Research progress on the kynurenine pathway in the prevention and treatment of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is characterised by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) and pathological accumulation of α-synuclein fibrils, as well as central nervous system inflammation. Elevated levels of central inflammatory factors in PD disrupt the kynurenine pathway (KP) and favour the activation of excitotoxic branches, leading to a significant reduction in the neuroprotective metabolite kynurenic acid (KYNA) and a significant increase in the neurotoxic metabolite quinolinic acid (QUIN), which exacerbates excitotoxicity and amplifies the inflammatory response, closely related to the occurrence and development of PD. KYNA analogs, precursor drugs, and KP enzyme modulators may represent a new therapeutic strategy for PD. This article reviews the role of KP in the neurodegenerative pathology of PD and its prevention and treatment, aiming to provide necessary theoretical basis and new ideas for the study of the neurobiological mechanisms underlying PD-related behavioural dysfunction and targeted interventions.

Keywords:

• Parkinson’s disease
• kynurenine
• kynurenic acid
• quinolinic acid

Parkinson’s disease (PD) is a complex multifactorial neurodegenerative disease with a prevalence second only to Alzheimer’s disease. The main pathological feature of the disease is the degeneration and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of misfolded α-synuclein (α-Syn) to form Lewy bodies (LB) in the brain, accompanied by the occurrence of neuroinflammation¹. Up to 10 million people worldwide are affected, with an estimated lifetime risk of about 2%². China is entering an ageing society, and it is estimated that by 2030, the number of PD patients in China will increase to 4.94 million, accounting for half of the global PD patients³. PD patients typically have four motor symptoms, including resting tremor, bradykinesia, postural instability, and rigidity of the neck, trunk, and limbs⁴. Although PD was first described by James Parkinson in 1817, its aetiology has not been fully elucidated to this day. Most scholars believe that the degeneration and necrosis of SNpc dopaminergic neurons lead to the dysfunction of the basal ganglia circuit, resulting in motor disorders⁵. Currently, there are two main treatment methods for PD, surgical treatment (such as deep brain stimulation) and drug treatment (such as levodopa and dopamine agonists)⁶, which can only temporarily relieve PD symptoms but cannot stop the progression of the disease. Therefore, the development of new treatments for PD has always been an urgent task for clinical doctors and scientists worldwide.

Although the molecular pathological mechanisms underlying PD are not yet clear, in recent years, researchers have found abnormal activation of microglia and enhanced inflammatory responses in brain tissue, both in post-mortem results of PD patients and in PD animal models^7–9. In the 6-OHDA animal model, it was found that the activation of microglia occurred earlier than the loss of DA neurons, and the release of inflammatory factors by activated microglia could further promote abnormal aggregation of α-synuclein, suggesting that the activation of microglia may be the primary factor in the onset of PD¹⁰. The kynurenine pathway (KP) of tryptophan metabolism is one of the main regulatory factors of immune response and may be related to the inflammation and neurotoxicity events of PD¹¹. Several neuroactive compounds produced by KP can be neurotoxic, neuroprotective or immunomodulatory. Among these metabolites, kynurenic acid (KYNA) produced by astrocytes is considered to have neuroprotective effects, while quinolinic acid (QUIN) released by activated microglia can activate the N-methyl-D-aspartate (NMDA) receptor signalling pathway, leading to excitotoxicity and amplifying the inflammatory response¹². Previous studies have shown that NMDA receptor antagonists can alleviate PD symptoms in vivo and in vitro and exert neuroprotective effects¹³. Multiple lines of evidence suggest that some KP intermediates are related to the neuro-pathogenesis of PD^14–16. In addition, some KP metabolites may serve as prognostic biomarkers, and pharmacological modulators of KP enzymes may represent a new therapeutic strategy for PD¹⁷. This article reviews the role of KP in PD neurodegeneration and PD motor prevention and treatment, in order to provide necessary theoretical basis and new ideas for the study of the neurobiological mechanisms of exercise intervention in alleviating PD-related behavioural dysfunction and targeted intervention.

