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Tuo Yang, Yang Sun, Leilei Mao, Meijuan Zhang, Qianqian Li, Lili Zhang, Yejie Shi, Rehana K Leak, Jun Chen, Feng Zhang
Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199)...
May 6, 2018: Redox Biology
Azhwar Raghunath, Kiruthika Sundarraj, Raju Nagarajan, Frank Arfuso, Jinsong Bian, Alan P Kumar, Gautam Sethi, Ekambaram Perumal
Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs), which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes...
May 7, 2018: Redox Biology
X K Ma, J S Liu
Objective: To investigate the expression of Nrf2 and Keap1 in nasopharyngeal carcinoma (NPC) and to analyze the relationship between the expression of Nrf2 and Keap1 and the clinicopathological features and prognosis of patients with nasopharyngeal carcinoma. Method: A total of 108 patients with biopsy-proven nonkeratinizing squamous cell carcinoma-undifferentiated type with available biopsy specimens for tissue microarray (TMA) construction were selected. The relationship between Nrf2 and Keap1 protein expression and the prognosis of radiotherapy in patients with nasopharyngeal carcinoma was analyzed...
May 2018: Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery
Kyoko Mashima, Shinichi Takahashi, Kazushi Minami, Yoshikane Izawa, Takato Abe, Naoki Tsukada, Takako Hishiki, Makoto Suematsu, Mayumi Kajimura, Norihiro Suzuki
Oxidative stress plays an important role in the onset and progression of Parkinson disease. Although released dopamine at the synaptic terminal is mostly reabsorbed by dopaminergic neurons, some dopamine is presumably taken up by astroglia. This study examined the dopamine-induced astroglial protective function through the activation of the pentose-phosphate pathway (PPP) to reduce reactive oxygen species (ROS). In vitro experiments were performed using striatal neurons and cortical or striatal astroglia prepared from Sprague-Dawley rats or C57BL/6 mice...
January 2018: ASN Neuro
Qianying Liu, Zhixin Lei, Jingchao Guo, Aimei Liu, Qirong Lu, Zainab Fatima, Haseeb Khaliq, Muhammad A B Shabbir, Muhammad Kashif Maan, Qinghua Wu, Menghong Dai, Xu Wang, Yuanhu Pan, Zonghui Yuan
Mequindox (MEQ), belonging to quinoxaline-di- N -oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice...
2018: Frontiers in Pharmacology
Claudia Orrù, Marta Szydlowska, Keiko Taguchi, Patrizia Zavattari, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano
BACKGROUND & AIMS: Dysregulation of the Keap1-Nrf2 pathway has been observed in experimental and human tumors, suggesting possible roles of the pathway in cancer development. Here we examined whether Nrf2 activation occurs at early steps of rat hepatocarcinogenesis, to assess critical contributions of Nrf2 to the onset of hepatocellular carcinoma (HCC). METHODS: We used wild type (WT) and Nrf2 knockout (Nrf2KO) rats treated with a single injection of diethylnitrosamine (DENA) followed by choline-devoid methionine-deficient (CMD) diet...
May 11, 2018: Journal of Hepatology
Pravin Shende, Chirag Patel
Diabetes is a condition that is not completely treatable but life of a diabetic patient can be smoothed by preventing or delaying the associate conditions like diabetic retinopathy, nephropathy, impaired wound healing process etc. Apart from conventional methods to regulate diabetic condition, new techniques using siRNA have been emerged to prevent the associated conditions. This paper focuses on how siRNA used as a tool to silence the expression of genes which plays critical role in pathogenesis of these conditions...
May 14, 2018: Journal of Drug Targeting
Jakob S Pallesen, Kim Tai Tran, Anders Bach
The transcription factor Nrf2 has a protective effect against oxidative stress and plays a major role in inflammation and CNS diseases. Inhibition of the protein-protein interaction (PPI) between Nrf2 and its repressor protein Keap1 leads to translocation of Nrf2 from the cytosol to the nucleus and expression of detoxifying antioxidant enzymes. To date, several non-covalent small-molecule Keap1-Nrf2 inhibitors have been identified; however, many of them contain carboxylic acids and are rather large in size, which likely prevents or decreases CNS permeability...
