Therapeutic potential of ginsenosides in circadian rhythm-based skin disorders

Abstract

The circadian rhythm, a biological system all living organisms possess, has become increasingly important as sleep patterns become more irregular. Circadian rhythms affect various cell types (fibroblasts, fat cells, muscles, etc.) and organs (the liver, pancreas, gut, etc.). This review focuses on the effects of the circadian rhythm on skin physiology. Under normal conditions, the circadian rhythm is involved in maintaining skin health, including DNA repair and wound healing. Disrupted circadian rhythm can cause skin disorders, including hyperpigmentation, melanoma, skin aging, sunburn, impaired wound healing, and an abnormal skin barrier.

Furthermore, the effects of ginsenosides, the primary bioactive component of Panax ginseng, were examined on recovery from skin disorders associated with circadian rhythm disruptions. Therefore, this review explains the relationship between skin physiology and circadian rhythm and suggests the potential of ginseng as a treatment for circadian rhythm-mediated skin disorders.

Graphical abstract

1. Introduction

The importance of circadian rhythm has been increasing as the relevance of circadian rhythm in various organs has been revealed. In particular, although reports on the importance of circadian rhythm in the skin have recently increased, there has been no systematic summary of the relevance of skin and circadian rhythm. In addition, the skin efficacy of ginseng and its effective ingredient, ginsenoside, has been revealed, but there has been no report on the relevance of circadian rhythm. Therefore, this review systematically summarizes the relationship between skin physiology and circadian rhythm and suggests that the skin efficacy of ginsenosides is related to circadian rhythm, which is expected to provide an opportunity to provide new research directions for ginsenosides in the future. Among the various skin physiology fields covered in this review, six skin physiology fields that are known to be related to circadian rhythm were selected and discussed (see Table 1).

Table 1.

Relationship between circadian rhythms, skin disorders, and the therapeutic potential of ginsenosides.

Skin physiological disorders	Circadian rhythm genes	Ginsenosides	Mode of actions of ginsenosides	Reference
Skin hyperpigmentation	BMAL1 PER1	Rd	Rd → CREB activation → induce BMAL1 and PER1	[8,13,15,16]
Melanoma	CRY1	Rg3 Rh2	Rg3 & Rh2 → suppress HDAC3 → downregulate Rev-erbα → upregulate BMAL1 → induce CRY1	[[22], [23], [24],28], [[31], [32], [33], [34], [35], [36]]
Wound healing disorder	PER2 BMAL1	Rb1 Rd	Rb1 & Rd → p38MAPK pathway activation → CREB activation → induce BMAL & PER2 → regulate VEGF	[42,43,[45], [46], [47], [48], [49]]
Skin aging	BMAL1/CLOCK PERs	Rb1	Rb1 → cAMP/PKA/CREB pathway activation → induce BMAL1/PERs → regulate Nrf-2	[19,69,75,78,79]
Skin barrier disruption	BMAL1/CLOCK	Rg5	Rg5 → induce BMAL1/CLOCK → regulate AQP3	[84,87]
Sunburn	PER2	Rb1 Rg5 F2	Rb1 & Rg5 & F2 → induce PER2 → regulate p53 function → suppress MMP-1 expression	[[95], [96], [97], [98]]

1.1. Central vs peripheral circadian rhythms

All living organisms have evolutionarily developed a circadian clock, which is an internal biological timing system. This biological clock enables organisms to predict and adapt to external changes, including the transition between day and night, by regulating various physiological processes in a 24-h cycle [1]. The regulation of physiology by the circadian clock exhibits circadian rhythms, which are periodic patterns in biological activity. This rhythm is governed by external cues, particularly environmental cycles of light and darkness [2]. Circadian rhythms are associated with hormone secretion, metabolism, and temperature and play crucial roles in health [3].

Biological clocks can be divided into central and peripheral clocks (Fig. 1). The central clock is located within the hypothalamus, specifically the suprachiasmatic nucleus (SCN), which receives external signals such as light and darkness. When the central clock receives external information, it either directly regulates the biological rhythm of behavioral patterns or synchronizes peripheral clocks by transmitting systemic cues such as hormones [4]. Peripheral clocks are in organs or tissues, and their activities are regulated by information from the central clock. However, they also have an independent biological clock system, which allows adjustments without relying on information from the central clock. Peripheral clocks exist not only in internal organs but also in the skin, specifically in keratinocytes, melanocytes, and dermal fibroblasts [5]. Therefore, studying skin cells alone can provide insights into the mechanisms of biological clocks.

Fig. 1.

Biological clocks consist of a central clock in the brain and peripheral clocks in the tissues or organs. The central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus receives external information. It either directly regulates the biological rhythm of behavioral patterns or synchronizes peripheral clocks by transmitting systemic cues, such as hormones.

1.2. Skin physiological diseases caused by circadian rhythm disruption

The skin, the largest organ in the body primarily defends organs against the external stresses by covering external surfaces. The skin comprises three layers: the top (epidermis), middle (dermis), and bottom (hypodermis) layers. The skin has various functions through these three layers, including protection, sensation, mobility, endocrine activity, immunity, and homeostasis [6].

