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/lp/wolters-kluwer-health/the-exciting-and-magical-journey-of-components-from-compound-formulae-Js8UjylyTO
- Publisher
- Wolters Kluwer Health
- Copyright
- Copyright © 2022 Tianjin University of Traditional Chinese Medicine.
- ISSN
- 2765-8619
- DOI
- 10.1097/hm9.0000000000000047
- Publisher site
- See Article on Publisher Site
Abstract
With its long-term empirical clinical practice and increasing number of health benefits reported, Chinese Materia Medica (CMM) is gaining increasing global acceptance. Importantly, the identification of chemical constituents in vitro and exposed forms in vivo is a prerequisite for understanding how CMM formulae prevent and treat diseases. This review systematically summarizes the exciting and magical journey of CMM components from compound formulae to where they fight, the possible structural transformation of CMM components in vitro and in vivo, and their pharmacological contribution. When a decoction is prepared, significant chemical reactions are observed, including degradation and production of polymers and self-assembling supramolecules, leading to the construction of a component library with diverse decoction structures. After ingestion, compounds pass through the intestinal and blood-brain barriers and undergo a more wonderful journey involving the gut microbiota, microbial enzymes, and endogenous drug-metabolizing enzymes (mainly liver enzymes). At this stage, they are modified and assembled into novel and complex compounds, such as newly generated metabolites, conjugates, and self-assembling superamolecules. This review might provide a strategic orientation to explore the active compounds of CMM formulae in vivo. Keywords: Chinese Material Medica, Formulae, Gut microbiota, Metabolites, Prototype components, Self-assembling supramolecule acupuncture, cupping, tuina (massage therapy), qigong Introduction (movement and breathing exercises), and moxibustion, Traditional Chinese medicine (TCM), a medical system are chosen to help the patient recover from an abnormal that differs from modern Western Medicine in theory, body state. This clinical diagnosis and treatment process [1] methodology, and substances , has been proven to be is known as TCM syndrome differentiation and treat- effective in clinical practice for more than 2000 years. [1–4] ment . As one of the important therapeutic methods TCM practitioners differentiate a patient’s TCM syn- of TCM, CMM formulae, usually composed of the mon- drome through TCM pathogenesis after a comprehen- arch, minister, assistant, and servant ingredients, is pre- sive analysis of information obtained from diagnostic scribed by practitioners following the compatibility law methods, including visual inspection, listening and smell- of “seven emotions”, namely single action, mutual rein- ing examination, inquiry, and palpation. Subsequently, forcement, mutual assistance, mutual restraint, mutual a suitable Chinese Materia Medica (CMM) formu- [5–6] suppression, mutual inhibition, and antagonism . lae or other traditional treatment procedures, such as Through reasonable compatibility, CMM formulae show more potent therapeutic effects and weaker adverse reac- tions than single herb. Long-term empirical information Ning Meng and Yun Lyu contributed equally to this work. from clinical practice shows that CMM formulae have State Key Laboratory of Component-based Chinese Medicine, better therapeutic effects on cardiovascular, metabolic, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin gynecological, and pediatric diseases. For example, University of Traditional Chinese Medicine, Tianjin, China; State compound Danshen formula (CDF) is effective against Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Holding Group Co., Ltd., Tianjin, China; School of Medicine, angina pectoris in patients with coronary heart disease. University of California San Diego, La Jolla, CA, USA; Haihe CDF has been formulated as dripping pills, tablets, etc, Laboratory of Modern Chinese Medicine, Tianjin, China; and has been comprehensively studied in various clini- * Corresponding author. Kefeng Li, School of Medicine, University of cal trials. Notably, CMM formulae also show curative California San Diego, La Jolla, CA 92093, USA, E-mail: kli@ucsd.edu; [7] effects in infectious diseases . This therapeutic connec- Yuefei Wang, State Key Laboratory of Component-based Chinese tion between CMM formulae and infectious diseases has Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, become particularly consequential during the ongoing Tianjin University of Traditional Chinese Medicine, Tianjin 301617, severe acute respiratory syndrome coronavirus 2 (SARS- China, E-mail: wangyf0622@tjutcm.edu.cn. CoV-2) pandemic, with three traditional Chinese patent Copyright © 2022 Tianjin University of Traditional Chinese Medicine. medicines (Jinhua Qinggan granule, Lianhua Qingwen This is an open-access article distributed under the terms of the capsule, and Xuebijing injection) and three CMM for- Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download mulae (Xuanfei Baidu decoction, Qingfei Paidu decoc- and share the work provided it is properly cited. The work cannot be tion, and Huashi Baidu formula) improving symptoms, changed in any way or used commercially without permission from the shortening the course, and preventing progression of journal. [8] the disease in China . In particular, Lianhua Qingwen Acupuncture and Herbal Medicine (2022) 2:4 capsules demonstrated anti-viral activity by significantly Received 17 June 2022 / Accepted 27 September 2022 repressing SARS-CoV-2 in African green monkey kidney [9] http://dx.doi.org/10.1097/HM9.0000000000000047 epithelial (Vero E6) cells . In addition to the individual 240 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com therapeutic effects of CMM formulae, there is grow- that can pass through the blood-brain barrier (BBB) are ing interest in the combination of CMM formulae and transported into the cerebrospinal fluid and serve as neu- [10] Western Medicine because a combination exhibits roprotective agents. profound efficacy against diseases and reduces the side CMM formulae with multi-herbs and multi-com- effects mediated by individual treatment. Currently, this pounds have multiple targets and pathways to prevent integrative treatment approach is advocated as a strategy and cure diseases. From the China National Knowledge to diminish the serious adverse effects associated with Infrastructure and PubMed, we collected relevant litera- Western chemotherapeutic drugs during cancer manage- ture on the structural transformation of CMM compo- [11] ment in clinics . In contrast, an increasing number of nents and provided an overview of exposed molecular bioactive compounds with excellent pharmacological forms originating from CMM formulae in vitro and in activity and definite action mechanisms have been iso- vivo (Figure 1), with the aim to identify active compo- [12] [13] lated from CMM, such as artemisinin and berberine . nents and elucidate the underlying mechanisms for pre- The journey of CMM components from compound venting and treating diseases. The cited references were formulae to where the components fight is a long, excit- published between the years 2000 and 2020. ing, and mysterious process, accompanied by interesting chemical and enzyme-catalyzed reactions. First, follow- Transformation of compounds from CMM formulae ing the processing and compatibility of Chinese herbs, during decocting the components in the compound formulae undergo Under the guidance of TCM theory, CMM formulae decoction in vitro. After oral administration, the com- mostly reach an ideal therapeutic effect when the quality ponents of the compound formula decoction enter the of CMM and CMM materials compatibility is strictly gastrointestinal tract, where they are partly or wholly controlled, and performed extensively. Miraculously, transformed by the gut microbiota. The migrating com- compounds from CMM formulae undergo metamor- pounds in the intestine exhibit curative effects through phosis during decocting, which usually gives rise to four three main processes: retention in the intestine, absorp- classes of compounds: prototype compounds, degraded tion into the blood, and absorption into the lymph. The products, polymers with covalent interactions, and compounds that are not absorbed are retained in the self-assembling superamolecules. intestine and might play therapeutic roles by regulating the immune response of intestinal mucosa, remodeling the gut microbiota, and inducing the biological effects Common types in CMM formulae: prototype compound and [14] of active products on gut microbiota . Commonly, degraded product compounds absorbed into the blood vessel are metab- olized by liver enzymes and migrate within the systemic Prototype and degraded compounds from CMM for- blood circulation, exerting pharmacological effects. mulae are an important source of active compounds. Meanwhile, a small portion of the migrating compounds Prototype molecules are primary and secondary in the intestine would be absorbed into the lymph vessels, metabolites isolated from Chinese herbs, which are performing a conducive effect. Furthermore, compounds categorized as low molecular weight compounds (such Figure 1. The possibly exposed molecular forms of CMM components from compound formulae to where they act. CMM: Chinese Materia Medica; SCFAs: short-chain fatty acids. 241 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com as flavonoids, saponins, and alkaloids) and high molec- melanoidin, is a mixture of multiple brown polymers [28] ular weight compounds (such as polysaccharides and generated by the condensation of cyclic subunits . proanthocyanidins). These prototype molecules have Emerging evidence has shown that melanoidins possess [29] shown beneficial effects in the amelioration of car - anti-tumor , anti-bacterial, and other enzyme-inhibi- [15] [30] diovascular diseases, diabetes, and other acute or tory bioactivities . Nevertheless, the deleterious effects [16] chronic diseases. For example, sodium tanshinone of Maillard reaction products on human health have IIA sulfonate, a water-soluble derivative of tanshinone also been studied; for instance, the negative effects of IIA, has been approved for the treatment of cardiovas- advanced glycation end products on Alzheimer disease [17] [31] cular diseases in China . have been reported . The degraded products originate from susceptive The Zhizichi decoction, composed of Gardeniae compounds exposed to light, heating, and pH fluctua- Fructus and Sojae Semen Praeparatum, a classical [32] tions during the decoction of the CMM formulae. This CMM formula used to treat depression , is usually triggers diverse chemical reactions, such as hydroly- decocted in sequence, that is, Gardeniae Fructus fol- sis, redox reactions, neutralization, and complex lowed by Sojae Semen Praeparatum. Furthermore, reactions, leading to toxicity reducing or efficiency owing to the high content of iridoid glycosides, that enhancement. For example, after the co-decoction of is geniposide, in Gardeniae Fructus, and β-glucosidase [33] aconite roots and licorice roots, the toxicity of aconite and tyrosine in Sojae Semen Praeparatum, Cui et al. roots was drastically decreased, wherein highly toxic proposed