May 11, 2018: Journal of Medicinal Chemistry
E T Zakharova, A V Sokolov, N N Pavlichenko, V A Kostevich, I N Abdurasulova, A V Chechushkov, I V Voynova, A Yu Elizarova, N N Kolmakov, M G Bass, I V Semak, A I Budevich, P M Kozhin, N K Zenkov, V M Klimenko, O V Kirik, D E Korzhevskii, E B Menshchikova, V B Vasilyev
Among the properties of lactoferrin (LF) are bactericidal, antianemic, immunomodulatory, antitumour, antiphlogistic effects. Previously we demonstrated its capacity to stabilize in vivo HIF-1-alpha and HIF-2-alpha, which are redox-sensitive multiaimed transcription factors. Various tissues of animals receiving recombinant human LF (rhLF) responded by expressing the HIF-1-alpha target genes, hence such proteins as erythropoietin (EPO), ceruloplasmin, etc. were synthesized in noticeable amounts. Among organs in which EPO synthesis occurred were brain, heart, spleen, liver, kidneys and lungs...
May 10, 2018: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Mikko Karttunen, Wing-Yiu Choy, Elio A Cino
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) is a transcription factor and principal regulator of the antioxidant pathway. The Kelch domain of Kelch-Like ECH-Associated Protein 1 (Keap1) binds to motifs in the N-terminal region of Nrf2, promoting its degradation. There is interest in developing ligands that can compete with Nrf2 for binding to Kelch, thereby activating its transcriptional activities, and increasing antioxidant levels. Using experimental ∆Gbind values of Kelch binding motifs determined previously, a revised hydrophobicity-based model was developed for estimating ∆Gbind from amino acid sequence, and applied to rank potential uncharacterized Kelch binding motifs identified from interaction databases and BLAST searches...
May 10, 2018: Journal of Physical Chemistry. B
Svetlana V Kostyuk, Lev N Porokhovnik, Elizaveta S Ershova, Elena M Malinovskaya, Marina S Konkova, Larisa V Kameneva, Olga A Dolgikh, Vladimir P Veiko, Vladimir M Pisarev, Andrew V Martynov, Vasilina A Sergeeva, Andrew A Kaliyanov, Anton D Filev, Julia M Chudakova, Margarita S Abramova, Serguey I Kutsev, Vera L Izhevskaya, Nataliya N Veiko
Cell-free DNA (cfDNA) is a circulating DNA of nuclear and mitochondrial origin mainly derived from dying cells. Recent studies have shown that cfDNA is a stress signaling DAMP (damage-associated molecular pattern) molecule. We report here that the expression profiles of cfDNA-induced factors NRF2 and NF- κ B are distinct depending on the target cell's type and the GC-content and oxidation rate of the cfDNA. Stem cells (MSC) have shown higher expression of NRF2 without inflammation in response to cfDNA. In contrast, inflammatory response launched by NF- κ B was dominant in differentiated cells HUVEC, MCF7, and fibroblasts, with a possibility of transition to massive apoptosis...
2018: Oxidative Medicine and Cellular Longevity
Panos G Ziros, Ioannis Habeos, Dionysios V Chartoumpekis, Eleni Ntalampyra, Emmanuel Somm, Cédric O Renaud, Massimo Bongiovanni, Ioannis P Trougakos, Masayuki Yamamoto, Thomas W Kensler, Pilar Santisteban, Nancy Carrasco, Carrie Ris-Stalpers, Elena Amendola, Xiao-Hui Liao, Luciano Rossich, Lisa Thomasz, Guillermo Juan Juvenal, Samuel Refetoff, Gerasimos P Sykiotis
BACKGROUND: The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Although antioxidant and detoxification enzymes presumably aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including under conditions of exposure to excess iodide, the factors that coordinate their expression with the cellular redox status are not known...
May 10, 2018: Thyroid: Official Journal of the American Thyroid Association
Wu Ying, Zheng-Cai Li, Yao Li-Qing, Li Mai, Tang Mei
Schisandrin B (Sch B), one of Fructus Schisandrae's main effective components, protects neurons from oxidative stress in the central nervous system. Here we investigated the neuroprotective effect of Sch B in the acute oxidative stress damage and attempted to define the possible mechanisms. From the elevated plus maze (EPM) and open field test (OFT), we found that forcing swimming, an acute stressor, significantly induced anxiety-like behavior which was alleviated by Sch B (p.o.) treatment. In addition, the Sch B treatment suppressed toxicity, malondialdehyde (MDA) and reactive oxygen species (ROS), an important factor for neuron damage...
