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bardoxolone methyl

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https://www.readbyqxmd.com/read/28438659/the-nrf2-activator-dh404-attenuates-adverse-ventricular-remodeling-post-myocardial-infarction-by-modifying-redox-signalling
#1
Kristen J Bubb, Cindy Kok, Owen Tang, Nathalie B Rasko, Asa B Birgisdottir, Thomas Hansen, Rebecca Ritchie, Ravinay Bhindi, Scott A Reisman, Colin Meyer, Keith Ward, Keyvan Karimi Galougahi, Gemma A Figtree
BACKGROUND: The novel synthetic triterpenoid, bardoxolone methyl, has the ability to upregulate cytoprotective proteins via induction of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. This makes it a promising therapeutic agent in disease states characterized by dysregulated oxidative signalling. We have examined the effect of a Nrf2 activator, dihydro-CDDO-trifluoroethyl amide (DH404), a derivative of bardoxolone methyl, on post-infarct cardiac remodeling in rats. METHODS/RESULTS: DH404, administered from day 2 post myocardial infarction (MI: 30min transient ischemia followed by reperfusion) resulted in almost complete protection against adverse ventricular remodeling as assessed at day 28 (left ventricular end-systolic area: sham 0...
April 21, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28375181/dietary-metabolites-and-chronic-kidney-disease
#2
REVIEW
Sho Hasegawa, Tzu-Ming Jao, Reiko Inagi
Dietary contents and their metabolites are closely related to chronic kidney disease (CKD) progression. Advanced glycated end products (AGEs) are a type of uremic toxin produced by glycation. AGE accumulation is not only the result of elevated glucose levels or reduced renal clearance capacity, but it also promotes CKD progression. Indoxyl sulfate, another uremic toxin derived from amino acid metabolism, accumulates as CKD progresses and induces tubulointerstitial fibrosis and glomerular sclerosis. Specific types of amino acids (d-serine) or fatty acids (palmitate) are reported to be closely associated with CKD progression...
April 4, 2017: Nutrients
https://www.readbyqxmd.com/read/28277986/bardoxolone-methyl-inhibits-migration-and-metabolism-in-mcf7-cells
#3
Alaa Refaat, Chathyan Pararasa, Muhammed Arif, James E P Brown, Amtul Carmichael, Sameh S Ali, Hiroaki Sakurai, Helen R Griffiths
Bardoxolone-methyl (BAR) is reported to have anti-inflammatory, anti-proliferative and anti-fibrotic effects. BAR activates Nrf2 and may ameliorate oxidative stress through induction of antioxidant genes. However, off-target effects, probably concentration and NFkB-dependent, have limited the clinical use of BAR. Nrf2 regulates expression of antioxidant and mitochondrial genes and has been proposed as a target for both obesity and breast cancer. Therefore, we explored whether BAR can alter migration and proliferation in the MCF7 cell line and whether metabolic function is affected by BAR...
February 2017: Free Radical Research
https://www.readbyqxmd.com/read/28275049/bardoxolone-methyl-and-a-related-triterpenoid-downregulate-cmyc-expression-in-leukemia-cells
#4
Un-Ho Jin, Yating Cheng, Beiyan Zhou, Stephen Safe
Structurally related pentacyclic triterpenoids methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate [bardoxolone-methyl (Bar-Me)] and methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF3DODA-Me) contain 2-cyano-1-en-3-one and 2-trifluoromethyl-1-en-3-one moieties, respectively, in their A-rings and differ in the position of their en-one structures in ring C. Only Bar-Me forms a Michael addition adduct with glutathione (GSH) and inhibits IKKβ phosphorylation. These differences may be due to steric hindrance by the 11-keto group in CF3DODA-Me, which prevents Michael addition by the conjugated en-one in the A-ring...
May 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28253885/the-nuclear-factor-erythroid-derived-2-like-2-nrf2-activator-dh404-protects-against-diabetes-induced-endothelial-dysfunction
#5
Arpeeta Sharma, Luddwi Rizky, Nada Stefanovic, Mitchel Tate, Rebecca H Ritchie, Keith W Ward, Judy B de Haan
BACKGROUND: Vascular dysfunction is a pivotal event in the development of diabetes-associated vascular disease. Increased inflammation and oxidative stress are major contributors to vascular dysfunction. Nrf2, a master regulator of several anti-oxidant genes and a suppressor of inflammatory NF-κB, has potential as a target to combat oxidative stress and inflammation. The aim of this study was to investigate the effects of a novel Nrf2 activator, the bardoxolone methyl derivative dh404, on endothelial function in vitro and in vivo...
March 3, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/28097824/mechanisms-of-metabolic-memory-and-renal-hypoxia-as-a-therapeutic-target-in-diabetic-kidney-disease
#6
REVIEW
Yosuke Hirakawa, Tetsuhiro Tanaka, Masaomi Nangaku
Diabetic kidney disease (DKD) is a worldwide public health problem. The definition of DKD is under discussion. Although the term DKD was originally defined as 'kidney disease specific to diabetes,' DKD frequently means chronic kidney disease with diabetes mellitus and includes not only classical diabetic nephropathy, but also kidney dysfunction as a result of nephrosclerosis and other causes. Metabolic memory plays a crucial role in the progression of various complications of diabetes, including DKD. The mechanisms of metabolic memory in DKD are supposed to include advanced glycation end-products, deoxyribonucleic acid methylation, histone modifications and non-coding ribonucleic acid including micro ribonucleic acid...
May 2017: Journal of Diabetes Investigation
https://www.readbyqxmd.com/read/27979484/microrna-125b-as-a-new-potential-biomarker-on-diagnosis-of-renal-ischemia-reperfusion-injury
#7
REVIEW
Aydın Güçlü, Cengiz Koçak, Fatma E Koçak, Raziye Akçılar, Yavuz Dodurga, Aydın Akçılar, Levent Elmas
BACKGROUND: Acute renal failure is commonly seen in the perioperative period. Ischemia-reperfusion (IR) injury plays a major role in acute renal failure and delayed graft function. MicroRNAs (miRs), which are pivotal modulators of cell activities, offer a major opportunity for affective diagnosis and treatment strategies because they are tissue specific and in the center of gene expression modulation. The effect of bardoxolone methyl (BM) on miR-21, miR-223-5p, and miR-125b in renal IR injury was evaluated in this study...
January 2017: Journal of Surgical Research
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
#8
Isabelle V Maucher, Michael Rühl, Simon B M 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 catalytically with 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...
February 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27818722/nrf2-is-an-attractive-therapeutic-target-for-retinal-diseases
#9
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
#10
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
#11
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
#12
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...
September 2016: Journal of Radiation Research
https://www.readbyqxmd.com/read/26920068/bardoxolone-methyl-prevents-high-fat-diet-induced-colon-inflammation-in-mice
#13
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
#14
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
#15
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
#16
REVIEW
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
#17
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
#18
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
#19
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
#20
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
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