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. 2024 Jan 20;10(2):e25091. doi: 10.1016/j.heliyon.2024.e25091

The modern scientific mystery of traditional Chinese medicine processing——take some common traditional Chinese medicine as examples

Yiwen Tian a,b,1, Yun Shi a,b,1, Yujie Zhu a,b, Huan Li d, Jinyang Shen a,b, Xun Gao a,b, Baochang Cai c, Weidong Li c,∗∗, Kunming Qin a,b,∗
PMCID: PMC10835376  PMID: 38312540

Abstract

The processing of traditional Chinese medicine (TCM) is a unique traditional pharmaceutical technology in China, which is the most important feature that distinguishes Chinese medicine from natural medicine and plant medicine. Since the record in Huangdi Neijing (Inner Canon of the Yellow Emperor), till now, the processing of TCM has experienced more than 2000 years of inheritance, innovation, and development, which is a combination of TCM theory and clinical practice, and plays an extremely important position in the field of TCM. In recent years, as a clinical prescription of TCM, Chinese herbal pieces have played a significant role in the prevention and control of the COVID-19 and exhibited their unique value, and therefore they have become the highlight of China's clinical treatment protocol and provided Chinese experience and wisdom for the international community in the prevention and control of the COVID-19 epidemic. This paper outlines the research progress in the processing of representative TCM in recent years, reviews the mechanism of the related effects of TCM materials after processing, such as changing the drug efficacy and reducing the toxicity, puts forward the integration and application of a variety of new technologies and methods, so as to reveal the modern scientific mystery of the processing technology of TCM.

Keywords: Processing of traditional Chinese medicine (TCM), Synergism and attenuation, Chemical component, Modern analysis technique

Graphical abstract

Image 1

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1. Introduction

Chinese medicinal materials need to be processed before used as medicine and processing is the most prominent feature that distinguishes traditional Chinese medicine (TCM) from natural medicines and plant medicines. The processing of TCM is a pharmaceutical technology based on the theory of TCM, the needs of syndrome differentiation and the nature of the medicine itself, as well as the different requirements of dispensing and preparation [1]. During the prevention and control of the COVID-19, TCM has played a unique role, and the TCM represented by the “three formulas and three medicines” has played an important role. According to statistics, more than 50 % of the Chinese medicinal materials in the guidelines and prescriptions issued by the state for the prevention and control of the COVID-19 epidemic need to be processed by different methods such as frying, frying with honey, and stir-frying with wine [2,3].

According to the processing theory of TCM, the processing of TCM has the functions of enhancing effect and reducing toxicity, changing drug properties, and facilitating dispensing [4]. Recently, with the development of modern science and technology and the wide application of various new technologies and methods, the processing mechanism of some TCMs has also been explained through the combination of chemical component research and pharmacological and pharmacodynamic research, making TCM processing shine again.

Due to the diversity of TCM ingredients and the complexity of efficacy, the scientific connotation of Chinese medicine processing has not yet been fully elucidated. Therefore, we would like to conduct a study on the mechanism of TCM processing, thereby clarifying the internal law and scientific connotation of TCM processing. We reviewed the published studies of TCM processing in recent years and took some common TCM processing as examples, that summarize the current research on the processing theory of TCM. In order to clarify the changes in chemical composition and their mechanisms during the processing of TCM, better understand the mechanism of TCM processing, and guide the improvement of processing technology and the formulation of quality standards.

2. Transformation of TCM ingredients and changes in drug efficacy caused by processing

2.1. The mechanism of ginseng processing

Ginseng is the dried root of Panax ginseng C. A. Mey, with ginsenoside as the main active ingredient, which has been used for thousands of years in China. Traditional processing methods of ginseng are mainly sun-drying and steaming. Red ginseng is a processed product obtained by steaming fresh ginseng at high temperature and then drying, while white ginseng is made by drying fresh ginseng under the sun (moisture ≤12 %) [5]. Studies have found that red ginseng has better pharmacological effects than fresh ginseng, including antioxidant activity, as well as antidiabetic, antitumor, and antistress effects [6,7]. Compared with fresh ginseng, the contents of total saponins and malonyl ginsenosides in white ginseng were decreased, but the contents of ginsenosides Rb1 and Rg1 were increased [8]. The content of ginsenosides Rg2, Rg3, Rh2, and Rh1 in red ginseng was greater than that in fresh ginseng, and there are also rare ginsenosides such as Rk1, Rs3 and Rg5 [9]. It can be seen that the efficacy changes in different processed products of ginseng are mainly attributed to the structural changes of ginsenosides [10].

