Chemical Characterization and Metabolic Profiling of the Compounds in the Chinese Herbal Formula Li Chang Decoction by UPLC-QTOF/MS

Lin, Baofu; Guo, Shaoju; Hong, Xinxin; Jiang, Xiaoyan; Li, Haiwen; Li, Jingwei; Guo, Linglong; Li, Mianli; Chen, Jianping; Huang, Bin; Xu, Yifei

doi:https://doi.org/10.1155/2022/1322751

Evidence-Based Complementary and Alternative Medicine

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Abstract Introduction Methods Results and Discussion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2022 | Article ID 1322751 | https://doi.org/10.1155/2022/1322751

Chemical Characterization and Metabolic Profiling of the Compounds in the Chinese Herbal Formula Li Chang Decoction by UPLC-QTOF/MS

Baofu Lin,¹Shaoju Guo,¹Xinxin Hong,¹Xiaoyan Jiang,¹Haiwen Li,¹Jingwei Li,¹Linglong Guo,¹Mianli Li,¹Jianping Chen,¹Bin Huang,¹and Yifei Xu¹

Academic Editor: Maria Grazia Ferraro

Received16 Feb 2022

Revised20 Mar 2022

Accepted30 Mar 2022

Published13 Apr 2022

Abstract

Background. Li Chang decoction (LCD), a Chinese medicine formula, is commonly used to treat ulcerative colitis (UC) in clinics. Purpose. This study aimed to identify the major components in LCD and its prototype and metabolic components in rat biological samples. Methods. The chemical constituents in LCD were identified by establishing a reliable ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF/MS) method. Afterwards, the rats were orally administered with LCD, and the biological samples (plasma, urine, and feces) were collected for further analyzing the effective compounds in the treatment of UC. Result. A total of 104 compounds were discriminated in LCD, including 26 flavonoids, 20 organic acids, 20 saponins, 8 amino acids, 5 oligosaccharides, 5 tannins, 3 lignans, 2 alkaloids, and 15 others (nucleosides, glycosides, esters, etc.). About 50 prototype and 94 metabolic components of LCD were identified in biological samples. In total, 29 prototype components and 22 metabolic types were detected in plasma. About 27 prototypes and 96 metabolites were discriminated in urine, and 34 prototypes and 18 metabolites were identified in feces. Conclusion. The flavonoids, organic acids, and saponins were the major compounds of LCD, and this study promotes the further pharmacokinetic and pharmacological evaluation of LCD.

1. Introduction

Traditional Chinese medicine (TCM) attracts more attention in the world since it possesses reliable therapeutic efficacy in some complex diseases, especially chronic illness [1]. The chemical composition of Chinese herbal compound is complex, and the composition of the multi-Chinese medicine is crossed, summarized as “multitarget and multicomponent,” which is the feature of TCM [2, 3]. This characteristic promotes the curative effect and reduces toxicity; however, it brings enormous challenge to figure out the effective components and mechanism for the therapeutic effect [4].

Li Chang decoction (LCD), a Chinese compound prepared from twelve Chinese medicine including Codonopsis Radix (CR), Notoginseng Radix et Rhizoma (NRR), Bletillae Rhizoma (BR), Sophorae Flos (SF), Glycyrrhizae Radix et Rhizoma (GRR), Cynanchi Paniculati Radix et Rhizoma (CPRR), Typhae Pollen (TP), Chebulae Fructus (CF), Atractylodis Macrocephalae Rhizoma (AMR), Ailanthi Cortex (AC), Coicis Semen (CS), and Halloysitum Rubrum (HR), has been commonly used to treat ulcerative colitis (UC) in clinics for over 20 years(Figure 1). UC is a chronic disease of inflammatory bowel diseases, which seriously impact the life quality of patients, and is sometimes life-threatening. LCD remarkably reduces the symptoms and recurrence rate of UC in clinical [5]. Although some of the major ingredients such as the polysaccharides from CR and AMR and rutin from SF have been proved effective in the treatment of UC, the effective components of LCD are still controversial and unclear [6–8]. Therefore, the systematic research on the effective component and metabolite profiling of LCD is an urgent need.

Ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF/MS) provides a rapid and reliable method to identify the component of natural medicine, which promotes the development of natural medicine component analysis and new drug discovery [9, 10]. Herein, we recruited an UPLC-QTOF/MS method to profile the effective components of LCD, and the unknown components were classified and assigned based on the fragmentation patterns and diagnostic ions of different structural types of components. According to the component characterization result of LCD in vitro, the prototypes in plasma, urine, and feces were further analyzed based on the similarity of mass spectrometry behavior (accurate molecular weight and secondary fragments) and chromatographic behavior (retention time). Metabolites were matched e mass defect filtering (MDF) caused by biotransformation and were further confirmed by MS/MS spectrum analysis.

2. Material and Methods

2.1. Chemicals and Drugs

LCD was prepared by the Pharmaceutical Department, Shenzhen Traditional Chinese Medicine Hospital. The Chinese medicine including Codonopsis Radix (Lot: 190505101, root of Codonopsis pilosula (Franch.) Nannf.), Atractylodis Macrocephalae Rhizoma (Lot: 1904001, rhizoma of Atractylodes macrocephala Koidz.), Chebulae Fructus (Lot: 181203361, fructus of Terminalia chebula Retz.), Halloysitum Rubrum (Lot: 190300991), Sophorae Flos (Lot: 190504381, flos of Sophora japonica L.), Typhae Pollen (Lot: 190401, pollen of Typha angustifolia L.), Ailanthi Cortex (Lot: 181001, cortex of Ailanthus altissima (Mill.) Swingle), Bletillae Rhizoma (Lot:HX19K01, rhizoma of Bletilla striata (Thunb.) Reichb. f), Coicis Semen (Lot: 1905002, semen of Coix lacryma-jobi L. var. ma-yuen (roman) Stapf), Notoginseng Radix et Rhizoma (Lot: 190401411, radix and rhizoma of Panax notoginseng (Burk.) F. H. Chen), Cynanchi Paniculati Radix et Rhizoma (Lot: 190403711, radix and rhizoma of Cynanchum paniculatum (Bge.) Kitag.), and Glycyrrhizae Radix et Rhizoma (Lot: 1905001, radix and rhizoma of Glycyrrhiza uralensis Fisch.) was purchased from Kangmei Pharmaceutical Co., Ltd (Puning, China). Trigonelline, chebulic acid, gallic acid, 6,7-dihydroxycoumarin, corilagin, typhaneoside, rutin, hyperoside, liquiritin, nicotiflorin, lobetyolin, ginsenoside Re, ginsenoside Rg1, quercetin, ginsenoside Rb1, naringenin, 20S-ginsenoside Rh1, isorhamnetin, ginsenoside Rd, and glycyrrhizic acid, a total of 20 reference standards, were purchased from Chengdu Alfa Biotechnology Co., Ltd. The purity of each compound was more than 98% determined by the HPLC analysis. Methanol was of HPLC grade. Ultrapure water was obtained by the filtration of distilled water using a Milli-Q system (Millipore, USA). LC-MS grade acetonitrile was purchased from Fisher Scientific (Fair Lawn, New Jersey, USA), and LC-MS grade formic acid was purchased from Sigma-Aldrich (St, Missouri, USA).