Kynurenine pathway

KP is the main metabolic pathway for the essential amino acid tryptophan (TRP) in the body. This pathway is responsible for 95%-99% of TRP metabolism in the body. The remaining TRP is used for protein synthesis or for the formation of serotonin and melatonin. The generation of kynurenine from TRP is the first rate-limiting step of KP, which is mediated by indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO). These three enzymes catalyse the production of kynurenine from TRP but are activated by different stimuli and have different tissue distributions¹⁸ (Figure 1). IDO1 is widely expressed in immune and non-immune tissues and is activated by certain immune and inflammatory stimuli. IDO2 is mainly located in the liver and kidneys, and has lower catalytic activity than IDO1²¹. TDO is mainly located in the liver, but also exists in nanomolar concentrations in brain astrocytes²². Under normal physiological conditions, IDO activity is low, and KP basic metabolism is mainly mediated by TDO in the liver, which is the rate-limiting enzyme for the core metabolic product of KP, kynurenine. When the body is in an immune response or stress state, the activity of TDO and its isozyme IDO is overactivated by pro-inflammatory cytokines such as interferon (IFN)-γ, tumour necrosis factor (TNF)-α, lipopolysaccharides (LPS), interleukin (IL)-1,2,6, IL-1β, and prostaglandins. IDO then becomes the rate-limiting enzyme for the core metabolic product of KP, kynurenine, leading to an increase in kynurenine levels in peripheral and central nervous tissues^23,24. Peripheral kynurenine can cross the blood-brain barrier and enter the central nervous system (60% of kynurenine in the central nervous system comes from the periphery)²⁵. Subsequently, depending on the cell type, kynurenine is further metabolised into neurotoxic products mainly composed of QUIN and neuroprotective products mainly composed of KYNA. In microglia and macrophages, kynurenine is mainly converted to 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), and QUIN by kynurenine-3-monooxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO)²⁶. Like TRP and kynurenine, 3-HK can cross the blood-brain barrier and, in addition to increasing the availability of substrates for QUIN production, is a neurotoxic intermediate that plays a neurotoxic role at nanomolar concentrations by generating free radicals and causing neuronal degeneration and apoptosis¹⁵. In addition, 3-HK can generate superoxide and hydrogen peroxide, promoting copper-dependent oxidative protein damage²⁷. 3-HK can also significantly synergize with QUIN neurotoxicity²⁸. QUIN promotes neurodegeneration by inducing excitotoxicity of ionotropic glutamate receptors (iGluRs) (N-methyl-D-aspartate receptors (NMDAR), α-amino − 3 - hydroxy − 5 - methy l − 4 - isoxazole propionic acid receptors (AMPAR), and kainate receptors (KAR)) and α7-nicotinic acetylcholine receptors (α7-nAChR). In addition, QUIN can promote the release of glutamate (Glu) in neurons, inhibit the reuptake of Glu by astrocytes, and block the expression of glutamine synthetase, thereby further activating iGluRs and disrupting the dynamic balance of the Glu-glutamine-γ-aminobutyric acid cycle, exacerbating the excitotoxicity of Glu and causing neuronal damage²⁹. QUIN can also induce immune imbalance and inflammation, leading to the production of various pro-inflammatory cytokines such as IFN-α, IFN-γ, TNF-α, IL-1,2,6, and IL-1β, activating IDO, while KMO is also upregulated under inflammatory conditions, leading to a vicious cycle of KP formation and further promoting the neurotoxic metabolite pathway of KP. In astrocytes and peripheral skeletal muscle cells, kynurenine is catalysed to KYNA by kynurenine aminotransferase (KAT), KAT II is responsible for synthesising the majority of KYNA in the central nervous system (CNS). In contrast to the neurotoxic activity of QUIN, KYNA is a neuroprotective metabolite that acts as a broad-spectrum antagonist of iGluRs (AMPAR, NMDAR, and KAR) and a potent negative allosteric modulator of α7-nAChR, thereby blocking the excitotoxic effects of QUIN on iGluRs and α7-nAChR. KYNA also has the ability to clear reactive oxygen and nitrogen species and extracellular glutamate, exerting a neuroprotective effect³⁰. Under inflammatory conditions, although IDO-1 is activated and overexpressed in astrocytes, QUIN cannot be synthesised because astrocytes do not express KMO. However, KAT II, which is specifically expressed in astrocytes, can synthesise neuroprotective KYNA. Although the neuroprotective effect of KYNA can counteract the toxic effects of QUIN, a three-fold concentration of KYNA is required to counteract the same amount of QUIN³¹. Under normal physiological conditions, the KP is in a state of good metabolic balance, producing all intermediate metabolites of the KP and ultimately generating the coenzyme nicotinamide adenine dinucleotide (NAD+). However, under inflammatory conditions, the balance of KP metabolites or enzyme expression levels is disrupted in the pathological process driven by inflammation, mainly manifested as an imbalance in the QUIN/KYNA balance towards overexpression of neurotoxic and/or pro-inflammatory molecules of KP.

