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Cheng-Wei Wu, Andrew Deonarine, Aaron Przybysz, Kevin Strange, Keith P Choe
SKN-1/Nrf are the primary antioxidant/detoxification response transcription factors in animals and they promote health and longevity in many contexts. SKN-1/Nrf are activated by a remarkably broad-range of natural and synthetic compounds and physiological conditions. Defining the signaling mechanisms that regulate SKN-1/Nrf activation provides insights into how cells coordinate responses to stress. Nrf2 in mammals is regulated in part by the redox sensor repressor protein named Keap1. In C. elegans, the p38 MAPK cascade in the intestine activates SKN-1 during oxidative stress by promoting its nuclear accumulation...
October 2016: PLoS Genetics
Bryan J Mathis, Taixing Cui
There has been a continued interest in translational research focused on both natural products and manipulation of functional groups on these compounds to create novel derivatives with higher desired activities. Oleanolic acid, a component of traditional Chinese medicine used in hepatitis therapy, was modified by chemical processes to form 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO). This modification increased anti-inflammatory activity significantly and additional functional groups on the CDDO backbone have shown promise in treating conditions ranging from kidney disease to obesity to diabetes...
2016: Advances in Experimental Medicine and Biology
Virve Sihvola, Anna-Liisa Levonen
Reactive oxygen species (ROS) and products of their reactions with cellular macromolecules such as unsaturated fatty acids have been implicated to be important regulators of signalling processes via oxidation or alkylation of redox active thiol residues in target proteins. One of key redox-sensitive signalling proteins mediating the response to oxidant stress is Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1), which is a negative regulator of transcription factor Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and the central hub for sensing endogenous and environmental oxidative and electrophilic stress...
October 18, 2016: Archives of Biochemistry and Biophysics
Izabela Jatczak-Pawlik, Michal Gorzkiewicz, Maciej Studzian, Dietmar Appelhans, Brigitte Voit, Lukasz Pulaski, Barbara Klajnert-Maculewicz
PURPOSE: Fourth-generation poly(propylene imine) dendrimers fully surface-modified by maltose (dense shell, PPI-m DS) were shown to be biocompatible in cellular models, which is important for their application in drug delivery. We decided to verify also their inherent bioactivity, including immunomodulatory activity, for potential clinical applications. We tested their effects on the THP-1 monocytic cell line model of innate immunity effectors. METHODS: To estimate the cytotoxicity of dendrimers the reasazurin assay was performed...
October 20, 2016: Pharmaceutical Research
Yunlong Shan, Zhonghong Wei, Li Tao, Siliang Wang, Feng Zhang, Cunsi Shen, Hongyan Wu, Zhaoguo Liu, Pingting Zhu, Aiyun Wang, Wenxing Chen, Yin Lu
Cancer prevention through intake of biologically active natural products appears to be an accessible way to reduce the risk of cancer. Diallyl disulfide (DADS), a major garlic derivative, has exhibited potential role in cancer therapy. The study is aimed to evaluate the prophylactic effect of DADS in chemically induced mouse skin carcinogenesis and investigate the molecular targets mediated by DADS. Two-stage chemically induced carcinogenesis model by cutaneous application of DMBA and subsequent TPA was established to study the prophylactic effect of DADS...
October 19, 2016: Scientific Reports
Rashi Arora, Sharad Sawney, Vikas Saini, Chris Steffi, Manisha Tiwari, Daman Saluja
BACKGROUND: A handful of studies have exploited antitumor potential of esculetin, a dihydroxy coumarine derivative; the targets to which it binds and the possible downstream mechanism for its cytotoxicity in cancer cells remain to be elucidated. Using pancreatic cancer cell lines as a model system, herein the study was initiated to check the efficacy of esculetin in inhibiting growth of these cancer cells, to decipher mechanism of its action and to predict its direct binding target protein...
October 18, 2016: Molecular Cancer
X Liu, X Zhang, K Ma, R Zhang, P Hou, B Sun, S Yuan, Z Wang, Z Liu
Matrine is a quinolizidine alkaloid derived from the herb Radix Sophorae Flavescentis, and possesses anti-oxidant, anti-inflammatory and anti-tumoral properties. However, its effectiveness against subarachnoid hemorrhage (SAH) is not well known. In this study, we investigated the effects of matrine on early brain injury (EBI) and the related potential mechanisms following SAH in rats. Our results showed that matrine pretreatment partially alleviated SAH-induced EBI, including neurological deficit, severity of SAH grade, brain edema, and blood-brain barrier (BBB) disruption in rats...