2.2. Animal

Male Sprague-Dawley rats (300 ± 20 g) were obtained from the Medical Experimental Animal Center of Guangzhou University of Chinese Medicine, China. Rats were housed in specified pathogen-free conditions (23 ± 2°C) under a 12-h light/12-h dark cycle and given free access to food and water. The protocols were approved by the Animal Experimental Ethics Committee of Guangzhou University of Chinese Medicine (Guangzhou, China).

2.3. LCD Preparation

The Medicine Codonopsis Radix, Atractylodis Macrocephalae Rhizoma, Chebulae Fructus, Halloysitum Rubrum, Sophorae Flos, Typhae Pollen, Ailanthi Cortex, Bletillae Rhizoma, Coicis Semen, Notoginseng Radix et Rhizoma, Cynanchi Paniculati Radix et Rhizoma, and Glycyrrhizae Radix et Rhizoma were weighed and mixed at a ratio of 6 : 3:3 : 6:3 : 3:6 : 3:6 : 2:6 : 2. The total weight of LCD is 245g, and the mixture was extracted twice by boiling in distilled water, and eight times distilled water (1960 ml) (w/v) was used to boil for 40 min in the first time, which changes to four times distilled water (980 ml) (w/v) in the second time. The two extracts were merged and centrifuged at 3,000 rpm, for 5 min to exclude dregs, and the supernatant was concentrated to 3.185 g/ml under reduced pressure at 55°C.

2.4. Rat Treatment and Sample Collection

The dose of LCD used in this experiment is 22.05 g/kg, which is the biological equivalent dose of humans. Three rats were fasted for 12 h with free access to drinking water, and then, the rats were orally administered with LCD. LCD was diluted to 2.205 g/ml with distilled water before giving to rat. Then, the blood samples were collected in the heparin anticoagulant tube through retro-orbital plexus at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 h. The plasma samples were obtained by centrifugation at 3000 rpm for 10 min. Samples of the same point were combined and stored at −80°C until use. Feces and urine samples were collected during 0–12 h.

2.5. Biological Sample Preparation

For the plasma sample, about 200 μl plasma was mixed with 600 μl acetonitrile (containing 0.2% methanoic acid). After vortexing for 2 min, the samples were centrifuged at 13000 rpm, 4°C, 10 min. Then, 400 μl supernatant was removed, dried under nitrogen gas, and redissolved in 100 μl acetonitrile (50%). Finally, the samples were centrifuged at 13000 rpm, 4°C, 10 min, and a 2 μl aliquot was injected into UPLC-QTOF-MS.

For the fecal sample, about 300 mg of feces was weighed and mixed with 1 ml methanol. After the addition of magnetic beads, the samples were homogenized using tissue grinders (Shanghai Jingxin, Shanghai, China) and centrifuged at 13000 rpm, 4°C, 10 min. About 200 μl supernatant was removed, dried under nitrogen gas, and redissolved in 200 μl acetonitrile (50%). Finally, the samples were centrifuged at 13000 rpm, 4°C, 10 min, and a 2 μl aliquot was injected into UPLC-QTOF-MS.

For the urine sample, the mixed urine was centrifuged at 4000 rpm for 10 min, and 1 ml supernatant was loaded on pre-activated Sep-Pak Vac C18 columns (3 cc, 500 mg, Waters, Ireland). After washing with 1 ml ultrapure water and eluting with 1 ml methanol, the elution was collected and centrifuged at 13000 rpm, 4°C, 10 min. About 400 μl supernatant was transferred and dried under nitrogen gas. The residues were redissolved in 400 μl acetonitrile (50%). Finally, the samples were centrifuged at 13000 rpm, 4°C, 10 min, and a 2 μl aliquot was injected into UPLC-QTOF-MS.

2.6. UPLC-QTOF-MS Analysis Condition

The separation equipment for this assay was Sciex Exion LC, and the chromatographic column was Waters Acquity HSS T3 (2.1 × 150 mm, 1.7 μm). The temperature was set at 35°C, and the flow rate was 0.3 ml/min. The mobile phases were 0.1% formic acid in water (A) and acetonitrile (B), with the optimized gradient as follows: 0–5 min from 3% B to 8% B, 5–11 min from 8% B to 30% B, 11–20 min from 30% B to 80% B, 20–21 min from 80% B to 95% B, 21–25 min was maintained at 95% B, and then back to the initial ratio and re-equilibration for 7 min.

The 5600 QTOF mass spectrometer (AB Sciex, Foster City, CA, USA) equipped with an ESI ion source was operated in positive and negative modes, and the mass range was m/z of 100–1250. The details of mass spectrometry conditions were summarized as follows: gas 1 and gas 2, 45 psi; curtain gas, 35 psi; heat block temperature, 500°C; ion spray voltage, −4.5 kV in negative mode and 5.5 kV in positive; declustering potential, 50V; collision energy, ±35 V; and the collision energy spread (CES), ±15 V. Sciex OS 1.6.1 was the basal data processing platform, and MetabolitePilot 2.0.4 software was applied for further metabolite fishing.

3. Results and Discussion

3.1. Characterization of Chemical Compounds in LCD

The base peak chromatograms of LCD in negative and positive ion modes are shown in Figure 2. A total of 104 chemical components, including 20 saponins, 26 flavonoids, 5 tannins, 20 organic acids, 8 amino acids, 2 alkaloids, 5 oligosaccharides, and 3 lignans, were identified or tentatively characterized by UPLC-QTOF-MS. As the result of chemical composition classification is summarized in Table 1, CR mainly contained alkaloid compounds and oligosaccharides, while NRR was characterized by saponins. Besides, the major constituents of SF were flavonoids. GRR contains saponins and flavonoids, and CPRR was as characterized by the C21 type steroidal saponins. The characteristic ingredients of TP were flavonoids and organic acids. CF was characterized by the component of tannins; AMR contains organic acids and esters.

Generally, the characteristic components of AC were triterpenes, and the CS was characterized by lipids. However, both chemical categories were difficult to extract by water so that only flavonoids and organic acids in AC and CS were still detected and identified. Figure 3 draws the part of representative structures of each medicine.

