Unlocking Mysteries: Exploring the Dynamic Interplay among Sleep, the Immune System, and Curcumin in Contemporary Research

Abstract

The scientific disciplines encompassing sleep, the immune system, and curcumin have garnered considerable interest due to their interconnectedness and potential implications for human health. Sleep is a crucial factor in maintaining optimal immune function, as it facilitates the release of cytokines, which are signaling molecules responsible for regulating immune responses. On the contrary, sleep deprivation has the potential of inhibiting immune function, thereby heightening the susceptibility to infection and disease. Curcumin, a naturally occurring polyphenol derived from the turmeric plant, has been observed to possess immunomodulatory characteristics through its ability to modulate the equilibrium between pro- and anti-inflammatory cytokines. It is worth noting that there is evidence suggesting that curcumin supplementation could enhance the quality of sleep. Scientific studies have indicated that curcumin supplementation has been associated with an increase in the duration of sleep and a decrease in wakefulness among individuals who are in good health. Additionally, curcumin supplementation has been found to enhance sleep quality and alleviate symptoms of depression in individuals diagnosed with major depressive disorder. The intricate interplay among sleep, the immune system, and curcumin is multifaceted, and scientific investigations indicate that curcumin may serve as a beneficial dietary adjunct to enhance immune function and optimize sleep quality. Nevertheless, additional investigation is required to fully comprehend the mechanisms through which curcumin alters the immune system and enhances sleep, as well as to ascertain the most effective dose and timing of curcumin supplementation.

Keywords

sleep loss - cytokines - curcumin - REM sleep - NREM sleep - neuro-inflammation

Simple Summary

Sleep is a fundamental physiological process that is essential for overall well-being. It can be categorized into rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, with NREM further subdivided into stages. During sleep, cerebral activity and muscle tone undergo alterations, with REM sleep characterized by rapid eye movements and vivid dreams, while NREM sleep comprises lighter and deeper stages. Sleep is crucial for physical and mental health, as it influences cognitive function and affects physiological health. Chronic sleep deprivation can lead to various sequelae, including cognitive impairment, mood disorders, and an increased risk of chronic diseases such as obesity and diabetes. Elucidating the biology of sleep remains an ongoing challenge, involving neural networks, neurotransmitters, and brain regions such as the hypothalamus. Disruptions in sleep patterns can result in conditions such as narcolepsy, which is characterized by hallucinations and muscle paralysis during sleep. Immune function is closely associated with sleep, as disruptions can lead to increased inflammation and susceptibility to infections. Curcumin, a compound found in turmeric, has garnered attention for its potential health benefits, including anti-inflammatory and antioxidant properties. Oxidative stress and inflammation are implicated in various pathologies, and curcumin's therapeutic potential has been investigated in conditions such as cancer, Alzheimer's disease, and metabolic disorders. The present review aims to explore the interrelationships involving diet, the immune system, and sleep, emphasizing the importance of understanding these interactions for overall health.

Introduction

Sleep is an important physiological and behavioral marvel that plays a fundamental role in supporting the optimal functioning of the peripheral body and the brain.[1] [2] [3] During a typical night's rest, various types of sleep can be observed. There are two primary classifications of sleep: REM and NREM.[4] [5] NREM sleep can be further categorized into three distinct stages: stage 1 of the sleep cycle is characterized by a state of light sleep, wherein individuals may retain a certain level of consciousness regarding their immediate environment. The brain generates alpha and theta waves, leading to a state of muscular relaxation; stage 2 of the sleep cycle is characterized by a slightly increased level of sleep depth. Deceleration of brain waves, reduction in body temperature, and decrease in heart rate are phenomena observed in this stage; And stage is the most profound, commonly referred to as slow-wave sleep. The production of delta waves by the brain is associated with a state of deep sleep, during which it becomes challenging to rouse an individual.[6] [7] In contrast, REM sleep is distinguished by the occurrence of rapid eye movements, the presence of vivid dreams, and heightened brain activity.[7] [8] During REM sleep, there is a state of muscle paralysis that is believed to inhibit the enactment of dream content. In general, a standard sleep cycle lasts for approximately 90 minutes, encompassing several intervals of NREM and REM sleep. Overall, the duration of REM sleep periods tends to increase as the night advances, whereas the duration of NREM sleep periods tends to decrease.[9] [10] [11] Sleep is additionally distinguished by a diminishment in conscious awareness, diminished bodily movement, and an alteration in the electroencephalographic patterns of the brain.[12] [13] The significance of sleep is emphasized by the fact that animals, particularly humans, spend roughly 1/3 of their lifespan in a state of sleep.[14] Despite its significance, the biological mechanisms that govern sleep remain poorly comprehended.[15] [16] [17] The phenomenon of sleep encompasses various neural networks and neurochemical pathways. Multiple brain regions have been identified as crucial for sleep, such as the hypothalamus, thalamus, and brainstem.[18] Furthermore, numerous neurotransmitters have been implicated in the regulation of sleep, such as serotonin, dopamine, norepinephrine, and acetylcholine.[14] [19] [20] [21] These neurochemical messengers exert their effects on distinct receptor sites within the brain, either facilitating or suppressing the process of sleep, resulting in positive or negative consequences of the process and behavior ([Fig. 1]).