If the SCN autonomously transmits signals to peripheral organs upon light irradiation, peripheral clocks are synchronized, leading to a light-dark cycle. This light-dark cycle directly regulates the clocks, which apply to the skin to maintain its function [7]. However, if the circadian rhythm is disrupted by extrinsic (shift work, chronic jetlag) or intrinsic (clock gene mutation, aging) factors, skin function cannot be maintained, resulting in various disorders of skin physiology, such as sunburn, skin aging, skin cancer, impaired wound healing, psoriasis, skin hyperpigmentation, and skin infections [8] (Fig. 2).

Fig. 2.

Peripheral clock in the skin. Its activity is regulated by information from the central clock, but it also has an independent biological clock system. This allows it to self-adjust without relying on information from the central clock.

The circadian rhythm is an oscillator that forms a transcription-translation feedback loop known as the core clock gene network, consisting of opposing negative and positive arms. Clock genes that form the core clock gene network include circadian locomotive output cycles kaput (CLOCK), brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), Periods 1, 2, and 3 (Per), cryptochrome 1 and 2 (Cry), retinoic acid receptor-related orphan recipients (RORs), and REV-ERBs. BMAL1, a transcription factor, interacts with CLOCK, forming a heterodimeric complex. This complex binds to an enhancer box (E-box) that activates Per and Cry transcription. This is the primary source of positive feedback. After translation, the expressed Per and Cry form the Per/Cry heterodimeric complex, which moves to the nucleus. The translocated complex, which is involved in secondary negative feedback, suppresses the binding of the BMAL1/CLOCK heterodimer to E-box. When primary positive feedback is provided, E-box, which is activated by the BMAL1/CLOCK heterodimeric complex, also activates ROR and REV-ERB transcription. After translation, ROR, responsible for positive feedback, binds to the ROR/REV-ERB response elements (RORE) that activate Bmal1 transcription. Conversely, REV-ERB, which is responsible for negative feedback, binds to the same site as RORE and inhibits BMAL1 transcription [[9], [10], [11], [12]]. Through this mechanism, the circadian rhythm affects skin function. Targeting intrinsic clock mechanisms with pharmacological agents is essential for effective treatment. Particularly, natural compounds are gaining interest for their role in modulating circadian rhythm [13]. Ginsenosides from Panax ginseng have been used for the improvement of skin health and beauty. Ginsenosides reportedly have protective roles in humans, including antioxidant, anti-aging, anti-neoplastic, anti-inflammatory, and immune- and melanogenesis-regulating effects [17]. Ginsenosides are categorized into dammarane, oleanene, and ocotillol type tricyclic triterpenoids based on aglycone structure [18]. Among these, dammarane type is composed of two subtypes, protopanaxadiol (PPD) and protopanaxatriol (PPT), that differ in sugar substituents attached to the steroid backbone.

Given this evidence of circadian rhythm-related skin disorders, this review aimed to classify the various skin disorders reportedly attributed to skin circadian rhythm disruption and to evaluate the reported evidence and potential of the effectiveness of ginseng as a treatment for circadian rhythm-mediated skin disorders.

2. Relationship between skin physiology and circadian rhythm

2.1. Skin pigmentation and circadian rhythm

Skin pigmentation affects the color of the skin, hair, and eyes. Skin color is due to melanin, a pigment naturally produced by melanocytes. When exposed to sunlight, skin produces more melanin to shield epidermal cells from ultraviolet (UV)-induced damage. However, deficient or excessive accumulation of melanin may cause severe dermatological disorders, such as albinism, vitiligo, and melasma [14].

2.1.1. Circadian rhythm genes regulate melanin production

Clock genes play pivotal regulatory roles in skin biology. Skin pigmentation is regulated by circadian rhythms because skin cells possess their own intrinsic clock gene machinery. Several studies have shown how the clock proteins BMAL1 and PER1 regulate melanin pigmentation [15]. Melanin production is controlled by BMAL1, one component of core circadian clock, which combines with microphthalmia-associated transcription factor (MITF). MITF has rhythmic expression levels that correlate with BMAL1 levels. Studies have shown that BMAL1 overexpression significantly increases melanin production via the melanogenesis pathway, providing skin cells superior protection against UV [8].

The melanogenic function of epidermal melanocytes is affected by BMAL1 and PER1 knockdown. A heterodimeric complex consisting of BMAL1 and CLOCK, induces the expression of PER and CRY by binding to an E-box, which exists in the genes encoding tyrosinase and tyrosinase-related proteins (TRP) 1 and 2 within the relevant promoters. Regarding the circadian oscillator mechanism, BMAL1 silencing is anticipated to considerably decrease PER1 expression, whereas PER1 silencing may not automatically overexpress BMAL1. Given these conditions, increased pigmentation and expression of tyrosinase and TRP 1 and 2, as well as MITF phosphorylation, are the effects of silencing either BMAL1 or PER1 [16].