and validated the hypothesis that genipo- diester alkaloids were hydrolyzed into low-toxicity side originated from Gardeniae Fructus was primarily [18] monoester alkaloids . The coexistence of acidic and converted into genipin by β-glucosidase, followed by a basic compounds can produce a soluble salt, which reaction with tyrosine to form a genipin-tyrosine com- [19] plays a critical role in increasing their dissolution . plex (GTC), which might be responsible for the anti-de- [34] In addition, the action of trace elements cannot be pressant effects . GTC, also known as gardenia blue neglected despite their low content in the CMM for- pigment, is the product of a cross-linking reaction that mulae. Metal complexes, formed by metal ions and occurs spontaneously between iridoid aglycones and [35] organic molecules with coordination groups (such as compounds containing primary amine groups . It is carboxyl, phenol hydroxyl, amino, and hydrosulfo- well established that genipin forms a cross-linked struc- nyl groups), have received increasing attention with ture with a primary amine group through active inter- the advent of coordination chemistry in TCM the- mediates by nucleophilic ring-opening reactions in the [20–21] [36–38] ory . Evidence indicates that baicalin, a flavonoid dihydropyran ring . from Scutellariae Radix, has better anti-microbial, With the existence of proteins and amino acids in [22] anti-tumor, and immunoregulation effects through the CMM formulae, critical attention should be given coordinated formation with copper or aluminum ions. to polymers analogous to melanoidins and gardenia Intriguingly, the profound coordination complex-in- blue pigment. Moreover, reports on the exact struc- duced pharmacological activity is partly attributed ture of such polymers in the CMM formulae remain to the synergistic effect between the metal ions and missing because of many reaction products formed [23] prototype compound . Their characteristics are and challenges in their purification and identification. generally described using a combination of multiple In the case of melanoidins, on the one hand, Maillard analytical methods. For example, with the assistance products contain not only complex melanoidins but [39] of infrared radiation spectroscopy, nuclear magnetic also several low molecular weight intermediates . resonance (NMR) spectroscopy, elemental analysis, On the other hand, Maillard products lack stability [24] [39–40] and mass spectrometry (MS) techniques, Chen et al. and are easily transformed . Finally, there may be [41] identified the crystal structures of metal complexes various interfering factors (such as temperature, pH, synthesized by oxoglaucine and transition metal salts and coexisting compounds) that disturb the detection. using X-ray diffraction. Characterization and formation mechanisms of mela- noidin have been explored, which were experimentally introduced by the reaction between mono-reducing Polymer with covalent interaction [42] sugars and mono-amino compounds , and several [43] Polymers are macromolecules cross-linked by multi- known intermediates , and isolation of products from [44] ple simple chemical units (monomers). Derived from enzymatic hydrolysis of melanoidin . For example, [44] various intense conditions during the decoction of Rodríguez et al. isolated melanoidins from dulce CMM formulae, polymers, such as the products of de leche (DL) through dialysis, enzymatic hydrolysis, the Millard reaction and cross-linking color reaction, and fractionation, followed by characterization using are one of the most important molecular forms in the ultraviolet-visible spectra, elemental analysis, NMR, CMM formulae. and high-performance liquid chromatography (HPLC), The Maillard reaction, a complicated cascade of suggesting that DL melanoidins are mainly protein non-enzymatic browning between reducing sugars and complexes formed by cross-linking reactions between [25] amino compounds , is a common pathway for poly- proteins, which probably contain aromatic groups and mer production during the preparation of CMM formu- sulfur. Its formation involves the condensation of lac- lae. For instance, the steaming and drying processes of tose and lysine residues from the protein. Such efforts [26] the Chinese herbs Rehmanniae Radix and Polygoni have not been entirely successful, and more efforts for [27] Multiflori Radix led to polymer formation. The final polymer identification in CMM formulae should be product of the Maillard reaction, collectively known as made. 242 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Self-assembling supramolecules the way for seeking pharmaceutical molecules from CMM formulae. Self-assembling supramolecules are complexes formed spontaneously by individual molecules via non-covalent bonds. In the past decade, there has been an increasing Transformation of CMM formulae decoction-derived interest in self-assembling supramolecules, which have parent compounds and production of endogenous also facilitated the elucidation of the pharmacological metabolites by gut microbiota in the intestine effects of CMM formulae. After the oral administration of the CMM formulae, [45] Zhuang et al. detected aggregates in 84 solution the decoction-derived components were exposed to mixtures of 60 medicinal herbs and 24 CMM formulae the gut microbiota. Gut microbiota not only produces using dynamic light scattering. They observed that the endogenous metabolites, such as short-chain fatty activities of two CMM formulae, Xuefu Zhuyu decoc- acids (SCFAs), trimethylamine (TMA), and secondary tion and Jingguan decoction, were aggregates-related, bile acids, but also participates in various