Fig. 1 Schematic representation of the positive consequences of proper sleep (right panel, marked in green) and the negative consequences of sleep deprivation (left panel, marked in red).

The significance of sleep is emphasized by the fact that persistent sleep deprivation can have detrimental effects on physical health and overall well-being.[22] [23] Sleep deprivation has been associated with a variety of adverse consequences, such as compromised cognitive function, heightened susceptibility to accidents, and the development of mood disorders.[24] [25] [26] [27] [28] [29] Furthermore, prolonged and consistent lack of sleep has been correlated with an elevated susceptibility to cardiovascular ailments, obesity, and diabetes.[22] [30] [31] [32] [33] Therefore, sleep is a multifaceted physiological phenomenon that is crucial for sustaining optimal physical and mental health.[34] [35] Despite the significant progress made in comprehending the intricacies of sleep, numerous inquiries persist without definitive resolutions. Gaining knowledge about the biological processes that govern sleep, and the repercussions of insufficient sleep will be crucial to develop strategies to enhance proper sleep patterns and mitigate the adverse effects of sleep deprivation. Studies have demonstrated that an abundance of sleep during the daytime may result in the onset of narcolepsy, a medical condition distinguished by hallucinations experienced during the transitional state between wakefulness and sleep (known as hypnagogia), REM sleep, and temporary muscle paralysis during sleep (referred to as sleep paralysis).[36] [37] [38] Disruptions in circadian rhythms and dysregulation of hypocretin levels can also contribute to the secretion of proinflammatory cytokines such as tumor necrosis factor 1 (TNF-1), interleukin-1 (IL-1), and interleukin-6 (IL-6) throughout the diurnal period, which play crucial roles in the regulation of sleep.[39] [40] [41] Moreover, heightened concentrations of TNF-1 and IL-6 have been correlated with augmented body mass index (BMI), elevated levels of proinflammatory cytokines, and symptoms characteristic of narcolepsy.[42]

The immune system comprises an intricate network of cells, tissues, and organs that collaborate to safeguard the body against detrimental pathogens and exogenous substances.[43] [44] It plays a crucial role in preserving the general health and well-being of an individual, since a compromised immune system can result in heightened vulnerability to infections and diseases.[45] [46] [47] Recent studies[43] [48] [49] [50] [51] have elucidated multiple facets of the immune system, encompassing its involvement in the prevention and treatment of cancer, the influence of gut microbiota on immune functionality, and the advancements in novel therapeutic approaches to augment immune response. Other recent sudies[52] [53] have reported that the modulation of a particular protein known as Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) could augment the functionality of T cells, a subset of immune cells that plays a pivotal role in combatting infectious diseases and malignancies. Moreover, another study[54] has provided evidence that the gut microbiota can regulate the functioning of immune cells and exert an impact on the progression of inflammatory bowel diseases. These findings underscore the significance of maintaining a robust immune system and the need for ongoing scientific investigation to enhance our comprehension of it, as well as its efficacy.

