Abstract
The Maillard reaction, also known as the ‘non-enzymatic browning reaction’, involves a reaction between reducing sugars and amino compounds, including amino acids and proteins. The Maillard reaction has been increasingly used in the production of traditional Chinese medicine and food. This study thoroughly examines the mechanism of the reaction, the factors that influence it and the techniques used for extracting, separating and purifying Maillard reaction products (MRPs) in food and Chinese medicine processing. Additionally, the article explores the physiological functions of MRPs, highlighting their antioxidant, hepato-protective, antibacterial, immune-boosting, anti-mutagenic, anti-inflammatory, health-promoting, detoxifying and antiviral effects. MRPs have diverse outcomes because of various influencing factors; they can contain trace amounts of potentially harmful constituents, such as acrylamide, 5-hydroxymethylfurfural and advanced glycosylation products. The study also includes a comparative analysis of common methods used for the separation and purification of concentrated MRPs. These methods consist of ultrafiltration, macroporous resin, gel chromatography, ion exchange chromatography and dialysis. Results indicate that each method has advantages and disadvantages, and thus careful consideration should be placed on specific applications. Furthermore, a future outlook for the research and development of Maillard reaction and its products is proposed. Given that the physiological activities of MRPs are diverse, thorough qualitative and quantitative analysis of the reaction mechanisms, influencing factors and pharmacologically active ingredients is needed. This study offers valuable insights into the advancement of MRPs for industries involved in food and traditional Chinese medicinal material processing. These insights can be effectively utilised in healthcare and clinical practice, offering innovative ideas for scientific and technological professionals involved in research and development.
Keywords
Introduction
The Maillard reaction, also referred to as the ‘non-enzymatic browning reaction’, was first proposed by French chemist LC Maillard in 1912. 1 This reaction involves the interaction between carbon-based compounds (reducing sugars) and amino compounds (amino acids and proteins), leading to condensation, rearrangement, cyclisation, deoxygenation and isomerisation. Subsequent condensation results in the formation of brown or even black macromolecular substances known as melanoids and in the generation of a burnt aroma. 2 The mechanism of the maillard reaction is summarized in Figure 1.
Mechanism of the Maillard reaction.
Research on the Maillard reaction has predominantly concentrated on its utilisation in the food industry, whereas studies on its use in the production of traditional Chinese medicinal materials are rare. Nevertheless, both botanical and animal-based medications encompass constituents capable of undergoing this reaction, including proteins, peptides, amino acids and reducing sugars. 3 The Maillard reaction can modify the colour and aroma of traditional Chinese medicinal materials, prolong its shelf life and generate novel active compounds. Additionally, the resulting products demonstrate a range of physiological effects, such as antioxidant properties, liver protection, bacteriostatic, immune-modulating, anti-mutagenic, anti-viral and anti-inflammatory effects, offer health benefits and mitigate specific conditions. 4 In addition, this study highlights the potential health risks associated with the Maillard reaction, such as the formation of toxic substances, including acrylamide, 5-hydroxymethylfurfural (5-HMF) and advanced glycation products.5–7
In conclusion, it emphasises the importance of investigating how the Maillard reaction affects the composition of traditional Chinese medicinal materials during processing. By understanding this effect, we can uncover the material basis of traditional Chinese medicinal materials’ efficacy and the production and mechanisms of harmful substances. Ultimately, this research aims to ensure the safety of medicinal use, reviewing existing research on the Maillard reaction's effects on Chinese medicine quality, including factors influencing the reaction, product extraction and bioactivities. It also discusses the possibility of regulating the Maillard reaction to improve Chinese medicine quality, offering a fresh perspective regarding on ways to enhance the efficacy of Chinese medicine.
Research on the Mechanism, History and Component of the Maillard Reaction
Reaction Mechanism
The Maillard reaction primarily involves amino compounds (derived from organic amines, amino acids and proteins, including some alkaloids in traditional Chinese medicine materials) and carbonyl compounds (such as reducing sugars, lipids and resulting aldehydes, ketones, polyphenols, ascorbate and steroids, including traditional Chinese medicine materials anthrine, flavonoids, cyclic ether terpene, volatile oil and steroids) undergoing a non-enzymatic reaction also known as the Amadori reaction. 8
Reaction Process
From 1912 to 1917, a fruitful study of the Maillard reaction was carried out, and then Hodge et al
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summarised this reaction in a reaction diagram, which can be summarised into three stages.The relevant process is illustrated in Figure 3.
Early stage: Nitrogen atoms in amino-containing compounds attack the base carbon in a nucleophilic manner, resulting in the addition of a hydroxyl amine (N-glucosylamine).
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The unstable imide derivative undergoes dehydration, leading to the formation of xue base. After an Amadori rearrangement reaction, 1-amino-1-deoxyy-2-ketone is generated, and the reaction is reversible. At 25°C, the reaction occurs spontaneously.
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The early stage response mechanisms are summarized in Figure 2. Advanced stage: 1-Amino-1-deoxy-2-ketones can undergo three reaction pathways.
