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Peng Xue, Xiangxiang Hu, James Powers, Nicole Nay, Emily Chang, Jane Kwon, Sing Wai Wong, Lichi Han, Tai-Hsien Wu, Dong-Joon Lee, Henry Tseng, Ching-Chang Ko
Metabolic bone diseases are global public health concerns and are primarily caused by uncontrolled osteoclast (OC) formation and activation. During OC differentiation, intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can serve as the signaling molecules to promote osteoclastic genes expression. Nuclear factor erythroid-2 related factor 2 (NRF2), a master mediator of cellular antioxidant response, also plays a critical role in OC differentiation through the regulation of redox homeostasis...
February 27, 2019: Biochemical and Biophysical Research Communications
Zheming Wu, Yang Geng, Xiaojuan Lu, Yuying Shi, Guowei Wu, Mengmeng Zhang, Bing Shan, Heling Pan, Junying Yuan
Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis...
February 4, 2019: Proceedings of the National Academy of Sciences of the United States of America
Xiali Zhong, Jiahuang Qiu, Jianmeng Kang, Xiumei Xing, Xiongjie Shi, Yanhong Wei
The growing production and extensive use of organophosphate flame retardants (OPFRs) have led to an increase in their environmental distribution and human exposure. Developmental toxicity is a major concern of OPFRs' adverse health effects. However, the impact of OPFRs exposure on vascular development and the toxicity pathway for developmental defects are poorly understood. In this study, we investigated the effects of exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a frequently detected OPFR, on early vascular development, and the possible role of nuclear factor erythroid 2-related factor (Nrf2)-dependent angiogenic pathway in TDCPP's vascular toxicity...
January 3, 2019: Environmental Pollution
Ryuichi Nagashima, Hitomi Kosai, Masahiro Masuo, Keiko Izumiyama, Taketo Noshikawaji, Motoko Morimoto, Satoru Kumaki, Yasunari Miyazaki, Hozumi Motohashi, Masayuki Yamamoto, Nobuyuki Tanaka
The Keap1-Nrf2 system plays a pivotal role in the oxidative stress response by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. In this article, we investigated the role of the Keap1-Nrf2 pathway in ILC2 homeostasis and allergic inflammation using Nrf2 knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response and underwent hyperproliferation in response to a combined stimulation of IL-33 with IL-2, IL-7, or TSLP...
January 23, 2019: Journal of Immunology: Official Journal of the American Association of Immunologists
Soma Jobbagy, Dario A Vitturi, Sonia R Salvatore, Lucía Turell, Maria F Pires, Emilia Kansanen, Carlos Batthyany, Jack R Lancaster, Bruce A Freeman, Francisco J Schopfer
Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state by glutathione reductase (GR). Nitro oleic acid (NO2 -OA) is an electrophilic fatty acid formed under digestive and inflammatory conditions that both reacts with GSH and induces its synthesis upon activation of Nrf2 signaling. The effects of NO2 -OA on intracellular GSH homeostasis were evaluated...
November 22, 2018: Redox Biology
Feng Gao, Qiang Zuo, Tao Jiang, Huanghe Song, Jinchun Zhou
Osteosarcoma (OS) is the primary malignant bone tumor with a peak incidence in children and adolescents. However, the little molecular mechanism of pathogenesis has been known and it is urgent to develop new therapeutical strategies to improve outcomes for patients. CDDO-NFM (N-formylmorpholine substituent of CDDO) is a newly synthesized triterpenoid, which is a derivative of oleanolic acid. In this study, we explored whether CDDO-NFM possesses a potential antitumor effect and revealed its molecular mechanism...
December 14, 2018: Journal of Cellular Biochemistry
Upayan Patra, Urbi Mukhopadhyay, Rakesh Sarkar, Arpita Mukherjee, Mamta Chawla-Sarkar
Acute watery diarrhea due to Rotavirus (RV) infection is associated with high infantile morbidity and mortality in countries with compromised socio-economic backgrounds. Although showing promising trends in developed countries, the efficacy of currently licensed RV vaccines is sub-optimal in socio-economically poor settings with high disease burden. Currently, there are no approved anti-rotaviral drugs adjunct to classical vaccination program. Interestingly, dissecting host-rotavirus interaction has yielded novel, non-mutable host determinants which can be subjected to interventions by selective small molecules...
