RESUMEN
Introduction: Phenolic phytochemicals are known for antioxidant-mediated pharmacological effects in various diseases (diabetes, cancer, CVDs, obesity, inflammatory and neurodegenerative disorders). However, individual compounds may not exert the same biological potency as in combination with other phytochemicals. Cyamopsis tetragonoloba (Guar), an underutilized semi-arid legume which has been used as a traditional food in Rajasthan (India), is also a source of the important industrial product guar gum. However, studies on its biological activity, like antioxidant, are limited. Methods: We tested the effect of C. tetragonoloba seed extract to enhance the antioxidant activity of well-known dietary flavonoids (quercetin, kaempferol, luteolin, myricetin, and catechin) and non-flavonoid phenolics (caffeic acid, ellagic acid, taxifolin, epigallocatechin gallate (EGCG), and chlorogenic acid) using DPPH radical scavenging assay. The most synergistic combination was further validated for its cytoprotective and anti-lipid peroxidative effects in in vitro cell culture system, at different concentrations of the extract. LC-MS analysis of purified guar extract was also performed. Results and discussion: In most cases, we observed synergy at lower concentrations of the seed extract (0.5-1 mg/ml). The extract concentration of 0.5 mg/ml enhanced the antioxidant activity of Epigallocatechin gallate (20 µg/ml) by 2.07-folds, implicating its potential to act as an antioxidant activity enhancer. This synergistic seed extract-EGCG combination diminished the oxidative stress nearly by double-fold when compared with individual phytochemical treatments in in vitro cell culture. LC-MS analysis of the purified guar extract revealed some previously unreported metabolites, including catechin hydrate, myricetin-3-galactoside, gossypetin-8-glucoside, and puerarin (daidzein-8-C-glucoside) which possibly explains its antioxidant enhancer effect. The outcomes of this study could be used for development of effective nutraceutical/dietary supplements.
RESUMEN
Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington's disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera) partially rescues defective proteostasis by activating heat shock response (HSR) and delays the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioral deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A-treated HD mouse brain. Withaferin A-treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.