2.1.2. Effects of ginseng and ginsenosides on pigmentation

Protopanaxatriol (PPT) exerts immunoregulation, anti-aging, and skin-depigmenting effects by modulating the activity and expression of specific proteins [18]. Studies have shown that ginsenoside Rh2 promotes B16 melanoma cell differentiation, thereby modulating melanogenic process. Also, Rg1 increases accumulation of melanin by triggering protein kinase A (PKA)/cAMP response element-binding protein (CREB)-dependent MITF signaling [17]. In addition, F1 decreases α-MSH-induced melanin secretion by reducing intracellular cAMP level and increasing the activity of PI3K and GTPase [18].

2.1.3. Ginsenosides that improve skin pigmentation through circadian rhythm recovery

To date, the direct relationship between the ginsenoside-mediated regulation of the circadian rhythm and skin pigmentation disorders has not been comprehensively investigated. The interconnected pathways involved in skin pigmentation and the regulatory role of circadian rhythms provide a foundation for studying the latent connections between circadian rhythms, skin pigmentation, and the effects of ginsenosides. MITF and CREB are transcription factors that regulate various cellular responses throughout the body. The activation of CRY1 downregulates MITF and phosphorylation of CREB via the cAMP/PKA pathway, leading to suppression of melanogenesis. KL044, CRY1 activator, inhibits the cAMP/PKA/CREB-mediated pathway and melanogenesis [14]. The role of CREB in circadian clock modulation is well known. Studies have documented the interaction of CREB with CLOCK, PER, and BMAL, which may regulate circadian machinery [19]. Additionally, previous studies have suggested that ginsenoside Rd directly affects CREB activation during melanogenesis and melanosome transport. Therefore, the correlation between CREB activation and circadian clock regulation suggests a potential mechanism by which ginsenoside Rd may regulate the circadian clock to influence pigmentation processes through CREB phosphorylation. However, additional study is required to clarify the precise interactions between ginsenosides, CREB, and the circadian clock during pigmentation [16].

2.2. Melanoma and circadian rhythm

Melanoma is defined as a tumor caused by the malignant transformation of melanocytes, which produce melanin. Melanoma is the most metastatic skin cancer and can spread to any organ, including the lymph nodes, bones, lungs, liver, spleen, central nervous system, and surrounding skin [20]. Depending on the location of the metastasis, it can cause various symptoms, including changes in moles or the appearance of new ones, skin ulcers, pain or discomfort in the affected area, and swollen lymph nodes. Owing to the metastasis, the fatality rate of melanoma is very high, approximately 40–50 % [21].

2.2.1. Relationship between circadian rhythm and melanoma

Most melanomas are caused by UV exposure through sunlight [22]. UV exposure induces the formation of photoproducts (PPs) and lesions known as cyclobutane-pyrimidine dimers (CPDs) in DNA. In animals, these DNA lesions are mutagenic and carcinogenic, resulting in melanoma [[22], [23], [24]].

In addition, DNA repair is a known effect of circadian rhythms [25]. When DNA damage occurs, the body addresses it via several mechanisms of DNA repair, including direct, nucleotide excision, base excision, and double-strand break/crosslink repair, among which nucleotide excision is modulated by circadian rhythms. The nucleotide excision repair mechanism involves DNA damage recognition by the cooperative activities of xeroderma pigmentosum complementation groups (XPA and XPC) and replication protein A (RPA), followed by the recruitment of transcription factor Ⅱ H (TFⅡH) by XPC and XPA. Subsequently, the helicase activity of TFⅡH unwinds the DNA around the damage region to make a stable pre-incision complex 1 (PIC1), which induces displacement from XPC to XPG to form PIC2. Thereafter, PIC2 binds to XPF excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1) to make PIC3. The PIC3 complex prompts XPG to form a 3′ incision at the damaged DNA regions, whereas the XPF-ERCC1 interaction makes the 5′ incision. Subsequently, the gap is filled by DNA polymerase and ligated, resulting in DNA repair [[25], [26], [27]]. In a previous report, the circadian rhythm controlled the expression of XPA, which critically contribute to DNA damage recognition. Based on these results, the excision repair level changes depending on XPA expression. At this time, XPA exhibits oscillations akin to circadian rhythms. In addition, researchers have discovered that XPA oscillations are converted into the clock transcriptional repressor Cry1. Results showing that XPA is always upregulated under CRY1 knockout conditions confirmed these data [28]. In other words, if the circadian rhythm is disrupted, DNA repair will not occur properly, resulting in failure to inhibit melanoma. Furthermore, several studies have shown that circadian rhythm disruption promotes tumor cell proliferation [29,30].

2.2.2. Ginsenosides that improve melanoma through circadian rhythm recovery

Ginsenosides Rg3 and Rh2 inhibit cell proliferation [31,32] by reducing the expression of histone deacetylase 3 (HDAC3) and inducing p53 acetylation. In a previous study, HDAC3 induced the expression of Rev-erbα, which reduced BMAL1 expression [33]. Therefore, since Rg3 and Rh2 inhibit HDAC expression, they may also reduce Rev-erbα expression. As mentioned above, reduced Rev-erbα expression results in the expression of BMAL1, which is known to induce p53 phosphorylation and acetylation [34]. This mechanism is in the same pathway as that of ginsenosides Rg3 and Rh2 action. Collectively, these data suggest that ginsenosides (Rh2 and Rg3) increase BMAL1 expression, which restores the circadian rhythm and reduces melanoma by inhibiting cell proliferation.

