An Eu₄L⁴₄ tetrahedron with multiple recognition sites: a luminescent sensor for rapid and sensitive detection of biogenic amines

Abstract

Biogenic amines are important bioactive substances in living organisms, and their abnormal metabolism can serve as biomarkers for certain diseases such as depression, Parkinson's disease and transient tic disorder. Therefore, developing a highly efficient and sensitive luminescent sensor for biogenic amines is essential. However, the biological system is a complex liquid environment containing multiple active substances, which can reduce effective collisions between the sensor and the target analyte, thereby diminishing the sensor's sensitivity. To address this issue, we introduced reaction sites that can undergo nucleophilic and hydrogen bonding interactions with amino groups into the structure of the sensor, and designed and synthesized a multi-site tetrahedral cage Eu₄L⁴₄ to achieve specific capture of biogenic amines. By leveraging these dual interactions between Eu₄L⁴₄ and amines, combined with the confined cavity effect of the cage, multiple spectroscopic analyses demonstrated that the detection limit for ethylenediamine (EDA) improved from 370 μM (Eu₄L¹₄) to 33 μM (Eu₄L⁴₄), while the response time decreased from 1.1 seconds to 0.81 seconds. This design provides an effective strategy for enhancing sensor sensitivity and paves the way for its application in detecting biogenic amines within biological systems.

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1. Introduction

Biogenic amines (BAs) are a group of biologically active amine compounds widely present in living organisms.¹ Among them, diamines are the most common, including cadaverine, putrescine, histamine, tyramine, spermine, and spermidine.² Trace amounts of biogenic amines are normal active components in living organisms and play important physiological roles in biological cells. However, abnormal amounts of biogenic amines are associated with cell division and have been reported as biomarkers for human diseases, such as depression, Parkinson's disease and transient tic disorder.³ Therefore, it is essential to develop a biogenic amine sensor capable of detecting these compounds in biological systems.

Currently, various analytical methods for evaluating biogenic amines have been reported, including electrochemical analysis (EC),⁴ capillary electrophoresis (CE),⁵ high-performance liquid chromatography (HPLC),⁶ and gas chromatography (GC) methods.⁷ However, these methods are often limited in practical applications due to their reliance on expensive instruments, complex sample pretreatment procedures, and cumbersome operations.⁸ In contrast, fluorescence sensors offer significant advantages, such as low cost, simple operation, rapid response time, high sensitivity and high selectivity.⁹ As a type of fluorescent sensor, lanthanide-based sensors have attracted increasing attention due to their high sensitivity, offering advantages such as high luminescence quantum yields, long luminescence lifetimes, and large Stokes shifts.¹⁰ Their long luminescence lifetimes enable lanthanide sensors to distinguish their signals from interfering background fluorescence in complex biological systems.¹¹ These sensors have been widely used for the detection of biogenic amines,¹² metal ions,¹³ anions,¹⁴ biomolecules,¹⁵ and amino acids¹⁶ in biological systems.

However, living organisms represent complex solution environments where numerous coexisting biomolecules with similar functional groups compete with the target analyte. This complexity significantly reduces the effective collisions between the sensor and the analyte, leading to poor selectivity and even erroneous signals. These drawbacks greatly compromise detection accuracy. In recent years, to improve selectivity and sensitivity, some sensors with increased reaction sites have been reported.¹⁷ When the analyte is added, the sensor with a specific functional group can recognize the analyte through covalent or non-covalent interactions. Once multiple recognition sites are introduced into the structure of the sensor, the interactions between the sensor and the target analytes will be enhanced, effectively improving the sensitivity and selectivity of the sensor.¹⁸

Herein, a discrete tetrahedral cage, Eu₄L⁴₄, with multiple recognition sites is designed based on a tris-β-diketone ligand (L¹). In previous studies, we confirmed that weak intermolecular nucleophilic interactions between β-diketones and analytes containing amino groups can occur in Eu₄L¹₄, Eu₄L²₄, and Yb₄L³₄ films at room temperature¹⁹ (the structures of ligands L¹, L², and L³ are shown in Fig. S1†). However, this weak nucleophilic effect is significantly diminished in the liquid state. To address this issue, Eu₄L⁴₄ is designed with multiple pyridine sites on the cage's skeleton, which can interact with analytes via weak intermolecular nucleophilic interactions and hydrogen bonding. Additionally, the confined environment of the tetrahedral cavity may selectively accommodate target molecules of a specific size, further enhancing the sensor's selectivity. Based on a series of sensing performance tests, the detection limit of Eu₄L⁴₄ for ethylenediamine (EDA) is reduced from 370 μM (Eu₄L¹₄) to 33 μM. This improvement demonstrates that introducing multiple reactive sites into the sensor significantly enhances its sensitivity. In summary, the design of a tetrahedral cage with multiple reactive sites provides a new strategy for improving the sensitivity and selectivity of sensors in complex biological systems (Chart 1).

