(-)-Epigallocatechin-3-gallate Ameliorates Intervertebral Disc Degeneration Through Reprogramming of the Circadian Clock.

Liangwei Mei,Yi Zheng,Bing Xia,Jinghui Huang,Zhuojing Luo,Xue Gao,Yiming Hao,Teng Ma

doi:10.3389/fphar.2021.753548

Abstract

The circadian clock is vital in the management of our daily physiological as well as metabolic processes. Disturbances of the clock can cause degenerative and age-related diseases. Increasing evidence has indicated that the intervertebral discs contain an internal biological clock related to degeneration. However, to date, no bioactive compounds have been found that can ameliorate intervertebral disc degeneration (IDD) by restoring the circadian clock. (-)-Epigallocatechin-3-gallate (EGCG) is a nutritious food with powerful antioxidant properties, as well as entraining biological clock to improve health. The purpose of this study was to determine whether the protective effects of EGCG on nucleus pulposus (NPCs) under oxidative stress is related to the circadian clock. First, we found that EGCG attenuated H2O2-induced extracellular matrix degradation in NPCs and inhibited H2O2-induced NPC apoptosis. Our in vivo experiments also confirmed this finding. Furthermore, EGCG attenuated H2O2-triggered dampening of phase shifts and daily oscillations in circadian clock gene transcription as well as protein expression levels. Intriguingly, core clock gene (Bmal1) knockdown notably blocked the protective effects of EGCG. To our knowledge, this study provides the first convincing evidence that EGCG prevents IDD in a Bmal1-dependent manner. In general, EGCG supplementation can be used as a nutritional prevention strategy for the rehabilitation of degenerative diseases related to the circadian clock.

Highlights

Due to Earth’s rotation, almost all living species have evolved an internal timing system referred to as the circadian clock that enables adaptation to changes in behavioral as well as physiological aspects of the daily environment (Ruan et al, 2021)
The primary antibodies against Bmal1, Aggrecan, Collagen II, matrix metalloproteinase 13 (MMP13), ADAM metallopeptidases with thrombospondin type 1 motif (ADAMTS5), Bcl-2, Bax, and GAPDH were obtained from Abcam (Cambridge, United Kingdom)
To establish the effects of EGCG and H2O2 on NP cells (NPCs) viability, cells were treated with varying concentrations of EGCG or H2O2 for 24 h, after which viability was assessed by the CCK-8 assay

Summary

Introduction

Due to Earth’s rotation, almost all living species have evolved an internal timing system referred to as the circadian clock that enables adaptation to changes in behavioral as well as physiological aspects of the daily environment (Ruan et al, 2021). Accumulating evidence suggests that there is a close correlation between the circadian clock and oxidative stress. Cellular redox state is critically important for the regulation of the Bmal and Clock genes transcriptional activities (Ranieri et al, 2015). Circadian clock involves in the regulation of reactive oxygen species (ROS) levels in vitro and in vivo (Liu et al, 2021). Night-shift work as well as frequent travel across time zones disrupts the circadian clock and can significantly increase the levels of oxidative stress markers (Ozyurek et al, 2021). As a core gene of the circadian clock, Bmal plays a role in regulation of tissue homeostasis by directly controlling ROS levels. The circadian clock mediates variations in cellular redox tone by regulating redox pathway expression. Since many aspects of oxidative stress and aging are closely related, age-associated alterations in clock function can promote oxidative-related damage

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