During the processing of ginseng, the change of saponin components involves a variety of transformation pathways (Fig. 1). For example, the unstable malonyl ginsenosides were transformed into the corresponding neutral ginsenosides at high-temperature degradation; Some ginsenosides will undergo acetylation reaction. Some ginsenosides lose the sugar groups at C-3, C-6 or C-20 positions to generate rare ginsenosides. For instance, ginsenosides Rb1, Rb2, and Rc can be transformed into ginsenosides Rg3 and Rh2. Some ginsenosides dehydrate at the C-20 position to form double bonds, resulting in producing different types of ginsenosides. For example, ginsenoside Rg3 can be converted into ginsenoside Rk1 and Rg5 after dehydration [11]. Meanwhile, studies have shown that when fresh ginseng is steamed, the content of ginsenosides increases at 98 °C but decreases at 120 °C, indicating that the content of ginsenosides changes along with the processing temperature [12]. Therefore, the time and temperature should be strictly controlled during the steaming process, so as to avoid the structural damage of ginsenosides.

Fig. 1.

Fig. 1

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The transformation pathway of ginsenosides during processing [8].

2.2. The mechanism of Rehmanniae Radix processing

Rehmanniae Radix is a commonly used TCM in clinical practice, which is the main prescription drug of Liuwei Dihuang Pills, a well-known Chinese patent medicine. It has been reported that different processing methods can cause changes in the chemical components of Rehmanniae Radix [13,14]. The processed Rehmanniae Radix products mainly refer to Rehmanniae Radix Praeparata. Rehmanniae Radix Praeparata are obtained by braising or steaming Rehmanniae Radix with wine, and are commonly used for the treatment of “blood deficiency syndrome” in clinical practice [15]. Studies have shown that the polysaccharides and iridoids in Rehmanniae Radix constitute its main material basis. Li et al. [16] clarified the transformation mechanism of the main chemical components during Rehmanniae Radix processing through the research method of marker discovery and simulated processing based on chemoomics. During the processing of Rehmanniae Radix, the sugar (polysaccharides, oligosaccharides, and monosaccharides) and glycosides (iridoid glycosides and phenylethanol glycosides) are gradually converted into furfural (glycosylated/non-glycosylated hydroxymethyl furfural) through desugar and dehydration.

The glycosidic bond between the furfuran fructose at the end of raffinose and glucose is easy to hydrolyze to produce melibiose and fructose, which are then dehydrated and converted into monosaccharide based 5-hydroxymethylfurfural (5-HMF) and HMF respectively during the processing of Rehmanniae Radix. Through simulating processing, it was found that in mannotriose and melibiose, besides the hydrolyzed furfural product, there was glycosylated HMF from its prototype, which further verified the gradual conversion process of sugar during the processing of Rehmanniae Radix. Chemical analysis results showed that HMF and the glycosylated analogs of HMF were the main characteristic components of Rehmanniae Radix Praeparata. Fig. 2 (A) revealed the main transformation mechanism of polysaccharide components during the processing of Rehmanniae Radix. 5-HMF can effectively bind to sickle hemoglobin to inhibit the sickling of red blood cells, which has the potential to treat sickle cell anemia [17]. Therefore, it is speculated that the 5-HMF-related components produced in the processing of Rehmanniae Radix are the material basis that causes the change of the drug efficacy of Rehmanniae Radix Praeparata, which provides a scientific basis for the effect of Rehmanniae Radix Praeparata on “tonifying blood and nourishing yin".

Fig. 2.

Fig. 2

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The main mechanism of the changes in polysaccharide composition and iridoids during the processing of Rehmannia glutinosa [16].