In addition, Rg3 induces p38 MAPK and p53 phosphorylation, resulting in the downregulation of matrix metalloproteinases (MMPs) 3, 9, and 13 to suppress metastasis. During this process, BMAL1 induces p53 phosphorylation [34], while Rg3 and Rh2, similar to BMAL1, inhibit the PI3K-Akt pathway, activating MMP-13 expression [30,35,36]. Therefore, these data suggest that the ginsenosides (Rh2 and Rg3) increase BMAL1 expression to recover the circadian rhythm, thereby inhibiting melanoma metastasis.

2.3. Healing process of wound

Wound healing is a complicated recovery process that involves the skin and other affected body parts following tissue injury. This process involves various cell types, growth factors, cytokines, mediators, etc [37]. The wound healing process consists of four phases: hemostasis, inflammation, proliferation, and remodeling. Hemostasis begins immediately after the wound is inflicted, with the body activating mechanisms to prevent excessive blood loss. This involves blood vessel vasoconstriction, aggregation of platelet, and blood clotting to minimize blood loss [37,38]. Subsequently, the inflammatory phase occurs with the arrival of various inflammation-related cells and cytokines, aiming to establish an immune barrier against potentially harmful foreign objects. After inflammation, the proliferative phase begins as the body attempts to repair the damaged tissue. This phase is characterized by cell migration and proliferation, as well as the synthesis of granulation tissue. The last phase of wound healing is the remodeling phase, during which new epithelium forms and scar tissue is generated [37,39]. These processes occur sequentially, ensuring the efficient progression of wound healing, and disruption among the phases leads to abnormal or delayed wound healing [39].

2.3.1. Relationship between circadian rhythm and wound healing

Circadian rhythms are also involved in the intricate wound-healing mechanism and can significantly influence the process and outcome. Therefore, disrupting these rhythms can severely affect the efficacy and overall outcomes of wound repair. Numerous studies have extensively documented how alterations in the circadian rhythm can influence the wound-healing process. Induction of circadian arrhythmia in Siberian hamsters (Phodopus sungorus) through disruptive light treatment delayed the wound-healing process compared with that in a group with an intact circadian rhythm. This outcome is believed to be facilitated by the circadian-regulated coordination of immune function involved in the wound-healing process [40]. Other evidence also suggests that disrupting the circadian rhythm, in this case through exposure to dim artificial light, can compromise the wound-healing process, likely due to impaired adaptive immune function [41].

2.3.2. Mode of action of circadian-related genes influencing fibroblasts in wound healing

Circadian rhythm-related genes have been shown to significantly affect wound-healing efficiency and success. In a mouse model, the deletion of Per2 was shown to positively affect skin wound-healing time in vivo. Specifically, the absence of Per2 increases the proliferative capacity of epithelial cells, enhances angiogenesis, and increases periostin expression [42]. Neuronal PAS domain-containing protein 2 (Npas2), another essential clock gene, is upregulated in aging fibroblasts. A previous study found that deletion of the Npas2 gene in a mouse model resulted in an improved wound-healing process compared with that in normal mice [40]. The lack of the Npas2 gene increases proliferation, migration, and contraction abilities and produces thicker collagen fibers. Another study explored the role of the minimal upstream open reading frame (uORF) which is encoded by Per2 as a regulator for the temperature-dependent circadian clock and its impact on wound healing [43]. Mice with a mutated Per2 minimal uORF exhibited delayed wound healing compared with that of the normal group, suggesting an important role for uORF-mediated Per2 modulation in optimal tissue wound healing [43]. Previous research explored the role of Non-POU domain-containing octamer-binding protein (NONO) in cell cycle regulation and, by extension, its role in wound healing [44]. NONO protein belongs to the Drosophila behaviour/human splicing family of proteins and is involved with many nuclear processes and binds to both DNA and RNA. The findings indicated that NONO interacts with the p16-Ink4A, the cell cycle checkpoint gene, thereby enhancing PER protein expression. Deficits in NONO result in disrupted expression of p16-Ink4A, which affects the circadian control of cell cycle and leads to wound healing disorder. This suggests that NONO is pivotal in coordinating cell division by allowing cells to proliferate when required for proper tissue organization, emphasizing its significance in regulating circadian-related genes and its impact on wound healing [44].

The intrinsic circadian rhythm of fibroblasts, pivotal cells in wound healing, significantly influences wound repair. Actin regulation triggers cell-intrinsic rhythms in actin dynamics modulated by the circadian clock, impacting crucial cellular functions, including migration and adhesion, which are essential for effective wound repair [45]. The timing of wound induction also significantly influences the healing process. Wounds sustained during the circadian cycle’s active phase, characterized by the peak expression of circadian-related genes, such as PER2 and BMAL1, experience enhanced healing efficiency [45]. This is attributed to increased fibroblast activity, including increased migration, proliferation, and overall efficacy, which can positively affect tissue repair. Clinical observations further support these findings, with daytime burn wounds showing a 60 % faster healing rate than that of nighttime wounds [45]. Another study explored the influence of circadian rhythms on the length of primary cilia, which indirectly affected the healing process of wound by affecting fibroblast migration speed. The use of SR9011 or BMAL1 knockdown disrupts the rhythmic length dynamics of fibroblast cilia, leading to uncontrolled fibroblast migration and eventual disruption of the overall wound-healing process [46].