Figure 1. (A B). Pathway of canine uric acid. Schematic diagram of the canine uric acid pathway in human peripheral and brain. Modified from^19,20. (A) In the periphery, tryptophan is metabolised into uric acid mainly by liver tryptophan 2,3-dioxygenase (TDO) (activated by glucocorticoids) and indoleamine 2,3-dioxygenase 1 (IDO1) (activated by inflammatory cytokines). After the first rate-limiting step, kynurenine is metabolised into kynurenic acid by kynurenine aminotransferase (KAT) through the neuroprotective branch (A: 1-2-3), or into quinone by kynurenine 3-monooxygenase (KMO) through the potential neurotoxic branch (A: 1-2-4-6-8). (B) Cytokines, tryptophan, kynurenin, and 3-hydroxyuric acid (3-HK) can cross the blood-brain barrier. Once in the brain, cytokines and glucocorticoids stimulate the uric acid pathway, and inflammation increases the favourable neurotoxic quinone branch due to its activation of KMO. The quinone branch of the uric acid pathway mainly occurs in activated and resting microglia [branch] and infiltrating macrophages (B:1-2-3-5-7), while the kynurenic acid branch mainly occurs in astrocytes (B:1-2-3). HAA: 3-hydroxyanthranilic acid; 3-HAO: 3,4-dioxygenase of 3-hydroxyanthranilic acid; 3-HK: 3-hydroxyuric acid; IDO1: indoleamine 2,3-dioxygenase 1; IFN: interferon; IL: interleukin; KA: uric acid; KAT: kynurenine aminotransferase; KMO: kynurenine 3-monooxygenase; KYN: kynurenine; KYNU: kynureninase; NAD +: nicotinamide adenine dinucleotide; PicA: picolinic acid; TDO: tryptophan 2,3-dioxygenase; TNF: tumour necrosis factor; TRP: tryptophan; QUIN: quinone; XA: xanthine acid.