processes of against plasminogen activator inhibitor one, angio- host metabolism and immune regulation, consequently tensin-converting enzyme, and inducible nitric oxide influencing the effectiveness and safety of CMM for - synthase. The mechanism behind this phenomenon is [14] mula decoctions . As shown in Figure 2, CMM for- that large colloid-like aggregates formed through the mula decoction-derived parent compounds, their self-association of candidate organic molecules revers- secondary gut microbiota-dependent compounds, and ibly sequester the enzymes, thereby inhibiting the CMM metabolites transformed by enterohepatic circu- [45–48] action . The colloid-like aggregates showed pro- lation are regarded as transitional compounds in the miscuous inhibition and may present activity opposite intestines. to the inherent activity of the compound. For example, [49] Zhou et al. evaluated the differences in bioactivities among Maxing Shigan decoction (MXSGT), ephed- CMM formulae decoction-derived parent compounds and rine-loaded colloid nanoparticles (NPs) fractionated their secondary compounds in the intestine from MXSGT, and ephedrine. They found that MXSGT CMM formulae decoction-derived parent compounds and ephedrine-loaded NPs showed higher cell prolifera- tion in human hepatoblastoma (HepG2) cells, whereas After the oral administration of the CMM formula ephedrine showed higher cytotoxicity in HepG2 cells. decoction, which emerged as prototype compounds, The differences between the activities of colloid-like degraded products, polymers, and self-assembling super- aggregates and pure compounds might depend on the amolecules, parent components traveled within the structure of the compound from the CMM formulae, gastrointestinal tract. The oral bioavailability of CMM [54] which remains to be further investigated. In addition, formulae is a conundrum because most CMM decoc- owing to the occurrence of colloid-like forms, aggre- tion-derived parent compounds are unabsorbed into gates can be protected from the gastrointestinal envi- circulation. However, parent CMM components in the ronment, and nano-aggregates are readily absorbed intestine, coordinating with their gut microbiota-de- through the intestine, increasing the bioavailability of pendent metabolites, could modulate therapeutic effects compounds with poor aqueous solubility and chemi- by improving intestinal barrier function or remodeling cal instability. From this perspective, multiple reports the gut microbiota. Gegen Qinlian decoction (GQLD), have documented that many proteins from Chinese a CMM formula composed of Puerariae lobatae Radix, herbs can be organized as nano-carriers based on their Scutellariae Radix, Coptidis Rhizoma, and Glycyrrhizae [50] self-assembly aggregation, such as licorice protein , Radix et Rhizoma, was orally administered to rats, and [51] and Radix Pseudostellariae protein . 95 decoction-derived parent compounds and 24 metab- With the requirements of high-loading content, low olites were detected in the fecal samples using ultra-per- toxicity, and biodegradability for drug delivery systems, formance liquid chromatography (UPLC) coupled [55] supramolecular self-assembled compounds formed by with Fourier transform ion cyclotron resonance MS . non-covalent bonds (such as hydrogen bands and elec- Moreover, with the improvement of symptoms of type trostatic and hydrophobic interactions) have gained 2 diabetes (T2D) after 12-week treatment with GQLD, [52–53] popularity , owing to excellent stability, better phar- including the reduction of fasting blood glucose and macological activity, and no need for extra delivery glycated hemoglobin, the amounts of beneficial bacteria [52] carriers. For example, Li et al. achieved a self-assem- from T2D patients were enriched in a randomized, dou- [56] bled nanomedicine formed with berberine and baicalin ble-blinded, and placebo-controlled clinical trial . (isoquinoline alkaloid and flavonoid glycoside from Coptidis Rhizoma-Scutellariae Radix). The primary Gut microbiota-derived transformation of parent compounds anti-bacterial mechanism of the NPs, mainly assembled originated from CMM formulae decoction by their electrostatic and hydrophobic interactions, was that the peripheral hydrophilic glucuronic acid of ber- Due to pH fluctuations within the stomach (acidity), berine–baicalin NPs showed stronger affinity for bacte- small intestine (alkalinity), and large intestine (acidity), ria, inducing aggregation and adhesion behavior of NPs and exposure to drug-metabolizing enzymes mainly on Staphylococcus aureus. from gut microbiota, CMM formula decoction-derived Taken together, self-assembling supramolecules might parent compounds are bio-transformed into diverse [57] be an approach for understanding the mechanisms structural orientations . Gut microbiota enzymes are underlying pharmacological effects and will also pave the most important catalyzers involved in biochemical 243 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Figure 2. The interaction between CMM formulae and gut microbiota in intestines. BCAA: branched-chain amino acids; CMM: Chinese Materia Medica; TMAO: trimethylamine N-oxide. and metabolic processes outside the intrinsic metabolic extracts. However, the bioavailability of these phyto- [58] machinery of the host . They usually trigger hydrolytic, chemical classes is extremely low because of structural [59] deglycosylated, and reductive reactions primarily . As limitations, such as high hydrogen-bonding capacity, [54] listed in Table 1, we summarized the metabolic pathways high molecular flexibility, and poor lipophilicity . mediated by gut microbiota on different CMM com- Gut microbiota