2.3.3. Effect of ginsenosides on wound healing and potential circadian rhythm modulation

Rb1, a major and well-known ginsenoside isolated from Panax notoginseng, has been thoroughly studied for its ability to promote wound healing. A previous study reported that Rb1 promoted burn wound healing in rats. This effect could be due to the increase of the FGF-2/PDGF-BB/PDGFR-β gene and its protein expression in Rb1-treated mice [47]. Another study elucidated Rb1 in enhancing skin wound healing, detailing how the enhanced wound healing process was mediated by senescent fibroblasts induced by a specific secretory phenotype (SASP). Furthermore, the mechanism by which mediation by ginsenoside Rb1 via the activation of the p38MAPK/MSK2/NF-κB pathway was elucidated [48]. In addition, ginsenoside Rd, often found in P. ginseng leaves, significantly increased keratinocyte progenitor cells and human dermal fibroblasts’ proliferation and migration. Both cell types play crucial roles in wound-healing and skin repair processes. This mechanism is related to increased cAMP levels and CREB expression in the nucleus, suggesting an elevation in the wound healing effect via PKA activation. This finding underscores the potential of Rd for skin regenerative medication as a natural source [49].

At the time of writing this paper, the direct relationship between the ginsenoside modulation of the circadian rhythm and its regulation of the wound-healing process has not been extensively studied. Nevertheless, owing to the interconnected pathways involved in the wound-healing process and the regulatory role of the circadian rhythm, we explored the potential relationship between the circadian rhythm, wound healing, and the effects of ginsenosides based on existing scientific basis.

CREB is activated by the phosphorylation of PKA. Previous studies have investigated the role of CREB as a key gene in modulation of wound healing process. The inhibition of CREB, combined with the activation of Akt, enhanced the efficiency of corneal wound healing, as CREB appears to modulate this process [50]. CREB also plays a pivotal role in wound healing during photobiomodulation treatment. The phosphorylated form of CREB has been suggested to serve as a biomarker for monitoring and evaluating wound healing, especially in inflammatory response modulation [51]. As mentioned above, ginsenoside Rd directly influences CREB activation during the wound-healing process [49]. Hence, CREB activation and circadian process modulation are correlated. Additionally, a potential mechanism by which ginsenoside Rd modulates the circadian clock has been identified, affecting the wound-healing process via CREB activation. However, further study is required to elucidate the precise interactions between ginsenosides, CREB, and the circadian clock during wound healing.

Another potential gene that could link these two processes is vascular endothelial growth factor (VEGF), a crucial protein for angiogenic activity [52]. Due to its nature, VEGF is a key gene in wound healing, primarily because of angiogenesis, which is a critical factor in this process. The presence of VEGF is beneficial for wound healing because it provides enhanced angiogenesis and granulated tissue formation, as well as supporting tissue repair mechanisms to ensure successful wound healing [53,54]. Concerning the circadian rhythm, BMAL1 and PER2 regulate VEGF expression [55]. Specifically, BMAL1 directly upregulates VEGF expression, whereas PER2 and CRY1 suppress VEGF activity [56]. This shows that angiogenesis, a crucial step in wound healing, is significantly modulated by the circadian machinery influencing blood vessel and tissue repair. Therefore, given that ginsenosides, such as Rg1, have been demonstrated to possess the ability to increase VEGF production, it is plausible to suggest a possible role of ginsenosides in regulating wound healing through their correlation with the circadian rhythm by regulating VEGF and clock gene expression. Further research is required to identify the underlying mechanism linking the overall effects of ginsenosides, VEGF, and circadian rhythms on wound healing.

2.4. Skin aging and circadian rhythm

Aging involves a gradual decline in physiological functions that affects various body systems [57]. Skin aging progressively deteriorates the skin function and its structure, driven by both intrinsic and extrinsic factors [58]. Intrinsic aging is caused by genetic and metabolic factors that weaken and break down important components that support skin structure by maintaining skin elasticity and firmness, such as collagen and elastin. Once proteins decline, the skin develops fine lines and wrinkles to lose elasticity and volume [58]. The other aging cause could be external factors such as UV radiation, pollution, and lifestyle choices. These external factors exacerbate skin aging by accelerating the breakdown of collagen and elastin and hastening structural changes within the skin [58].

Skin aging involves multiple interconnected biochemical processes that are significantly influenced by circadian rhythms. These rhythms protect the skin by regulating physiological functions such as cell proliferation and maintaining redox balance [59,60]. Therefore, disrupting circadian rhythmicity can severely affect the balance of cellular processes within the skin, hastening the aging process. Substantial evidence indicates disturbance in circadian rhythm can contribute to escalated skin aging [61].

