT1 by targeted siRNA exacerbated H2O2-induced HUVEC injury. For the mechanism study, we show that LV-MALAT1 induced Keap1 downregulation, leading to nuclear-factor-E2-related factor 2 (Nrf2) stabilization and activation...
December 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29273684/sp600125-suppresses-keap1-expression-and-results-in-nrf2-mediated-prevention-of-diabetic-nephropathy
#12
Huan Zhang, Xiuxia Liu, Shanshan Zhou, Ye Jia, Ying Li, Yuguo Song, Junnan Wang, Hao Wu
c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125's protection against DN...
December 22, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/29258755/effects-of-dietary-dandelion-extract-on-intestinal-morphology-antioxidant-status-immune-function-and-physical-barrier-function-of-juvenile-golden-pompano-trachinotus-ovatus
#13
Xiaohong Tan, Zhenzhu Sun, Chuanpeng Zhou, Zhong Huang, Lianjie Tan, Pengwei Xun, Qianqian Huang, Heizhao Lin, Chaoxia Ye, Anli Wang
Intestinal morphology, antioxidant status, immune function and tight junction proteins mRNA expression were examined in golden pompano (Trachinotus ovatus) that fed respectively six diets containing dandelion extracts (DE) at 0, 0.5, 1, 2, 4 and 10 g kg-1 after 8 weeks feeding. The study indicated that dietary DE significantly improved intestinal antioxidant abilities by increasing SOD, CAT, T-AOC activities and up-regulating intestinal cat, gpx mRNA levels, but by decreasing MDA content and down-regulating intestinal keap1 mRNA levels in golden pompano...
December 16, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29249781/nrf2-inhibition-affects-cell-cycle-progression-during-early-mouse-embryo-development
#14
Ying Lin, Liu-Cai Sui, Rong-Hua Wu, Ru-Jun Ma, Hai-Yan Fu, Juan-Juan Xu, Xu-Hua Qiu, Li Chen
Brusatol, a quassinoid isolated from the fruit of Bruceajavanica, has recently been shown to inhibit nuclear factor erythroid 2-related factor 2 (Nrf2) via Keap1-dependent ubiquitination and proteasomal degradation or protein synthesis. Nrf2 is a transcription factor that regulates the cellular defense response. Most studies have focused on the effects of Nrf2in tumor development. Here, the critical roles of Nrf2 in mouse early embryonic development were investigated. We found that brusatol treatment at the zygotic stage prevented the early embryo development...
December 16, 2017: Journal of Reproduction and Development
https://www.readbyqxmd.com/read/29248720/ckip-1-affects-the-polyubiquitination-of-nrf2-and-keap1-via-mediating-smurf1-to-resist-hg-induced-renal-fibrosis-in-gmcs-and-diabetic-mice-kidneys
#15
Wenyan Gong, Zhiquan Chen, Yezi Zou, Lei Zhang, Junying Huang, Peiqing Liu, Heqing Huang
Our previous study indicated that Casein kinase 2 interacting protein-1 (CKIP-1) could promote the activation of the nuclear factor E2-related factor 2 (Nrf2)/ antioxidant response element (ARE) pathway, playing a significant role in inhibiting the fibrosis of diabetic nephropathy (DN). However, the underlying mechanism is still unknown. Here, we investigated whether CKIP-1 affects the polyubiquitination of Nrf2 and its cytosolic inhibitor kelch like ECH-associated protein 1 (Keap1) via mediating Smad ubiquitylation regulatory factor-1 (Smurf1) to promote the activation of the Nrf2/ARE signaling and resist high glucose (HG)-induced renal fibrosis in glomerular mesangial cells (GMCs) and diabetic mice kidneys...
February 1, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29247444/effect-of-arsenic-exposure-on-nrf2-keap1-pathway-and-epigenetic-modification
#16
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/29245136/small-maf-functions-in-the-maintenance-of-germline-stem-cells-in-the-drosophila-testis
#17
Sharon Wui Sing Tan, George W Yip, Toshio Suda, Gyeong Hun Baeg
Reactive oxygen species (ROS) are byproducts generated during normal cellular metabolism, and redox states have been shown to influence stem cell self-renewal and lineage commitment across phyla. However, the downstream effectors of ROS signaling that control stem cell behavior remain largely unexplored. Here, we used the Drosophila testis as an in vivo model to identify ROS-induced effectors that are involved in the differentiation process of germline stem cells (GSCs). In the Affymetrix microarray analysis, 152 genes were either upregulated or downregulated during GSC differentiation induced by elevated levels of ROS, and a follow-up validation of the gene expression by qRT-PCR showed a Spearman's rho of 0...
December 8, 2017: Redox Biology
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/29242678/keap1-and-done-targeting-the-nrf2-pathway-with-sulforaphane
#19
Albena T Dinkova-Kostova, Jed W Fahey, Rumen V Kostov, Thomas W Kensler
Background: Since the re-discovery of sulforaphane in 1992 and the recognition of the bioactivity of this phytochemical, many studies have examined its mode of action in cells, animals and humans. Broccoli, especially as young sprouts, is a rich source of sulforaphane and broccoli-based preparations are now used in clinical studies probing efficacy in health preservation and disease mitigation. Many putative cellular targets are affected by sulforaphane although only one, KEAP1-NRF2 signaling, can be considered a validated target at this time...
November 2017: Trends in Food Science & Technology
https://www.readbyqxmd.com/read/29241092/trehalose-protects-against-oxidative-stress-by-regulating-the-keap1-nrf2-and-autophagy-pathways
#20
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
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