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When pH ≤ 7, 1,2-enylation occurs. If pentose participates in the reaction, the primary product of the Amadori rearrangement reaction is predominantly 1,2-enolised to produce furfural. As for hexose, it forms 5-HMF. This process can be perceived as sugar reacting with the three molecules of water to produce furfural derivatives. The amino compounds are added first before removed and serve as catalysts. When pH > 7 and temperature is low, the 2,3-enolisation of 1-amino-1-deoxyl-2-ketose preferentially occurs to produce reduced ketones (reductones), such as acetylenediol. Reduced ketones are relatively unstable and have a strong reducing effect but can form dehydroreducing ketones, such as 1-methyl-2 and 3-dicyl compounds. This amino-containing compounds play a catalytic role, facilitating the removal of two molecules of water by sugars to produce o-two derivatives. When pH > 7 and temperature is high, 1-amino-1-deoxyl-2-ketosugar produces many highly active intermediates, such as 1-hydroxy-2-acetone, acetonaldehyde and diacetyl groups. These intermediates, such as dehydroreducketone, can participate in reactions and are susceptible to amino acid decarboxylation and deamination, forming aldehydes and α-aminidones through the Strecker degradation reaction. Final phase: The aldehydes and ketones formed during the reactions are unstable and may undergo condensation to produce aldehydes and denitrification polymers. In the presence of an amino group, these substances undergo a series of reactions, such as condensation, dehydrogenation, rearrangement and isomerisation, which lead to further condensation and finally culminate in the formation of complex macromolecular nitrogen-containing brown polymers or copolymers, which are collectively referred to as melanoidin.
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Early stage response mechanisms.
Maillard reaction process.
(Figure 3).
Isolation and Purification Study of the Maillard Reaction Products (MRPs)
Current methods for separating and purifying MRPs in Chinese medicine, food and other substances include ultrafiltration, macroporous resin column chromatography, gel chromatography, ion exchange chromatography and dialysis (Table 1). The end product of black is the outcome of a complex series of cascade reactions, involving dehydration, cyclisation, rearrangement, isomerisation and polymerisation. 14 Consequently, the structure cannot be precisely characterised, and thus separation and purification are challenging. Current methods involve determining the relative content of black products by measuring light absorption values at 420 or 470 nm or by differentiating its components using molecular weight analysis. In this study, an analysis of 75 volatile components and MRPs was conducted using GC-MS technology. Moreover, 52 aromatic substances were identified through distillation extraction, and considerably high extraction efficiency for esters and nitrogen-containing rings was observed. Ketones, oxygen and nitrogen-containing rings were among the 20 aromatic substances detected through solvent extraction. Additionally, solid-phase microextraction revealed 27 aromatic substances, and notably extraction efficiency for esters and alkane substances was observed. 31
Methods for Isolation and Purification of MRPs in Chinese Medicine and Food.
Ultrafiltration
Currently, the predominant technique for isolating and purifying MRPs entails separating various molecular weight fractions from burnt crataegi fructus torrefactionis (Shanzha) and investigating their antioxidant properties in vitro. The notable antioxidant effects of these components have been demonstrated. 14 The components of hordei fructus germinates (Maiya) were classified using ultrafiltration into three components with different molecular weight: MW-L (10 kDa). Interestingly, it was observed that the MW-H fraction increased proportionally with the hordei fructus germinatus content. 15 To obtain the corresponding component, the black garlic filters were passed through 3, 10, 30 and 50 kDa. Samples greater than 3.5 kDa or 25 kDa were produced by filters with 3.5 kDa or 25 kDa. 16 A black garlic sample solution was prepared and passed through filter membranes of 50 and 10 kDa, resulting in a solution with three different components. 17 In summary, ultrafiltration can facilitate the production of MRPs, presenting benefits, such as simple operation, speedy separation and excellent separation efficiency. These benefits ensure convenience for large-scale sample preparation. 32 The Maillard reaction is a multifaceted cascade reaction. Ultrafiltration can be used in assessing the proportionate content of varying molecular weight. This analysis facilitates the examination of each reaction stage and contributes the improvement of quality control measures. However, ultrafiltration does not differentiate among substances present in a sample; instead, it groups samples according to filter membrane aperture. 33
Macroporous Resin
Owing to the force exerted on molecular surfaces and the porous structures of resins, macroporous adsorption resins possess a wide range of benefits, such as softness, strong selectivity, easy regeneration and low cost. 34 Thus, they have been extensively utilised in the separation and purification of flavonoids, alkaloids, terpenoids, saponins and other traditional Chinese and ethnic medicines. 18 However, their utilisation is hindered by the accumulation of impurities on their surfaces and within their internal structures; these impurities eventually lead to a dark colour and a decrease in separation efficiency. Furthermore, resin crushing is a setback to separation. Substances can be purified through macroporous resin refining. For example, the extracts of the ripening products of barbary wolfberry can be obtained using macroporous adsorption resins. 19 Through ultrafiltration and purification technologies using large porous resins, black essence containing fractions with various molecular weight can be obtained; the small-molecule fraction (<10 kDa) of the black essence exhibited high antioxidant activity and content. 21
Chromatography Techniques
Tomography is a technique that relies on variations in the physical and chemical properties of different substances. In the separation of MRPs, two primary techniques are commonly used: glucan gel and ion exchange chromatography. 24 To investigate MRPs present in red ginseng, a previous study extracted compounds through silica gel column chromatography, Sephadex LH-20 column chromatography and thin-layer and high-performance liquid chromatography; nine compounds were identified and characterised according to their physicochemical properties and spectroscopic data. 25 A variety of scientific methods were employed to accurately isolate and identify the compounds. DEAE-Sepharose fast flow and Superdex were utilised to fractionate vinegar essence with a molecular weight exceeding 3.5 kDa. The initial products of the Maillard reaction yielded four distinct components, which exhibited prominent absorption peaks at 290 nm. 26 The reaction products were further separated using glucose gel chromatography. The MRPs were then fractionated using glucan gel column chromatography, revealing two main components denoted as MRPs-1 and MRPs-2. Under optimal isolation and purification conditions, Three separate fractions were extracted according to their relative molecular mass (83.70%, 49.20% and 36.91%) through fish proteolysis and G-15 glucan gel chromatography. 35
Dialysis Technology
This method is used by some researchers to obtain relatively pure MRPs. MRPs flow halfway through the membrane, and unreacted raw materials and small molecules flow through the other side, effectively eliminating other substances in MRPs. Different modalities of dialysis can be used in selecting MRPs with varying molecular weight, allowing for the precise analysis of their molecular structures and composition. The reactions of glucose (>12,500 molecular weight) and maltose (3500 molecular weight) with glycine were examined through microanalysis. Subsequently, the correlation between the molecular weight of melanoids and the elemental composition of amino acids and sugars was discussed. 28 After the extracts of black ginseng and black garlic were rotated and evaporated, the undialysed extract was freeze-dried for the preparation of two fractions: MRPs with high molecular weight >10 kDa and low molecular weight (1 kDa < molecular weight < 10 kDa). MRPs were analysed before and after dialysis with cellulose membranes with molecular weight of 12–14 kDa.29,30 This method effectively removes interference from small molecules, such as glucose and amino acids, resulting in the isolation of pure MRPs. The only minor drawback is that dialysis may be prolonged.