3.2. Fragmentation Mechanisms of Medicine Representative Structures

3.2.1. Codonopsis Radix-Derived Compounds

A total of 17 compounds were identified in CR. Among them, saccharides (P4 fructose, P6 sucrose, P7 raffinose, P8 stachyose, and P14 verbascose) and alkaloids (P5 trigonelline and P25 codonopsine) were characteristic components [11, 12]. Saccharides showed [M-H]^- in the negative ion mode and [M + NH₄]⁺/[M + Na]⁺in the positive ion mode. The successive neutral loss of hexose (−162 Da) and H₂O (−18 Da) was used for identification. The typical fragmentation pattern of P14 verbascose is drawn in Figure 4(a). Alkaloid P5 trigonelline produced a [M + H]⁺ ion at m/z of 138.0546 and had fragment ions at m/z of 94, 92, and 78, which correspond to [M - CO₂ + H]⁺, C₆H₆N⁺, and C₅H₄N⁺, respectively. P25 codonopsine showed [M + H]⁺ ion at m/z of 268.1546, and the fragment ions at m/z of 161, 88, and 58 were produced by penta-heterocycle cracking. The typical fragmentation pathways of P5 trigonelline are drawn in Figure 4(b).

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

3.2.2. Notoginseng Radix et Rhizoma-Derived Compounds

About 9 compounds were identified in Notoginseng Radix et Rhizoma, and all of the compounds were triterpenoid saponins (P55 notoginsenoside E, P58 ginsenoside Re, P59 ginsenoside Rg1, P72 ginsenoside Rb1, P74 notoginsenoside R2, P76 20s-ginsenoside Rh1, P77 ginsenoside Rh4/Rk3, P82 ginsenoside Rd, and P91 ginsenoside F2) [13–15].

The neutral loss of Glc (162 Da) and Rha (146 Da) was characteristically appeared in saponin compounds. P59 ginsenoside Rg1 is taken as example, and it had the [M + HCOO]^- ion at m/z of 845.4899 and [M + H]⁺ ion at m/z of 801.4983. The characteristic product ions at m/z of 621 [M-Glc-H₂O]⁺, 603 [M-Glc-2H₂O]⁺, 441 [M-2Glc-2H₂O]⁺, 423 [M-2Glc-3H₂O]⁺, and 405 [M-2Glc-4H₂O]⁺ were observed. The typical fragmentation pathways of P59 ginsenoside Rg1 are drawn in Figure 4(c).

3.2.3. Bletillae Rhizoma-Derived Compounds

A total of 5 characteristic compounds were detected in Bletillae Rhizoma. P47 dactylorhin A [16], P56 gymnoside III, and P61 militarine [17] were structurally similar to that contained two molecules of gastrodin (P22). Neutral loss of Glc (162 Da), H₂O (18 Da), and gastrodin (268 Da) was used for identification. P47 dactylorhin A showed the [M - H]^- ion at m/z of 887.3181 and [M + NH₄]⁺ ion at m/z of 906.3601, while it had characteristic fragment ion at [M-Glc-H₂O–H]^- at m/z of 707, [M-gastrodin-H]^- at m/z of 619, [M-gastrodin-Glc- H₂O–H]^- at m/z of 439, [M-gastrodin-Glc + H]⁺ at m/z of 459, [gastrodin]⁺ at m/z of 269, and [gastrodin-Glc]⁺ at m/z of 107. The typical fragmentation pathways of P47 dactylorhin A are drawn in Figure 4(d).

3.2.4. Sophorae Flos-Derived Compounds

Thirteen compounds were isolated from Sophorae Flos [18–20], and more than half of them were flavonoids, or specifically flavonols (P37 quercetin 3-O-glucosyl-rutinoside [21], P39 manghaslin [22], P43 rutin [23–25], P45 isoquercitrin [26], P48 nicotiflorin [27], P50 narcissin [24, 28], P70 quercetin [23, 29, 30], and P79 isorhamnetin [22]). In negative mode, flavonoid glycosides were trend to neutral loss of glycosides. In addition, neutral losses of CH3 (15 Da), CO (28 Da), and RDA cracking could also be observed. P43 rutin was a vital constituent of Sophorae Flos. It had the [M + H]⁺ ion at m/z of 611.1607 and gave characteristic fragment ions at m/z of 465 and 303 by successive loss of Glc (162 Da) and Rha (146 Da). The typical fragmentation pathways of P43 rutin are drawn in Figure 4(e).

3.2.5. Glycyrrhizae Radix et Rhizoma-Derived Compounds

A total of 23 compounds were discriminated in Glycyrrhizae Radix et Rhizoma, and 14 of them were flavonoids (P44 licuraside/liquiritin apioside, P46 liquiritin, P54 naringenin-7-O-glucoside, P60 violanthin, P67 pallidiflorin, P69 isoliquiritigenin [31–33], P63 licorice glycoside B/D1, P64 licorice glycoside C2, P66 licorice glycoside E, P75 naringenin [34], P53 choerospodin [35], P62 ononin/ononin isomer [36], P90 glyasperin C [37],and P93 sophoraisoflavone A/semilicoisoflavone B [38]). Different from sophorae, the flavonoids in glycyrrhiza were more abundant, including chalcone, flavones, and flavanones. However, the primary cracking patterns such as neutral loss of glycosides were similar. In addition to flavonoids, triterpenoid saponins were characteristic components as well. Representative compound licorice saponin A3 (P73, [M - H]^- at m/z of 983.4455, [M + H]⁺ at m/z of 985.4644) observed fragments ions at [M-GlcA + H]⁺ at m/z of 809, [M-Glc-GlcA + H]⁺ at m/z of 647, [M-2GlcA-H₂O + H]⁺ at m/z of 615, [M-Glc-2GlcA + H]⁺ at m/z of 471, and [M-Glc-2GlcA-H₂O + H]⁺ at m/z of 453. The fragmentation pathways were similar to P59 drawn in Figure 4(c).

3.2.6. Cynanchi Paniculati Radix et Rhizoma-Derived Compounds

Only one special saponin (steroidal glycoside), namely paniculatumoside A or B (P89) [39], was identified in Cynanchi Paniculati Radix et Rhizoma. The cracking mainly occurred at A (m/z of 331) and A’ rings (m/z of 145, 113). The typical fragmentation pathways of P89 are drawn in Figure 4(f).

3.2.7. Typhae Pollen-Derived Compounds

In this experiment, the characteristic components detected in Typhae Pollen were flavonoids (P42 typhaneoside [40], P43 rutin [23–25], P49 isorhamnetin-3-O-rutinoside-7-O-rhamnoside [24], P50 narcissin [24, 28], and P52 isorhamnetin-3-O-beta-galactoside [40]) and carboxylic acids (P9 L-malic acid [23, 40], P10 citric acid [40], P18 succinic acid [40], P27 3,4-dihydroxybenzoic acid, P51 vanillic acid [23], and P68 decanedioic acid [41]).