November 19, 2018: Antiviral Research
Luc J M Bischoff, Isoude A Kuijper, Johannes P Schimming, Liesanne Wolters, Bas Ter Braak, Jan P Langenberg, Daan Noort, Joost B Beltman, Bob van de Water
Oxidative stress leads to the activation of the Nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway. While most studies have focused on the activation of the Nrf2 pathway after single chemical treatment, little is known about the dynamic regulation of the Nrf2 pathway in the context of repeated exposure scenarios. Here we employed single cell live imaging to quantitatively monitor the dynamics of the Nrf2 pathway during repeated exposure, making advantage of two HepG2 fluorescent protein reporter cell lines, expressing GFP tagged Nrf2 or sulfiredoxin 1 (Srxn1), a direct downstream target of Nrf2...
November 20, 2018: Archives of Toxicology
Derek D Poore, Glenn Hofmann, Lawrence A Wolfe, Hongwei Qi, Ming Jiang, Michael Fischer, Zining Wu, Thomas D Sweitzer, Subhas Chakravorty, Brian Donovan, Hu Li
Nrf2, a master regulator of the phase II gene response to stress, is kept at low concentrations in the cell through binding to Keap1, an adaptor protein for the Cul3 ubiquitin ligase complex. To identify Nrf2 activators, two separate time-resolved fluorescence resonance energy transfer (TR-FRET) assays were developed to monitor the binding of Nrf2-Keap1 and Cul3-Keap1, respectively. The triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im) and its analogs, exhibited approximately 100-fold better potency in the Cul3-Keap1 assay than in the Nrf2-Keap1 assay, and this difference was more profound at 37 °C than at room temperature in the Nrf2-Keap1 assay, but this phenomenon was not observed in the Cul3-Keap1 assay...
November 1, 2018: SLAS Discovery
Jay Mehta, Srujana Rayalam, Xinyu Wang
Oxidative stress, an imbalance between reactive oxygen species and antioxidants, has been witnessed in pathophysiological states of many disorders. Compounds identified from natural sources have long been recognized to ameliorate oxidative stress due to their inherent antioxidant activities. Here, we summarize the cytoprotective effects and mechanisms of natural or naturally derived synthetic compounds against oxidative stress. These compounds include: caffeic acid phenethyl ester (CAPE) found in honey bee propolis, curcumin from turmeric roots, resveratrol abundant in grape, and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im), a synthetic triterpenoid based on naturally occurring oleanolic acid...
October 20, 2018: Antioxidants (Basel, Switzerland)
Partha K Chandra, Samantha L Gerlach, Chengxiang Wu, Namrata Khurana, Lauren T Swientoniewski, Asim B Abdel-Mageed, Jian Li, Stephen E Braun, Debasis Mondal
Persistence of latent HIV-1 in macrophages (MACs) and T-helper lymphocytes (THLs) remain a major therapeutic challenge. Currently available latency reversing agents (LRAs) are not very effective in vivo. Therefore, understanding of physiologic mechanisms that dictate HIV-1 latency/reactivation in reservoirs is clearly needed. Mesenchymal stromal/stem cells (MSCs) regulate the function of immune cells; however, their role in regulating virus production from latently-infected MACs & THLs is not known. We documented that exposure to MSCs or their conditioned media (MSC-CM) rapidly increased HIV-1 p24 production from the latently-infected U1 (MAC) & ACH2 (THL) cell lines...
October 2, 2018: Scientific Reports
Jie Liu, Yuan-Fu Lu, Qin Wu, Shang-Fu Xu, Fu-Guo Shi, Curtis D Klaassen
Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. OA is included in some dietary supplements and is used as a complementary and alternative medicine (CAM) in China, India, Asia, the USA and European countries. OA is effective in protecting against various hepatotoxicants, and one of the protective mechanisms is reprogramming the liver to activate the nuclear factor erythroid 2-related factor 2 (Nrf2). OA derivatives, such as CDDO-Im and CDDO-Me, are even more potent Nrf2 activators...
August 6, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
Hsi-Ju Wei, Ashish Gupta, Wei-Ming Kao, Omar Almudallal, John J Letterio, Tej K Pareek
Aplastic anemia (AA) is a rare disease characterized by immune-mediated suppression of bone marrow (BM) function resulting in progressive pancytopenia. Stem cell transplant and immunosuppressive therapies remain the major treatment choices for AA patients with limited benefit and undesired side effects. Here, we report for the first time the therapeutic utility of Nrf2-induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in the suppression of AA in mice. CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-β and suppression of TNFα, IFN-γ, and IL-12 levels in Nrf2+/+ but not Nrf2-/- DCs...