Current status of MRPs in Traditional Chinese Medicinal Materials
MRPs are compounds formed through the reactions of amino acids and reducing sugars, playing a significant role in the flavour, colour and aroma of food products. In traditional Chinese medicinal materials, MRPs to contribute to the therapeutic properties. However, the scientific basis of this notion remains incompletely understood. Numerous studies have explored the formation and characteristics of MRPs in traditional Chinese medicinal materials but have yielded inconsistent results. Some studies have highlighted the antioxidant, anti-inflammatory and anti-tumour properties of MRPs, whereas others have suggested potential adverse effects, including increased diabetes and cancer risks. Further research is essential to comprehensively grasp the role of MRPs, and advanced analytical methods are needed for the identification and quantification of diverse MRPs in traditional Chinese medicinal materials. In addition, clinical trials are needed for the assessment of the therapeutic benefits and potential risks associated with the consumption of traditional Chinese medicinal materials containing MRPs. 36
Traditional Chinese medicinal materials contain sugars, amino acids, reducing bases and alkaloids, which can participate in Maillard reactions, which are crucial to the processing of Chinese medicines and affect their quality and safety. The effects of Maillard reactions on the quality and safety of Chinese medicine should be always considered. 37 Their influence on the processing of traditional Chinese medicinal materials is mainly manifested in the establishment of processing methods, processing mechanisms, processing product quality, product quality standards and product quality standards. 38
In recent years, the link between Maillard reactions and the processing of traditional Chinese medicinal materials have been explored. The connections of ginseng radix et rhizoma, polygonate rhizome, paeoniae radix alba, rehmanniae radix praeparata and gardenia fructus praeparatus with the production of 5-HMF and black essence during processing have been found (Table 2). Maillard reactions with crataegi fructus in coke-producing processes result in the production of melanin in thecrataegi fructus water solutions, facilitating the production of a series of MRPs, including nitrogen heterocyclic compounds, cyclic enone alcohol structures, polybasic compounds and monobasic compounds, which are classified (Figures 4 and 5). 69 Jiao sanxian combustion results in the formation of burnt aroma compounds and MRPs, and these compounds exert beneficial effects on digestion. The interaction of these burnt substances with other chemicals, such as organic acids, synergistically promotes smooth muscle contraction in the gastrointestinal tract, triggers the secretion of digestive fluids and activates mechanisms related to the ‘brain–gut link’. These combined actions enhance jiao sanxian's ability to alleviate the symptoms of ‘digestion and stagnation’. 46
Nitrogenous heterocyclic compounds, cycloketenol structures, colycarbonylic compounds in the products of the Jiao Sanxian Maillard reaction.
Monocarbonyl compounds in the products of the Jiao Sanxian Maillard reaction.
Detection of MRPs in Chinese Medicine.
Factors Influencing the Maillard Reactions
The Maillard reaction is a series of complex reactions that produce a variety of products with intricate structures. In traditional Chinese medicinal materials, factors that influence the Maillard reaction include the substrate used, reaction temperature and duration, pH value, water content of medicinal materials and other variables. 3
Reaction Substrate
The Maillard reaction is a condensation reaction that occurs between basic compounds, including reducing sugars, unsaturated fatty acids, aldehydes and ketones, and amino compounds, such as amino acids, peptides, proteins and other nitrogen-containing compounds. This reaction results in the formation of a complex structure and a diverse range of products, which are collectively referred to as MRPs. 70 The rate of browning in five-carbon sugars is reportedly 10 times that in six-carbon sugars. As for reducing monosaccharides, the order for five-carbon sugars is ribose > arabinose > xylose; for six-carbon sugars, galactose > mannose > glucose. Additionally, the order of activity for sugars reacting with lysine is xylose > galactose > glucose > fructose > sucrose. 71 The types and concentrations of amino acids play a critical role in determining the outcome of the Maillard reaction. 72 Various amino acids can produce a wide range of flavour compounds during this reaction, which are highly relevant to the food industry. Moreover, it significantly affects the quality of traditional Chinese medicinal material preparations and processing products. The rate order for the Maillard reaction is as follows: amine > amino acid > protein; basic amino acid > acidic amino acid; ε-amino group > α-amino. 73 In addition, MRPs affect the sensory characteristics of various food products, including whole grains rich in phenols. This association potentially alter the Maillard reaction pathway during thermal processing, consequently affecting the overall sensory properties of whole grains.