Processing can also lead to changes in the iridoid components in Rehmanniae Radix [18]. HPLC/Q-TOF-MS technology was used to characterize the chemical components before and after Rehmanniae Radix processing. The results showed that the content of iridoid glycosides decreased and the content of furfural derivatives increased after Rehmanniae Radix processing, which may be the material basis for the change of drug efficacy, see Fig. 2 (B). The iridoids in Rehmanniae Radix are mainly catalpol. Experimental results demonstrated that under heating conditions, the enene ether structure and acetal group of catalpol would be decomposed, casuing the lose of sugar groups and rearrangement, or the occurrence of nucleophilic reaction to generate black substances, which would lead to changes in the color and drug properties of the medicinal materials, and thus result in changes in the antithrombotic and hematopoietic effects of Rehmanniae Radix and Rehmanniae Radix Praeparata [19]. By establishing a mouse model of cyclophosphamide-induced myelosuppression, the pharmacological effects of casuing before and after processing were evaluated, and the results showed that the hematopoietic effect of Rehmanniae Radix Praeparata was more obvious [20].

2.3. The mechanism of Polygoni Multiflori Radix processing

Polygoni Multiflori Radix raw products have the functions of relaxing bowel and detoxification. After processing, it has the effects of blacking hair, nourishing liver and kidney, tonifying blood essence, strengthening muscles and bones, eliminating dampness and decreasing lipid, which belongs to the typical TCM with different uses of raw and cooked products [21]. Since the Song Dynasty, Polygoni Multiflori Radix has undergone various processing methods, such as steaming, and processing with black bean juice, wine, and fermentation. According to the records in “Compendium of Materia Medica” of the Ming Dynasty, Polygoni Multiflori Radix has a better curative effect after being processed “nine-time repeat of steaming and drying”. The main chemical components of Polygoni Multiflori Radix include stilbene glycosides, anthraquinones, and phospholipids, etc, which will change significantly after being processed by different methods [22]. However, the research on its processing and transformation mechanism still lacks of systematic elaboration. Stilbene glucoside is a kind of component with a higher content in Polygoni Multiflori Radix, among which 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) has the highest content, and has various biological activities such as anti-inflammatory and anti-oxidation [23]. It has also been reported that excessive or long-term use of TSG will produce certain toxic and side effects [24]. Dong et al. [25] found that the content of stilbene glycosides in Polygoni Multiflori Radix presented a downward trend after nine-time repeat of steaming and drying. The reason is that stilbene glycosides can be hydrolyzed to the corresponding aglycones in the process of steaming and drying. Therefore, the speculated mechanism of the TSG degradation reaction was deduced under heating condition.

Anthraquinone derivatives in Polygoni Multiflori Radix are mainly divided into free anthraquinone and conjugated anthraquinone, which have important functions such as purgative, diuretic, anti-inflammatory, and hemostatic effects, etc. [26]. Studies have shown that the toxicity of Polygoni Multiflori Radix is reduced after processing. It is speculated that processing can decompose anthraquinone glycosides in Polygoni Multiflori Radix to convert into anthraquinone aglycones, and therefore the content of total anthraquinones decreases as a whole, thereby achieving the purpose of reducing toxicity and increasing efficiency [27]. Sugar is also an important component of Polygoni Multiflori Radix. The “Properties” of Polygonum Multiflorum Radix Preparata in “Chinese Pharmacopoeia” and local processing specifications are described as “brown color inside and outside after steaming”. Color is used as an important index to distinguish raw Polygoni Multiflori Radix and Polygonum Multiflorum Radix Preparata. Studies have found that the main reason for the color change during the processing of Polygoni Multiflori Radix is the Maillard reaction, that is, the chemical reaction between the carbohydrate components and proteins or amino acids under the acidic high temperature environment leads to the change of the property. Thus, the color becomes darker and darker, from yellow to brown [28].

3. Reduction of toxicity and efficacy retention of TCM caused by processing

3.1. The mechanism of the detoxification of aconitum processing

The raw Aconitum is highly toxic and may lead to cardiotoxicity [29]. and therefore it is often used after processing of boiling. On the basis of inheriting the traditional processing experience, Aconitum can be used safely and effectively to treat various rheumatic pain diseases [30] by boiling processing and reasonable compatibility. Studies have found that alkaloids are the main pharmacodynamic components of Aconitum, and are also the main toxic components. Previous researches have explored that alkaloids are the main medicinal components of aconitum, which are also the main toxic components. During the processing of Aconitum, various alkaloid components are changed, resulting in the reduction of toxicity, while the pharmacodynamic effect is preserved [31]. Therefore, it is of great significance to study the processing method and mechanism of Aconitum, so as to provide a scientific basis for the safe clinical application of Aconitum.

