Possible activation of NRF2 by Vitamin E/Curcumin against altered thyroid hormone induced oxidative stress via NFĸB/AKT/mTOR/KEAP1 signalling in rat heart

Abstract

Oxidative stress is implicated in both hypo- and hyper-thyroid conditions. In the present study an attempt has been made to elucidate possible interaction between vitamin E or/and curcumin (two established antioxidants) with active portion (redox signaling intervening region) of nuclear factor erythroid 2-related factor 2 (NRF2) as a mechanism to alleviate oxidative stress in rat heart under altered thyroid states. Fifty Wistar strain rats were divided into two clusters (Cluster A: hypothyroidism; Cluster B: hyperthyroidism). The hypo- (0.05% (w/v) propylthiouracil in drinking water) and hyper- (0.0012% (w/v) T4 in drinking water) thyroid rats in both clusters were supplemented orally with antioxidants (vitamin E or/and curcumin) for 30 days. Interactive least count difference and principal component analyses indicated increase in lipid peroxidation, reduced glutathione level, alteration in the activities and protein expression of antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase under altered thyroid states. However, the expression of stress survival molecules; nuclear factor κB (NFκB) and the serine-threonine kinase B (Akt), in hyper-thyroidism only points towards different mechanisms responsible for either condition. Co-administration of vitamin E and curcumin showed better result in attenuating expression of mammalian target for rapamycin (mTOR), restoration of total protein content and biological activity of Ca 2+ ATPase in hyperthyroid rats, whereas, their individual treatment showed partial restoration. Since NRF2 is responsible for activation of antioxidant response element and subsequent expression of antioxidant enzymes, possible interactions of both vitamin E or/and curcumin with the antioxidant enzymes, NRF2 and its regulator Kelch ECH associating protein (KEAP1) were studied in silico . For the first time, a modeled active portion of the zipped protein NRF2 indicated its interaction with both vitamin E and curcumin. Further, curcumin and vitamin E complex showed in silico interaction with KEAP1. Reduction of oxidative stress by curcumin and/or vitamin E may be due to modulation of NRF2 and KEAP1 function in rat heart under altered thyroid states.

Inter nation social lockdown versus medical care against COVID-19, a mild environmental insight with special reference to India

“…Eventually, it is clear that no direct or specific drugs are invented for the treatment of COVID-19 and all the available drugs focus on a particular aspect of the clinical consequences in COVID-19 patients (Caly et al, 2020). Although many alternative broad spectrum medicines are suggested to be helpful against COVID-19, but no research yet has been initiated on them (Hati et al, 2012;Paital et al, 2014;Paital et al, 2017;Mishra et al, 2019;Raja et al, 2020). Also, in silico screening of inhibitors against the viral replicase enzymes can be done but research on it is scanty .…”

Nurture to nature via COVID-19, a self-regenerating environmental strategy of environment in global context

“…Still the world is eagerly waiting for a vaccine against COVID-19 and hopefully, it will be available soon (Ahn et al, 2020). To come up with specific drugs or vaccines, several research institutions are working 24/7 although, conventional or alternative medicines using both wet and dry laboratory approaches are suggested for the treatment of COVID-19 (Hati et al, 2012a(Hati et al, , 2012bPaital et al, 2014Chu et al, 2004, Chafekar andFielding, 2018;Mishra et al, 2019;Caly et al, 2020;Dong et al, 2020;Huang et al, 2020;Raja et al, 2020;Swain et al, 2020; Vellingiri et al, 2020;Zhou et al, 2020). High throughput in silico screening is also suggested to find a suitable inhibitors against the viral proteins, like it has been found for other enzymes Paital et al, 2011Paital et al, , 2015aPaital et al, , 2015bSwain et al, 2020).…”

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

“…Although a direct interaction of quinone compounds with KEAP1 Cys residues has not yet been described, indirect proof has led to the proposal that these molecules are NRF2 inducers. In addition to their antioxidant activity: (i) coenzyme Q 10 , vitamin E, idebenone, EPI-743, and MitoQ are able to increase NRF2 stability/expression and to induce NQO1 activity in cells and in animal models [77,[102][103][104][105][106], which is a renowned method to evaluate the functionality of NRF2 inducers [107]; (ii) the chemical characteristics of the para-benzoquinone moiety make these molecules able to react with thiol compounds [108] and with protein-contained cysteine residues [109]; (iii) in silico modeling analyses showed a potential interaction between the vitamin E and KEAP1 [110], suggesting a common behavior for molecules sharing the same biochemical structure; and (iv) in particular conditions, especially in an oxidative stress-induced environment [111][112][113][114], these compounds can act as pro-oxidants thus directly inducing NRF2 activity (i.e., by interacting with KEAP1) or increasing the amount of oxidative species in the cell.…”