Temperature and Time
In general, the Maillard reaction can occur at temperatures greater than 20–25 °C. Colour darkens as heating time increases under consistent conditions. Although the reaction rate is accelerated at high temperatures, it still stays below 80 °C. 74 For every 10 °C increase in temperature, the Maillard reaction rate increases three to five times, leading to a considerable in the variety and quantity of MRPs. 75 Temperature influences not only the rate of reaction but also the concentration of reactants and their interactions. As processing times and temperatures increase, the levels of reducing sugars and polyphenols decrease along with amino nitrogen content. Moreover, high water content accelerates the Maillard reaction, resulting in enhanced browning during drying. Drying at 70 °C is more effective than that in the two temperatures mentioned. 76 At the beginning of soybean milk preparation, the Maillard reaction progresses slowly due to low temperature. As the temperature increases, the concentration of reduced sugars increases from 0.58 mg/mL to 0.80 mg/mL. Additionally, the amino group on the amino acid slightly decreases from 4.51 mmol/L to 4.43 mmol/L in bean paste systems, suggesting that the group initially binds to the amino groups on the amino acids. 77 In the processing of ginseng through steaming, ginsenosides Rh1, 20(S)-Rg2, 20(S,R)-Rg3 and MRPs, such as arginine–fructose, arginine–fructose–glucose and maltol, were newly generated or enhanced concentrations were enhanced. 78
pH Value of the Reaction System
pH value plays a crucial role in the various pathways of the Maillard reaction, considerably affecting the reaction rate. Typically, the Maillard reaction intensifies with increasing pH within a range of 3–10, whereas acidic pH levels inhibit this reaction. Moreover, the pH of the reaction system greatly influences the type of products formed during the Maillard reaction. Changes in the concentration of hydrogen ions lead to alterations in functional and amino groups, and the ionisation of these groups is a critical factor. Non-enzymatic browning relies on ammonia condensation, which is a rate-limiting step. In acidic environments, the nucleophilic addition of beta-ammonia is more challenging, resulting in the low yield of nitrogen-containing substances. However, sugar isomerism and dehydration are prevalent, leading to the production of furfural compounds. The aroma profile of heat-treated Tribolium castaneum is notably affected by pH. Acidic conditions are conducive to the formation of 5-HMF, and alkaline conditions promote the production of esters, particularly methyl 2-butyl acid. Browning is minimal at pH levels below 10, indicating a negligible Maillard reaction but becomes pronounced above pH 10. Exceeding a pH of 10 triggers a Maillard reaction, resulting in visible browning. 79
Water Content
Moisture plays a crucial role as a medium in food and herbs, with its content is closely related to the Maillard reaction. The Maillard reaction rate is accelerated when water activity falls between 0.3 and 0.7 but slows down when it goes above or below this range. Typically, the reaction occurs more readily when the water content in food falls between 10% and 15%, and it is hindered when the water content is below 3%. The Maillard reaction is nearly non-existent in the absence of water because of the fixed positions of amino and carbonyl compounds. Notably, a high water content does not always lead to a favourable Maillard reaction because excessive water can dilute reactants and decrease the reaction rate. Moreover, the water content influences the products produced during the Maillard reaction. In low moisture systems, the presence of amino acids results in a decrease in 5-HMF formation from sucrose and fructose but an increase in 5-HMF formation from glucose. In systems with moderate moisture content, the presence of amino acids leads promotes the formation of 5-HMF from glucose, fructose and sucrose. When amino acids are in the reaction system, 5-HMF is produced from glucose, fructose and sucrose through the 3-DG pathway in systems with low and intermediate moisture content. 80 The formation of 2,5-dimethylpyrazine exhibited a decrease initially, followed by an increase with time and temperature. Conversely, it showed an initial increase followed by a decrease as substrate concentration and moisture content in the solvent composition changed. 81
Influence of High Pressure
High pressure generally refers to pressure between 100 and 800 MPa, and high pressure result in a fast Maillard reaction. 82 In a glucose–glycine simulation system, we studied the effect of high-voltage pulsed electric fields on the Maillard reaction. We discovered that when the field strength was 28 kV/cm and pH was 7.96, PEF treatment considerably enhanced the Maillard reaction of the glucose–glycine analogue solution without any thermal effect. If the electric field intensity was below 24 kV/cm, the PEF treatment had no significant effect on the Maillard reaction. 83 The degree of Maillard reaction was intensified by high-pressure steam, causing a reduction in the whiteness of rice from 78.19 to 73.93. Additionally, heterocyclic volatile substances were produced, considerably changing the rice's flavour. 84
Metal ion
The influence of metal ions on the Maillard reaction is predominantly reliant on the specific type of metal ion and varies across distinct reaction stages. Upon the introduction of metal ions (Al3+, Ca2+, Cu2+, Fe2+, Mg2+ and Zn2+) to the advanced glycosylation end products (AGEs) fashioned throughout the Maillard reaction, minor amounts of metal ions hindered AGE origination. By contrast, high amounts facilitated AGE synthesis. Metal ions had no significant effect at high concentrations (P > 0.05) on LPPC's ability to inhibit AGEs but were found to diminish the ability at low concentrations. 85 Furthermore, the formation of carboxymethyllysine and carboxyethyllysine was not predominant in the tea simulation system. Nevertheless, metal elements are crucial for the growth and quality development of tea and the Maillard reaction. 86
Effects of Radiation
As a rapidly advancing field, x-ray and γ-ray radiation sterilisation is widely used across different industries and is considered a key method in various fields, such as food, medical and chemical fields. Irradiation can trigger the Maillard reaction, which presents differences compared with reactions occurring during traditional heating. 87 After the an intense drying treatment (150 °C from infrared radiation and hot air for 120 min and high thermal microwave radiation heating for 20 min), the drying content of acetone aldehyde showed a ranking of infrared radiation > microwave radiation > hot air. Similarly, the 3-deoxyosol content followed the same order of ranking for infrared radiation > microwave radiation > hot air. 88 For the three drying modes, 1,1-diphenyl-2–3-trinitrophenylhydrazine radical clearance was highest for infrared radiation, followed by microwave radiation and hot air. 89
Influence of Source Materials and Processing Methods on Changes in the Biological Activity of MRPs
Influence of Source Materials
Different source materials contain different types and quantities of MRPs, vary in structure and function. Therefore, selecting different source materials may have an effect on the biological activity of MRPs in traditional Chinese medicinal materials. For example, MRPs contained in different species of plants may have different physiological and pharmacological effects. 90
Influence of Processing Methods
The processing methods of traditional Chinese medicinal materials include processing, decoction, extraction and other steps. These steps have an important effect on the biological activity of MRPs in traditional Chinese medicinal materials. Different processing methods may lead to changes in the structure and function of MRPs, thereby affecting their biological activity. For example, high-temperature decoction may destroy the structure and active sites of MRPs and reduce their biological activity, and ultrafine grinding technology can increase the dissolution rate of the active ingredients of MRPs and enhance their biological activity. 91
In summary, comparative analysis of the physiological effects of MRPs from different traditional Chinese medicinal material ingredients and discussions on changes in biological activity based on source materials and processing methods will deepen understanding of the action mechanism and pharmacology of MRPs in traditional Chinese medicinal materials. These endeavors provide theoretical basis and practical guidance for the development and application of traditional Chinese medicinal materials.
