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bardoxolone methyl

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https://www.readbyqxmd.com/read/27823964/michael-acceptor-containing-drugs-are-a-novel-class-of-5-lipoxygenase-inhibitor-targeting-the-surface-cysteines-c416-and-c418
#1
Isabelle V Maucher, Michael Rühl, Simon Bm Kretschmer, Bettina Hofmann, Benjamin Kühn, Jasmin Fettel, Anja Vogel, Karsten T Flügel, Georg Manolikakes, Nadine Hellmuth, Ann-Kathrin Häfner, Vahid Golghalyani, Ann-Katrin Ball, Matthias Piesche, Carmela Matrone, Gerd Geisslinger, Michael J Parnham, Michael Karas, Dieter Steinhilber, Jessica Roos, Thorsten J Maier
Recently, we published that nitro-fatty acids (NFA) are potent electrophilic molecules which inhibit 5-lipoxygenase (5-LO) by interacting with catalytically cysteine residues next to a substrate entry channel. The electrophilicity is derived from an intramolecular Michael acceptor moiety consisting of an electron-withdrawing group in close proximity to a double bond. The potential of the Michael acceptor moiety to interact with functionally relevant cysteines of proteins potentially renders them effective and sustained enzyme activity modulators...
November 4, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27818722/nrf2-is-an-attractive-therapeutic-target-for-retinal-diseases
#2
REVIEW
Yasuhiro Nakagami
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases...
2016: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/27474227/a-novel-nuclear-factor-erythroid-2-related-factor-2-nrf2-activator-rs9-attenuates-brain-injury-after-ischemia-reperfusion-in-mice
#3
Keita Yamauchi, Yusuke Nakano, Takahiko Imai, Toshinori Takagi, Kazuhiro Tsuruma, Masamitsu Shimazawa, Toru Iwama, Hideaki Hara
Recanalization of occluded vessels leads to ischemia-reperfusion injury (IRI), with oxidative stress as one of the main causes of injury, despite the fact that recanalization therapy is the most effective treatment for ischemic stroke. The nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the transcription factors which has an essential role in protection against oxidative stress. RS9 is a novel Nrf2 activator obtained from bardoxolone methyl (BARD), an Nrf2 activator that has already been tested in a clinical trial, using a biotransformation technique...
October 1, 2016: Neuroscience
https://www.readbyqxmd.com/read/27417254/bardoxolone-methyl-prevents-obesity-and-hypothalamic-dysfunction
#4
Danielle Camer, Yinghua Yu, Alexander Szabo, Hongqin Wang, Chi H L Dinh, Xu-Feng Huang
High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet...
August 25, 2016: Chemico-biological Interactions
https://www.readbyqxmd.com/read/27242339/a-novel-nrf2-activator-from-microbial-transformation-inhibits-radiation-induced-dermatitis-in-mice
#5
Yasuhiro Nakagami, Kayoko Masuda
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that regulates many antioxidants, and we have recently succeeded in obtaining a novel Nrf2 activator, RS9, from microbial transformation. RS9 is categorized as a triterpenoid, and well-known triterpenoids such as RTA 402 (bardoxolone methyl) and RTA 408 have been tested in clinical trials. RTA 408 lotion is currently being tested in patients at risk for radiation dermatitis. This prompted us to study the profiles of RS9 in the skin...
May 29, 2016: Journal of Radiation Research
https://www.readbyqxmd.com/read/26920068/bardoxolone-methyl-prevents-high-fat-diet-induced-colon-inflammation-in-mice
#6
Chi H L Dinh, Yinghua Yu, Alexander Szabo, Qingsheng Zhang, Peng Zhang, Xu-Feng Huang
Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt...
April 2016: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
https://www.readbyqxmd.com/read/26908173/design-and-synthesis-of-irreversible-analogues-of-bardoxolone-methyl-for-the-identification-of-pharmacologically-relevant-targets-and-interaction-sites
#7
Michael H L Wong, Holly K Bryan, Ian M Copple, Rosalind E Jenkins, Pak Him Chiu, Jaclyn Bibby, Neil G Berry, Neil R Kitteringham, Christopher E Goldring, Paul M O'Neill, B Kevin Park
Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro...