Chart 1 The synthetic method for preparing the lanthanide tetrahedron.

2. Results and discussion

2.1 Synthesis and characterization

The ligand synthesis follows a four-step process outlined in Scheme 1 (details in the ESI†). The first step involves the copper-catalyzed Ullmann coupling of 3-methoxyaniline with 1-iodo-3-methoxybenzene to form 3,3′,3′′-trimethoxytriphenylamine (TTA). In the second step, Friedel–Crafts acylation is employed to synthesize 3,3′,3′′-trihydroxy-4,4′,4′′-triacetyltrianiline (TTTA). The third step involves the Ullmann reaction of TTTA with trichloromethylpyridine hydrochloride, yielding tri(3-(2-)pyridyl methoxy)-tri(4-acetyl)triphenylamine (TPTA). Finally, a Claisen condensation between TPTA and ethyl trifluoroacetate produces the target ligand L⁴. The successful synthesis of the ligand and its intermediates was confirmed using ¹H NMR and ESI-TOF-MS (Fig. S2–S11†).

Scheme 1 The synthetic pathway for L⁴.

The ligand was then reacted with the corresponding Ln(III) salts in a methanol solution at a 1 : 1 stoichiometric ratio for 24 hours to form a lanthanide tetrahedron. ESI-TOF-MS analysis confirmed the formation of the tetrahedron. In Fig. 1a, the inset shows the isotopic pattern for the peak at m/z = 4541.4255, corresponding to [Eu₄L⁴₄ + Na]⁺, which aligns with the calculated values. The lanthanum complex La₄L⁴₄ is shown in Fig. S9.† To further confirm that the tetrahedron exists as a single species in solution, ¹H NMR spectroscopy was employed. Given the low resolution of Eu(III) complexes in ¹H NMR, La(III) complexes were used for the NMR experiments. Compared to the free ligand, the result in Fig. 1b reveals that La₄L⁴₄ exhibits only a single set of signals, indicating the formation of a single species in solution.

Fig. 1 (a) ESI-TOF-MS spectrum of Eu₄L⁴₄, with insets displaying the experimental (Obs.) and theoretical (Sim.) isotopic distribution; (b) ¹H NMR (400 MHz) spectra of the free ligand L⁴ and La₄L⁴₄ in (CD₃)₂CO; (c) crystallographic structures of Eu₄L¹₄; and (d) optimized ground-state geometry of Eu₄L⁴₄.

In order to determine the structure of the tetrahedral cage Eu₄L⁴₄, a molecular mechanical model was constructed using the MOPAC 2016 program integrated into the LUMPAC 3.0 software, employing the Sparkle/PM6 approach.²⁰ Considering the steric hindrance of the ligand, water was selected as the coordinating solvent to satisfy the coordination requirement (8–12) of the lanthanide ions. The optimization results showed that the tetrahedral cage Eu₄L⁴₄ was synthesized by ligand and lanthanide ions at a stoichiometric ratio of 1 : 1. As shown in Fig. 1c and d, the optimized structure of Eu₄L⁴₄ is similar to the single crystal structure of Eu₄L¹₄. They share similarities in that four Eu(III) ions are chelated with four ligands and located at four vertices of a tetrahedron. Each Eu(III) ion center is coordinated with three β-diketone units in three ligands and two solvent molecules. However, they differ in that the introduced pyridine group in Eu₄L⁴₄ is distributed along the three arms of the ligand like a propeller, which increases the interaction between the tetrahedron and the analytes. The cavity volume of the tetrahedral cage is calculated to be 301 ų, and the specific cavity size imposes certain limitations on host–guest recognition.