Curcumin, the main bioactive constituent of turmeric, has garnered scientific interest due to its potential therapeutic advantages across diseases and physiologies.[55] [56] [57] Curcumin is composed of three distinct compounds: curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exert regulatory effects on inflammation, cellular proliferation, and programmed cell death.[58] [59] [60] The therapeutic efficacy of curcumin has been demonstrated in various diseases, due to its antioxidative and antiinflammatory attributes.[61] [62] [63] These conditions include oxidative stress-induced ailments such as cancer, atherosclerosis, Alzheimer's disease, and metabolic disorders.[64] [65] Oxidative stress and oxidative damage play a pivotal role in the development of chronic inflammation and neurodegenerative diseases.[66] Oxidative stress is characterized by a disruption in the equilibrium between the generation of reactive oxygen species (ROS) and the protective mechanisms of antioxidants, resulting in potential harm to biomolecules and cellular structures. Reactive oxygen species are integral components of the upstream and downstream mechanisms of nuclear factor-kβ (NF-kβ) and tumor necrosis factor-alpha (TNF-α), with hydroxyl radicals being identified as the most detrimental among all ROS.[67] [68] Therefore, curcumin, as a bioactive constituent present in the rhizomes of the Curcuma longa plant, exhibits promising therapeutic potential as an alternative treatment for sleep disorders due to its notable antiinflammatory and antioxidant properties. The goal of the present review is to determine whether there is a balance and proper interactions involving curcumin, the immune system, and sleep.

Sleep and the Immune System

Sleep is an essential element of human well-being, providing a diverse array of physiological and psychological advantages. One of the notable crucial functions of sleep is bolstering immune system activity.[69] During sleep, the human body undergoes the release of different proinflammatory cytokines, a class of proteins that play a crucial role in the immune response against infections and in the regenerative processes that repair tissue damage resulting from inflammation.[70] [71] [72] Studies[73] [74] [75] [76] have demonstrated that sleep deprivation can have detrimental effects on the functioning of the immune system. Studies[69] [77] have reported that the absence of sleep for a single night can result in a decline in the activity of natural killer (NK) cells, which play a crucial role in combating viral infections and cancerous cells. Another study[78] reported that individuals who achieved a minimum of 7 hours of sleep per night presented reduced susceptibility to infections in comparison to those who slept for fewer than 6 hours per night, showing the importance of sleep. The phenomenon can have noteworthy ramifications for general well-being, as a compromised immune system can augment the susceptibility to acquiring infections, autoimmune disorders, and various other health complications. Conversely, obtaining an adequate amount of sleep can have a beneficial influence on immune system functionality.[79] [80] Other studies[70] have also demonstrated that obtaining sufficient sleep can enhance the efficacy of vaccines, as they depend on the immune system's ability to generate an immune response. Further, there is still contradictory evidence about insufficient sleep and levels of proinflammatory cytokines, such as IL-6, TNF-α, and interferon-gamma (IFN-γ).[81] [82] On the contrary, sufficient sleep can enhance the synthesis of antiinflammatory cytokines, specifically interleukin-10 (IL-10) and transforming growth factor-β (TGF-β).[69] [77] Moreover, sleep disturbances modulate the activity of cytokines, whereby disrupted sleep patterns result in heightened cytokine activity and inflammation within the body.[82] [83]

Chronic disruptions in sleep patterns, such as insomnia or sleep apnea, have been associated with various health complications, such as elevated susceptibility to infections, heightened levels of inflammation, and increased likelihood of developing chronic conditions like diabetes, obesity, and cardiovascular disease.[69] [77] [83] Furthermore, a recent studies[84] [85] have revealed that disruptions in sleep patterns can induce persistent inflammation, thereby potentially exacerbating the onset and progression of autoimmune disorders. Elevated levels of inflammatory biomarkers, namely C-reactive protein (CRP) and IL-6, have been observed in individuals experiencing sleep disorders,[86] [87] [88] which implies a potential association between inadequate sleep and the presence of persistent inflammation. On the other hand, cytokines, which are proteins, are synthesized by diverse immune cells as a reaction to infection, inflammation, or injury, also play a pivotal function in the regulation of the immune response.[89] [90]

Curcumin and Sleep

The intricate connection between sleep and immunological responses is crucial for the maintenance of optimal health. Sleep is a fundamental requirement for optimal immune system functionality, as sleep deprivation can compromise the body's immune response, rendering it more susceptible to infections and diseases.[91] [92] [93] [94] [95]