KP and PD

Research has shown that immune dysfunction³², excitotoxicity of Glu³³, and depletion of DA³⁴ are all related to the increased risk and development of PD. The potential intersection of the immune system, Glu system, and monoaminergic system involved in these factors is KP³⁵. Under the induction of pro-inflammatory cytokines, KP activation disrupts the balance between neuroprotection and neurotoxicity branches, tending to produce neurotoxic products 3-HK (a strong inducer of neurotoxic free radicals) and QUIN, which play an important role in the pathogenesis of PD through excitotoxicity, oxidative stress, and/or inflammatory reactions. The first description of KP abnormalities in PD patients was in the early 1990s. Ogawa et al.³⁶ reported that the concentration of KYN and KYNA in the substantia nigra pars compacta (SNpc), striatum, and prefrontal cortex of PD patients was significantly decreased, while the concentration of the neurotoxin 3-HK in the striatum and SNpc was significantly increased. At the same time, Beal et al.³⁷ found that the levels of KYNA in the cortical areas, caudate nucleus, and cerebellum of PD patients were significantly decreased. The direct consequence of this low endogenous KYNA level is a reduced ability to limit the excitotoxicity induced by QUIN and/or excess glutamate through NMDAR. It has been reported that the KYN/TRP ratio in the CSF and serum of PD patients is significantly increased compared to age- and gender-matched healthy controls³⁸. Animal experiments have confirmed that the expression level of KP enzyme kynurenine aminotransferase-I (KAT-I), which leads to KYNA formation, is significantly decreased in the SNpc of MPTP-treated mice³⁹. According to data from post-mortem PD brain tissue and MPTP-treated mice, the activity of KAT-I and KAT-II is significantly decreased, consistent with lower plasma KYNA levels⁴⁰. Subsequently, more and more research evidence has shown that KP is closely related to the occurrence and development of PD^14,41. Heilman et al.³⁹ used a mass spectrometry-based targeted metabolomics analysis method, confirmed that plasma 3-HK levels were significantly elevated in PD patients, while the metabolic products 3-hydroxyanthranilic acid (3-HAA) and NAD+ (the final product of the KP pathway) were significantly reduced. The 5-HT/KYN ratio in the plasma of PD patients is also lower; the level of neuroprotective metabolite KYNA in the cerebrospinal fluid of PD patients is significantly decreased, the KYNA/KYN ratio is lower, and the ratio of neurotoxicity (QUIN/KYNA) is significantly increased. The plasma 3-HK level in PD patients is significantly correlated with the score reflecting the severity of PD symptoms (Unified Parkinson’s Disease Rating Scale, UPDRS I, II, and III), and the cerebrospinal fluid QUIN level is significantly correlated with higher UPDRS II and III scores. The higher KYN/TRP ratio is also significantly correlated with higher ADL and motor scores. The QUIN/PIC and QUIN/3-HK ratios are both closely related to the severity of ADL symptoms in PD patients (UPDRS II). The QUIN/KYNA ratio is related to higher non-motor daily life symptom scores (UPDRS I). In addition, it has been found that the increase in the QUIN/PIC ratio in the cerebrospinal fluid of PD patients is related to the increase in R2* value (a magnetic resonance imaging (MRI) index reflecting iron content) in the substantia nigra. C-reactive protein and serum amyloid protein α in the blood are associated with signs of increased KP activity in the cerebrospinal fluid of PD patients. These findings indicate that the levels of KP metabolites are altered in both the peripheral and central nervous systems in PD, and these changes are closely related to the severity of symptoms, consistent with previous research results^42–44. Sorgdrager et al.⁴⁴ used solid-phase extraction-liquid chromatography-tandem mass spectrometry to detect KP metabolites in the serum and cerebrospinal fluid of PD patients with clear clinical features and age-matched controls. The results showed that age was closely related to the increase in KYN, KYNA, and QUIN concentrations in the serum and cerebrospinal fluid, but the KYNA concentration in PD patients was significantly decreased compared to the age-matched control group. There was a strong positive correlation between KYN and QUIN levels in the serum and cerebrospinal fluid, and the concentrations of other metabolites, 3-HK, KYNA, and XA, were correlated with their corresponding concentrations in the cerebrospinal fluid. Bai et al.⁴⁵ studied the urinary KYN levels in early PD patients and found that urinary KYN levels could distinguish early PD patients from healthy controls. Urinary KYN levels were positively correlated with Hoehn-Yahr staging and disease duration, and negatively correlated with mini-mental state examination (MMSE) scores in PD patients. These results suggest that urinary KYN may be a new biomarker for detecting early PD and evaluating PD progression. Urinary KYN measurement may help clinicians identify early PD patients.

In summary, the levels of KP metabolites are altered in both the peripheral and central nervous systems in PD, and are closely related to the occurrence and development of PD. KP metabolites may become biomarkers for PD.