March 24, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26850917/nrf2-activator-ameliorates-hemorrhagic-transformation-in-focal-cerebral-ischemia-under-warfarin-anticoagulation
#8
Takahiko Imai, Toshinori Takagi, Akira Kitashoji, Keita Yamauchi, Masamitsu Shimazawa, Hideaki Hara
BACKGROUND AND PURPOSE: Oxidative stress has been reported to be a main cause of neuronal cell death in ischemia reperfusion injury (IRI). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important factor involved in anti-oxidative responses. We previously reported that bardoxolone methyl (BARD), an Nrf2 activator, prevented damage induced by IRI. In this study, we investigated the effect of BARD on hemorrhagic transformation in the context of blood brain barrier (BBB) protection...
May 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/26676665/improvements-in-the-management-of-diabetic-nephropathy
#9
Evangelia Dounousi, Anila Duni, Konstantinos Leivaditis, Vasilios Vaios, Theodoros Eleftheriadis, Vassilios Liakopoulos
The burden of diabetes mellitus is relentlessly increasing. Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) worldwide and a major cause of morbidity and mortality in patients with diabetes. The current standard therapy of diabetic nephropathy involves intensive treatment of hyperglycemia and strict blood pressure control, mainly via blockade of the renin-angiotensin system (RAS). Attention has been drawn to additional beneficial effects of oral hypoglycemic drugs and fibrates on other aspects of diabetic nephropathy...
April 2015: Review of Diabetic Studies: RDS
https://www.readbyqxmd.com/read/26666161/-the-trend-of-new-drug-development-for-the-treatment-of-diabetes-mellitus
#10
Kohei Kaku
The trend of new drug development in the field of diabetes mellitus is overviewed. The hypoglycemic drugs such as glucagon receptor antagonists, glucokinase activators, and GPR agonists and oral medication of GLP-1 receptor agonist are under phase 2 trial in Japan. As for therapeutic medicines for diabetic nephropathy, atrasentan as an endothelin A receptor antagonist is in phase 3 trial, and bardoxolone methyl as Nrf2 activator in phase 2 in Japan. Canagliflozin, a SGLT2 inhibitor, is in phase 3 study to obtain new indication of diabetic nephropathy...
December 2015: Nihon Rinsho. Japanese Journal of Clinical Medicine
https://www.readbyqxmd.com/read/26618193/bardoxolone-methyl-prevents-mesenteric-fat-deposition-and-inflammation-in-high-fat-diet-mice
#11
Chi H L Dinh, Alexander Szabo, Yinghua Yu, Danielle Camer, Hongqin Wang, Xu-Feng Huang
Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins...
2015: TheScientificWorldJournal
https://www.readbyqxmd.com/read/26612656/bardoxolone-methyl-prevents-the-development-and-progression-of-cardiac-and-renal-pathophysiologies-in-mice-fed-a-high-fat-diet
#12
Danielle Camer, Yinghua Yu, Alexander Szabo, Hongqin Wang, Chi H L Dinh, Xu-Feng Huang
Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water...
January 5, 2016: Chemico-biological Interactions
https://www.readbyqxmd.com/read/26515498/effects-of-captopril-telmisartan-and-bardoxolone-methyl-cddo-me-in-ischemia-reperfusion-induced-acute-kidney-injury-in-rats-an-experimental-comparative-study
#13
COMPARATIVE STUDY
Cengiz Kocak, Fatma Emel Kocak, Raziye Akcilar, Zeynep Bayat, Bekir Aras, Mehmet Huseyin Metineren, Mehmet Yucel, Hasan Simsek
Renal ischemia-reperfusion (IR) injury is one of the most common causes of acute kidney injury. This study investigated the effects of captopril (CAP), telmisartan (TEL) and bardoxolone methyl (BM) in animals with renal IR injury. Adult male Wistar-Albino rats were divided into six groups: control, vehicle, IR, IR with CAP, IR with TEL and IR with BM. Before IR was induced, drugs were administered by oral gavage. After a 60-min ischemia and a 120-min reperfusion period, bilateral nephrectomies were performed...
February 2016: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/26422507/integrated-transcriptomic-and-proteomic-analyses-uncover-regulatory-roles-of-nrf2-in-the-kidney
#14
Luke M Shelton, Adam Lister, Joanne Walsh, Rosalind E Jenkins, Michael H L Wong, Cliff Rowe, Emanuele Ricci, Lorenzo Ressel, Yongxiang Fang, Philippe Demougin, Vanja Vukojevic, Paul M O'Neill, Christopher E Goldring, Neil R Kitteringham, B Kevin Park, Alex Odermatt, Ian M Copple
The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO-Me, compared with those of vehicle control...
