The circadian rhythm: A new target of natural products that can protect against diseases of the metabolic system, cardiovascular system, and nervous system

Abstract

Background: The treatment of metabolic system, cardiovascular system, and nervous system diseases remains to be explored. In the internal environment of organisms, the metabolism of substances such as carbohydrates, lipids and proteins (including biohormones and enzymes) exhibit a certain circadian rhythm to maintain the energy supply and material cycle needed for the normal activities of organisms. As a key factor for the health of organisms, the circadian rhythm can be disrupted by pathological conditions, and this disruption accelerates the progression of diseases and results in a vicious cycle. The current treatments targeting the circadian rhythm for the treatment of metabolic system, cardiovascular system, and nervous system diseases have certain limitations, and the identification of safer and more effective circadian rhythm regulators is needed.

Aim of the review: To systematically assess the possibility of using the biological clock as a natural product target for disease intervention, this work reviews a range of evidence on the potential effectiveness of natural products targeting the circadian rhythm to protect against diseases of the metabolic system, cardiovascular system, and nervous system. This manuscript focuses on how natural products restore normal function by affecting the amplitude of the expression of circadian factors, sleep/wake cycles and the structure of the gut microbiota.

Key scientific concepts of the review: This work proposes that the circadian rhythm, which is regulated by the amplitude of the expression of circadian rhythm-related factors and the sleep/wake cycle, is crucial for diseases of the metabolic system, cardiovascular system and nervous system and is a new target for slowing the progression of diseases through the use of natural products. This manuscript provides a reference for the molecular modeling of natural products that target the circadian rhythm and provides a new perspective for the time-targeted action of drugs.

Keywords: Cardiovascular system; Circadian rhythm; Metabolic system; Natural products; Nervous system.

Graphical abstract

Fig. 1

Transcriptional-translational feedback loops. Explanatory notes: In cells, the main circadian rhythm factors CLOCK and BMAL1 promote the transcription of Rev-erbs, RORs, Pers, Crys, E4B4, and Dbp by forming the heterodimer CLOCK-BMAL1 and are negatively regulated by these transcription factors, forming transcriptional-translational feedback loops (TTFLs). In addition to the TTFLs, CLOCK can regulate glucose receptor expression and lipid cell proliferation, and BMAL1 is associated with cellular autophagy and intracellular oxidative stress, among other processes. Rev-erbs and RORs can participate in inflammatory responses, Pers is associated with vascular sensitivity, Crys can participate in cellular communication, and E4BP4 and Dbp can affect the body’s immune system. These factors outside the loops bring all important cellular activities into the TTFLs. The black and red dotted lines represent the diversion of circadian factors; the blue solid and blue dotted lines represent physiological processes such as transport and translation; and the red solid and red dotted lines represent inhibition. Abbreviations: BMAL1, brain and muscle Arnt-like 1; CLOCK, circadian locomotor output cycles kaput; Crys, cryptochromes; Dbp, D-box-binding protein; E4BP4, E4 promoter-binding factor 4; IκBα, inhibitor kappa B alpha; NF-κB, nuclear factor kappa-B; Pers, period circadian proteins; Rev-erbs, nuclear hormone receptors; RORs, retinoic acid-related orphan receptors; TTFLs, transcriptional-translational feedback loops; SCN, superior optic chiasm nucleus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Protective effects of natural products against metabolic system diseases through effects on the circadian rhythm. The red solid line represents the targeting effect of natural products, the blue solid line represents the secretion process, and the black solid and black virtual solid lines represent transport and action processes, respectively. Abbreviations: AKT, protein kinase B; AMPK, intracellular cyclic adenosine 5′-monophosphate-activated protein kinase; BMAL1, brain and muscle Arnt-like 1; CLOCK, circadian locomotor output cycles kaput; Cry, cryptochrome; FGF21, fibroblast growth factor 21; Per, period circadian protein; RORα, retinoic acid-related orphan receptor α; ROS, reactive oxygen species. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Protective effects of natural products against cardiovascular system diseases through effects on the circadian rhythm. The red solid line represents the targeting effect of natural products, the blue solid line represents the secretion process, and the black solid and black virtual solid lines represent transport and action processes, respectively. Abbreviations: BMAL1, brain and muscle Arnt-like 1; CLOCK, circadian locomotor output cycles kaput; Rev-erbs, nuclear hormone receptors; RORα, retinoic acid-related orphan receptor α; ROS, reactive oxygen species; SCN, superior optic chiasm nucleus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Protective effects of natural products against nervous system diseases through effects on the circadian rhythm. The red solid line represents the targeting effect of natural products, the blue solid line represents the secretion process, and the black solid and black virtual solid lines represent transport and action processes, respectively. Abbreviations: Crys, cryptochromes; Pers, period circadian proteins; SCN, superior optic chiasm nucleus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)