Physiological Activities of the MRPs
The physiological functions of MRPs have been explored, including their activities that provide protection against antioxidant and liver injury, induce immune response, and exert antibacterial, anti-mutagenic, anti-inflammatory and health-promoting effects. These properties include effects against diabetes and lipid anti-thrombotic action, inhibiting cholesterol and regulating gastrointestinal systems and anti-ageing processes. Additionally, the cytotoxic effects and attenuated and antiviral characteristics of MRPs have been examined.
Antioxidant Activity
MRPs demonstrate strong antioxidant activity in various food and pharmaceuticals through the chelation of metal ions, disruption of free radical chains and hydrogen peroxide and removal of reactive oxygen species (ROS). 92 MRPs consist of a dark-coloured substance, reducing ketone and a variety of volatile heterocyclic compounds containing nitrogen and sulphur, which exhibit antioxidant properties. MRPs in some traditional Chinese medicinal materials and certain antioxidant effects. These materials include green tea and ginkgo leaves. The MRPs in these traditional Chinese medicinal materials can scavenge free radicals in the body and reduce the damage caused by oxidative stress to the body, thereby protecting cells and tissues from oxidative damage. Moreover, arginyl–fructosyl–glucose is a main non-saponin (ginsenoside) component produced in red ginseng processing, with high antioxidant, anti-apoptotic and neuroprotective efficiency. 93
Hepatoprotective Effect
The protective effect of MRPs of Corni fructus (Shanzhuyu) on acute liver injury in mice was explored using carbon tetrachloride, which can induce acute liver injury. The levels of alanine aminotransferase and aspartate aminotransferase, liver index, malondialdehyde content and glutathione peroxidase were assessed. Histological examination with HE staining revealed that MRPs had a protective effect against acute liver injury in mice. 94 Furthermore, MRPs derived from fish protein hydrolysates and ribose exhibited hepatoprotective properties. 95
Regulate Immune Function
MRPs in some traditional Chinese medicinal materials, such as ginseng and Lycii fructus regulate immune function. The MRPs in these traditional Chinese medicinal materials can enhance the body's immunity and increase the activity and number of immune cells, thereby enhancing the body's resistance to diseases. In addition, MRPs in different traditional Chinese medicinal materials may have different immune-regulating functions, such as by promoting the proliferation, differentiation and apoptosis of immune cells.96–98
Toxic Action
Advancements in science and technology have allowed for the discovery of novel MRPs. Although some MRPs may benefit human health, some can be harmful. The identified harmful substances in MRPs are mainly 5-HMF, acrylamide and AGEs. These compounds are strongly associated with the development of various chronic degenerative diseases, such as cataracts, Alzheimer's disease, diabetes, uraemia and retinopathy, and ageing.99,100
The complex structures of MRPs pose a challenge to the isolation of individual AGE products. Likewise, the analysis and detection of AGEs are constrained by current methods and instruments. Thus, the inhibition of AGE production in food processing and traditional Chinese medicinal materials products is impeded by limited understanding of the formation mechanism of these harmful substances.
Potential Health Risks of AGEs and Reduction Strategies
AGEs constitute a diverse group of molecules with stable properties and complex structures and can accumulate in the human body over time. AGEs formed during food processing are mainly produced through the Maillard reaction. Terminal AGEs in the diet are associated with the onset of various chronic non-communicable diseases, including chronic inflammation, degenerative diseases, ageing, insulin resistance and tumours. 101 AGEs inhibit the growth of LO2 and HKC cells, leading to apoptosis in a manner that is positively correlated with AGE concentration and exposure time. The detrimental effects of AGEs on these cells may be linked to the increased mRNA levels of pro-inflammatory cytokines IL-1β, TNF-α and HMGB1. Moreover, AGEs cause surface roughness and damage to the cell membrane in LO2 cells, resulting in decreased viability and reduced PKLR mRNA expression. Furthermore, an increase in AGE concentration is associated with increased ROS content and superoxide dismutase activity in HKC cells, suggesting a relationship between the toxic effects of AGEs and cellular oxidative stress.102,103
Health Risks
Related to diabetes complications, ageing, Alzheime's disease and other diseases, causing damage to liver, lungs, kidneys and other organs.
Reduction Strategies
Adjust dietary structure: intake of high-sugar and high-oil food is reduced to inhibit the production of glycation end products in the body.
Improve living habits: staying up late and smoking are avoided to reduce the production of glycation end products.