December 2015: Kidney International
https://www.readbyqxmd.com/read/26239562/horizon-2020-in-diabetic-kidney-disease-the-clinical-trial-pipeline-for-add-on-therapies-on-top-of-renin-angiotensin-system-blockade
#15
REVIEW
Maria Vanessa Perez-Gomez, Maria Dolores Sanchez-Niño, Ana Belen Sanz, Catalina Martín-Cleary, Marta Ruiz-Ortega, Jesus Egido, Juan F Navarro-González, Alberto Ortiz, Beatriz Fernandez-Fernandez
Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways...
2015: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/26124639/therapeutic-effects-of-c-28-methyl-ester-of-2-cyano-3-12-dioxoolean-1-9-dien-28-oic-acid-cddo-me-bardoxolone-methyl-on-radiation-induced-lung-inflammation-and-fibrosis-in-mice
#16
Yan-Yang Wang, Cui-Ying Zhang, Ya-Qiong Ma, Zhi-Xu He, Hong Zhe, Shu-Feng Zhou
The C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), one of the synthetic triterpenoids, has been found to have potent anti-inflammatory and anticancer properties in vitro and in vivo. However, its usefulness in mitigating radiation-induced lung injury (RILI), including radiation-induced lung inflammation and fibrosis, has not been tested. The aim of this study was to explore the therapeutic effect of CDDO-Me on RILI in mice and the underlying mechanisms. Herein, we found that administration of CDDO-Me improved the histopathological score, reduced the number of inflammatory cells and concentrations of total protein in bronchoalveolar lavage fluid, suppressed secretion and expression of proinflammatory cytokines, including transforming growth factor-β and interleukin-6, elevated expression of the anti-inflammatory cytokine interleukin-10, and downregulated the mRNA level of profibrotic genes, including for fibronectin, α-smooth muscle actin, and collagen I...
2015: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/26066016/bardoxolone-methyl-prevents-fat-deposition-and-inflammation-in-brown-adipose-tissue-and-enhances-sympathetic-activity-in-mice-fed-a-high-fat-diet
#17
Chi H L Dinh, Alexander Szabo, Yinghua Yu, Danielle Camer, Qingsheng Zhang, Hongqin Wang, Xu-Feng Huang
Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks...
June 9, 2015: Nutrients
https://www.readbyqxmd.com/read/26016608/novel-targets-of-drug-treatment-for-pulmonary-hypertension
#18
REVIEW
Jian Hu, Qinzi Xu, Charles McTiernan, Yen-Chun Lai, David Osei-Hwedieh, Mark Gladwin
Biomedical advances over the last decade have identified the central role of proliferative pulmonary arterial smooth muscle cells (PASMCs) in the development of pulmonary hypertension (PH). Furthermore, promoters of proliferation and apoptosis resistance in PASMCs and endothelial cells, such as aberrant signal pathways involving growth factors, G protein-coupled receptors, kinases, and microRNAs, have also been described. As a result of these discoveries, PH is currently divided into subgroups based on the underlying pathology, which allows focused and targeted treatment of the condition...
August 2015: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/26001833/bardoxolone-methyl-prevents-insulin-resistance-and-the-development-of-hepatic-steatosis-in-mice-fed-a-high-fat-diet
#19
Danielle Camer, Yinghua Yu, Alexander Szabo, Chi H L Dinh, Hongqin Wang, Licai Cheng, Xu-Feng Huang
High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that bardoxolone methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR...
September 5, 2015: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/25930007/dose-dependent-deleterious-and-salutary-actions-of-the-nrf2-inducer-dh404-in-chronic-kidney-disease
#20
Nosratola D Vaziri, Shuman Liu, Seyed H Farzaneh, Sohrab Nazertehrani, Mahyar Khazaeli, Ying-Yong Zhao
Oxidative stress and inflammation play a central role in the progression and complications of chronic kidney disease (CKD) and are, in part, due to impairment of the Nrf2 system, which regulates the expression of antioxidant and detoxifying molecules. Natural Nrf2-inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However, owing to adverse outcomes a clinical trial of a synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via covalent modification of reactive cysteine residues in the Nrf2 repressor molecule, Keap1...
September 2015: Free Radical Biology & Medicine
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