structurally modifies medicinal-based pounds and highlighted their pharmaceutical contribu- natural products (i.e., parent compounds undergoing tions after modification. hydrolysis, deglycosylation, deacetylation, etc), con- [74] Alkaloids, triterpene glycosides, flavonoids, anthra- sequently improving their bioavailability , reducing [61] quinones, steroidal, lignan, and tannins are highly toxicity, and enhancing efficacy . For example, albi- abundant phytochemical classes in most CMM florin, an anti-depressant compound isolated from Table 1 The metabolic pathways mediated by gut microbiota on representative CMM compounds Representative Classification compounds Reactions of metabolism Pharmaceutical contribution References [60] Alkaloids Berberine Reduction Improvement of absorption [61] Diester diterpenoid alkaloids Hydroxylation, deoxylation, demethylation, Reduction of toxicity demethylation, deoxylation, and ester hydrolysis [62] Glycosides 6‴-p-coumaroylspinosin Hydrolysis Enhancement of lipid solubility (flavonoid glycosides) [63] Anemoside B4 (triterpenoids) Oxygenation and deglycosylation Enhancement of anti-tumor activity against SMMC-7721, Hela, and MCF-7 cell [64] Albiflorin (terpenoids) Hydrolysis Improvement of absorption across the blood-brain barrier [65] Sennosides (anthraquinones) Hydrolysis Promotion of intestinal peristalsis [66–67] Tannis Ellagitannins Hydrolysis, fissuration, and dehydroxylation Improvement of absorption [68] Steroids Cinobufagin and cinobufotalin Deacetylation Inactivation [69] Polysaccharides Lycium barbarum Hydrolysis Promotion of SCFAs production polysaccharides [70] Chondroitin sulfate Hydrolysis Improvement of intestinal absorption [71] Conjugates Shikonin Inter-polymerization – [72] (-)-Epigallocatechin-3-gallate Conjugation Elimination of toxic reactive metabolic wastes [73] Prenylated flavonol glycosides Conjugation Improvement of the gastrointestinal (Xian-Ling-Gu-Bao capsule) environment CMM: Chinese Materia Medica. 244 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Paeoniae Radix Alba, is hydrolyzed into benzoic acid metabolites are synthesized or structurally modified from [81] by intestinal carboxylesterase, which crosses the BBB dietary components and primary bile acids . The most [64] and exerts anti-depressant activity . To determine the widely known and characterized gut microbiota-depen- metabolites and metabolic pathways of compounds dent metabolites include SCFAs, TMA, and secondary from CMM formulae in the intestine, in vitro co-in- bile acids (Table 2). cubation for target compounds and intestinal flora With a key role in governing the homeostasis of the [75] human body, the gut microbiota positively synthesizes is an alternative approach to the routine methods . Through the anaerobic incubation of Mogroside V beneficial metabolites when exposed to CMM formula [76] and human intestinal bacteria, Xu et al. identified decoction. 14 metabolites using HPLC-ion trap (IT)/time-of-flight SCFAs, important functional microbiota-emanated (TOF)-MS in the coculture, whose transformation metabolites, are primarily fermented from plant- [110] involved isomerization and deglycosylation. based carbohydrates and dietary fibers . SCFAs As macromolecular compounds, carbohydrates and not only have various bioactivities but also facilitate proteins are prevalent in CMM formulae. Polysaccharides host-gut microbiota axis communication by acting as and oligosaccharides, for example, are abundant in most carbon sources for the generation of endogenous host [83] CMM, but humans are unable to utilize them because metabolites . Derived from ruminant meat and dairy of the lack of digestible enzymes in the human genome. products, branched-chain fatty acids (BCFAs) with [77] structures different from those of SCFAs have also Intriguingly, they can be fermented into SCFAs by enzymes of the gut microbiota. SCFAs function as cru- gained attention recently because of their perceived cial physiological signaling molecules, and during patho- health benefits, such as anti-inflammatory and anti-car - [111] cinogenic activities . After oral administration for 8 physiological conditions such as obesity, inflammation, and hyperlipidemia, they act to inhibit inflammation and weeks, feruloylated oligosaccharides and ferulic acid [78] improve dysregulated glucose and lipid metabolism . slightly restored BCFAs concentrations (including isobutyric acid and isovaleric acid) to a level that sig- Growing evidence from studies has revealed profound [112] pharmacological effects (including immunomodulatory, nificantly inhibited diabetes in rats . In addition, as anti-tumor, and hypoglycemic effects) mediated by plant- an important endocrine organ, intestinal microbiota based carbohydrates. The emerging therapeutic effects can generate neurotransmitters and neuromodulators of plant-based carbohydrates can be partly attributed to (mainly by tryptophan metabolism), such as serotonin [78] (5-HT), dopamine, kynurenic acid, and indole deriv- SCFAs . [113–114] Stable polymers are synthesized within the intestine atives . Through metabolomic studies, Tiansi through conjugation reactions owing to the high reactiv- liquid was found to ameliorate depressive symptoms by increasing plasma kynurenic acid and 5-HT levels ity of metabolic intermediates from CMM compounds. For example, gut microbiota facilitates the emergence through the gut microbiota-dependent tryptophan-ky- [96] of reactive carbonyl species (RCS) conjugates of (-)-epi- nurenine metabolic pathway . Additionally, gut microbiota can negatively regulate gallocatechin-3-gallate (EGCG) and aminated EGCG by trapping RCS, which prevents the development