Curcumin, a polyphenolic compound derived from the rhizomes of the turmeric plant, which belongs to the Zingiberaceae family,[56] [64] [96] [97] has undergone thorough investigation regarding its potential physiological advantages. Many studies provide evidence of its antioxidative stress, antiapoptotic, and antiinflammatory properties.[98] [99] [100] [101] Moreover, a study[102] has also demonstrated that curcumin influences the regulation of molecular targets within diverse pathways, consequently safeguarding the functionality of multiple organs. It has also shown antiparasitic, hepatoprotective, bactericidal, and antioxidant properties.[103] [104] [105] [106] [107] Curcumin is also hypothesized to possess neuroprotective properties.[102] Sleep deprivation perturbs the equilibrium between oxidative and antioxidative defense mechanisms, resulting in an elevation of free radicals and a reduction in oxidative defense.[108] [109] Stress-related disorders (SRDs) have been linked to various neurological consequences in individuals experiencing chronic stress.[110] Furthermore, the disruptions in sleep-wake cycles activate the DNA damage response, resulting in hindered growth and death of neurons, and in a decrease in the formation of glial cells and in the length of dendritic spines in various brain regions.[111] [112] Studies[113] [114] have reported that sleep deprivation causes differential gene expression in organs and brain dysfunctions, such as compromised memory, depressive symptoms, and psychotic experiences. Furthermore, curcumin influences sleep through its ability to modulate neurotransmitter systems and inflammation. As a potent antioxidant and antiinflammatory compound, curcumin may be beneficial for the treatment of various neurological disorders and stress-related conditions.[115] By decreasing proinflammatory cytokines and oxidative stress in the brain, curcumin promotes a more balanced sleep architecture, potentially improving sleep quality and duration.[116] The antiinflammatory effects of curcumin are particularly important because chronic inflammation is associated with sleep disturbances and disorders such as insomnia. During sleep, the immune system undergoes various changes such as increased activity of NK cells and elevated cytokine production.[69] The antiinflammatory properties of curcumin help regulate these immune responses, ensuring that they do not become excessive, which can disturb sleep.[102] Additionally, curcumin enhances brain-derived neurotrophic factor (BDNF) and serotonin pathways, which are crucial for mood regulation and sleep-wake cycles. This balanced interplay between the modulation of immune function by curcumin and its neuroprotective effects makes it a potential adjunctive treatment for sleep disorders linked to inflammation and immune dysregulation.

Nanocurcumin is an altered form of curcumin that exhibits high bioavailability, which means that it can be readily absorbed and used by the body.[117] [118] [119] Nanocurcumin has been extensively investigated for its antiinflammatory, antioxidant, neurodegeneration, and neuroprotective properties.[65] [120] [121] Recent scientific investigations have indicated that nanocurcumin may have a favorable influence on sleep patterns. In a randomized, double-blinded, placebo-controlled study,[122] the administration of nanocurcumin resulted in a noteworthy enhancement in the quality and duration of sleep among individuals without any underlying health conditions as compared with the placebo group;. it also resulted in elevated concentrations of serotonin, which plays a crucial role in the regulation of sleep-wake patterns. A study conducted with mice[123] reported that the administration of nanocurcumin results in enhancements in the quality and quantity of sleep, and it reduces the time until falling asleep and increases the duration of REM sleep.

The sleep-enhancing properties of nanocurcumin are believed to stem from its capacity to regulate different neurotransmitters and inflammatory markers implicated in the sleep-wake cycle. A study[124] reported that nano-curcumin increases serotonin levels in the brain, thereby potentially facilitating relaxation and promoting sleep. Another study[125] has shown that nanocurcumin decreases the concentrations of proinflammatory cytokines, specifically IL-6, which have been associated with disruptions in sleep patterns.

In summary, nanocurcumin exhibits potential as a sleep aid, as evidenced by its effectiveness and safety reported in various studies conducted on animals and humans[126] [127]; these studies indicate that nanocurcumin may be a natural adjunct to improve the quality and duration of sleep in both individuals with insomnia and those who are in good health. Additional investigation is required to clarify the exact mechanisms underlying its sleep-enhancing properties and to refine the dose, the formulation, and the duration of nanocurcumin supplementation for optimal effectiveness.