2.2 Photophysical properties of Eu₄L⁴₄

The photophysical properties of a tetrahydrofuran solution of Eu₄L⁴₄ (0.25 × 10^–5 mol L⁻¹) are shown in Fig. 2. The UV-Vis spectrum exhibits two prominent absorption bands, one between 300 and 330 nm and another between 350 and 450 nm. The lower-energy absorption band is attributed to the π–π* charge transfer from the triphenylamine skeleton to the β-diketone unit, while the higher-energy absorption band (300–330 nm) arises from contributions of both the triphenylamine and β-diketone units. When the characteristic emission of the Eu(III) ion at 612 nm is used as the emission wavelength, the excitation spectrum of the complex largely overlaps with the UV absorption spectrum, confirming efficient energy transfer from the ligand to the Eu(III) ions. Upon excitation at 380 nm, the emission spectrum of the Eu₄L⁴₄ complex in solution reveals a series of sharp transitions corresponding to ⁵D₀ → ⁷D_J (J = 0–4) emissions from the Eu(III) ion, with observed wavelengths at 579, 593, 612, 650, and 702 nm.

Fig. 2 The graph of emission, excitation and UV-vis absorption spectra of Eu₄L⁴₄ in THF/CH₃CN (vTHF/v_CH3CN = 1 : 9, c = 0.25 × 10^–5 M).

2.3 Responses of Eu₄L⁴₄ to biogenic amine

As shown in Fig. 3a, to explore the sensitivity of the lanthanide tetrahedron Eu₄L⁴₄ to biogenic amines with different steric hindrance in the solution state, ethylenediamine (EDA), putrescine (DAB), cadaverine (DAP), propylamine (PA), dipropylamine (DPA), and tripropylamine (TPA) were gradually added to a tetrahydrofuran (THF) solution of the Eu(III) complex (concentration: 0.25 × 10⁻⁵ mol L⁻¹). The concentration-dependent curve of the luminescence intensity at 612 nm was then recorded. In the solution state, the sensing performance of Eu₄L⁴₄ and Eu₄L¹₄ toward monoamines are shown in Fig. 3c and d. It can be observed that as the concentration of various monoamines increases, the luminescence intensity of both complex solutions gradually increases. However, at the same concentration of Eu₄L¹₄ and Eu₄L⁴₄ in THF solution, the change in luminescence intensity of Eu₄L⁴₄ is significantly more pronounced than that of Eu₄L¹₄ upon the addition of the same concentration of monoamine.

Fig. 3 (a) Biogenic amines studied in this paper; (b) the structure produced by the reaction of Ln₄L⁴₄ with diamine; (c) emission spectra of Eu₄L¹₄ after adding PA; (d) emission spectra of Eu₄L⁴₄ after adding PA; (e) emission spectra of Eu₄L¹₄ after adding EDA; and (f) emission spectra of Eu₄L⁴₄ after adding EDA (c = 0.25 × 10^–5 M in THF).

The detection performance of tetrahedral Eu₄L⁴₄ and Eu₄L¹₄ for diamines is shown in Fig. 3e and f. Notably, the luminescence intensity of Eu₄L⁴₄ increases up to 16 times its initial value when 40 equiv. of EDA are added to the THF solution, whereas the luminescence intensity of Eu₄L¹₄ increases only 3-fold. This demonstrates that Eu₄L⁴₄ exhibits significantly better diamine detection performance in solution compared to Eu₄L¹₄. The emission spectral changes for other biogenic amines are shown in Fig. S12.† Additionally, the luminescence lifetimes of Eu₄L⁴₄ before and after the addition of DAB were measured. As shown in Fig. S13,† when 12 equiv. of DAB were added, the luminescence lifetime of Eu₄L⁴₄ increased to twice its original value. This change in lifetime is consistent with the observed increase in luminescence intensity upon amine addition.

Sensitivity is one of the most essential properties of high-quality sensors; therefore, the lower detection limit has always been a challenge in this field. The limit of detection (LOD) was estimated at a signal-to-noise ratio of 3. The linear relationship between the luminescence intensity of the two cages and the concentration of various amines are shown in Fig. 4 and Fig. S14,† as well as Tables S1 and S2.† The detection limits of the two tetrahedral cages for various amines range from micromolar to millimolar levels. The low detection limit provides a necessary prerequisite for the detection of biogenic amines by the tetrahedral cage Eu₄L⁴₄. As seen in Fig. 4a and b, the detection limit of Eu₄L⁴₄ for PA is 0.22 mM, whereas that of Eu₄L¹₄ for propylamine is 1.12 mM. Additionally, Eu₄L⁴₄ exhibits slightly lower detection limits for other monoamines compared to Eu₄L¹₄ in tetrahydrofuran solution.