Studies have shown that the detoxification of Aconitum after processing is due to the fact that diester diterpene alkaloids (aconitine and hypoconitine) are hydrolyzed into monoester diterpene and amine diterpene alkaloids. According to the differences in substituents, aconitine alkaloids are divided into highly toxic diester diterpene alkaloids (DDA), low toxic monoester diterpene alkaloids (MDA) and non-toxic non-esterified diterpene alkaloids (NDAs). Thereinto, DDA is unstable, and the acetyl group at the C8 position and the benzoyl group at the C14 position are easily hydrolyzed or decomposed in the presence of water or heating. First of all, DDA loses one acetyl group to generate corresponding MDA with the toxicity decreased to 1/200–1/500. Secondly, the C14 position will lose benzoyl group to generate corresponding NDA, as shown in Fig. 3. Therefore, the toxicity of Aconitum can be reduced by heat treatment, mainly due to the promotion of the hydrolysis of DDA into low toxic MDA and NDA [32].

Fig. 3.

Fig. 3

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Hydrolysis process of alkaloids during the processing of Aconitum.

3.2. The mechanism of the detoxification of Genkwa Flos processing

Genkwa Flos is the dry bud of Daphne genkwa Sieb. et Zucc, which has sedative, analgesic, antiviral, anti-cancer, and anti-inflammatory effects [33]. Modern studies have shown that excessive or long-term use of Genkwa Flos can cause damage to the heart, liver, kidney, and gastrointestinal tract [34]. After stir-baking with vinegar, the volatile components and contents in Genkwa Flos are changed significantly, causing toxicity reduction and curative effect improvement [35].

Genkwakine and genkwain in Genkwa Flos may be one of the potential hepatotoxic substances [36]. Tao et al. [37] established a UHPLC-MS/MS method to conduct a comparative study on the pharmacokinetics of raw Genkwa Flos and the samples fried with vinegar, as shown in Fig. 4 (A-F). After oral administration of Genkwa Flos fried with vinegar, the parameters of Cmax and AUC0-t of genkwain, 3′-hydroxygenkwaline, apigenin, and luteolin significantly increased (p < 0.05), while that of genkwakine in raw Genkwa Flos significantly decreased (p < 0.05). The results showed that Genkwa Flos fried with vinegar could increase the bioavailability of genkwain, 3′-hydroxygenkwain, apigenin, and luteolin, and produce synergistic and detoxifying effects.

Fig. 4.

Fig. 4

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Pharmacokinetic curves of six components in Daphne genkwa before and after stir-baking with vinegar [37].

3.3. The mechanism of the detoxification of Kansui Radix stir-baked with vinegar

Kansui Radix is the dry root tuber of Euphorbiakan-sui T.N. Liou ex T.P. Wang, which is first recorded in “Shen Nong's Herbal Lection”. Due to the extreme irritation to the skin, gastrointestinal tract, and mucous membrane, the " stir-baking with vinegar method” has been used in the past dynasties to alleviate the purgative effect and reduce the toxicity of raw Kansui Radix in vivo and in vitro. At present, some scholars have investigated the toxicity reduction mechanism of Kansui Radix fried with vinegar, the changes of chemical components before and after processing, and the effects of different processing methods on reducing toxicity [38]. Diterpenoids are the main toxic components of kanziol, and the changes of these components may be the potential mechanism of the toxicity reduction of Kansui Radix after vinegar processing. The content of the main diterpenoid 3-O-(2′E, 4′Z-decadienoyl)-20-O-acetylingenol (3-O-EZ) in Kansui Radix is significantly reduced after vinegar processing, and the ester bond structure is broken and transformed into the less toxic compound of ingenol.

The conversion reaction of 3-O-EZ in Kansui Radix is discovered by simulating the vinegar processing of Kansui Radix (Fig. 5) to verify the change process and mechanism of the diterpene structure [39]. The experimental results showed that 3-O-EZ could not be converted into ingenol without vinegar treatment, which indicated that vinegar processing had a crucial effect on the changes of terpenoids [40]. Through the study of metabolomics, it was found that Kansui Radix stir-baked with vinegar can cause changes in metabolites in the liver and kidney of rats, adjust glycolysis and amino acid metabolism disorders, and significantly reduce toxicity [41]. Further studies have found that Kansui Radix stir-baked with vinegar can inhibit the intrinsic pathway of liver cell apoptosis by blocking the release of mitochondrial cytochrome C and the activation of Caspase-3 and Caspase-9, thereby reducing liver toxicity [42], which lays a foundation for further elucidating the detoxification mechanism of Kansui Radix stir-baked with vinegar.