Curcumin and the Immune System

Curcumin increases lymphocyte counts while decreasing neutrophil and eosinophil counts. Additionally, type-2 CD4+ T helper (Th2) cells generate IL-4, IL-10, and TGF-β, whereas type-1 (Th1) cells produce IFN-γ, TNF-β, and IL-1.[128] The immune suppressive regulatory T (Treg) cells stop autoimmune illness, while type-17 Th (Th17) cells release IL-17. The modulation of this T cell subset depends on the balance of the defense mechanism. The Th1 and Th2 cells are represented by proinflammatory M1 macrophages and antiinflammatory M2 macrophages respectively. The balance of M1 and M2 macrophages is crucial to maintain the immune system.[129] Hence, in ovalbumin-sensitized rats, curcumin regulates the Th1/Th2 balance through a stimulatory effect on Th1 cells and an inhibitory effect on Th2 cells.[130] When the amount of blood lymphocytes is reduced by the immunotoxicity caused by 2-amino-3-methylimidazole (4,5-f) quinoline, curcumin demonstrates protective properties.[131] Guo et.al.[132] reported that in vitro and in vivo investigations on the treatment of B-cell lymphoma yielded remarkable results from the synergistic action of curcumin with doxorubicin. In xenografted mice, they discovered that the coadministration of curcumin and doxorubicin (loading rates of curcumin and doxorubicin: 8.1% and 9.7%) decreased the invasive B-cell lymphoma. Additionally, they claimed that through controlling the apoptotic pathways, curcumin and doxorubicin effectively treated invasive B-cell lymphomas in vitro.[126] On the other hand, Chen et. al.[133] demonstrated that by suppressing and controlling the expression of microRNA 21 (miR-21) and Von Hippel-Lindau (VHL) messenger RNA (mRNA) respectively, curcumin inhibited the invasion, mitigation, and cell proliferation activities and promoted apoptosis in diffuse large B-cell lymphoma cell line Stanford University-Diffuse Histiocytic Lymphoma-8 (SU-DHL-8). Similar to this, an in vivo study[134] found that curcumin, when used to treat Dalton's lymphoma cells, reduced the regulation of the NF-B signaling pathway and the release of proinflammatory cytokines by strengthening the body's antioxidant defenses ([Fig. 2]) ([Table 1]).

Fig. 2 Summary of the interaction of curcumin with the immune system and its responses.

Table 1 List of the effects of curcumin on sleep, the immune system, and their respective interactions.

Processes/pathways	Sleep-related functions	Immune system-related functions	Bidirectional correlations	References
Antiinflammatory action	Curcumin reduces inflammation in the brain, which can improve sleep quality by decreasing disruptions caused by pro-inflammatory cytokines like TNF-α and IL-6.	Curcumin downregulates inflammatory cytokines (TNF-α, IL-1β, IL-6) by inhibiting NF-κB, reducing systemic inflammation.	Inflammation can disrupt sleep by altering cytokine levels, which curcumin helps to normalize, leading to better sleep and balanced immune responses.	[98] [137]
Oxidative stress reduction	By scavenging free radicals and enhancing antioxidant enzymes (SOD, glutathione), curcumin lowers oxidative stress in the brain, helping to protect sleep-regulating neurons.	Curcumin reduces oxidative stress in peripheral tissues, protecting immune cells and preventing immune dysfunction.	Lower oxidative stress improves sleep quality and immune system function, as oxidative stress is linked to poor sleep and immune dysregulation.	[138] [139] [140]
Regulation of neurotransmitters	Curcumin modulates serotonin, a neurotransmitter involved in regulating the sleep-wake cycle, which can improve sleep onset and duration.	Curcumin indirectly affects immune function by modulating neurotransmitter levels that influence immune-cell activity.	Neurotransmitter regulation supports both immune homeostasis and the sleep-wake cycle, reducing immune-related sleep disturbances.	[141]
Improvement in BDNF levels	Curcumin increases the levels of BDNF, which supports healthy sleep architecture and cognitive function.	Increased BDNF promotes neuroplasticity, which may improve the communication between the brain and the immune system.	Better BDNF levels improve sleep patterns, which support optimal immune system function, particularly during deep sleep, when immune processes are heightened.	[142]
Modulation of melatonin levels	Curcumin may boost melatonin production, promoting better circadian rhythm alignment and improved sleep.	Curcumin modulates immune function indirectly by improving sleep, which enhances immune responses (such as T cell activity) during the night.	Melatonin is a key hormone for sleep and immune synchronization. Curcumin's boost of melatonin production improves sleep and nighttime immune activity.	[143]
Immunoregulatory function	Curcumin's balancing of pro- and antiinflammatory cytokines leads to better regulation of sleep, as immune dysregulation can cause insomnia or disturbed sleep.	Curcumin helps balance immune responses by regulating the activity of T cells, B cells, and macrophages.	Proper immune function during sleep, aided by curcumin, helps maintain the restorative function of sleep and prevents excessive inflammation.	[105] [144]