July 16, 2018: Journal of Autoimmunity
Min Sung Gee, Sung-Bae Kang, Namkwon Kim, Jiyoon Choi, Nam-Jung Kim, Bum-Joon Kim, Kyung-Soo Inn, Jong Kil Lee
Bardoxolone methyl (CDDO-me) is a synthetic triterpenoid that has been shown to suppress various cancers and inflammation. It has been implicated for the suppression of signal transducer and activator of transcription 3 (STAT3)-mediated signaling, which plays crucial roles in the development and progression of hepatocellular carcinoma (HCC). Previously, we showed that hepatitis B virus (HBV) large surface protein (LHB) variant W4P promotes carcinogenesis and tumor progression through STAT3 activation. Thus, we examined the anti-cancer activity of CDDO-me against HCC using W4P-LHB-expressing NIH3T3 cells and HepG2 and Huh7 HCC cell lines...
2018: Pharmacology
Hsi-Ju Wei, John J Letterio, Tej K Pareek
The immune system operates by maintaining a tight balance between coordinating responses against foreign antigens and maintaining an unresponsive state against self-antigens as well as antigens derived from commensal organisms. The disruption of this immune homeostasis can lead to chronic inflammation and to the development of autoimmunity. Dendritic cells (DCs) are the professional antigen-presenting cells of the innate immune system involved in activating naïve T cells to initiate immune responses against foreign antigens...
May 18, 2018: Journal of Visualized Experiments: JoVE
Brent D Cameron, Konjeti R Sekhar, Maxwell Ofori, Michael L Freeman
The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell's response to radiation...
August 2018: Radiation Research
Ping Gong, Kun Li, Ying Li, Dan Liu, Linxiang Zhao, Yongkui Jing
Methyl 2-cyano-3,12-dioxo-18β-olean-1,9(11)-dien-30-oate (CDODO-Me, 10d) derived from glycyrrhetinic acid and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) derived from oleanoic acid are potent apoptosis inducers developed to clinical trials. Both compounds have high affinity for reduced  glutathione (GSH), which needs to be overcome to improve their target selectivity. We generated a new 10d analogue methyl 2-cyano-3-oxo-18β-olean-1,9(11), 12-trien-30-oate (COOTO, 10e), which retains high apoptosis inducing ability, while displaying decreased affinity for GSH, and explored the acting targets...
May 24, 2018: Cell Death & Disease
Fenghua Kang, Yong Ai, Yihua Zhang, Zhangjian Huang
To search for new drugs for intervention of drug-resistant lung cancer, a series of hybrids 4-15 from 2-cyano-3,12-dioxooleana-9-dien-28-oic acid (CDDO) and O2 -(2,4-dinitrophenyl) diazeniumdiolate were designed, synthesized and biologically evaluated. The most active compound 7 produced relatively high levels of nitric oxide (NO) and reactive oxygen species (ROS) in drug-resistant lung cancer A549/Taxol cells which over-express glutathione S-transferase π (GSTπ), and significantly inhibited the cells' proliferation (IC50  = 0...
April 10, 2018: European Journal of Medicinal Chemistry
Yusheng Cheng, Yan Gong, Shuai Qian, Yi Mou, Hanrui Li, Xijing Chen, Hui Kong, Weiping Xie, Hong Wang, Yihua Zhang, Zhangjian Huang
Given the clinical therapeutic efficacy of oral-dosed bardoxolone methyl (1) and the selective vasodilatory effect caused by inhalation of nitric oxide (NO) on pulmonary arterial hypertension (PAH) patients, a new hybrid (CDDO-NO, 2) from 1 and NO donor isosorbide 5-mononitrate (3) was designed and synthesized. This hybrid could liberate 1 and NO in the lungs of rats after trachea injection. Significantly, 2 lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), decreased right ventricular hypertrophy (RVH), and attenuated pulmonary artery medial thickness (PAMT) and vascular muscularization in monocrotaline (MCT)-induced PAH rats...
February 22, 2018: Journal of Medicinal Chemistry
Ryan S Wible, Quynh T Tran, Samreen Fathima, Carrie Hayes Sutter, Thomas W Kensler, Thomas R Sutter
The Keap1-Nrf2 signaling pathway is the subject of several clinical trials evaluating the effects of Nrf2 activation on the prevention of cancer, diabetes, and the treatment of chronic kidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two distinct series of Nrf2 chemical activators. Previous reports have described activator-specific effects on Nrf2-dependent gene regulation and physiological outcomes...
January 24, 2018: Molecular Pharmacology
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