2.4.1. Oxidative stress

Reactive oxygen species (ROS) are reactive species that are usually removed by cellular metabolism [62]. Moderate ROS levels elicit cellular signals and trigger immune responses that maintain health. However, excessive ROS can cause cellular damage and contribute to chronic inflammation [63]. Normally, the body maintains the balance of the redox state as a defense mechanism using antioxidant enzymes. This defense system maintains cellular health and prevents damage [64]. A disrupted balance between ROS and the defense system of antioxidant may cause excessive oxidative stress. The overproduction of ROS may significantly damage various cellular components of the skin, triggering skin aging [65]. Therefore, maintaining redox balance is essential for mitigating damage. The circadian rhythm is intertwined with the maintenance of redox balance. This balance fluctuates throughout the day and is influenced by the body’s circadian rhythm in a 24-h cycle. Research has demonstrated the rhythmicity of antioxidant pathway activity, indicating that these processes are synchronized with the internal clock [66]. Antioxidant enzymes (glutathione peroxidase and superoxide dismutase) show rhythmicity in their expressions [57].

Another rhythmic antioxidant pathway is the nuclear factor erythroid 2-related factor 2 (Nrf2) defense mechanism. Nrf2 act as a transcription factor involved in defense mechanisms that attenuate oxidative damage. Nrf2 controls the expression of enzymes that protect cells against oxidative stress. This implies that clock genes regulate the transcription of antioxidant pathways, thereby influencing cellular responses to oxidative stress [67]. Disrupted circadian rhythm decreases the rhythmicity and transcription levels of NRF2 pathway, thereby increasing oxidative stress [68]. Thus, maintaining this balance is crucial. Studies have highlighted that clock genes such as Bmal1 and CLOCK are transcription factors regulating the defense mechanism of antioxidant, which explains the rhythmicity in the antioxidant pathway. Dimerized Bmal1 and CLOCK directly binds to the E-box of Nrf2 and regulates its transcription levels in a circadian manner. A separate study further elucidated that the circadian clock balances the cellular redox states. Bmal1 regulated the expression of critical antioxidant enzymes, including peroxiredoxin 6 (PRDX6) [69]. The same study also showed that Bmal1, and Nrf2, regulate Prdx6 transcription together.

2.4.2. Collagen homeostasis and circadian rhythm

Collagen, the main component of the dermis, provides support and elasticity to the skin [70]. As we age, collagen production decreases naturally due to the decreasing activity and number of fibroblasts. Collagen fibers begin to break down and become less organized [71]. This decrease significantly affects skin health and appearance by reducing firmness and elasticity, leading to wrinkle formation and sagging. Therefore, sustaining collagen production is key to preventing visible signs of aging [72]. However, collagen overproduction can cause severe skin problems such as fibrosis or keloids [73]. Therefore, balancing collagen synthesis and degradation is essential to keep the structural integrity of the skin. Studies have reported that the preservation of collagen homeostasis are affected by the circadian clock by controlling its production and secretory pathways to ensure that collagen levels are balanced throughout the day. For example, the regulatory components of collagen secretion, EC61, TANGO1, PDE4D, and VPS33B, are sequentially located from the endoplasmic reticulum to the plasma membrane. Research has shown a 24-h rhythmic expression pattern in these components, suggesting that the circadian clock may control pro-collagen transport from the endoplasmic reticulum to the plasma membrane based on this rhythmic expression pattern [74]. In addition, the circadian clock gene PER suppresses collagenases, such as MMP-1, via PKA/cAMP signaling [75]. Collectively, disruption of the circadian rhythmicity of collagen synthesis and degradation can contribute to aging, as it can lead to imbalances in collagen homeostasis and impair the structural integrity of the skin over time.

2.4.3. Effect of ginsenosides on anti-aging process and potential modulation of circadian rhythm

Ginsenosides, a group of natural compounds found in the roots of Korean ginseng, have various pharmacological properties, including anti-aging effects [76].

Limited research has been conducted on the direct relationship between ginsenoside modulation of the circadian rhythm and its impacts on anti-aging. Given the mutual connections between anti-aging and circadian rhythm pathways, investigating the potential interplay between circadian rhythms, anti-aging mechanisms, and the effects of ginsenosides is possible.

Ginsenoside Rb1 activates the cAMP/PKA/CREB pathway, which affects circadian rhythm transcription [77]. CREB binds to the specific DNA sequence named the cAMP response element (CRE). When activated by cAMP/PKA, circadian genes such as PER2 are upregulated by CREB [19]. Since PER 2 is known to downregulate MMP-1, activating CREB by Rb1 would promote PER2 transcription. This may lead to decreased MMP-1 expression. Through this mechanism, Rb1 can potentially restore disrupted circadian rhythms and may ameliorate various health issues associated with circadian rhythm disorders.

Rb1 also serves as a precursor for producing ginsenosides, including compound K (CK) [78], which potentially prevents skin aging owing to its strong ability to maintain collagen homeostasis. One study reported that CK influences collagen degradation by modulating MMP-1 expression [79].

Ginsenosides enhance clock gene expression by activating the cAMP/PKA/CREB pathway and preserving collagen homeostasis. Thus, they could be a potential treatment for preventing skin aging associated with the circadian rhythm.

