China
Africa
Explore chapters and articles related to this topic
Oxidative Stress, Inflammation, Immune System and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Damiano Rizzoni, Livia L. Camargo, Francisco J. Rios, Augusto C. Montezano, Rhian M. Touyz
Nrf-2 is the master regulator of antioxidants through its control of genes that contain antioxidant response element (ARE) (37). Nrf-2 induces transcriptional activation of antioxidant genes containing ARE, including glutathione peroxidases, heme oxygenase-1, thioredoxin reductase, glutathione-S-transferase, and SOD (38). Nrf2 is constitutively controlled by ROS and by repressor protein Kelch-like ECH-associated protein 1 (Keap1) and increases antioxidant defence mechanisms in conditions of oxidative stress and cell stress. In rodent models of hypertension Nrf-2 activity is reduced, oxidative stress is increased and redox-sensitive vascular function is impaired (38). These phenomena are reversed with Nrf2 activators, bardoxolone and l-sulforaphane. Treatment of DOCA-salt rats with epicatechin, another Nrf-2 activator, decreased blood pressure (39).
Cardiovascular Disease and Oxidative Stress
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marco Fernandes, Alisha Patel, Holger Husi
Counter-balance of the deleterious effects of oxidative-stress can also be attainable by promoting activation of up-stream factors responsible for the regulation of cell-mediated response to oxidative stress (Gazaryan and Thomas, 2016). This is in part orchestrated by binding of the nuclear factor erythroid 2-related factor 2 (NFE2L2) to cis-regulatory elements, commonly known as antioxidant response elements (ARE) in the promotor region of target genes (Huang et al., 2000). Without external oxidoreductive stimuli, the Kelch-like ECH-associated protein 1(KEAP) promotes continuous ubiquitination and consequent proteasome degradation of NFE2L2, leading to suppression of its transcriptional activity (Lo et al., 2006). Along this line, a number of drugs are currently being developed to attempt to explore how to disrupt the NFE2L2-KEAP1 interface, like the tecfidera (dimethyl fumarate), bardoxolone, and BTB domain and CNC homolog 1 (Bach1) and consequently activating the NFE2L2/ARE pathway. This would then lead to an increased expression of ROS detoxifying enzymes and/or synthesis of pro-antioxidant molecules (Gazaryan and Thomas, 2016; Gesslbauer and Bochkov, 2017). Another approach encompasses mechanisms to cope with damage induced by oxidative stress without changing either basal activity of detoxifying enzymes or levels of pro-antioxidant molecules (Gesslbauer and Bochkov, 2017), thereby lessen the effect of inflammation and aiming to correct disrupted intracellular events due to ROS-induction damage (Gesslbauer and Bochkov, 2017). Attenuation of inflammation by pharmacological intervention has been addressed by altering or interfering with key players in the inflammatory process, such as acting on secretory mediators like inhibiting IL-18, chemokines, and TNF-alpha, using compounds such as Anakinra (Brown, 1989; Toldo et al., 2012), Etanercept (Gao et al., 2015), Infliximab (Gerlach et al., 2014), and Evasin-3 (Montecucco et al., 2010).
Renal ciliopathies: promising drug targets and prospects for clinical trials
Published in Expert Opinion on Therapeutic Targets, 2023
Laura Devlin, Praveen Dhondurao Sudhindar, John A. Sayer
In conclusion, renal ciliopathies pose a significant challenge to healthcare professionals, as current treatments are largely supportive, and a long-term cure is only possible through kidney transplantation. However, recent clinical trials have shown promising results for drugs such as tolvaptan, pioglitazone, and bardoxolone methyl and clinical indications for use of these agents will hopefully broaden to pediatric disease settings for ADPKD and ARPKD. Although there are no ongoing trials for NPHP, there is recognition that patient cohorts need to be identified and characterized so that they will be trial ready. Across the spectrum of renal ciliopathies, preclinical models have provided insight into the understanding the function of PKD- and NPHP-related proteins, highlighting their ciliary and extraciliary functions. Dissecting further their role in cellular biology is a prerequisite to developing novel specific therapies for these complex disorders.
New therapeutic targets in chronic kidney disease progression and renal fibrosis
Published in Expert Opinion on Therapeutic Targets, 2020
Sandra Rayego-Mateos, Jose M. Valdivielso
In the clinical field, there are some studies regarding the role of antioxidants such as NRF2 inducers as a potential treatment for kidney disease (Table 1). The use of bardoxolone, a synthetic tri-terpenoid that activates NRF2, showed an increase in the estimated glomerular filtration rate (eGFR) in patients with DN and CKD [33,34] by a mechanism that appears to involve the restoration of endothelial function [35]. Nevertheless, the BEAM trial (NCT00811889) found that bardoxolone at high doses significantly increased albuminuria [36]. Furthermore, cardiovascular events were increased in patients treated with bardoxolone in the BEACON (NCT01351675) study, so the drug never made it to the market [33]. Another phase-2 randomized control study (TSUBAKY study; NCT02316821) also showed the improvement of GFR in patients with T2DM and stages 3–4 CKD. The PHOENIX study (NCT03366337), which analyzed the effect of bardoxolone in IgA nephropathy, FSGS, and autosomal dominant polycystic kidney disease (ADPKD), has also shown improvements in renal function with the treatment. In addition, in the CARDINAL study (NCT03019185) in alport syndrome patients, an increase in eGFR in the patients treated with bardoxolone was also reported [37].
Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies
Published in Expert Opinion on Therapeutic Targets, 2019
Annabelle M. Warren, Søren T. Knudsen, Mark E. Cooper
NF-κB inhibition with pyrrolidine dithiocarbamate (PDTC) has been found to be renoprotective in animal models, but with significant toxicity [91]. Bardoxolone methyl is a compound that acts as an NF-κB inhibitor and Nrf2 agonist with initially promising clinical findings. Bardoxolone has been shown to increase eGFR in patients with DKD in the BEAM phase II study followed by the BEACON phase III trial of over 2000 participants [92]. Unfortunately BEACON was terminated early in setting of increased hospitalizations for heart failure, particularly in patients with elevated B-type natriuretic peptide (BNP) and prior heart failure hospitalization, which was thought to be related to fluid overload mediated by modulation of the endothelin pathway resulting in sodium and water retention [93]. Nevertheless, a new phase III trial named AYAME with updated exclusion criteria designed to reduce CV risk is currently recruiting with estimated completion in 2022. If the promising renal results are replicated and the CV risks can be attenuated, bardoxolone will be an exciting future therapy given its ability to not only halt but indeed reverse eGFR decline.