Fig. 5.

Fig. 5

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The conversion reaction of diterpenoid 3-O-EZ in Euphorbia Kansui [39].

4. Changes in the internal process of TCM and efficacy enhancement caused by processing

4.1. In vivo pharmacokinetic study of Rhei Radix Et Rhizoma

Rhei Radix Et Rhizoma is the dried root and rhizome of Rhubarb palmatum of the Polygonaceae plant with bitter in taste and cold nature. It is originally recorded in “the Shennong Classic of Materia Medica” and has the functions of purgation, clearing heat and fire, cooling blood and detoxifcation, removing blood stasis and restoring menstrual flow, remove-dampness and relieving jaundice [43]. In order to alleviate its severe laxative effect, wine-treated rhubarb is often prepared by cooking with yellow rice wine for a long time [44]. The processed rhubarb products were first recorded in the “Jin Kui Yu Han Jing” by Zhang Zhongjing in the Han Dynasty, which said: “All the black skins of processed rhubarb or raw rhubarb are removed, followed by washing with wine and soaking in wine. “The 2020 edition of “Chinese Pharmacopoeia” records that “cooked rhubarb” is prepared by steaming with wine or stewing with wine. The sennosides and anthraquinone glycosides in Rhei Radix Et Rhizoma are the main purgative components [45]. Some studies explored the differences between raw rhubarb and wine rhubarb from the perspective of in vivo processes.

The concentrations of 6 components in rat plasma after oral administration of raw and processed rhubarb are determined. The results showed that cooking with wine could change the pharmacokinetics of rhubarb in vivo. The pharmacokinetic parameters of the representative free anthraquinone compounds (emodin and aloe-emodin) were significantly changed, and the maximum plasma concentration (RP value) was significantly increased (Fig. 6) [46]. Studies have shown that the content of bound anthraquinones in raw rhubarb is the highest. After processing, the content of bound anthraquinones decreases and the content of free anthraquinones increases. This is because the bound anthraquinones in rhubarb are transformed into free anthraquinones under heat treatment [47]. Therefore, it is very important to investigate the effects of processing methods on the main chemical components, metabolism and in vitro biological activity of rhubarb, so as to expand the application range of rhubarb, enhance its efficacy and improve the safety of use.

Fig. 6.

Fig. 6

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Comparison of pharmacokinetics between raw rhubarb and rhubarb stir-fried with wine [46].

4.2. In vivo pharmacokinetic study of Bupleuri Radix

Bupleuri Radix is the dried root of umbelliferae Bupleurum chinense D C. or Bupleurum scorzonerifolium Willd., which has pharmacological effects such as antipyretic, analgesic and antidepressant effects. “Chinese Pharmacopoeia” contains two kinds of processed products: raw Bupleuri Radix and Bupleuri Radix fried with vinegar. Some studies have shown that the antidepressant effect of vinegar-baked Bupleuri Radix is stronger [48]. Saikosaponins is the main pharmacodynamic ingredient in Bupleuri Radix [49]. Lu et al. [50] developed a UPLC-MS/MS method to simultaneously and quantitatively analyze eight saikosaponins (SSa, SSb1, SSb2, SSb3, SSb4, SSc, SSd and SSf) in rat plasma, and study the pharmacokinetic differences of the above ingredients in the depression rat model before and after Bupleuri Radix was stir-baked with vinegar. The results showed that there were significant differences in AUC0−t and Cmax of each component after oral administration of the extracts of raw Bupleuri Radix and vinegar-baked Bupleuri Radix, as shown in Fig. 7, and these changes may be related to the different contents of ingredients in raw and vinegar-baked Bupleuri Radix [51].

Fig. 7.

Fig. 7

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Structural transformation and pharmacokinetic curves of saikosaponins in Radix Bupleuri before and after stir-baked with vinegar [51].

