Rhythm and ROS: Hepatic Chronotherapeutic Features of Grape Seed Proanthocyanidin Extract Treatment in Cafeteria Diet-Fed Rats

Abstract

Polyphenols play a key role in the modulation of circadian rhythms, while the cafeteria diet (CAF) is able to perturb the hepatic biological rhythm and induce important ROS production. Consequently, we aimed to elucidate whether grape seed proanthocyanidin extract (GSPE) administration recovers the CAF-induced hepatic antioxidant (AOX) misalignment and characterize the chronotherapeutic properties of GSPE. For this purpose, Fischer 344 rats were fed a standard diet (STD) or a CAF and concomitantly treated with GSPE at two time-points (ZT0 vs. ZT12). Animals were euthanized every 6 h and the diurnal rhythms of hepatic ROS-related biomarkers, hepatic metabolites, and AOX gene expression were examined. Interestingly, GSPE treatment was able to recover the diurnal rhythm lost due to the CAF. Moreover, GSPE treatment also increased the acrophase of Sod1, as well as bringing the peak closer to that of the STD group. GSPE also corrected some hepatic metabolites altered by the CAF. Importantly, the differences observed at ZT0 vs. ZT12 due to the time of GSPE administration highlight a chronotherapeutic profile on the proanthocyanin effect. Finally, GSPE could also reduce diet-induced hepatic oxidative stress not only by its ROS-scavenging properties but also by retraining the circadian rhythm of AOX enzymes.

The Pharmacological Properties of Red Grape Polyphenol Resveratrol: Clinical Trials and Obstacles in Drug Development

“…Several pharmacological interactions involving resveratrol were also discovered and because of the potential for these interactions to reduce the efficacy of the medication, they are considered hazardous [27]. High-dose resveratrol has hormetic effects in vitro (micromolar range in cell culture media) and in vivo (nanomolar range in the blood) [28][29][30], including pro-oxidant effects [29][30][31][32][33][34], but it also has toxic side effects, such as disrupting the thyroid and causing goiter if used for an extended period of time. Thus, it is important to identify the actual biologically effective concentration range at which this compound should be supplemented in human subjects [35,36].…”

Abrupt Photoperiod Changes Differentially Modulate Hepatic Antioxidant Response in Healthy and Obese Rats: Effects of Grape Seed Proanthocyanidin Extract (GSPE)

“…Furthermore, GSPE was reported to improve the metabolic status after light/dark cycle disruption [40]. More recently, we have also shown that GSPE administration restored the diurnal rhythms of antioxidant enzyme gene expression lost by the CAF in the liver [19].…”

“…In line with this, our group recently described the restoration of the diurnal rhythmicity of GPx1, lost by the CAF, through GSPE treatment in a time-of-day dependent manner. This mechanism could explain the increase in the expression of this gene and the enhancement of the antioxidant response [19]. However, the expressions of two main targets of NRF2, including Sod2, the mitochondrial isoform of SOD, and Sesn2, which is fundamental against oxidative stress, remained unresponsive to the GSPE treatment, as no differences were found regardless of the photoperiod condition.…”

“…All of this, in turn, leads to a chronic, low-grade inflammatory state which can increase the production of reactive oxygen species (ROS), which accumulate and generate oxidative stress that damages cells and tissues [17]. In this regard, it has been recently described that there is a bidirectional relationship between oxidative stress and circadian dysregulation, wherein misaligned cues disrupting circadian rhythms can induce oxidative stress and vice versa [18,19].…”