Adjustment of traditional Chinese medicinal materials formula: In the MRPs formula, Chinese medicinal materials with antioxidant, anti-inflammatory and other effects are added to reduce the damage caused by glycation end products. 104
Potential Health Risks of Acrylamide and Reduction Strategies
The Maillard reaction has considerable consequences, including neurotoxic, reproductive, hepatotoxic, genotoxic and potentially carcinogenic effects. Additionally, acrylamide can trigger the NLRP3 inflammasome in Kupffer and HepG2 cells by inducing oxidative stress and activating the MAPK signalling pathway through ER stress response. This effect leads to the release of inflammatory cytokines, such as IL-1β and IL-18, resulting in an inflammatory response and toxicity (Figure 6). 105
Mechanism of toxic action of acrylamide.
Health risks 106
Neurotoxicity: Acrylamide may cause damage to neurological functions, such as numbness of limbs and ataxia.
Immunotoxicity: The normal functions of immune organs are affected, and cellular immune function weakens.
Potential carcinogenicity: acrylamide is listed as a Class 2A carcinogen by the International Agency for Cancer.
Reproductive toxicity: It may affect the fertility of animals and may cause potential harm to the human reproductive system.
Reduction strategies 107
Source control: In the preparation of traditional Chinese medicinal materials, raw materials that do not contain or have low levels of acrylamide are selected.
Improve the process: Production is performed using low temperature, low pressure and other conditions to reduce the generation of acrylamide.
Post-processing measures: Adsorption, filtration and other post-processing measures are adopted to remove acrylamide in MRPs. Materials that reduce damage caused by glycation end products are used.
Potential Health Risks of 5-HMF and Reduction Strategies
Health Risks
5-HMF can lead to embryotoxicity, nephrotoxicity, hepatotoxicity and reproductive toxicity (Figure 7A). Given that the therapeutic and toxic doses of 5-HMF are similar, its safe use as a drug in clinical settings should be guaranteed. The ADMET lab 2.0 database (https://admetmesh.scbdd.com/) was utilised to predict the absorption, distribution, metabolism, excretion and toxicity (ADMET) of 5-HMF. The ADMET features of 5-HMF are depicted in Figures 7B–C. Pharmacological and toxicological activities are prevalent in food and drugs. 5-HMF can be detrimental to human health, and risk of harm is influenced by the method of exposure and dosage. 5-HMF has been associated with a range of adverse effects, including irritation of the eyes, mucous membranes and skin. In severe cases, it can lead to poisoning when interacting with human proteins, leading to conditions, such as rhabdomyolysis and organ damage. Furthermore, 5-HMF exhibits neurotoxic properties and has potential genetic and reproductive toxicity. 108 5-HMF toxicity tests conducted on mice indicate that the intake of 188 or 375 mg/kg for two years increases the incidence of hepatocellular adenoma in B6C3F1 females. Moreover, long-term exposure to high levels of 5-HMF is carcinogenic. 109 A study explored the carcinogenic effects of 5-HMF and 5-SMF, concluding that neither compound has a negative effect on the growth of colonic small sac or bowel cancer. 110 Exposure to 5-HMF for 32 h at levels ranging from 19.8 μM to 3808.0 μM may lead to altered sister chromatids in cells.Male and female F344/N rats and B6C3F1 mice were given doses of 188 and 375 mg/kg 5-HMF, respectively, resulting in observed effects on olfactory and respiratory epithelial cells. 111
Toxicity of 5-HMF. A. The toxicity of 5-HMF on organs or sites; B. The radar map of 5-HMF ADMET. C. The property and decision of 5-HMF toxicity.
Reduction strategy 112
Raw material selection: Choose Chinese herbal medicines that contain no or low 5-HMF as raw materials.
Optimization of processing conditions: control heating temperature and time to reduce the generation of 5-HMF.
Quality standard formulation: Establish a limit standard for 5-HMF in MRP to ensure product safety.
In summary, regarding the potential health risks associated with trace components such as acrylamide, 5-HMF, and advanced glycosylation products in traditional Chinese medicinal materials MRPs, it is necessary to comprehensively consider raw material selection, production process optimization, post-processing measures, and quality standard formulation to reduce these risks. At the same time, adjusting dietary structure and lifestyle habits and other auxiliary measures can also help reduce the potential impact of these trace ingredients on human health.
Anti-Inflammatory Action
MRPs from high-temperature food can reduce inflammatory response in patients with IBD by preventing increase in mast cell number and inflammation. 113 Multiple active ingredients in traditional Chinese medicinal materials, such as astragali radix (Huangqi) and angelicae sinenis radix, demonstrate notable anti-inflammatory properties. These active ingredients can modulate immune cell activity and the intensity of inflammatory responses to reduce inflammation. Furthermore, different active ingredients in traditional Chinese medicinal materials may employ various anti-inflammatory mechanisms, including inhibiting the production of inflammatory factors and regulating the migration and aggregation of immune cells. 114
Health Care
Tetramethylpyrazine, also known as ligustrazine, is an active alkaloid derived from chuanxiong. It serves as the primary active component in Chinese medicine chuanxiong and is naturally formed during a Maillard reaction in the fermentation of shanxi-aged vinegar. The ageing process involves the use of smoked and fermented grains, which not only contribute to its colour and alcohol content but also imparts health benefits, such as blood pressure–lowering effects, enhanced blood circulation and inhibited blood stasis and free radical production. 115 The promotion of gastrointestinal peristalsis after arecae semen (Binglang) processing may not be attributable to alkaloids. Arecae semen (Binglang) after frying, it can produce a Maillard reaction, promote the secretion of GLP-1, bile and CHO and promote gastrointestinal motility. 116
Influence of Maillard Reaction on Chinese Medicine Processing and Preparation Research
Impact on Processing Mechanism and Products
Traditional Chinese medicinal materials not only contain carbohydrates and amino acids but also contain active ingredients, sucn as reducing carbonyl groups and alkaloids. These components participate in the Maillard reaction, leading to complex outcomes. Therefore, the Maillard reaction can occur during the processing of traditional Chinese medicinal materials, affecting the colours and flavours of the final products, and generating new compounds that influence product quality. The influence of the Maillard reaction on the processing of traditional Chinese medicinal materials is mainly evident in the following aspects:
Effects on Processing Methods