May 9, 2018: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
Ali Ramezani, Mehdi Parsa Nahad, Ebrahim Faghihloo
The nuclear factor erythroid 2 related factor 2 (Nrf2) is a major regulator of intracellular inducible defense systems against harmful endogenous and exogenous substances in the body. Under normal conditions Nrf2 is mainly binds to keap1 and located in the cytoplasm. However, in response to oxidative and electrophile stress, Nrf2 translocated to the nucleus and link to anti-oxidant response elements to induce the transcription of cytoprotective genes. Most viruses cause oxidative stress and increase the activity of radicals and reactive oxygen species (ROS), subsequently, the cellular protection system activates the Nrf2 and increases the expression of cytoprotective genes...
May 8, 2018: Journal of Cellular Biochemistry
Shumin Ding, Xuefeng Hou, Fujing Wang, Gang Wang, Xiaobin Tan, Ying Liu, Yuanli Zhou, Huihui Qiu, E Sun, Nan Jiang, Zihao Li, Jie Song, Liang Feng, Xiaobin Jia
Cigarette smoking extract (CSE)-induced autophagic injury has been regarded as an important contributor to the pathogenesis of lung cancer. We previously found that Eclipta prostrata L. component (CCE) reduced CSE-induced bronchial epithelial cells damage. However, the mechanism remains unknown. Human normal bronchial epithelial cells (NHBE) were exposed to CSE to establish stress model. Nrf2-siRNA and Keap1-siRNA transfection were performed. mRFP-GFP-LC3 dual fluorescence and transmission electron microscopy were used to observe the autophagic characteristics...
May 4, 2018: Environmental Toxicology
Erik Klapproth, Ellen Dickreuter, Falk Zakrzewski, Michael Seifert, Andreas Petzold, Andreas Dahl, Evelin Schröck, Barbara Klink, Nils Cordes
Intrinsic and acquired resistances are major obstacles in cancer therapy. Genetic characterization is commonly used to identify predictive or prognostic biomarker signatures and potential cancer targets in samples from therapy-naïve patients. By far less common are such investigations to identify specific, predictive and/or prognostic gene signatures in patients or cancer cells refractory to a specific molecular-targeted intervention. This, however, might have a great value to foster the development of tailored, personalized cancer therapy...
April 6, 2018: Oncotarget
Masayuki Yamamoto, Thomas W Kensler, Hozumi Motohashi
The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exogenous and endogenous origins. KEAP1 acts as a cysteine thiol-rich sensor of redox insults, whereas NRF2 is a transcription factor that robustly transduces chemical signals to regulate a battery of cytoprotective genes. KEAP1 represses NRF2 activity under quiescent conditions, whereas NRF2 is liberated from KEAP1-mediated repression on exposure to stresses...
July 1, 2018: Physiological Reviews
Qingwei Meng, Tao Guo, Gaoqiang Li, Shishuai Sun, Shiqi He, Baojing Cheng, Baoming Shi, Anshan Shan
Background: Resveratrol, a plant phenol, affords protection against inflammation and oxidative stress. The objective of this study was to investigate the effects of dietary resveratrol supplementation during pregnancy and lactation on the antioxidant status of sows and piglets and on antioxidant gene expression and pathway in placenta. Methods: Forty sows were allotted to 2 dietary treatments 20 d after breeding. Sows were fed a control diet and a control diet with 300 mg/kg resveratrol...
2018: Journal of Animal Science and Biotechnology
Li-Ping Liu, Bin Li, Tian-Kui Shuai, Lei Zhu, Yu-Min Li
BACKGROUND: Recent studies reported that soluble epoxide hydrolase (sEH) plays an important role in lung diseases. However, the role of sEH in hyperoxia-induced ALI is unclear. METHODS: ALI was induced by exposure to 100% oxygen in an airtight cage for 72 h in wild-type (WT) and sEH gene deletion (EPHX2-/- ) mice. ALI was assessed by the lung dry/wet ratio, alveolar capillary protein leak, and the infiltration of inflammatory cells in the lung. RESULTS: Hyperoxia elevated sEH activity in WT mice...
April 27, 2018: BMC Anesthesiology
Alexandros Priftis, Antonia-Eugenia Angeli-Terzidou, Aristidis S Veskoukis, Demetrios A Spandidos, Dimitrios Kouretas
Coffee is a popular beverage that contains various bioactive compounds. However, its molecular mechanism of action is not fully elucidated. In this context, two previously characterized coffee extracts, a lightly roasted and the corresponding green one, were investigated for their effect on nuclear factor erythroid 2‑related factor 2 (Nrf2) target gene expression in myoblasts and endothelial cells using quantitative PCR. The tested concentrations were non‑cytotoxic and led to improved redox cell status, as was evident by increased reduced glutathione (GSH) levels...
April 24, 2018: Molecular Medicine Reports
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