Typhaneoside (P42), [M-H]^- at m/z of 769.2194, [M +H ]⁺ at m/z of 771.2327) was a flavonol, and fragment ions were observed after successive loss of Rha (146 Da) and Glc (162 Da). The fragmentation pathways were similar to P43 drawn in Figure 4(e). Simple carboxylic acids were generally responded in the negative mode, and neutral loss of·CH3 (15 Da), H2O (-18 Da), and CO₂ (-44 Da) was the most usual fragments.

3.2.8. Chebulae Fructus-Derived Compounds

In Chebulae Fructus, gallic acid structure was found in carboxylic acids (P13 chebulic acid [42], P23 gallic acid [23, 43], P26 5-galloylshikimic acid [44], P33 brevifolincarboxylic acid [45], and P40 3,4,8,9,10-pentahydroxydibenzo[b,d]pyran-6-one [44]), while ellagic acid (gallic acid dimer) structure was tannins (P28 hamamelitannin [46], P29 1,6-di-O-galloyl-β-D-glucose [47], P34 chebulanin(1-O-galloyl-2,4-O-chebuloyl-b-D-Glc [44]), P36 corilagin [48], and P41 chebulagic acid [46]). Thus, ellagic acid fragment (m/z of 300) and neutral loss of gallic acid (170 Da) could be generally observed. The typical fragmentation pathways of P36 corilagin are drawn in Figure 4(g).

3.2.9. Atractylodis Macrocephalae Rhizoma-Derived Compounds

The characteristic compound in Atractylodis Macrocephalae Rhizoma was lactone (P92 atractylenolide III [11, 49]). Lactone was generally responded in the positive mode. Atractylenolide III (P92, [M + H]⁺ at m/z of 249.1487) showed fragment ions at [M-H₂O + H]⁺ at m/z of 231, [M-H₂CO₂+H]⁺ at m/z of 185, [M-C₃H₄O + H]⁺ at m/z of 175, C₁₀H₁₀O₂⁺ at m/z of 163, and C₆H₇⁺ at m/z of 79. The typical fragmentation pathways of P92 atractylenolide III are drawn in Figure 4(h).

3.2.10. Coicis Semen-Derived Compounds

A total of 15 compounds could be attributed to coicis semen, including 10 carboxylic acid (P9 L-malic acid [23, 40], P23 gallic acid [23, 43], P51 vanillic acid [23], P95 pseudolaroside B, P96 quinic acid [23], P97 protocatechuic acid [50], P98 caffeic acid [50], P99 nonanedioic acid [51], P100 1-caffeoylquinic acid [52], and P101 3-O-feruloylquinic acid [52]), 3 flavonoids (P43 rutin [23–25], P70 quercetin [23, 29, 30],and P103 kaempferol [29, 50]), 1 phenylpropanoid (P19 p-coumaric acid [11, 53]), and 1 nucleoside (P102 adenosine [53]).

3.2.11. Ailanthi Cortex-Derived Compounds

In Ailanthi Cortex, 4 compounds were attributed: briefly, 2 flavonoids (P70 quercetin [23, 29, 30] and P103 kaempferol [29, 50]), 1 carboxylic acid (P99 nonanedioic acid [51]), and 1 terpene (P104 20-R-hydroxydammara-24-en-3-one). However, only P104 was characteristic, and it had the [M + H]⁺ ion at m/z of 443.3881 and gave fragment ions at m/z of 425 by neutral loss of H₂O (18 Da). The crack of C ring formed ions at m/z of 221 and 207. The typical fragmentation pathways of P104 are drawn in Figure 4(i).

3.3. Characterization of LCD-Related Xenobiotics in Rat Biological Samples

According to the compound characterization of LCD, the fragmentation patterns of mass spectrometry (accurate molecular weight and secondary debris) and retention time of chromatography were adopted to analyze the components in plasma, urine, and feces. P59 ginsenoside Rg1 is taken as example, as shown in the XIC of LCD (Figure 5(a)) and multiple XICs of 6 bio-samples (Figure 5(b)), and a peak at 13.4 min was clearly observed in administration of bio-samples but not in the blanks. Importantly, the MS/MS spectra (m/z of 621, 441, 423, 405, and 203) of ginsenoside Rg1 in LCD (Figure 5(c)) and bio-samples (Figure 5(d)) were similar.

(a)

(b)

(c)

(d)

Figure 5

Identification of prototypes in bio-samples, and P59 ginsenoside Rg1 is taken as an example. (a) XIC of ginsenoside Rg1 in LCD; (b) multiple XICs of ginsenoside Rg1 in bio-samples. From top to bottom: administration plasma, blank plasma, administration urine, blank urine, administration feces, and blank feces. Ginsenoside Rg1 showed the highest intensity in feces, lowest in plasma, and no response in blank samples; (c) MS/MS spectrum of ginsenoside Rg1 in LCD; (d) MS/MS spectrum of ginsenoside Rg1 in feces.

Based on the above principles, a total of 50 components were matched in biological samples, and these components would play a key role in explaining the mechanism of LCD in the future. In particular, flavonoids (P43, P46, and P50) and saponins (P55 and P72) deserved higher attention as the five components were observed in all three bio-samples besides that were common to organisms (P1, P11, P15, P24, P31, and P68). In addition, 12 compounds were just observed in the fecal sample, mainly including some alkaloids (P25 and P65), flavonoids (P37, P42, P45, P52, and P70), saponin (P74), and other small molecules (P6, P9, P35, and P40). These compounds may not be absorbed into the blood, but are still effective in regulating gut microbiota. The detailed information about the distribution of components in plasma, urine, and feces is summarized in Table 2.

Furtherly, the phase I and phase II metabolic regularity, as well as the similarity of secondary mass spectrum profile, was used to identify the metabolite. Those metabolites were annotated through automatic matching with prototype components by MetabolitePilot Software. Briefly, MetabolitePilot operated prototype-metabolite matching through mass defect filter (MDF), characteristic product ion filter (PIF), and neutral loss filter (NLF). As shown in Figure 6, the mass defect from P50 to M70/71 was -148 Da with the biotransformation named “loss of C₆H₁₀O₄ and O (hydrolysis, phase I) + ketone formation (phase I).” Furthermore, neutral loss of glycosides and methylene was both observed in the MS/MS spectra of P50 and M70/71, which implied the similar skeleton. That was to say, these compounds were structurally related, and M70/71 could be the metabolites of P50. As a result, a total of 107 metabolites were matched with 25 prototypes in plasma, urine, or feces. The network of prototype-metabolite matching is drawn as in Figure 7. The details involving the distribution and biotransformations of metabolites are listed in Table 3. It was worth noting that although some prototypes have not been observed in bio-samples, they still are effective through metabolites. For example, P28 hamamelitannin produced 14 metabolites that were all detected in urine, and 5 were found in plasma and 2 in feces. It could be metabolized in the gut, and metabolites were furtherly absorbed into the bloodstream. In total, 29 prototype components and 22 metabolites were detected in plasma. About 27 prototypes and 96 metabolites were detected in urine, and 34 prototypes and 18 metabolites were detected in feces. These substances were considered to constitute the pharmacodynamic substance basis of LCD.