The extent of the Maillard reaction is related to temperature, time, components in a system, water content and pH value. In other words, the degree of Maillard reaction during processing is affected by the types and quantities of sugars, amino acids and pharmaceutical ingredients in raw materials and excipients and is related to the processing method. According to the pharmacological activity of the Maillard product produced by a medicinal material, appropriate processing methods and conditions can be selected, such as heat, solid excipients added, type of heat transfer medium and amount of liquid excipients to achieve the required type of Maillard products. 117
Elucidation of the Processing Mechanism
For some medicinal materials containing reducing sugars, reactive aldehyde-based drugs and amino acid components, such as rehmannia radix praeparata (Shudihuang), dioscoreae rhizoma (Shanyao) and corni fructus (Shanzhuyu), the Maillard reaction can be used in elucidating the processing mechanism. For example, rehmannia radix (Shengdihuang) has a golden yellow texture, sweet taste and cold nature and has the effects of clearing away heat and cooling blood, nourishing yin and promoting fluid production. Rehmannia radix praeparata (Shudihuang) has an oily black texture, sweet flavour and warm nature and has the function of nourishing yin and promoting fluid production. Rehmannia radix praeparata (Shudihuang) is produced by roasting rehmannia radix (Shengdihuang), and the processing mechanism can be elucidated by the Maillard reaction. 118
Impact on the Quality of Processed Traditional Chinese Medicine Products
The Maillard reaction produced during processing can cause the colour of the medicine to turn brown and give the medicine a certain special smell. For example, galli gigerii endothelium corneum (Jineijin) turns yellow and bright after frying; hordei fructus germinatus (Maiya), oryzae fructus germinates (Daoya) turn fragrant after frying; polygoni multiflori radix (Heshouwu) and rehmannia radix praeparata (Shudihuang) turn brown after processing. 119 To a large extent, these effects may be the results of the Maillard reaction. These changes can be observed throughout the processing period of traditional Chinese medicinal materials. In addition, during picking, drying and processing of fresh medicinal plants, most traditional Chinese medicinal materials undergo a non-enzymatic browning process from green to yellow and then from yellow to dark brown. Therefore, introducing the Maillard reaction into the field of traditional Chinese medicinal material processing can elucidate the colour and aroma the change mechanisms of traditional Chinese medicinal material processing; ingredients produced by processing and the influencing factors that affect the intrinsic quality of the product can be thus examined. 120
Effect on the Establishment of Quality Standards for Processed Products
Different processing methods and heat treatments have different effects on the quality of products. Most current processing quality standards are established according to experience, especially appearance indicators, such as smell, colour, moisture and ash. These indicators are not unrelated to the Maillard reaction. Therefore, we can incorporate MRPs as indicators into the quality standards of processed traditional Chinese medicinal material products to supplement and improve the quality standards of processed traditional Chinese medicinal materials. 121
Effect on the Preparation Process and Quality of Traditional Chinese Medicinal Materials Compound Preparations
Traditional Chinese medicinal materials compounds need to be decoctioned and extracted into appropriate dosage forms before they can be used in clinical applications. In addition to being rich in reducing sugars and amino acids, traditional Chinese medicinal materials contain highly reducing aldehyde groups and highly alkaline alkaloids. Therefore, a more complex Maillard reaction occurs during the decoction and extraction and affect food quality. 122 The physical properties, efficacy and subsequent preparation process of extracts have important effects. Chinese medicine extracts all look ‘black’. In pharmacy, this feature has long been considered a disadvantage of Chinese medicine preparations and has been eliminated. However, this “black” substance is a black complex or melanoidin, which is a product of the Maillard reaction. Drug compatibility can considerably change the type and characteristics of a product. 123 The production of this product is closely related to the amount of Maillard reaction precursors or vitamin C, pH value, water activity, oxygen concentration and temperature. In the presence of oxygen, the reaction rate is greatly increased, but the amount of melanoidin produced depends on the concentrations of reducing sugars and amino acids. 63
Effect on the Extraction Process
The traditional Chinese medicinal materials are decoctioned and extracted to obtain a dark brown decoction. In this process, single-flavoured Chinese medicinal materials of various colours are decoctioned with water, and finally a dark brown extract is obtained, indicating that the chemical composition of the medicinal materials has undergone Maillard changes during decoction and extraction. Given that reducing sugars and amino acids are commonly found in Chinese herbal medicines, material changes in the decoction of Chinese herbal medicine compounds should be examined according to the Maillard reaction. This approach can provide a scientific basis for determining the research methods of Chinese herbal medicine extraction. 3
Effect on the Physical Properties of the Extract
The extracts of traditional Chinese medicinal materials are dark brown because of the Maillard reaction. Different raw materials and extraction methods affect MRPs, and the physical properties of extracts change. Therefore, the Maillard reaction is used to change the physical properties of extracts, such as hygroscopicity, solubility, diffusivity, absorptivity and dissolution of the main drug, to provide scientific basis for the preparation of traditional Chinese medicinal materials and selection of excipients. 124
Effect on the Moulding Process
Given that the Maillard reaction changes the physical properties of leachates, the effects of this reaction on the process methods, procedures and auxiliary materials should be considered when the moulding process is being studied. The effect of this reaction on a product should be considered, particularly the influences of biopharmaceutics on colour, odour and ingredients. 3 Moreover, whether the Maillard reaction occurs again during moulding should be considered. Therefore, a suitability study of the moulding based on the MRPs is necessary to provide scientific basis for determining the research methods of traditional Chinese medicinal material moulding. 125
Effect on the Quality of Finished Products
Whether new ingredients produced by the Maillard reaction are active and the impact of Maillard products on the active ingredients of traditional Chinese medicinal materials should be considered. Moreover, whether the main active ingredients participate in the reaction and whether the MRPs are active should be determined.The Maillard reaction affects the release of the main ingredients and whether the Maillard product is toxic. Therefore, research based on the Maillard reaction and product characteristics is necessary to provide scientific basis for research methods on traditional Chinese medicinal material preparation technologies and product quality. 124