of many detrimental metabolites after the oral administration [72] chronic diseases . of CMM. A prime example of deleterious metabolites of the gut microbiota is TMA. TMA is metabolized by the gut microbiota from western diets enriched in leci- CMM metabolites transformed by enterohepatic circulation thin, L-carnitine, and choline, which are absorbed and As the important part of enterohepatic circulation, the oxidized into trimethylamine N-oxide (TMAO) by fla- gut microbiota coordinates with the liver to participate vin-containing monooxygenase 3 in the liver. Recently, in the relay-reaction of CMM metabolism, which pro- reports have defined TMA and TMAO as possible [87] longs the residence time of CMM compounds in vivo biomarkers of cardiovascular disorders . After res- and is of particular significance in clinical application. veratrol treatment, serum TMA and TMAO levels For example, after absorption, baicalin is transformed were reduced in choline-challenged female C57BL/6J into glucuronidated metabolites, which are subsequently mice, and TMA production in cecal content collected -/- excreted into the gut through bile, where it is readily from 1% choline-fed ApoE mice was significantly hydrolyzed by β-glucuronidase from the gut microbi- decreased, suggesting resveratrol may suppress TMA [79] [88] ota into the free aglycone form , which begins the new generation . Furthermore, undigested proteins and journey from the gut to the blood. unabsorbed amino acids within the gastrointestinal tract can be primarily fermented into detrimental nitrogen-and sulfide-containing compounds by the Endogenous metabolites derived from gut microbiota [115] gut microbiota . As shown in Table 2, these gut regulated by CMM formulae microbiota-dependent nitrogen-and sulfide-containing The gut microbiota and CMM formulae are involved in metabolites (including branched-chain amino acids mutually beneficial interactions. Gut microbiota ferment [BCAAs], indoles, sulfurous compounds, and N,N,N- compounds from CMM formulae into structurally mod- trimethyl-5-aminovaleric acid) are associated with ified metabolites. In turn, the gut microbiota is regulated T2D, cardiovascular diseases, cancer, and nonalco- by CMM formulae, resulting in its rebalance and con- holic fatty liver diseases. The combination of Moutan sequently improving gut microbiota metabolic activity Cortex and Paeoniae Radix Rubra (PRR) reduced the [80] . Endogenous and endogenous metabolite production serum levels of BCAAs by modulating gut microbiota, 245 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Table 2 Endogenous metabolites from gut microbiota regulated by CMM Origin of endogenous Endogenous Analytical Potentially biological metabolites Food origin metabolites techniques functions or hazards Regulation by CMM Metabolites Carbohydrates SCFAs Gas chromatography- Enhancement of host A Chinese herbal formula composed of 8 herbs, transformed mass spectrometry health by suppressing namely, Anemarrhenae Rhizoma, Momordica [82] by gut (GC-MS) inflammatory responses, charantia, Coptidis Rhizoma, Salviae miltiorrhizae microbiota maintaining intestinal Radix et Rhizoma, Fermentum Rubrum, Aloe, from diets barrier function, and Schisandrae Chinensis Fructus, and Zingiberis modulating colonization Rhizoma, enriched the SCFAs-producing bacteria, resistance to enteric such as Blautia spp., in type 2 diabetic patients with [83] [84] pathogens hyperlipidemia Phospholipids TMAO Liquid Biomarker for cardiovascular Resveratrol attenuated serum TMA and TMAO levels in [87] [88] chromatography- disorders mice administered choline intragastrically tandem mass spectrometry [85] (LC-MS/MS) and facile fluorescence [86] detection [89] Proteins BCAAs LC-MS A possible biomarker for Berberine decreased BCAAs-producing bacteria and [92] cancer, obesity, insulin serum BCAAs in high-fat diet-fed mice resistance and type 2 [90–91] diabetes [93] [95] Serotonin GC-MS , LC-MS Neurotransmitters Tiansi Liquid increased plasma kynurenic acid and [94] and imagingMS 5-HT levels in rats with hydrocortisone-induced [96] depression [97] [98] Phenols/ GC-MS , LC-MS A risk factors for damaging Compatibility of Euphorbiae Semen and Glycyrrhizae indoles and nuclear epithelial barrier function Radix et Rhizoma enhanced the metabolic ability magnetic and inducing oxidative of gut microbiota on aromatic amino acids, which resonance stress in endothelial cells, might increase the levels of its metabolites, such as [102] spectroscopy the incidence of tumors and indole and p-cresol [99] [100–101] (NMR) chronic renal failure Sulfurous Gas-profiling A beneficial substance of Glycyrrhizae Radix et Rhizoma-Genkwa Flos [103] compounds technology reducing dysbiosis and combination induces fecal H S production in [104] and colorimetric helping mucus layer mice [104] method reconstitution in colitis, and a health hazard at high concentration in inflammatory bowel [105] disease [106] [106] TMAVA LC-MS and NMR Exacerbation for fatty liver – [107] Metabolites – Secondary GC-MS Contribution to the Berberine inhibited the conversion of cholic acid to [107] excreted Bile acids pathogenesis of obesity deoxycholic acid (secondary bile acids) from bile colon cancer, gallstones, and modified and inflammatory by gut diseases of the digestive [108–109] microbiota system BCAA: branched-chain amino acid; CMM: Chinese Materia Medica; SCFAs: short-chain fatty acids; TMAVA: N,N,N-trimethyl-5-aminovaleric acid. providing new pharmacological understanding and acid (glycochenodeoxycholic acid) and decreasing sec- [116] [117] strategies against obesity and T2D . ondary bile acid (deoxycholic acid) content . Finally, bile acids (primary bile