During the process of Bupleuri Radix fried with vinegar, saikosaponins a and saikosaponins d will be transformed into secondary saikosaponins b1 and saikosaponins b2, which is an effective ingredient for anti-inflammation, enhancing immunity, inhibiting lipolysis, and stimulating PGE2 synthesis [52]. The transformation of the above components is caused by the hydrolysis of the glycosidic bond under heating or acidic conditions. Meanwhile, the vinegar processing of Bupleuri Radix can promote the hydrolysis of the allyl oxygen bonds at 13 and 28 positions in bupleurum saponins to their corresponding heterocyclic diene structure, which is transformed from type I to type II [53], as shown in Fig. 7. As an important medicine for dispersing liver and relieving depression, these effects of Bupleuri Radix can be enhanced after stir-baking with vinegar. The above study explains the effect of stir-frying with vinegar on the composition of saikosaponins, thereby providing a scientific basis for exploring the processing.

5. Conclusions and prospect

Since the processing of TCM is closely related to the efficacy, safety, and quality of TCM, it is very important to study the changes of chemical components during the processing of TCM for the development of reliable quality control methods of TCM. The chemical component is the main material basis for the efficacy of TCM, and the change of composition is the basis for the efficacy change of TCM before and after processing. In order to clarify the effect of different processing methods on the properties of TCM, many scholars have carried out a large number of studies on impact of the processing on the changes in chemical components of TCM by modern analytical techniques [[54], [55], [56]].

In recent years, various new technologies and methods have emerged continuously, the main technologies and methods are listed in Table 1 below. As a new technology to study metabolites, metabolomics has been used in previous researches on the processing theory of TCM and the processing technology and quality standard of TCM decoction pieces, which is helpful to promote the standardization of processing technology and the improvement of quality standard of TCM decoction pieces [[57], [58], [59]]. In a recent study, Song et al. established a research strategy of integrating metabolomics and pseudo-targeted spectrum-effect relationships to elucidate potential hepatotoxic components in Polygoni Multiflori Radix [60]. It was found that the combination of metabolomics and chemometrics could quickly screen the difference markers before and after Polygoni Multiflori Radix processing, which provides a reference for elucidating the hepatotoxicity of Polygoni Multiflori Radix. To sum up, the processing of TCM can change the structure and content of the effective ingredients in drugs, improve the efficacy, reduce or alleviate the toxicity of drugs, etc., which is a key link in the production and use of TCM. With the deep integration of traditional processing technology and modern technology, it is helpful to display the processing mechanism more scientifically and visually. Conducting researches on the processing of TCM can effectively avoid the risk of drug use, guide clinical rational drug use and the development of TCM, which is of great significance to promote the development of the TCM industry.

Table 1.

Techniques applied in the study of the processing of TCM.

Technologies and methods Type of reaction Example Reactive component Chemical reaction References
Pharmacokinetic and Toxicokinetic Study dehydration reaction Psoraleae Fructus psoralen and isopsoralen Image 1 [61]
Metabolomic strategies and biochemical analysis hydrolysis reaction Rehmanni-ae Radix iridoids Image 2 [19]
Simulation processing hydrolysis reaction Kansui Radix diterpenoid Image 3 [39]
Non-targeted metabonomics combining with SIBDV method decomposition reaction Zingiberis Rhizoma 6-gingerol Image 4 [62]
Spectrum-effect relationship analysis hydrolysis reaction Rehmanniae Radix polysaccharide Image 5 [1]
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Funding

National Nature Science Foundation of China (No. 82374038, 82104349, 81973484); Major Projects of Natural Science Foundation of Jiangsu Higher Education Institutions (No. 21KJA360005).

Declarations

Conflict of interest The authors declare no known conflict of interest.

Data availability statement

All data generated or analysed during this study are included in this published article.

CRediT authorship contribution statement

Yiwen Tian: Writing – original draft, Visualization, Methodology, Investigation. Yun Shi: Writing – original draft, Resources, Investigation. Yujie Zhu: Investigation, Data curation. Huan Li: Methodology, Investigation. Jinyang Shen: Resources, Methodology, Investigation. Xun Gao: Formal analysis, Data curation. Baochang Cai: Resources, Investigation, Funding acquisition, Formal analysis, Data curation. Weidong Li: Writing – review & editing, Funding acquisition, Data curation. Kunming Qin: Writing – review & editing, Writing – original draft, Investigation, Funding acquisition, Formal analysis, Data curation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by National Nature Science Foundation of China (No. 82374038, 82104349, 81973484), Major Projects of Natural Science Foundation of Jiangsu Higher Education Institutions (No. 21KJA360005).

Contributor Information

Weidong Li, Email: liweidong0801@163.com.

Kunming Qin, Email: qinkm123@126.com.

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