Abbreviations: BDNF, brain-derived neurotrophic factor; Il-1β, interleukin-1 beta; IL-6, interleukin 6; NF-κB, nuclear factor kappa B; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-alpha.

The Connection Involving Sleep, the Immune System, and Curcumin

The relationship between sleep and the immune system is complex and bidirectional. Sleep disturbances, such as chronic sleep deprivation or sleep disorders, weaken the immune system, making individuals more susceptible to infections.[23] [135] [136] In contrast, immune system activation influences sleep patterns, often leading to increased sleep during illness as part of the body's healing response. Studies[92] have consistently shown that poor sleep quality, characterized by reduced sleep duration or disrupted sleep patterns, compromises immune function. Sleep-deprived individuals experience a decrease in the production of immune cells, such as T cells and NK cells, and an increase in proinflammatory cytokines. Conversely, adequate and restorative sleep supports a well-functioning immune system. During deep sleep stages, the body undergoes various repair and maintenance processes, contributing to immune resilience.[1] [145] [146] [147]

Curcumin's potential influence on sleep regulation is an emerging area of research. Studies suggest[148] [149] that curcumin enhances sleep quality by modulating neurotransmitters like serotonin and dopamine, which play a role in regulating sleep-wake cycles. Curcumin's antiinflammatory properties also indirectly improve sleep by reducing inflammation, which can contribute to sleep disturbances.[150] Studies[104] [137] [151] have suggested that curcumin can downregulate the expression of proinflammatory cytokines, potentially reducing the risk of excessive inflammation and immune dysregulation.

Conclusion and Future Directions

The complex interplay among sleep processes, immune function, and curcumin presents a fascinating area of research. Adequate sleep is crucial for optimal immune system performance, and disruptions in sleep patterns can negatively impact immune responses. Curcumin has shown notable antiinflammatory effects and the capacity to influence immune system function. These properties suggest that it may play a role in regulating sleep patterns and enhancing immune function. However, further research is necessary to fully elucidate the underlying mechanisms of these effects and determine optimal dosages and administration methods. Overall, findings by now highlight a strong link between sleep and immune health, suggesting that interventions targeting both factors could significantly impact disease prevention and treatment strategies.

While preliminary research supports the notion that curcumin may have a positive impact on sleep quality and immune function, more rigorous clinical trials are needed to establish causality and determine optimal doses. Controlled trials[105] [152] on the effects of curcumin on sleep quality and duration and sleep disorders in humans are limited. Future research should focus on elucidating the mechanisms through which curcumin influences sleep patterns. Curcumin's role in immune modulation is well-documented in cell and animal studies.[153] [154] [155] However, more human trials are essential to determine its efficacy in supporting immune health and preventing infections, especially in clinical populations with compromised immunity. Afterall, the interplay among sleep, the immune system, and curcumin is an exciting area of research with promising potential. Sleep quality and immune function are intimately connected, and curcumin, as a natural compound with antiinflammatory and immunomodulatory properties, may hold therapeutic promise. However, further investigation is needed to establish the extent of curcumin's impact on sleep and immune health in humans. In the meantime, incorporating curcumin-rich foods or supplements into a balanced diet may offer potential benefits for overall well-being ([Fig. 3]).

Fig. 3 Representation of the connection among antioxidants, sleep, and the immune system.

Conflict of Interests

The authors have no conflict of interests to declare.

Authors' Contributions

RK, AP, RPP: Writing-review and editing, supervision, conceptualization. AV, MA: writing-review and editing. All authors have read and agreed regarding the version of the manuscript submitted for publication.

^# The authors have contributed equally.

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Publication History

Received: 10 May 2024

Accepted: 28 October 2024

Article published online:
27 March 2025