acids), which favor the hypolipidemic effect by promoting the conjugation and CMM compounds absorbed in the blood excretion of lipids, are produced in the liver from cho- lesterol and metabolized into secondary bile acids (e.g., Despite the caveats highlighted above, massive data deoxycholic acid) by gut microbiota-mediated bile salt from studies show that some CMM formula decoc- hydrolysis and bile acid 7α-dehydroxylation. In a mul- tion-derived parental compounds are absorbed into the ticenter, randomized, double-blind, placebo-controlled circulation. Research on bioactive compounds detected clinical trial, berberine exerted a hypoglycemic effect within the blood can be traced back to the discovery by inhibiting deoxycholic acid transformation in newly of the antibiotic sulfonamide in the 1930s, the serum diagnosed T2D patients, thereby increasing primary bile metabolite metabolized from Prontosil (first sulfonamide 246 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com [118] antibiotic) . Until the late 1980s, Japanese scholar On the one hand, the hepatic enzymes could trans- Hiroko Iwama conducted relevant research and first form compounds from CMM formulae, while on the proposed the concept of serum pharmacology and serum other hand, electrophilic reactive species of compounds [119] [130] [131] pharmacochemistry . In the early 1990s, Chinese (such as nitidine chloride and geniposide ) could [132] scholar Professor Xijun Wang introduced serum phar- covalently integrate with hepatic enzymes or other [119] [133] macochemistry regarding CMM formulae . Here, macromolecules (protein and DNA), leading to inac- we divided CMM compounds that circulate within the tivation of hepatic enzymes and unexpected adverse blood into original compounds from the intestine, their reactions. The covalent binding of reactive species to metabolites, and other molecular forms for the conve- proteins or DNA circulating within the blood results in nience of understanding. the formation of covalent adducts, which are involved in [134] nucleophilic substitution and Schiff base mechanism . n [135] Using UPLC-MS , Yun et al. quantified 7-(deoxyade- Original compounds absorbed from the intestine nosine-N -yl) aristolactam I (dA-AL-I) and 7-(deoxygua- The original compounds detected in the blood primarily nosine-N -yl) aristolactam I (dG-AL-I)-DNA adducts in contained the CMM formula decoction-derived com- the mouse liver and kidney, and in patients with upper pounds, as well as their gut microbiota metabolites. urinary tractcarcinomas, which are associated with the [120] Liang et al. detected these compounds in rat plasma carcinogenesis and nephrotoxicity of aristolochic acid. using the HPLC-IT/TOF-MS technique after the oral administration of Chishao decoction. In this study, Other molecular forms formed by compounds from CMM 15 PRR parent chemical compounds and 90 metabo- and endogenous substances lites were identified. Moreover, 7R-paeonimetabolin I, 7S-paeonimetabolin I, and paeonimetabolin II are Clinically, Epimedii Folium is traditionally processed by [136] metabolites of paeoniflorin transformed by intestinal frying with suet oil. Jiang et al. found that suet oil [121–122] microflora . could interact with sodium deoxycholate, an inherent bile acid salt in vivo, to prepare self-assembled micelles, which serve as carriers for active compounds (icariin and CMM metabolites transformed by enzymes in the liver circinal-icaritin) from Epimedium brevicornu Maxim. In the process of screening active compounds from tra- This accounts for the increase in solubility and intestinal ditional Chinese herbs, some compounds only exhibited absorption, and enhancement of the anti-osteoporosis [136–137] excellent activity in vivo but not in vitro, or the active effect . Collectively, owing to the complex environ- compounds screened possessed low bioavailability due ment of blood, other special forms of CMM formulae-de- to the hepatic first-pass effect. The therapeutic effects of rived compounds in the blood, such as self-assembled most CMM formulations are mediated by their hepatic supramolecules and their metal complexes, might be metabolites. For example, demethyleneberberine, the responsible for the pharmacological activity. Hopefully, plasma metabolite of berberine, exhibits better hepato- studies on detecting and evaluating special molecules in [123] protection than berberine . Considering the abundance plasma will emerge in the future. of inherent enzymes in the liver, the hepatic metabolites of CMM compounds account for a substantial proportion CMM compounds detected in other interstitial fluids of the blood, including phase I and phase II metabolites. Consistent with Western medicine, phase I metabolites Besides transportation into the blood, compounds from from CMM formulae involve compounds produced via CMM formulae might be transported through other functionalization reactions, such as oxidation, reduction, body fluids to the brain, lymph, and other target tissues hydrolysis, and demethylation. Phase II metabolites refer or organs. Of importance, particularly in the BBB and to conjugation reaction products such as glucuronidation, lymph, we introduce CMM compounds transported [124] sulfation, methylation, and acetylation . Among the through the cerebrospinal fluid and lymph. metabolites produced in rat plasma after oral administra- tion of Gegen Qinlian pills, p-Hydroxyphenylpropionic CMM compounds migrating in cerebrospinal fluid acid, a hydrolytic product, was the phase I metabolite, and puerarin-O-glucuronide, daidzein-O-glucuronide, In the central nervous system, the BBB is composed of and chrysin-7-O-glucuronide, glucuronides conjugates, endothelial