As mentioned above, the circadian dimers, Bmal1 and CLOCK, directly regulate Nrf2 and antioxidant enzyme expression by acting as transcription factors. This implies that maintaining redox balance, a crucial step in the anti-aging process, is strongly controlled by the circadian rhythm. Therefore, given that ginsenosides demonstrate the ability to enhance Nrf2 defense, they have been suggested to regulate anti-aging correlated with the circadian rhythm by regulating antioxidant product expression. Ginsenosides could potentially influence anti-aging by affecting clock gene activity by controlling Nrf2 expression along with its downstream effectors. Further research is required to elucidate the overall effects of ginsenosides and circadian rhythms in the anti-aging process.

2.5. Skin barrier and circadian rhythm

The skin act as a barrier to protect our bodies from the environment. This barrier protects our skin from diseases by defending against chemical and physical hazards while regulating the loss of water and solutes. Various factors help maintain skin barrier function. Thus, disruption in the barrier system causes diverse skin conditions, particularly inflammatory disorders such as psoriasis [80].

2.5.1. Circadian regulation of gene expression and its implications for skin barrier function

Numerous research indicates that the circadian rhythm significantly influences the modulation of skin barrier function, underscoring its complex interaction with various physiological processes. Understanding the mechanisms underlying this effect will offer valuable insights into how circadian biology impacts skin health.

The circadian rhythm regulates the epidermal water balance, which is essential for maintaining the skin's barrier function. Studies have demonstrated that daily variations in skin hydration are linked to fluctuations in the expression levels of aquaporins (AQPs), a family of water channel proteins [81].

AQPs are membrane proteins for skin hydration, controlling water transport and influencing immune responses [81,82]. Disruptions in AQP expression have been implicated in various inflammatory skin disorders, including atopic dermatitis and psoriasis. AQP3 was reported to transport water and glycerol to the stratum corneum, enhancing hydration and promoting keratinocyte proliferation [81,83]. The circadian clock genes, CLOCK and BMAL1, regulate AQP3 expression by directly binding to its promoter. Conversely, PER and CRY proteins inhibit this activation, creating a 24-h oscillatory pattern [84]. Therefore, disruptions in the circadian rhythm can lead to altered AQP3 expression, consequently compromising the skin barrier.

2.5.2. Protective role of ginsenosides in the skin barrier

UVB irradiation disrupts the skin barrier by affecting the expression and localization of AQP3 [84]. Exposure to UVB rays causes dryness, desquamation, and hyperkeratosis, which lead to water loss and compromised skin barriers [86]. Specifically, UVB radiation reduces AQP3 expression and disrupts its localization within skin cells, preventing the skin from maintaining water and further weakening its barrier function [87].

Ginsenosides improve the barrier function of skin by increasing the expression of AQP3. When applied to UVB-damaged skin, ginsenosides boosted AQP3 levels in a dose-dependent manner, helping the skin retain water and reduce dryness and desquamation. Ginsenoside treatment also corrects AQP3 mislocalization, thereby ensuring efficient water transport across the skin barrier. Additionally, ginsenosides upregulate essential barrier proteins such as filaggrin and involucrin and restore tight junction structures crucial for skin integrity. Moreover, ginsenosides inhibit UVB-induced activation of the MAPK pathway, reducing the phosphorylation of JNK, p38, and ERK, which mitigates UVB-induced damage and supports overall skin barrier function. This process also helps regulate AQP3 expression via the MAPK pathway [85].

Ginsenosides positively regulate circadian rhythms and indirectly prevent circadian gene-related skin barrier disruption. This effect has been demonstrated in a rat model. Ginsenoside Rg5 has sleep-promoting effects due to its sedative and hypnotic properties, which are achieved by regulating energy metabolism, enhancing mitochondrial function, and modulating neurotransmitter systems [87]. Consequently, in humans, ginsenoside Rg5 may support circadian rhythm regulation and prevent circadian gene-related skin barrier disruption.

2.5.3. Ginsenosides that improve skin barrier through circadian rhythm recovery

AQP, which controls hydration, is crucial to skin barrier function. As mentioned previously, CLOCK and BMAL1 regulate the expression of AQP3 in human keratinocytes [84]. Additionally, ginsenosides boost AQP3 levels in UVB-damaged human keratinocytes [85]. These findings suggest that ginsenosides modulate the circadian clock, thereby improving skin barrier function by increasing AQP3 expression. However, further study is required to understand the precise interactions among ginsenosides, AQP3, and the circadian clock in skin barrier function.

2.6. Skin sunburn and circadian rhythm

Sunburn is a radiation-induced burn caused by overexposure to UV radiation, leading to an inflammatory reaction in the skin known as erythema. This results from UV-induced DNA damage, particularly the formation of pyrimidine dimers [88]. To prevent malignant transformation, keratinocytes undergo apoptosis and become sunburn cells that release autoantigens and trigger immune responses. Tumor necrosis factor-alpha aids in the migration of immune cells to the affected area [89].

Chronic sun exposure significantly increases the major risk factor for skin cancers, including squamous cell carcinoma and actinic keratosis, both of which are associated with mutations in the p53 gene [90]. UV radiation can damage DNA in various ways, leading to genetic alterations like mutations in the p53 gene and mitochondrial DNA [91]. Additionally, UV exposure generates reactive oxygen species (ROS), which contribute to skin cancer development. The incidence of both melanoma and non-melanoma skin cancers is on the rise. Melanoma is rapidly increasing among older populations. Sunburn can double the risk of developing melanoma [89].

