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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
Joseph W Zagorski, Alexandra E Turley, Robert A Freeborn, Kelly R VanDenBerg, Heather E Dover, Brian R Kardell, Karen T Liby, Cheryl E Rockwell
We previously demonstrated that activation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) promotes CD4+ Th2 differentiation. In the current study, we assessed the role of Nrf2 in early events following T cell activation. The Nrf2 activators, tBHQ (tert-butylhydroquinone) and CDDO-Im (the imidazolide derivative of the triterpenoid CDDO), were used in conjunction with splenocytes derived from wild-type and Nrf2-null mice to distinguish between Nrf2-specific and off-target effects...
January 2018: Biochemical Pharmacology
Valerie M Crowley, Kodjo Ayi, Ziyue Lu, Karen T Liby, Michael Sporn, Kevin C Kain
BACKGROUND: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection associated with high mortality and neurocognitive impairment in survivors. New anti-malarials and host-based adjunctive therapy may improve clinical outcome in CM. Synthetic oleanane triterpenoid (SO) compounds have shown efficacy in the treatment of diseases where inflammation and oxidative stress contribute to pathogenesis. METHODS: A derivative of the SO 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), CDDO-ethyl amide (CDDO-EA) was investigated for the treatment of severe malaria in a pre-clinical model...
November 14, 2017: Malaria Journal
Xin-Yu Wang, Xue-Hong Zhang, Li Peng, Zheng Liu, Yin-Xue Yang, Zhi-Xu He, Hong-Wan Dang, Shu-Feng Zhou
Chronic myeloid leukemia (CML) treatment remains a challenge due to drug resistance and severe side effect, rendering the need on the development of novel therapeutics. CDDO-Me (Bardoxolone methyl), a potent Nrf2 activator and NF-κB inhibitor, is a promising candidate for cancer treatment including leukemia. However, the underlying mechanism for CDDO-Me in CML treatment is unclear. This study aimed to evaluate the molecular interactome of CDDO-Me in K562 cells using the quantitative proteomics approach stable-isotope labeling by amino acids in cell culture (SILAC) and explore the underlying mechanisms using cell-based functional assays...
2017: American Journal of Translational Research
Namrata Chaudhari, Priti Talwar, Christian Lefebvre D'hellencourt, Palaniyandi Ravanan
Neuroblastoma is the most common solid extra cranial tumor in infants. Improving the clinical outcome of children with aggressive tumors undergoing one of the multiple treatment options has been a major concern. Differentiating neuroblastoma cells holds promise in inducing tumor growth arrest and treating minimal residual disease. In this study, we investigated the effect of partial PPARγ agonist 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) on human neuroblastoma IMR32 cells. Our results demonstrate that treatment with low concentration of CDDO and particularly in combination with all trans retinoic acid (ATRA) induced neurite outgrowth, increased the percentage of more than two neurites bearing cells, and decreased viability in IMR32 cells...
2017: Frontiers in Molecular Neuroscience
Zhangjian Huang, Yi Mou, Xiaojun Xu, Di Zhao, Yisheng Lai, Yuwen Xu, Cen Chen, Ping Li, Sixun Peng, Jide Tian, Yihua Zhang
Currently, no effective and safe medicines are available to treat diabetic nephropathy (DN). Bardoxolone methyl (CDDO-Me) has displayed promising anti-DN activity as well as serious side effects in clinical trials, probably because the highly reactive α-cyano-α,β-unsaturated ketone (CUK) in ring A of CDDO-Me can covalently bind to thiol functionalities in many biomacromolecules. In this study, we designed and synthesized a γ-glutamyl transpeptidase (GGT)-based and CUK-modified derivative of CDDO-Me (2) to address this issue...
November 9, 2017: Journal of Medicinal Chemistry
Timothy K Eitas, Wesley H Stepp, Lucas Sjeklocha, Clayton V Long, Caitlin Riley, James Callahan, Yolanda Sanchez, Peter Gough, Laquanda Knowlin, David van Duin, Shiara Ortiz-Pujols, Samuel W Jones, Robert Maile, Zhi Hong, Scott Berger, Bruce A Cairns
Burn patients suffer from immunological dysfunction for which there are currently no successful interventions. Similar to previous observations, we find that burn shock patients (≥15% Total Burn Surface Area (TBSA) injury) have elevated levels of the innate immune cytokines Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1)/CC-motif Chemokine Ligand 2(CCL2) early after hospital admission (0-48 Hours Post-hospital Admission (HPA). Functional immune assays with patient Peripheral Blood Mononuclear Cells (PBMCs) revealed that burn shock patients (≥15% TBSA) produced elevated levels of MCP-1/CCL2 after innate immune stimulation ex vivo relative to mild burn patients...
2017: PloS One
Hsi-Ju Wei, Tej K Pareek, Qi Liu, John J Letterio
Tolerogenic dendritic cells (DCs) have emerged as relevant clinical targets for the treatment of multiple sclerosis and other autoimmune disorders. However, the pathways essential for conferring the tolerizing DC phenotype and optimal methods for their induction remain an intense area of research. Triterpenoids are a class of small molecules with potent immunomodulatory activity linked to activation of Nrf2 target genes, and can also suppress the manifestations of experimental autoimmune encephalomyelitis (EAE)...
August 29, 2017: Scientific Reports
Dongwei Xu, Lili Chen, Xiaosong Chen, Yankai Wen, Chang Yu, Jufang Yao, Hailong Wu, Xin Wang, Qiang Xia, Xiaoni Kong
Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidants has been implicated to have protective roles in ischemia-reperfusion (I/R) injury in many animal models. However, the in vivo effects of CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole), a Nrf2 activator, in hepatic I/R injury is lacking and its exact molecular mechanisms are still not very clear. The goals of this study were to determine whether CDDO-Im can prevent liver injury induced by I/R in the mouse, and to elucidate the molecular target of drug action...
August 10, 2017: Cell Death & Disease
Liangfeng Fu, Qi-Xian Lin, Evans O Onyango, Karen T Liby, Michael B Sporn, Gordon W Gribble
We report the synthesis and biological activity of C-24 demethyl CDDO-Me 2 and the C-28 amide derivatives 3 and 4, which are analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1. Demethylation of the C-24 methyl group was accomplished via "abnormal Beckmann" rearrangement and subsequent ring A reformation. Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro.
July 19, 2017: Organic & Biomolecular Chemistry
Karoline V Gleixner, Mathias Schneeweiss, Gregor Eisenwort, Daniela Berger, Harald Herrmann, Katharina Blatt, Georg Greiner, Konstantin Byrgazov, Gregor Hoermann, Marina Konopleva, Islam Waliul, Abbarna A Cumaraswamy, Patrick T Gunning, Hiroshi Maeda, Richard Moriggl, Michael Deininger, Thomas Lion, Michael Andreeff, Peter Valent
In chronic myeloid leukemia, resistance against BCR-ABL1 tyrosine kinase inhibitors can develop because of BCR-ABL1 mutations, activation of additional pro-oncogenic pathways, and stem cell resistance. Drug combinations covering a broad range of targets may overcome resistance. CDDO-Me (bardoxolone methyl) is a drug that inhibits the survival of leukemic cells by targeting different pro-survival molecules, including STAT3. We found that CDDO-Me inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines and primary leukemic cells, including cells harboring BCR-ABL1 T315I or T315I+ compound mutations...
September 2017: Haematologica
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