Keap1/Nrf2/ARE signaling unfolds therapeutic targets for redox imbalanced-mediated diseases and diabetic nephropathy

Adelusi, Temitope Isaac; Du, Lei; Meng, Hao; Zhou, Xueyan; Qian, Xuan; Chowdhury, Apu; Sun, Ying; Lü, Qian; Yin, Xiaoxing

doi:10.1016/j.biopha.2019.109732

Cited by 85 publications

(46 citation statements)

References 217 publications

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“…42 Numerous study have reported TGF-β1 involved in the pathogenesis of diabetic nephropathy and over-expressed TGF-β1 were one of the consequence of ROS stimulation. 43 In this study, mefunidone significantly inhibited the over-expression of TGF-β1 in vitro and in vivo. SMAD2 and SMAD3 are the canonical downstream of the TGF-β1 signaling pathway.…”

Section: Discussionmentioning

confidence: 54%

“…TGF‐β is considered a “master” cytokine/growth factor produced within injured or diseased tissues, where it activates fibroblasts and facilitates ECM production 42 . Numerous study have reported TGF‐β1 involved in the pathogenesis of diabetic nephropathy and over‐expressed TGF‐β1 were one of the consequence of ROS stimulation 43 . In this study, mefunidone significantly inhibited the over‐expression of TGF‐β1 in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 59%

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Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Jiang

Xie

et al. 2020

FASEB j.

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Diabetic kidney disease (DKD) a kind of microvascular complication, is a primary cause of end-stage renal disease (ESRD) worldwide. 1,2 Characteristic pathological features of DKD include glomerular basement membrane (GBM) thickening, mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis, owing to high expression of extracellular matrix (ECM), such as collagen, fibronectin, and so on. 3,4 Type 1 diabetes millitus (T1D) and type 2 diabetes millitus (T2D) are the most common cause of DKD. The incidence of DKD complicated by T1D and T2D is about 50%

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 59%

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Jiang

Xie

et al. 2020

FASEB j.

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“…e nuclear factor erythroid 2-related factor 2 (Nrf2) is an intracellular transcription factor that could maintain cellular redox homeostasis and upregulate cytoprotective proteins, such as heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Under normal conditions, the binding of Kelch-like ECH-associated protein 1 (Keap1) to Nrf2 could suppress the Keap1/Nrf2 pathway, which leads to the ubiquitination and degradation of cytoplasmic Nrf2 [8].…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Almond Oil on Streptozotocin-Induced Diabetic Rats via Regulating Nrf2/HO-1 Pathway and Gut Microbiota

Shi

et al. 2021

Journal of Food Quality

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Almond oil has been used as a medicine substitution for its numerous health benefits. This study aimed to evaluate the effect of almond oil on streptozotocin- (STZ-) induced diabetic rats for 4 weeks. The results showed that the administration of almond oil could significantly increase body weight, attenuate abnormally elevated blood glucose, promote insulin secretion, and improve glucose tolerance. Almond oil treatment also suppressed oxidative stress, reduced inflammation reaction, improved liver and kidney function, upregulated the expressions of Nrf2, HO-1, and NQO1, while downregulating the expression of Keap1. Furthermore, almond oil reversed the gut microbiota change by STZ and regulated the gut microbiota associated with glucose metabolism. At the phylum level, the relative abundance of Firmicutes was decreased, while Bacteroidetes was increased by almond oil treatment. More importantly, the ratio of Firmicutes/Bacteroidetes was significantly increased. At the genus level, administration of almond oil increased the abundances of Lactobacillus, Bacteroides, and Lachnospiraceae_NK4A136_group, while decreased the abundances of Ruminococcaceae_UCG-014, Clostridium_sensu_stricto_1, and Fusicatenibacter. These results provided evidence for the regulating effect of almond oil on diabetic rats via the Nrf2/HO-1 pathway and gut microbiota.

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“…The regulation of signaling pathways associated with various pathologies through the targeting of their key protein components could serve as molecular therapeutic targets for the management/treatment of various diseases [ 31 , 32 , 33 , 34 , 35 ]. In light of this, we used reported antioxidant compounds to target Nrf2 repressor (Keap1) using in silico methodologies in order to figure out the compounds with the best inhibitory potential against Keap1.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Adelusi

Abdul-Hammed

Idris

et al. 2021

Heliyon

Self Cite

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Inhibitors of Keap1 would disrupt the covalent interaction between Keap1 and Nrf2 to unleash Nrf2 transcriptional machinery that orchestrates its cellular antioxidant, cytoprotective and detoxification processes thereby, protecting the cells against oxidative stress mediated diseases. In this in silico research, we investigated the Keap1 inhibiting potential of fifty (50) antioxidants using pharmacokinetic ADMET profiling, bioactivity assessment, physicochemical studies, molecular docking investigation, molecular dynamics and Quantum mechanical-based Density Functional Theory (DFT) studies using Keap1 as the apoprotein control. Out of these 50 antioxidants, Maslinic acid (MASA), 18-alpha-glycyrrhetinic acid (18-AGA) and resveratrol stand out by passing the RO5 (Lipinski rule of 5) for the physicochemical properties and ADMET studies. These three compounds also show high binding affinity of -10.6 kJ/mol, -10.4 kJ/mol and -7.8 kJ/mol at the kelch pocket of Keap1 respectively. Analysis of the 20ns trajectories using RMSD, RMSF, ROG and h-bond parameters revealed the stability of these compounds after comparing them with Keap1 apoprotein. Furthermore, the electron donating and accepting potentials of these compounds was used to investigate their reactivity using Density Functional Theory (HOMO and LUMO) and it was revealed that resveratrol had the highest stability based on its low energy gap. Our results predict that the three compounds are potential drug candidates with domiciled therapeutic functions against oxidative stress-mediated diseases. However, resveratrol stands out as the compound with the best stability and therefore, could be the best candidate with the best therapeutic efficacy.

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Keap1/Nrf2/ARE signaling unfolds therapeutic targets for redox imbalanced-mediated diseases and diabetic nephropathy

Cited by 85 publications

References 217 publications

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Protective Effects of Almond Oil on Streptozotocin-Induced Diabetic Rats via Regulating Nrf2/HO-1 Pathway and Gut Microbiota

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

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