Fig. 4 (a) The variation in luminescence emission of Eu₄L¹₄ upon the addition of PA; (b) the variation in luminescence emission of Eu₄L⁴₄ upon the addition of PA; (c) the luminescence emission change of Eu₄L¹₄ with the addition of EDA; (d) the luminescence emission change of Eu₄L⁴₄ with the addition of EDA (0 → 10 mM).

The detection limits of Eu₄L⁴₄ and Eu₄L¹₄ for various diamines are shown in Fig. 4c and d. Eu₄L⁴₄ (33 μM) has a much lower detection limit for diamines than Eu₄L¹₄ (370 μM). This is due to the fact that Eu₄L⁴₄ has two sites, trifluoroacetyl and pyridine, which can both interact with amines, and is more likely to form a ring-like stable structure with diamines than Eu₄L¹₄ with only one site of trifluoroacetyl²¹ (as shown in Fig. 3b). Therefore, Eu₄L⁴₄ has stronger interaction with diamines than monoamines. This stronger intermolecular interaction results in a lower detection limit for diamines.

To further validate that Eu₄L⁴₄ exhibits higher sensitivity towards biogenic amines than Eu₄L¹₄, we employed the following Hill equation (luminescence turn on) to calculate the binding constants.²²

where F₀ and F are luminescence intensities in the absence and presence of biogenic amines, F_max is the luminescence intensity at saturation binding, and [c] is the biogenic amine concentration. K_d is the intercept of the linear regressions, which corresponds to the dissociation constant, and K_a is the binding constant.

Luminescence intensities of Eu₄L⁴₄ and Eu₄L¹₄ with biogenic amines at the concentration range of 2.5 mM–10 mM were recorded. The dissociation constants (K_d) were determined by plotting log F – F₀/F_max − F versus log[c]. As shown in Fig. 5, the linear fitting results show that the binding constants of Eu₄L⁴₄ for PA and EDA are 0.2820 × 10³ M⁻¹ and 0.4229 × 10³ M⁻¹, respectively, while the binding constants of Eu₄L¹₄ for these two amines are 0.04968 × 10³ M⁻¹ and 0.07447 × 10³ M⁻¹, respectively. Eu₄L⁴₄ exhibits significantly higher binding constants for monoamines and diamines compared to Eu₄L¹₄, which is consistent with the calculated detection limits. This indicates that Eu₄L⁴₄ has stronger interactions with biogenic amines, demonstrating higher sensitivity than Eu₄L¹₄. The other spectra and binding constants for these amines are shown in the ESI (Fig. S15, S16 and Tables S3, S4†).

Fig. 5 Linear range of log F − F₀/F_max − F for Eu₄L¹₄ and Eu₄L⁴₄ towards log[amine]. The reciprocal of the intercept of the linear regressions is the binding constant of Eu₄L¹₄ and Eu₄L⁴₄.

Compared with chromatographic detection, the fast response time is a prominent advantage of luminescent sensors. In order to investigate the response time of Eu₄L⁴₄ to various amines, the time-dependent luminescence intensity curves were obtained after adding PA and EDA, as shown in Fig. 6a and b. When 40 equiv. of PA and EDA were added, the luminescence intensity of Eu₄L⁴₄ increased instantaneously. By fitting the enhancement part of the luminescence intensity enhancement curve, the response times of Eu₄L⁴₄ were determined to be 1.1 seconds and 0.81 seconds, respectively. As shown in Fig. S17,† it can be observed that the response times of Eu₄L⁴₄ to all biogenic amines are all in the second range, which is far faster than that of any previously reported amine luminescence sensor (Table S5†). Such a fast response time makes Eu₄L⁴₄ suitable for real-time monitoring of biogenic amines.

Fig. 6 (a) Response time and time-resolved emission of Eu₄L⁴₄ before and after the addition of PA; (b) response time and time-resolved emission of Eu₄L⁴₄ before and after the introduction of EDA; and (c) emission changes of Eu₄L⁴₄ upon adding various biogenic amines and O-containing compounds.