cells, pericytes, and astrocytes, which reg- [125] were phase II metabolites . Interestingly, some phase I ulate the influx of compounds from the blood to the [138] and II metabolites usually undergo enterohepatic circula- brain . Therefore, a great disparity is often observed tion, leading to their reabsorption into the blood as active between compounds circulating within the blood and [126] compounds. Evidence from Yang et al. projected that cerebrospinal fluid. In 2000, based on the question of berberrubine, a demethylation metabolite of berberine, how CMM formulae treat cerebrovascular diseases, might exert a glucose-lowering effect when it undergoes Professor Boli Zhang proposed a new concept in cerebro- glucuronidation in the liver, hydrolysis in the intestine, spinal fluid pharmacology. The study confirmed differ - [127–128] and is subsequently absorbed into the blood . Based ent pharmacological effects of serum-containing CMM [139] on serum metabolite activities, a serum pharmacology and cerebrospinal fluid-containing CMM in vitro . approach has been used to study CMM formulae. For This cerebrospinal fluid pharmacology approach effec- [129] example, Song et al. observed that serum containing tively employs the idea of collecting cerebrospinal fluid Qili Jiegu capsules promoted osteogenesis by activating containing CMM compounds from animals and subse- the Wnt/β-catenin pathway. quently utilizing CMM-enriched cerebrospinal fluid on 247 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com in vitro central nervous disorder assays. This approach using microfluidic organ chips to model influx/efflux helps investigate the efficacy and exact mechanisms of across the BBB and the brain parenchymal compartment. action mediated by CMM formulae for central nervous This model mimics the metabolic and physiological func- [140] disorders . tions of the neurovascular unit, thereby facilitating the The CMM compounds present in the cerebrospinal assessment of drug delivery systems aiming at the human fluid are usually decoction-derived parent compounds BBB. With emerging in vitro BBB models, it is possible and their secondary compounds metabolites derived to uncover the metabolic situation of CMM formulae in from the action of gut microbiota and liver drug enzymes. brain tissue in vitro. These compounds may be responsible for the neuropro- tection mediated by CMM formulae, such as benzoic CMM compounds migrating in lymph [141] acid (gut microbiota metabolites of paeoniflorin) and quercetin-3-O-glucuronide (hepatic metabolites of quer- Lymphatic transport plays a crucial role in the absorp- [142] tion and pharmacological action of poorly water-sol- cetin) . Using UPLC-quadrupole (Q)/TOF-MS com- bined with orthogonal partial least-squares discriminant uble and highly lipophilic compounds from CMM [143] formulae and their intestinal microbiota metabolites in analysis, Mi et al. identified 17 parent constituents and 14 metabolites from CMM formulae (Danzhi tablet) vivo. After being absorbed into enterocytes from orally administered CMM formulations, the vast majority of in rat cerebrospinal fluid. For screening, permeation, and metabolism studies compounds are directly transported into the systemic circulation via the portal vein. Highly lipophilic com- for neuroprotective agents in vitro, conventional static [144] BBB models, such as transwell co-cultured models pounds with log octanol/water partition coefficients >5 and high affinities for enterocyte lipoproteins access and multidrug-resistant Madin-Darby Canine kidney [145] (MDCK-MDR1) cell line , have been employed in systematic circulation through intestinal lymphatics. [146] This route of transport effectively bypasses hepatic first- studying CMM formulae. Yu et al. established a BBB model by co-culturing rat primary astrocytes seeded on pass metabolism (Figure 3), namely intestinal lymphatic [150–151] transport . the opposite side of the microporous membrane and rat primary cerebral microvascular endothelial cells incu- Given the permeation of small molecules from the systemic circulation to the peripheral lymph, decoction- bated on the positive side of the microporous membrane. Using the above BBB model and glucocorticoid-induced derived parent compounds, intestinal microbiota- dependent CMM formula metabolites, and low molec- BBB damage, they demonstrated that Xiaoyao powder has neuroprotective effects. In addition, several emerging ular weight hepatic metabolites will occur in the lymph. [147] Lymph duct cannula surgery is used to collect lymph in vitro BBB models, including microfluidic models , [152] [148] BBB-on-chip models, and in silico models , have been samples . For example, after intraduodenal admin- istration of quercetin and quercetin-3-glucoside, and developed to assist with the investigation of BBB per- [149] meability and metabolism. Maoz et al. constructed a thoracic lymph-cannulated surgery in rats, Nakamura [153] et al. revealed quercetin lymphatic metabolites and coupled organ-on-chip of the human neurovascular unit Figure 3. Lymphatic transport of compounds from CMM formula. CMM: Chinese Materia Medica. 248 Meng et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com References putative metabolic pathways for quercetin and its glu- coside using HPLC-MS/MS. However, because of the [1] Cheung F . TCM: Made in China. Nature 2011;480(7378):S82–S83. [2] Jiang M, Lu C, Zhang C, et al. Syndrome differentiation in mod- cumbersome nature of lymph-cannulated surgery, recent ern research of traditional Chinese medicine. 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Acupuncture & Herbal Medicine – Wolters Kluwer Health
Published: Dec 26, 2022