P2 arginine [54–56], P5 trigonelline [57], P59 ginsenoside Rg1 [58], P69 isoliquiritigenin [59], P82 ginsenoside Rd [60, 61], and P84 glycyrrhizic acid [62–64] would alleviate the symptom of UC based on anti-inflammation or antioxidant activities. Besides, P15 isoleucine [65], P17 uridine [12, 66], P21 guanosine [67], P23 gallic acid [68, 69], P43 rutin [70, 71], P51 vanillic acid [72], P70 quercetin [73, 74], P72 ginsenoside Rb1 [75], and P81 betulin [76]were confirmed to treat UC through NF-κB pathway. P8 stachyose increased beneficial microbiota and bacterial diversity to alleviate colitis mice [77]. P45 hyperoside ameliorates ulcer colitis mice through MKRN1-mediated regulation of PPARγ signaling and Th17/Treg balance [78]. The effect of those metabolisms on UC was worth to study for new drug development.

Data Availability

The data used to support the findings of this study are included within the article.

Conflicts of Interest

None.

Authors’ Contributions

Baofu Lin, Shaoju Guo, and Xinxin Hong performed the experiments and wrote the manuscript. Xiaoyan Jiang, Haiwen Li, and Jingwei Li summarized and analyzed the data. Linglong Guo and Mianli Li assisted with the assay and checked the statistics. JianPing Chen, Bin Huang, and Yifei Xu designed the study and finally revised the manuscript.

Acknowledgments

This research was supported by National Science Foundation of China (82104482); Project of Administration of Traditional Chinese Medicine of Guangdong Province of China (20213015); and Shenzhen Science and Technology Plan Project (JCYJ20180302173834208).