Effect on the Establishment of Finished Product Quality Standards
Different extraction and preparation processes have different effects on the Maillard reaction. The current quality standards for traditional Chinese medicinal materials preparations do not consider the effects of MRPs. Therefore, when formulating quality standards for traditional Chinese medicinal materials preparations, additional quality standards should be established for appearance, such as colour, odour, moisture and ash. Effective and toxic Maillard products should be prepared, and the quality standards of traditional Chinese medicinal material preparations should be established.3,63
Generate Supramolecules
The micelles of traditional Chinese medicinal materials decoctions appear with the generation of MRPs. This multi-component self-assembles into supramolecules. Due to different single medicinal materials and different processing processes, their structure and shape will not respond to environmental changes (such as pH) response is also different. After processing, the inherent components and new components of medicinal materials are assembled to form supramolecular structures, which respectively play different roles in construction, delivery, recognition, release and efficacy. Therefore, when elucidating the Maillard reaction mechanism in the processing process of traditional Chinese medicinal materials, the supramolecular existence form of traditional Chinese medicinal materials can be studied, which provides novel ideas for the research on the material basis of traditional Chinese medicinal materials. 126
Conclusions
In addition to investigating the effect of the Maillard reaction on food quality, research has also delved into areas closely linked to human health.The Maillard reaction process is influenced by various factors, such as reaction time, temperature, pH, solvent, types of reaction substrates (sugars, amino acids, proteins), their properties and the proportions in which they react. These factors play a crucial role in the overall reaction process, and variations in any of them can lead to considerable differences in the reaction process and resulting products. 127 Moreover, the final product, melanoidin, is not only composed of irregular molecules but also exists in different forms. Its composition and properties vary greatly depending on the starting materials and reaction conditions, and its structure remains unclear, making quantitative analysis extremely challenging. The proper regulation of each factor during the processing of food and drugs can enhance production efficiency and product quality, thereby contributing positively to product development and utilisation. 128
MRPs in the processing of traditional Chinese medicinal materials have received widespread attention in recent years. They exhibit a variety of physiological functions in terms of efficacy, nutritional value and safety, providing clear inspiration for future research and practical applications. 129 Certain components in MRPs, such as melanoidins and certain heterocyclic compounds, have antioxidant, anti-inflammatory, anti-tumour and other biological activities. These substances can enhance the efficacy of traditional Chinese medicinal materials and improve the overall effect of the drug. Effect. 130 Although MRPs exhibit various physiological functions in traditional Chinese medicinal materials, some products, such as acrylamide, may be toxic. Therefore, the safety of MRPs in traditional Chinese medicinal materials should be evaluated. 131
Different traditional Chinese medicinal materials and processing methods will lead to different types and quantities of MRPs. These differences may further affect the efficacy and safety of traditional Chinese medicinal materials, and thus the impact of individual differences on the efficacy of traditional Chinese medicinal materials needs to be considered. Through in-depth study of the mechanism of the Maillard reaction and understanding the role of various products in the efficacy of traditional Chinese medicinal materials, it will help to further optimise the processing methods and processing techniques of traditional Chinese medicinal materials and improve the quality and efficacy of traditional Chinese medicinal materials. 129 A comprehensive assessment of the safety of MRPs in traditional Chinese medicinal materials, especially the monitoring and control of potentially toxic substances, is the key to ensuring the safe use of traditional Chinese medicinal materials. Taking into account the effects of individual differences on the efficacy of traditional Chinese medicinal materials, individualised medication research and development of precise medication plans based on the physiological and pathological characteristics of different patients should be carried out. 132 Through innovative traditional Chinese medicinal materials processing technologies, such as modern physical processing technologies such as microwaves and ultrasonics, as well as biological processing technologies such as enzymatic and microbial methods, we can optimise the processing methods and processing techniques of traditional Chinese medicinal materials and improve the quality and efficacy of traditional Chinese medicinal materials. 133 Based on the physiological functions of MRPs, explore new applications of traditional Chinese medicinal materials in antioxidant, anti-ageing, health care, and further expand the application fields and market space of traditional Chinese medicinal materials. 134
MRPs in traditional Chinese medicinal materials processing exhibit a variety of physiological functions in terms of efficacy, nutritional value and safety of traditional Chinese medicinal materials. Through in-depth study of its mechanism and characteristics, strengthening safety assessment, optimising processing technology and processing methods, we can provide strong support for the modern research and application of traditional Chinese medicinal materials. 135
Footnotes
Acknowledgements
I want to acknowledge all the authors of the references that I used.
Authors’ Contributions
Meniga Shengbu wrote the manuscript. Qi Zhao, Qian Shi and Xinan Liu conceptualized the study. Li Ai and Xianrong Lai provided valuable suggestions. All authors read and approved the final version of the manuscript.
Availability of Data and Materials
This paper is a review of the previously published data. All data generated during this study was included in this published article.
Consent for Publication
Not applicable.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethics Approval and Consent to Participate
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Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China Youth Science Fund Project (No.81403105) ,Project of Science and Technology Department of Sichuan Province (No.2021YJ0112), Sichuan Administration of Traditional Chinese Medicine (2024MS046) and Xinglin Scholars Program of Chengdu University of Traditional Chinese Medicine (QJJJ2023017).