The role of KP in the treatment of PD

The role of KP metabolites in PD treatment

In animal models of Parkinson’s disease (PD), many studies have shown that increasing endogenous KYNA or reducing QUIN production can prevent and/or delay PD progression. Miranda et al.⁴⁶ demonstrated that injection of QUIN (60 nmol) or N-methyl-D-aspartic acid (15 nmol) into the substantia nigra of rats significantly depleted tyrosine hydroxylase activity in the striatum. However, co-infusion of nicotinylalanine (5–6 nmol), an inhibitor of kynureninase and kynurenine hydroxylase activity, with kynurenine (the precursor of KYNA) (450 mg/kg i.p.) and probenecid (an inhibitor of organic acid transport) (200 mg/kg i.p.) into the lateral ventricle of rats for 3 h resulted in a 3.3-fold increase in KYNA in the whole brain and a 1.5-fold increase in the substantia nigra, and the elevation of endogenous KYNA prevented the decrease in tyrosine hydroxylase induced by QUIN. This suggests that increasing the level of endogenous KYNA can prevent the loss of dopaminergic neurons in the substantia nigra induced by focal infusion of quinolinic acid or N-methyl-D-aspartic acid. Silva-Adaya et al.⁴⁷ treated 6-OHDA-lesioned PD model rats with the precursor of KYNA, L-kynurenine (L-KYN), and probenecid (PROB), an inhibitor of organic acid transport, for 7 consecutive days. The results showed that systemic administration of L-KYN + PROB significantly increased KYNA and DA levels in the striatum of PD model rats, significantly decreased (hydroxycinnamic acid + dihydroxyphenylacetic acid)/DA and glial fibrillary acidic protein (GFAP) expression levels, significantly reduced Fluoro Jade staining fluorescence intensity, and significantly improved motor dysfunction (as evidenced by a significant decrease in apomorphine-induced rotations). In addition to regulating the release of glutamate from the cortex to the striatum, the elevation of KYNA can also directly antagonise NMDA receptors, thereby reducing Glu excitotoxicity. Studies have shown that zonisamide, a sulphonamide antiepileptic drug used to treat PD, can significantly improve the motor symptoms of PD patients with levodopa-induced dyskinesia and significantly increase KYNA production¹⁷; injection of KYNA (50 μg) into the bilateral internal pallidum of MPTP-induced PD model monkeys can significantly alleviate motor disorders, tremors, and muscle stiffness⁴⁷. This further supports the potential role of KYNA in alleviating PD-related behavioural and functional disorders. Fukuyama et al.⁴⁸ further demonstrated that acute and chronic exposure of astrocytes to zonisamide not only resulted in the production of KYNA but also led to the production of other neuroactive metabolites in the KP pathway, such as xanthurenic acid and quinolinic acid. It has been shown that xanthurenic acid, quinolinic acid, and cinnamic acid are endogenous agonists of group II and III metabotropic glutamate receptors⁴⁹. The activation of group II and III metabotropic glutamate receptors is a potential important drug target for PD symptom relief and neuroprotection⁵⁰, in addition to KYNA, other neuroactive metabolites of KP may also have therapeutic importance in PD⁴³. Furthermore, long-term exposure to zonisamide can promote IFN-γ-mediated increase in quinolinic acid while reducing QUIN generation¹⁷. This provides evidence for the enhancement of neuroprotection by KYNA, uric acid, and quinolinic acid, while limiting the excitotoxicity of QUIN at lower levels.

The role of KP key enzyme regulators in the treatment of PD

Inhibitors of key KP enzymes are a potential method for management. KMO is a midstream enzyme in the KP metabolic pathway responsible for converting KYN to downstream neurotoxic metabolite 3-HK. Pharmacological inhibition of KMO has been widely shown to stimulate KYNA production⁵¹. Studies have shown that KMO inhibitors can significantly reduce the severity of hamster muscle tone disorders. Therefore, KMO inhibitors may be potential candidate drugs for managing movement disorders associated with striatal dysfunction in PD⁵². Several studies have demonstrated that selective pharmacological inhibitors of KMO, such as Ro61-8048, not only promote dose-dependent increases in peripheral and central KYNA production but also alleviate levodopa-induced motor dysfunction in MPTP-treated non-human primate PD models without impairing the therapeutic effects of levodopa^53,54. Another study showed that co-administration of KYNase, propentofylline (which prevents KYNA clearance from the brain), and KMO inhibitor nicotine propionyl-L-carnitine strongly promotes KYNA production, preventing NMDA and QUIN-induced excitotoxicity in dopaminergic neurons of the substantia nigra^55,56. IDO is one of two rate-limiting enzymes (IDO-1 and IDO-2 and TDO) that convert TRP to KYN in the initial step of KP. When the body is in an immune response or stress state, IDO is overactivated. Studies have shown that treatment of 6-OHDA-induced PD model mice with IDO-1 inhibitor 1-methyltryptophan (1-MT) significantly reduces cortical and striatal lipid peroxidation markers and serum nitrite levels. Cortical and striatal reduced glutathione, catalase, superoxide dismutase, mitochondrial complex I and IV activity significantly increased. Expression levels of pro-inflammatory cytokines (IL-6, NF-κB, TNF-α, and IFN-ϒ) and apoptosis markers caspase-3 significantly decreased. Expression levels of antioxidant damage markers such as haem oxygenase-1 (HO-1) and neurotrophic factors such as brain-derived neurotrophic factor significantly increased. Striatal extracellular DA and homovanillic acid content significantly increased, while QUIN content significantly decreased. Motor coordination and spontaneous movement significantly improved, as evidenced by a significant increase in the latency period of falling off the rod, and an increase in the distance and number of standing in the open field⁵⁷. TDO, a tryptophan degradation enzyme, was identified as a potential drug target for PD in a genome-wide RNA interference screen for ageing-related α-synuclein toxicity regulators in C. elegans⁵⁸. Studies have shown that after 21 days of oral administration of TDO inhibitor (NTRC 3531–0) to PD model mice induced by rotenone, TDO activity was inhibited, and TRP levels in plasma and brain significantly increased. The number of TH-positive cells in the substantia nigra significantly increased, the volume of microglia significantly decreased, the number of branches significantly increased, the expression of glial fibrillary acidic protein, a marker of enteric glia, decreased, and the accumulation of α-synuclein in enteric plexus decreased. The latency period of falling off the rotating rod significantly increased, the time spent exploring shifted objects significantly increased⁵⁹.