References

F. Cheung, “TCM: made in China,” Nature, vol. 480, no. 7378, pp. S82–S83, 2011.
View at: Publisher Site | Google Scholar
Z. Liu, F. Guo, Y. Wang et al., “BATMAN-TCM: a bioinformatics analysis tool for molecular mechANism of traditional Chinese medicine,” Scientific Reports, vol. 6, no. 1, Article ID 21146, 2016.
View at: Publisher Site | Google Scholar
Y. Han, H. Sun, A. Zhang, G. Yan, and X.-J. Wang, “Chinmedomics, a new strategy for evaluating the therapeutic efficacy of herbal medicines,” Pharmacology & Therapeutics, vol. 216, Article ID 107680, 2020.
View at: Publisher Site | Google Scholar
G.-Z. Xin, L.-W. Qi, Z.-Q. Shi et al., “Strategies for integral metabolism profile of multiple compounds in herbal medicines: pharmacokinetics, metabolites characterization and metabolic interactions,” Current Drug Metabolism, vol. 12, no. 9, pp. 809–817, 2011.
View at: Publisher Site | Google Scholar
J. D. Feuerstein, A. C. Moss, and F. A. Farraye, “Ulcerative colitis,” Mayo Clinic Proceedings, vol. 94, no. 7, pp. 1357–1373, 2019.
View at: Publisher Site | Google Scholar
Y. Jing, A. Li, Z. Liu et al., “Absorption of Codonopsis pilosula saponins by coexisting polysaccharides alleviates gut microbial dysbiosis with dextran sulfate sodium-induced colitis in model mice,” BioMed Research International, vol. 2018, Article ID 1781036, 2018.
View at: Publisher Site | Google Scholar
W. Feng, J. Liu, Y. Tan, H. Ao, J. Wang, and C. Peng, “Polysaccharides from Atractylodes macrocephala Koidz. Ameliorate ulcerative colitis via extensive modification of gut microbiota and host metabolism,” Food research international (Ottawa, Ont.), vol. 138, no. Pt B, Article ID 109777, 2020.
View at: Publisher Site | Google Scholar
S. Habtemariam and A. Belai, “Natural therapies of the inflammatory bowel disease: the case of rutin and its aglycone, quercetin,” Mini Reviews in Medicinal Chemistry, vol. 18, no. 3, pp. 234–243, 2018.
View at: Publisher Site | Google Scholar
Y. Chen, R. Yu, L. Jiang et al., “A comprehensive and rapid quality evaluation method of traditional Chinese medicine decoction by integrating UPLC-QTOF-MS and UFLC-QQQ-MS and its application,” Molecules, vol. 24, no. 2, 2019.
View at: Publisher Site | Google Scholar
F. Wang, S. Huang, Q. Chen et al., “Chemical characterisation and quantification of the major constituents in the Chinese herbal formula Jian‐Pi‐Yi‐Shen pill by UPLC‐Q‐TOF‐MS/MS and HPLC‐QQQ‐MS/MS,” Phytochemical Analysis, vol. 31, no. 6, pp. 915–929, 2020.
View at: Publisher Site | Google Scholar
M.-H. Liu, X. Tong, J.-X. Wang, W. Zou, H. Cao, and W.-W. Su, “Rapid separation and identification of multiple constituents in traditional Chinese medicine formula Shenqi Fuzheng Injection by ultra-fast liquid chromatography combined with quadrupole-time-of-flight mass spectrometry,” Journal of Pharmaceutical and Biomedical Analysis, vol. 74, pp. 141–155, 2013.
View at: Publisher Site | Google Scholar
W.-W. Tao, J.-A. Duan, N.-Y. Yang et al., “Determination of nucleosides and nucleobases in the pollen of Typha angustifolia by UPLC-PDA-MS,” Phytochemical Analysis, vol. 23, no. 4, pp. 373–378, 2012.
View at: Publisher Site | Google Scholar
J. Li, R.-F. Wang, Y. Zhou et al., “Dammarane-type triterpene oligoglycosides from the leaves and stems of Panax notoginseng and their antiinflammatory activities,” Journal of Ginseng Research, vol. 43, no. 3, pp. 377–384, 2019.
View at: Publisher Site | Google Scholar
Q. Xie, H. Yuan, Y. Liu et al., “Simultaneous determination of 19 bioactive constituents in QishenYiqi dropping pills by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry,” Journal of AOAC International, vol. 102, no. 4, pp. 1102–1111, 2019.
View at: Publisher Site | Google Scholar
C.-Z. Gu, J.-J. Lv, X.-X. Zhang et al., “Triterpenoids with promoting effects on the differentiation of PC12 cells from the steamed roots of Panax notoginseng,” Journal of Natural Products, vol. 78, no. 8, pp. 1829–1840, 2015.
View at: Publisher Site | Google Scholar
D. Xu, Y. Pan, and J. Chen, “Chemical constituents, pharmacologic properties, and clinical applications of Bletilla striata,” Frontiers in Pharmacology, vol. 10, p. 1168, 2019.
View at: Publisher Site | Google Scholar
Y. Zhao, J.-J. Niu, X.-C. Cheng et al., “Chemical constituents from Bletilla striata and their NO production suppression in RAW 264.7 macrophage cells,” Journal of Asian Natural Products Research, vol. 20, no. 4, pp. 385–390, 2018.
View at: Publisher Site | Google Scholar
Y.-H. Lo, R.-D. Lin, Y.-P. Lin, Y.-L. Liu, and M.-H. Lee, “Active constituents from Sophora japonica exhibiting cellular tyrosinase inhibition in human epidermal melanocytes,” Journal of Ethnopharmacology, vol. 124, no. 3, pp. 625–629, 2009.
View at: Publisher Site | Google Scholar
Y. Zhang, L. Qu, L. Liu et al., “New maltol glycosides from flos sophorae,” Journal of Natural Medicines, vol. 69, no. 2, pp. 249–254, 2015.
View at: Publisher Site | Google Scholar
W. Zhang, H. Jiang, J. Yang et al., “Safety assessment and antioxidant evaluation of betulin by LC-MS combined with free radical assays,” Analytical Biochemistry, vol. 587, Article ID 113460, 2019.
View at: Publisher Site | Google Scholar
R. Liu, Z. Cai, and B. Xu, “Characterization and quantification of flavonoids and saponins in adzuki bean (Vigna angularis L.) by HPLC-DAD-ESI-MSn analysis,” Chemistry Central Journal, vol. 11, no. 1, p. 93, 2017.
View at: Publisher Site | Google Scholar
G. C. Kite, C. A. Stoneham, and N. C. Veitch, “Flavonol tetraglycosides and other constituents from leaves of Styphnolobium japonicum (Leguminosae) and related taxa,” Phytochemistry, vol. 68, no. 10, pp. 1407–1416, 2007.
View at: Publisher Site | Google Scholar
L. Wang, C. Chen, A. Su, Y. Zhang, J. Yuan, and X. Ju, “Structural characterization of phenolic compounds and antioxidant activity of the phenolic-rich fraction from defatted adlay (Coix lachryma-jobi L . var. ma-yuen Stapf) seed meal,” Food Chemistry, vol. 196, pp. 509–517, 2016.
View at: Publisher Site | Google Scholar
Y. Chen, H. Yu, H. Wu et al., “Characterization and quantification by LC-MS/MS of the chemical components of the heating products of the flavonoids extract in pollen Typhae for transformation rule exploration,” Molecules, vol. 20, no. 10, pp. 18352–18366, 2015.
View at: Publisher Site | Google Scholar
M. Xu, Z. Jin, J.-B. Ohm, P. Schwarz, J. Rao, and B. Chen, “Effect of germination time on antioxidative activity and composition of yellow pea soluble free and polar soluble bound phenolic compounds,” Food & Function, vol. 10, no. 10, pp. 6840–6850, 2019.
View at: Publisher Site | Google Scholar
X. Jin, Y. Lu, S. Chen, and D. Chen, “UPLC-MS identification and anticomplement activity of the metabolites of Sophora tonkinensis flavonoids treated with human intestinal bacteria,” Journal of Pharmaceutical and Biomedical Analysis, vol. 184, Article ID 113176, 2020.
View at: Publisher Site | Google Scholar
H. Cedeño, S. Espinosa, J. M. Andrade, L. Cartuche, and O. Malagón, “Novel flavonoid glycosides of quercetin from leaves and flowers of gaiadendron punctatum G.don. (violeta de Campo), used by the saraguro community in southern Ecuador, inhibit α-glucosidase enzyme,” Molecules, vol. 24, no. 23, 2019.