2.6.1. Relationship between circadian rhythm and sunburn

The circadian clock profoundly influences the development of erythema following exposure to UV radiation. During early mornings, the DNA repair of UV photoproducts is less efficient, whereas DNA synthesis is heightened, leading to increased DNA replication stress and subsequent stalling of DNA polymerases at unrepaired sites [92,93]. This heightened stress triggers a more robust induction of p53, a tumor suppressor crucial for the DNA damage response. Moreover, diminished levels of the Mdm2 protein in early mornings may disrupt the primary proteolytic pathway of p53, further amplifying p53 activity post-UV exposure [93]. Ultimately, the circadian orchestration of p53 activity promotes sunburn, apoptosis, and erythema.

The circadian influence on expression of basal p53 and Mdm2 may stem from Per2’s crucial involvement in regulating p53 function during DNA damage, affecting both its stability and transcriptional activity [94]. Therefore, circadian genes such as per2 may potentially affect sunburn.

2.6.2. Ginsenosides that improve skin sunburn through circadian rhythm recovery

Ginsenosides, particularly Rb1, have several beneficial effects under UV exposure. They enhance DNA repair through the nucleotide excision repair process, reduce apoptosis, and lower the risk of skin cancer [95]. Collectively, these effects contribute to a reduced likelihood and severity of sunburn, highlighting the protective role of ginsenosides against UVB-induced skin damage.

As previously described, ginsenoside Rg5 helps regulate circadian rhythms in rats, indirectly preventing sunburn related to circadian genes. Moreover, it promotes sleep through various mechanisms [96]. Consequently, in humans, ginsenoside Rg5 may assist in regulating circadian rhythms and genes such as Per2, which are crucial for regulating p53 function, potentially helping prevent circadian gene-related sunburn.

UVB radiation damages DNA, which triggers the release of a protein called activator protein-1 (AP-1). This protein then stimulates the production of MMP-1. However, when the skin repairs the DNA damage caused by UV exposure, the production of MMP-1 decreases [96]. Thus, MMP-1 expression levels indicate whether UV-induced DNA damage or subsequent DNA repair occurs in the skin. Since sunburn results from UV-induced DNA damage, MMP-1 may be associated with sunburn. Circadian genes influence MMP-1 expression, with PER3 suppressing MMP-1 expression via the cAMP pathway [74]. These data suggest that circadian genes affect DNA damage and repair. Because PER can regulate MMP-1, targeting circadian clock components may offer new therapeutic approaches for alleviating DNA damage [75]. Additionally, ginsenoside F2 and CK reduce MMP-1 expression [97,98]. Therefore, ginsenosides regulate MMP-1 expression and enhance DNA repair. The interaction between circadian genes and MMP-1 may be a potential mechanism for mitigating UV-induced sunburn. However, further study is required to discover interactions between ginsenosides, MMP-1, and circadian clock genes involved in DNA damage and repair.

3. Conclusion

Disturbances in intact circadian rhythms can cause significant changes to the body and lead to various health problems, skin health being no exception. In this review, we highlight the documented pathogenesis that links circadian rhythm interference with the occurrence of skin disorders and the contributing role of circadian rhythms in overall skin health. Moreover, we explored the role of ginsenosides in improving skin health and promoting recovery from various dermatological issues while considering their possible influence on circadian rhythm modulation. Currently, few studies specifically correlate the effects of ginsenosides on skin issues with circadian rhythm regulation. Nonetheless, considering the intricate pathways through which ginsenosides can improve skin-related issues and the role of circadian genes in modulating such issues, a plausible basis for this correlation exists, although further research is needed to accurately specify the correlation.

In addition, various substances including ginsenosides have specific biological effects, but sometimes show unexpected toxicity or side effects. It is considered very important whether the side effects and toxicity caused by the substance are related to the circadian rhythm. Therefore, it will be an important research to clarify the relationship between the toxicity of the substance and the circadian rhythm. Moreover, when trying to verify the efficacy of ginsenosides identified through preclinical studies through clinical studies, it is important to determine the optimal concentration that can exhibit efficacy without toxicity and to determine an effective drug administration method. If these matters are also clarified to be related to the circadian rhythm, it will contribute to solving the difficulties in ginsenoside research. Overall, this review provides valuable insights into the interplay between overall skin health, skin disease development, circadian rhythms, and the potential impact of ginsenosides on skin health, suggesting the possible therapeutic potential of ginsenosides as modulators of skin circadian rhythms in skin disorders.

Author contributions

HH, HS, SM, NCS, KY, EJ, MS, JYC, and JL searched and collected the literature, summarized the contents, and described the articles. HH, HS, SM, and JL organized the tables and created the pictures. EJ, MS, JYC, and JL provided valuable suggestions during manuscript preparation and critically revised the manuscript accordingly. MS, JYC, and JL conceptualized and wrote the manuscript. All authors have read and approved the final manuscript.

Declaration of competing interests

The authors declare no conflicts of interest associated with this study. There has been no significant financial support for this study that could have influenced its outcome.