September 30, 2016: Cellular and Molecular Biology
Masahiro Nezu, Tomokazu Souma, Lei Yu, Hiroki Sekine, Takashi Moriguchi, Nobuyuki Takahashi, Sadayoshi Ito, Norio Suzuki, Masayuki Yamamoto
OBJECTIVE: Placental activation of the renin-angiotensin system (RAS) plays an important role in pathogenesis of preeclampsia. RAS induces reactive oxygen species (ROS) production by activating NADPH oxidases. Keap1-Nrf2 system is a critical regulator for cellular anti-oxidative stress response through controlling transcription of antioxidant genes. This study has explored the relationship between RAS-induced ROS signaling and Keap1-Nrf2 system in preeclampsia. DESIGN AND METHOD: To examine the contribution of Keap1-Nrf2 system to preeclampsia pathology, we generated transgenic mouse models of preeclampsia/pregnancy-associated hypertension (PAH mice), in which RAS is activated selectively in late pregnancy, under deficient, normal or active Nrf2 conditions...
September 2016: Journal of Hypertension
Asad Jan, Brandon Jansonius, Alberto Delaidelli, Syam Prakash Somasekharan, Forum Bhanshali, Milène Vandal, Gian Luca Negri, Don Moerman, Ian MacKenzie, Frédéric Calon, Michael R Hayden, Stefan Taubert, Poul H Sorensen
Soluble oligomers of amyloid-β (Aβ) impair synaptic plasticity, perturb neuronal energy homeostasis, and are implicated in Alzheimer's disease (AD) pathogenesis. Therefore, significant efforts in AD drug discovery research aim to prevent the formation of Aβ oligomers or block their neurotoxicity. The eukaryotic elongation factor-2 kinase (eEF2K) plays a critical role in synaptic plasticity, and couples neurotransmission to local dendritic mRNA translation. Recent evidence indicates that Aβ oligomers activate neuronal eEF2K, suggesting a potential link to Aβ induced synaptic dysfunction...
October 17, 2016: Acta Neuropathologica
Anton Chechushkov, Natalia Zaitseva, Elena Vorontsova, Petr Kozhin, Elena Menshchikova, Vyacheslav Shkurupiy
AIMS: Linear dextrans are often proposed as drug delivery systems with milder adverse effects and lower effective drug concentrations. Linear dextrans are polysaccharides that can potentially be used to load macrophages with drugs to transport them to a site of inflammation. Recently, it was reported that dextrans may exert a protective effect vis-à-vis drug cytotoxicity and during wound healing. The aim of the current work was to evaluate molecular mechanisms of action of dextrans that may be relevant to the cytoprotective effects...
October 13, 2016: Life Sciences
Wei-Jun Wu, Wan-Wan Jia, Xin-Hua Liu, Li-Long Pan, Qiu-Yan Zhang, Di Yang, Xiao-Yan Shen, Liang Liu, Yi Zhun Zhu
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. Hydrogen sulfide (H2S), the third physiological gasotransmitter, is well recognized as an anti-inflammatory mediator in various inflammatory conditions. Herein, we explored the protective effects of S-propargyl-cysteine (SPRC, also known as ZYZ-802), an endogenous H2S modulator, on RA and determined the underlying mechanisms. In the present study, SPRC concentration-dependently attenuated inflammatory mediator expression, reactive oxidase species generation, and the expression and activity of matrix metalloproteinases (MMP)-9 in interleukin (IL)-1β-induced human rheumatoid fibroblast-like synoviocytes MH7A...
October 6, 2016: Redox Biology
Shohei Murakami, Hozumi Motohashi
The KEAP1-NRF2 system is an inducible molecular mechanism enhancing transcriptions of several cytoprotective genes in response to xenobiotics and oxidative stress. Recently, the KEAP1-NRF2 system has been suggested to directly regulate a portion of the genes related to cell proliferation and differentiation. In hematopoietic cells, NRF2 activation plays a role in maintenance and cell fate determination of hematopoietic stem cells, as well as in maturation processes and homeostasis of megakaryocytes and erythrocytes...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Dushani L Palliyaguru, Dionysios V Chartoumpekis, Nobunao Wakabayashi, John J Skoko, Yoko Yagishita, Shivendra V Singh, Thomas W Kensler
Small molecules of plant origin offer presumptively safe opportunities to prevent carcinogenesis, mutagenesis and other forms of toxicity in humans. However, the mechanisms of action of such plant-based agents remain largely unknown. In recent years the stress responsive transcription factor Nrf2 has been validated as a target for disease chemoprevention. Withania somnifera (WS) is a herb used in Ayurveda (an ancient form of medicine in South Asia). In the recent past, withanolides isolated from WS, such as Withaferin A (WA) have been demonstrated to be preventive and therapeutic against multiple diseases in experimental models...