In order to investigate the selectivity of Eu₄L⁴₄ to biogenic amines, we selected a series of nucleophilic substances containing oxygen atoms for comparative testing. As shown in Fig. 6c, when 40 equiv. of these nucleophiles were added to the tetrahydrofuran solution of Eu₄L⁴₄, the luminescence intensity enhancement ratio (I/I₀ − 1) of Eu₄L⁴₄ showed no significant change, with all values remaining below 2%. This result indicates that Eu₄L⁴₄ exhibits high specificity for biogenic amines over these nucleophiles.

2.4 Sensing mechanism and luminescence turn on analysis

The interaction mechanism between Eu₄L⁴₄ and biogenic amines primarily originates from two aspects: the coordination between biogenic amines and lanthanide ions, or the interaction between amines and ligands in the tetrahedral cage. First, we investigated the intensity ratio of the ⁵D₀ → ⁷F₂ to ⁵D₀ → ⁷F₁ transitions (I_⁷F2/I_⁷F1), which reflects the symmetry and nature of the Eu(III) ion coordination environment. As shown in Table S6,† the addition of EDA did not induce a significant change in I_⁷F2/I_⁷F1; all the values are around 20, indicating that the introduction of amines did not alter the symmetry around Eu(III). Meanwhile, if amine molecules coordinate to Eu(III), the luminescence intensity of the sensor will decrease due to non-radiative decay. Thus, the possibility of amine coordination to the lanthanide ions can be ruled out.

In order to further explore the interaction mechanism of the lanthanide tetrahedron Eu₄L⁴₄ with biogenic amines, the ¹H NMR of Eu₄L⁴₄ was measured before and after the addition of DAB. The testing procedure is detailed in ESI 1.3.† Due to the paramagnetism of the Eu(III) complex, the resolution of its ¹H NMR spectrum is low; La₄L⁴₄ was selected as substitution for testing. As shown in Fig. 7, when 12, 24 and 48 equivalents of DAB were titrated into THF-d₈ containing 1 equiv. of La₄L⁴₄, all the hydrogen protons in the complex remained observable. Upon the addition of DAB, the signal intensities of all hydrogen protons gradually decreased. The hydrogen proton i on the diketone moiety and the hydrogen protons e, f, and g on the phenyl rings of the triphenylamine shifted slightly upfield. These changes are consistent with the trend observed when La₄L¹₄ was treated with amines,^19a indicating that La₄L⁴₄, similar to La₄L¹₄, can undergo weak intermolecular nucleophilic interactions with biogenic amines. However, the difference is that the hydrogen protons a, b, c, and d on the pyridine ring shifted downfield; generally, hydrogen bonding causes the hydrogen proton to shift downfield. Meanwhile, a new signal peak at 7.45 ppm is obtained, which indicates that there is a stronger intermolecular interaction between La₄L⁴₄ and DAB compared to nucleophilic interaction. This additional interaction can only be attributed to intermolecular hydrogen bonding between the nitrogen atom on the pyridine ring and the hydrogen atom on the amine.

Fig. 7 ¹H NMR studies of La₄L⁴₄ with the addition of DAB.

To further investigate the interaction mechanism between La₄L⁴₄ and biogenic amines, the NOESY spectrum of La₄L⁴₄ was tested after adding DAB. The NOE effect requires the distance of adjacent protons to be shorter than 4.5 Å.²³ However, as shown in Fig. S18,† no correlation signals were observed between La₄L⁴₄ and DAB. Therefore, we can further confirm that no chemical bond was formed between the tetrahedral cage La₄L⁴₄ and DAB, and the interaction is more likely to involve weak intermolecular nucleophilic interactions and hydrogen bonding. In addition, the 2D-1H-DOSY NMR spectra of La₄L⁴₄ were examined before and after the addition of DAB. As shown in Fig. S19,† no new diffusion rates were generated; the diffusion rates of both La₄L⁴₄ and DAB decreased, which may be attributed to their intermolecular nucleophilic interactions and hydrogen bonding interaction leading to a reduction in mobility.