View at: Publisher Site | Google Scholar
W.-Y. Yang, T. H. Won, C.-H. Ahn et al., “Streptococcus mutans sortase A inhibitory metabolites from the flowers of Sophora japonica,” Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 7, pp. 1394–1397, 2015.
View at: Publisher Site | Google Scholar
J. Ryu, J. S. Kim, and S. S. Kang, “Cerebrosides from longan arillus,” Archives of Pharmacal Research, vol. 26, no. 2, pp. 138–142, 2003.
View at: Publisher Site | Google Scholar
G. Wang, Q. Cui, L.-J. Yin et al., “Efficient extraction of flavonoids from Flos Sophorae Immaturus by tailored and sustainable deep eutectic solvent as green extraction media,” Journal of Pharmaceutical and Biomedical Analysis, vol. 170, pp. 285–294, 2019.
View at: Publisher Site | Google Scholar
Q. Yin, P. Wang, A. Zhang, H. Sun, X. Wu, and X. Wang, “Ultra-performance LC-ESI/quadrupole-TOF MS for rapid analysis of chemical constituents of Shaoyao-Gancao decoction,” Journal of Separation Science, vol. 36, no. 7, pp. 1238–1246, 2013.
View at: Publisher Site | Google Scholar
C. Schmid, C. Dawid, V. Peters, and T. Hofmann, “Saponins from European licorice roots (Glycyrrhiza glabra),” Journal of Natural Products, vol. 81, no. 8, pp. 1734–1744, 2018.
View at: Publisher Site | Google Scholar
M. A. Farag, A. Porzel, and L. A. Wessjohann, “Comparative metabolite profiling and fingerprinting of medicinal licorice roots using a multiplex approach of GC-MS, LC-MS and 1D NMR techniques,” Phytochemistry, vol. 76, pp. 60–72, 2012.
View at: Publisher Site | Google Scholar
T. Xu, M. Yang, Y. Li et al., “An integrated exact mass spectrometric strategy for comprehensive and rapid characterization of phenolic compounds in licorice,” Rapid Communications in Mass Spectrometry, vol. 27, no. 21, pp. 2297–2309, 2013.
View at: Publisher Site | Google Scholar
L. Shan, N. Yang, Y. Zhao, X. Sheng, S. Yang, and Y. Li, “A rapid classification and identification method applied to the analysis of glycosides in Bupleuri radix and liquorice by ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry,” Journal of Separation Science, vol. 41, no. 19, pp. 3791–3805, 2018.
View at: Publisher Site | Google Scholar
W. Song, X. Qiao, K. Chen et al., “Biosynthesis-based quantitative analysis of 151 secondary metabolites of licorice to differentiate medicinal Glycyrrhiza species and their hybrids,” Analytical Chemistry, vol. 89, no. 5, pp. 3146–3153, 2017.
View at: Publisher Site | Google Scholar
Z. Li, T. Liu, J. Liao, N. Ai, X. Fan, and Y. Cheng, “Deciphering chemical interactions between Glycyrrhizae Radix and Coptidis Rhizoma by liquid chromatography with transformed multiple reaction monitoring mass spectrometry,” Journal of Separation Science, vol. 40, no. 6, pp. 1254–1265, 2017.
View at: Publisher Site | Google Scholar
S. Fang, Q. Qu, Y. Zheng et al., “Structural characterization and identification of flavonoid aglycones in threeGlycyrrhizaspecies by liquid chromatography with photodiode array detection and quadrupole time-of-flight mass spectrometry,” Journal of Separation Science, vol. 39, no. 11, pp. 2068–2078, 2016.
View at: Publisher Site | Google Scholar
S.-L. Li, H. Tan, Y.-M. Shen, K. Kawazoe, and X.-J. Hao, “A pair of new C-21 steroidal glycoside epimers from the roots of Cynanchum paniculatum,” Journal of Natural Products, vol. 67, no. 1, pp. 82–84, 2004.
View at: Publisher Site | Google Scholar
X. Wang, X. Chen, J. Li et al., “Thrombin-based discovery strategy of bioactive-chemical quality marker combination for pollen of Typha orientalis by metabolomics coupled with chemometrics,” Phytomedicine, vol. 75, Article ID 153246, 2020.
View at: Publisher Site | Google Scholar
M. Ding, Y. Jiang, X. Yu et al., “Screening of combinatorial quality markers for natural products by metabolomics coupled with chemometrics. A case study on pollen Typhae,” Frontiers in Pharmacology, vol. 9, p. 691, 2018.
View at: Publisher Site | Google Scholar
D. Y. Lee, H. Yang, H. W. Kim, and S. H. Sung, “New polyhydroxytriterpenoid derivatives from fruits of Terminalia chebula Retz. and their α-glucosidase and α-amylase inhibitory activity,” Bioorganic & Medicinal Chemistry Letters, vol. 27, no. 1, pp. 34–39, 2017.
View at: Publisher Site | Google Scholar
S. Sarabhai, P. Sharma, and N. Capalash, “Ellagic acid derivatives from Terminalia chebula Retz. downregulate the expression of quorum sensing genes to attenuate Pseudomonas aeruginosa PAO1 virulence,” Plos One, vol. 8, no. 1, Article ID e53441, 2013.
View at: Publisher Site | Google Scholar
B. Pfundstein, S. K. El Desouky, W. E. Hull, R. Haubner, G. Erben, and R. W. Owen, “Polyphenolic compounds in the fruits of Egyptian medicinal plants (Terminalia bellerica, Terminalia chebula and Terminalia horrida): characterization, quantitation and determination of antioxidant capacities,” Phytochemistry, vol. 71, no. 10, pp. 1132–1148, 2010.
View at: Publisher Site | Google Scholar
N. M. Fahmy, E. Al-Sayed, M. M. Abdel-Daim, M. Karonen, and A. N. Singab, “Protective effect ofTerminalia muelleriagainst carbon tetrachloride-induced hepato and nephro-toxicity in mice and characterization of its bioactive constituents,” Pharmaceutical Biology, vol. 54, no. 2, pp. 303–313, 2016.
View at: Publisher Site | Google Scholar
K. Li, X. Han, R. Li et al., “Composition, antivirulence activity, and active property distribution of the fruit ofTerminalia chebulaRetz,” Journal of Food Science, vol. 84, no. 7, pp. 1721–1729, 2019.
View at: Publisher Site | Google Scholar
F. Pellati, R. Bruni, D. Righi et al., “Metabolite profiling of polyphenols in a Terminalia chebula Retzius ayurvedic decoction and evaluation of its chemopreventive activity,” Journal of Ethnopharmacology, vol. 147, no. 2, pp. 277–285, 2013.
View at: Publisher Site | Google Scholar
D. Y. Lee, H. W. Kim, H. Yang, and S. H. Sung, “Hydrolyzable tannins from the fruits of Terminalia chebula Retz and their α-glucosidase inhibitory activities,” Phytochemistry, vol. 137, pp. 109–116, 2017.
View at: Publisher Site | Google Scholar
X. Sun, X.-B. Cui, H.-M. Wen et al., “Influence of sulfur fumigation on the chemical profiles of Atractylodes macrocephala Koidz. evaluated by UFLC-QTOF-MS combined with multivariate statistical analysis,” Journal of Pharmaceutical and Biomedical Analysis, vol. 141, pp. 19–31, 2017.
View at: Publisher Site | Google Scholar
L. Lin, Q. Yang, K. Zhao, and M. Zhao, “Identification of the free phenolic profile of Adlay bran by UPLC-TOF-MS/MS and inhibitory mechanisms of phenolic acids against xanthine oxidase,” Food Chemistry, vol. 253, pp. 108–118, 2018.
View at: Publisher Site | Google Scholar
A. Zhang, D. Zou, G. Yan, Y. Tan, H. Sun, and X. Wang, “Identification and characterization of the chemical constituents of Simiao Wan by ultra high performance liquid chromatography with mass spectrometry coupled to an automated multiple data processing method,” Journal of Separation Science, vol. 37, no. 14, pp. 1742–1747, 2014.
View at: Publisher Site | Google Scholar