October 4, 2016: Free Radical Biology & Medicine
Masaaki Konishi, Anna Baumgarten, Junichi Ishida, Masakazu Saitoh, Stefan D Anker, Jochen Springer
No abstract text is available yet for this article.
October 1, 2016: International Journal of Cardiology
Eijun Nishihara, Akira Hishinuma, Takahiko Kogai, Nami Takada, Mitsuyoshi Hirokawa, Shuji Fukata, Mitsuru Ito, Tomonori Yabuta, Mitsushige Nishikawa, Hirotoshi Nakamura, Nobuyuki Amino, Akira Miyauchi
BACKGROUND: A germline mutation of KEAP1 gene was reported as a novel genetic abnormality associated with familial multinodular goiter. That report was limited, and the pathogenic features were not well established. PATIENT FINDINGS: We report a 47-year-old Japanese woman who presented with hyperthyroidism and a large multinodular goiter. The family history was notable for a paternal history of goiter. Graves' disease was diagnosed based on positive TRAb, but scintiscan imaging showed that the patient's radioiodine uptake was restricted in the non-nodular areas, indicating largely cold nodules...
2016: Frontiers in Endocrinology
Tatsuro Iso, Takafumi Suzuki, Liam Baird, Masayuki Yamamoto
The transcription factor Nrf2 (NF-E2-related-factor-2) is essential for the oxidative and electrophilic stress responses. Keap1 (Kelch-like-ECH-associated-protein-1), an adaptor for a Cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 activity through proteasomal degradation, and acts as a sensor for oxidative and electrophilic stresses. The Keap1-Cul3 complex is a critical regulator of the cellular Nrf2 level, yet quantitative information regarding their endogenous intracellular concentrations in homeostatic conditions and during stress responses is unknown...
October 3, 2016: Molecular and Cellular Biology
Zhengyu Jiang, Mengchen Lu, Qi-Dong You
The transcription factor Nrf2 is the primary regulator of the cellular defense system, and enhancing Nrf2 activity has potential usages in various diseases, especially chronic age-related and inflammatory diseases. Recently, directly targeting Keap1-Nrf2 protein-protein interaction (PPI) has been an emerging strategy to selectively and effectively activate Nrf2. This Perspective summarizes the progress in the discovery and development of Keap1-Nrf2 PPI inhibitors, including the Keap1-Nrf2 regulatory mechanisms, biochemical techniques for inhibitor identification, and approaches for identifying peptide and small-molecule inhibitors, as well as discusses privileged structures and future directions for further development of Keap1-Nrf2 PPI inhibitors...
October 3, 2016: Journal of Medicinal Chemistry
Ludovic J Deny, Hussein Traboulsi, André M Cantin, Eric Marsault, Martin V Richter, Guillaume Bélanger
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator that promotes the transcription of cytoprotective genes in response to oxidative/electrophilic stress. Various Michael-type compounds were designed and synthesized and their potency to activate the Keap1/Nrf2/ARE pathway was evaluated. Compounds bearing two Michael-type acceptors proved to be the most active. Tether length and rigidity between the acceptors was crucial. This study will help to understand how this feature disrupts the interaction between Keap1 and Nrf2...
September 28, 2016: Journal of Medicinal Chemistry
Youngtae Jeong, Ngoc T Hoang, Alexander Lovejoy, Henning Stehr, Aaron M Newman, Andrew J Gentles, William Kong, Diana Truong, Shanique Martin, Aadel Chaudhuri, Diane Heiser, Li Zhou, Carmen Say, Justin N Carter, Susan M Hiniker, Billy W Loo, Robert B West, Philip Beachy, Ash A Alizadeh, Maximilian Diehn
Lung squamous cell carcinomas (LSCC) pathogenesis remains incompletely understood and biomarkers predicting treatment response remain lacking. Here we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histological and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model...
September 23, 2016: Cancer Discovery
Meng-Chen Lu, Shi-Jie Tan, Jian-Ai Ji, Zhi-Yun Chen, Zhen-Wei Yuan, Qi-Dong You, Zheng-Yu Jiang
Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC50 = 15...
September 8, 2016: ACS Medicinal Chemistry Letters
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