The luminescence quantum yield of Eu(III) complexes mainly depends on the sensitization efficiency of ligands. The alignment between the excited-state energy level and the ⁵D₀ energy level of Eu(III) plays a crucial role in influencing the luminescence intensity of the complex. To explore the reason for the enhanced luminescence intensity of Eu₄L⁴₄ after the addition of amines, we need to determine the energy levels before and after the addition of amines. The singlet (S₁, ¹ππ*) and triplet (T₁, ³ππ*) energy levels of the ligand were calculated using Gd₄L⁴₄; the UV absorption spectra and phosphorescence spectra of Gd₄L⁴₄ were examined before and after adding various amines in THF and CH₃CN solution (Fig. S20 and S21†). As shown in Fig. 8a, when 12 equiv. of DAB were added to the acetonitrile solution of Gd₄L⁴₄, the UV absorption spectrum and phosphorescence emission spectrum exhibited a blue shift, indicating that the singlet and triplet energy levels of the ligand increased after the addition of DAB.

Fig. 8 (a) Phosphorescence and UV/vis absorption spectra of Gd₄L⁴₄ in THF/CH₃CN before and after DAB addition (v_THF/v_CH3CN = 1 : 9, c = 0.25 × 10⁻⁵ M). (b) Schematic illustration of the energy transfer mechanism for Gd₄L⁴₄ upon DAB addition.

The singlet energy of the ligand is determined by the maximum absorption edge of the UV spectrum of the complex Gd₄L⁴₄, as shown in Fig. 8b. Upon adding DAB to the solution of Gd₄L⁴₄, the singlet energy level of the ligand increases from 21 459 cm⁻¹ (466 nm) to 22 124 cm⁻¹ (451 nm). The triplet energy level of the ligand is calculated based on the lower emission peak wavelength in the phosphorescence spectrum. With the addition of DAB to the Gd₄L⁴₄ solution, the triplet energy level rises from 19 417 cm⁻¹ (515 nm) to 19 881 cm⁻¹ (503 nm). Consequently, the energy difference ΔE (3ππ* − 5D₀) between the ligand's triplet state and the excited state of Eu₄L⁴₄ increases from 1917 cm⁻¹ to 2381 cm⁻¹. For Eu(III) complexes, an optimal energy level difference ΔE is typically between 5000 cm⁻¹ and 2500 cm⁻¹. After adding DAB, the energy difference of ΔE = 2381 cm⁻¹ is closer to the optimal value of 2500 cm⁻¹. This results in a significant inhibition of energy transfer from the excited state of Eu(III) to the ligand, leading to a noticeable enhancement in the luminescence intensity of Eu₄L⁴₄.

3. Conclusion

In conclusion, L⁴ with multiple reaction sites was synthesized by introducing pyridine groups into the structure of ligand L¹; the tetrahedral cage Eu₄L⁴₄ was synthesized by coordination-directed self-assembly with lanthanide for the detection of biogenic amines. Combining the comprehensive spectral analyses, an intermolecular weak nucleophilic interaction and a hydrogen-bonding interaction are proposed for this response mechanism. The fitting electrophilic capability of the β-diketonate units to amine nitrogen and hydrogen-bonding interaction endows Eu₄L⁴₄ with high sensitivity toward biogenic amines. In addition, the confined effect of the tetrahedral cavity could further improve the selectivity of the sensor. Compared with Eu₄L¹, a series of sensing tests showed that the detection limit of Eu₄L⁴₄ for DAB was reduced from 370 μM (Eu₄L¹₄) to 33 μM, and the response time was reduced from 1.1 seconds (Eu₄L¹₄) to 0.8 seconds. These results illustrate the effectiveness of increasing the reaction site to improve the sensitivity and selectivity of the sensor, and provide a new strategy for the application of lanthanide sensors in complex organisms.

Author contributions

Yuan Yao: investigation, writing – original draft, data curation, and software. Li Li and Tongxi Zhou: software, formal analysis, and validation. Su Wang and Ying Qin: supervision, data curation, and resources. Chao Fan and Yuying Fu: supervision and writing – review & editing. Guoliang Liu and Hongfeng Li: design, supervision, resources, and writing – review & editing.

Conflicts of interest

The authors declare no competing financial interest.

Data availability

The data that support the findings of this study are available in the ESI† of this article.

Acknowledgements

The authors acknowledge financial support from the Natural Science Foundation of Heilongjiang (No. LH2022B014) and Basic Scientific Research Expenses Project of Provincial Undergraduate Universities of Heilongjiang (No. 2023KYYWF-TD03). We also acknowledge the Sport Molecular Biology Laboratory, College of Sports Science and Health, Harbin Sport University, Harbin 150008, Heilongjiang, People's Republic of China.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5dt00720h

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