J.-J. Lu, X.-W. Hu, P. Li, and J. Chen, “Global identification of chemical constituents and rat metabolites of Si-Miao-Wan by liquid chromatography-electrospray ionization/quadrupole time-of-flight mass spectrometry,” Chinese Journal of Natural Medicines, vol. 15, no. 7, pp. 550–560, 2017.
View at: Publisher Site | Google Scholar
S. Y. Kim, C. W. Choi, S. S. Hong, H. Shin, and J. S. Oh, “A New Neolignan from Coix lachryma-jobi var. mayuen,” Natural product communications, vol. 11, no. 2, pp. 229–231, 2016.
View at: Publisher Site | Google Scholar
M. E. R. Andrade, R. D. G. C. D. Santos, A. D. N. Soares et al., “Pretreatment and treatment WithL-arginine attenuate weight loss and bacterial translocation in dextran sulfate sodium colitis,” Journal of Parenteral and Enteral Nutrition, vol. 40, no. 8, pp. 1131–1139, 2016.
View at: Publisher Site | Google Scholar
W. Ren, J. Yin, M. Wu et al., “Serum amino acids profile and the beneficial effects of L-arginine or L-glutamine supplementation in dextran sulfate sodium colitis,” Plos One, vol. 9, no. 2, Article ID e88335, 2014.
View at: Publisher Site | Google Scholar
L. A. Coburn, X. Gong, K. Singh et al., “L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis,” Plos One, vol. 7, no. 3, Article ID e33546, 2012.
View at: Publisher Site | Google Scholar
H. Omidi-Ardali, Z. Lorigooini, A. Soltani, S. Balali-Dehkordi, and H. Amini-Khoei, “Inflammatory responses bridge comorbid cardiac disorder in experimental model of IBD induced by DSS: protective effect of the trigonelline,” Inflammopharmacology, vol. 27, no. 6, pp. 1265–1273, 2019.
View at: Publisher Site | Google Scholar
J. Jin, Y. Zhong, J. Long et al., “Ginsenoside Rg1 relieves experimental colitis by regulating balanced differentiation of Tfh/Treg cells,” International Immunopharmacology, vol. 100, Article ID 108133, 2021.
View at: Publisher Site | Google Scholar
Y. H. Choi, J.-K. Bae, H.-S. Chae et al., “Isoliquiritigenin ameliorates dextran sulfate sodium-induced colitis through the inhibition of MAPK pathway,” International Immunopharmacology, vol. 31, pp. 223–232, 2016.
View at: Publisher Site | Google Scholar
X.-L. Yang, T.-K. Guo, Y.-H. Wang, M.-T. Gao, H. Qin, and Y.-J. Wu, “Therapeutic effect of ginsenoside Rd in rats with TNBS-induced recurrent ulcerative colitis,” Archives of Pharmacal Research, vol. 35, no. 7, pp. 1231–1239, 2012.
View at: Publisher Site | Google Scholar
N. Yang, G. Liang, J. Lin et al., “Ginsenoside Rd therapy improves histological and functional recovery in a rat model of inflammatory bowel disease,” Phytotherapy Research, vol. 34, no. 11, pp. 3019–3028, 2020.
View at: Publisher Site | Google Scholar
X.-r. Wang, H.-g. Hao, and L. Chu, “Glycyrrhizin inhibits LPS-induced inflammatory mediator production in endometrial epithelial cells,” Microbial Pathogenesis, vol. 109, pp. 110–113, 2017.
View at: Publisher Site | Google Scholar
H. Ali, B. Weigmann, E.-M. Collnot, S. A. Khan, M. Windbergs, and C.-M. Lehr, “Budesonide loaded PLGA nanoparticles for targeting the inflamed intestinal mucosa-pharmaceutical characterization and fluorescence imaging,” Pharmaceutical Research, vol. 33, no. 5, pp. 1085–1092, 2016.
View at: Publisher Site | Google Scholar
M. Zeeshan, H. Ali, S. Khan, M. Mukhtar, M. I. Khan, and M. Arshad, “Glycyrrhizic acid-loaded pH-sensitive poly-(lactic-co-glycolic acid) nanoparticles for the amelioration of inflammatory bowel disease,” Nanomedicine, vol. 14, no. 15, pp. 1945–1969, 2019.
View at: Publisher Site | Google Scholar
X. Mao, R. Sun, Q. Wang et al., “l-Isoleucine administration alleviates DSS-induced colitis by regulating TLR4/MyD88/NF-kappaB pathway in rats,” Frontiers in Immunology, vol. 12, Article ID 817583, 2021.
View at: Google Scholar
M. K. Jeengar, D. Thummuri, M. Magnusson, V. G. M. Naidu, and S. Uppugunduri, “Uridine ameliorates dextran sulfate sodium (DSS)-Induced colitis in mice,” Scientific Reports, vol. 7, no. 1, p. 3924, 2017.
View at: Publisher Site | Google Scholar
M. G. Zizzo, G. Caldara, A. Bellanca, D. Nuzzo, M. Di Carlo, and R. Serio, “Preventive effects of guanosine on intestinal inflammation in 2, 4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rats,” Inflammopharmacology, vol. 27, no. 2, pp. 349–359, 2019.
View at: Publisher Site | Google Scholar
L. Zhu, P. Gu, and H. Shen, “Gallic acid improved inflammation via NF-κB pathway in TNBS-induced ulcerative colitis,” International Immunopharmacology, vol. 67, pp. 129–137, 2019.
View at: Publisher Site | Google Scholar
A. K. Pandurangan, N. Mohebali, N. MohdEsa, C. Y. Looi, S. Ismail, and Z. Saadatdoust, “Gallic acid suppresses inflammation in dextran sodium sulfate-induced colitis in mice: possible mechanisms,” International Immunopharmacology, vol. 28, no. 2, pp. 1034–1043, 2015.
View at: Publisher Site | Google Scholar
C. Mascaraque, C. Aranda, B. Ocón et al., “Rutin has intestinal antiinflammatory effects in the CD4+ CD62L+ T cell transfer model of colitis,” Pharmacological Research, vol. 90, pp. 48–57, 2014.
View at: Publisher Site | Google Scholar
H. Kim, H. Kong, B. Choi et al., “Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease,” Pharmaceutical Research, vol. 22, no. 9, pp. 1499–1509, 2005.
View at: Publisher Site | Google Scholar
S.-J. Kim, M.-C. Kim, J.-Y. Um, and S.-H. Hong, “The beneficial effect of vanillic acid on ulcerative colitis,” Molecules, vol. 15, no. 10, pp. 7208–7217, 2010.
View at: Publisher Site | Google Scholar
Y. Bian, P. Liu, J. Zhong et al., “Quercetin attenuates adhesion molecule expression in intestinal microvascular endothelial cells by modulating multiple pathways,” Digestive Diseases and Sciences, vol. 63, no. 12, pp. 3297–3304, 2018.
View at: Publisher Site | Google Scholar
Y. Dong, J. Lei, and B. Zhang, “Dietary quercetin alleviated DSS-induced colitis in mice through several possible pathways by transcriptome analysis,” Current Pharmaceutical Biotechnology, vol. 21, no. 15, pp. 1666–1673, 2020.
View at: Publisher Site | Google Scholar
J. Zhang, L. Cao, H. Wang et al., “Ginsenosides regulate PXR/NF-κB signaling and attenuate dextran sulfate sodium-induced colitis,” Drug Metabolism and Disposition, vol. 43, no. 8, pp. 1181–1189, 2015.
View at: Publisher Site | Google Scholar
M. El-Sherbiny, N. H. Eisa, N. F. Abo El-Magd, N. M. Elsherbiny, E. Said, and A. E. Khodir, “Anti-inflammatory/anti-apoptotic impact of betulin attenuates experimentally induced ulcerative colitis: an insight into TLR4/NF-kB/caspase signalling modulation,” Environmental Toxicology and Pharmacology, vol. 88, Article ID 103750, 2021.
View at: Publisher Site | Google Scholar
Q. He, L. He, F. Zhang et al., “Stachyose modulates gut microbiota and alleviates dextran sulfate sodium-induced acute colitis in mice,” Saudi Journal of Gastroenterology, vol. 26, no. 3, pp. 153–159, 2020.
View at: Publisher Site | Google Scholar
C. Cheng, W. Zhang, C. Zhang et al., “Hyperoside ameliorates DSS-induced colitis through MKRN1-mediated regulation of PPARγ signaling and Th17/treg balance,” Journal of Agricultural and Food Chemistry, vol. 69, no. 50, pp. 15240–15251, 2021.
View at: Publisher Site | Google Scholar

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