The role of analogs or precursor drugs of KP major neuroprotective metabolites in the treatment of PD

KYNA analogs or KYNA precursor drugs are another potential method for preventing and/or delaying PD progression. Since KYNA is difficult to penetrate the blood-brain barrier (BBB), its use as a neuroprotective agent is limited. However, KYNA precursor drugs or analogs can easily penetrate the BBB and be converted to KYNA in the brain⁶⁰. The precursor drug 4-chloro-KYN (a KYNA analog) of 7-chloro-KYNA (a synthetic KYNA precursor drug) overcomes the difficulty of KYNA penetrating the BBB and provides excitotoxic neuroprotection after systemic administration⁶¹. Conjugated compounds of 7-Cl-KYNA with D-glucose or D-galactose esters can promote the transport of 7-Cl-KYNA across the BBB. Intraperitoneal injection of these substances indicates their potential significance in experimental treatment of neurodegenerative diseases⁶². Studies have also shown that a newly synthesised KYNA analog, aminoglycoside-KYNA, is more easily penetrable through the BBB than KYNA and can more effectively modify the conformational site of NMDA receptors⁶³. In addition, FK506, a ligand for pro-neurotrophins used clinically as an immunosuppressant, stands out in PD treatment. FK506 not only enhances KYNA formation in the cortex but also eliminates the inhibition of KYNA synthesis induced by 1 - methy l − 4 - phenylpyridinium and 3-nitropropionic acid⁶⁴.

In summary, the use of regulators of the main KP enzyme system (such as agonists or antagonists) and their main neuroprotective metabolites or analogs to increase KYNA levels in the brain may reduce the overactivation of excitatory amino acid receptors and may delay and/or alleviate the progression of PD neurodegenerative diseases, making it a potential therapeutic strategy for PD treatment (Figure 2).

Figure 2. KP putative targets for drug development. TDO: tryptophan 2,3-dioxygenase; IDO1: indoleamine 2, 3 - dioxygenases; KYN: kynurenine; KYNA: kynurenic acid; AA: Anthranilic acid; KATs:kynurenine aminotransferase; KMO: kynurenine - 3 - monooxygenase; 3 - HAA: 3-hydroxyanthranilic acid; 3-HAO: 3,4-dioxygenase of 3-hydroxyanthranilic acid; 3-HK: 3-hydroxyuric acid; NAD +: nicotinamide adenine dinucleotide; PicA: picolinic acid; QUIN: quinone; XA: xanthine acid; ACMS: aminocarboxymuconate - semialdehyde; AMS: 2-aminomuconic 6-semialdehyde.

Summary

The levels of KP metabolites are altered in both the peripheral and central nervous systems in PD, and are closely related to the development of PD. KP metabolites may serve as biomarkers for PD. Modulation of the KP main enzyme system (such as agonists or antagonists) and its major neuroprotective metabolites or analogs may become a potential therapeutic strategy for PD.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the 1) Hunan Provincial Natural Science Foundation Project [2021JJ30552]; 2) Hunan Provincial Education Department Scientific Research Project [19B469]; 3) National Ethnic Sports Key Research Base Open Fund Project [MZTY2203].