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Article

Metabolic Profiling for Unveiling Mechanisms of Kushenol F against Imiquimod-Induced Psoriasis with UHPLC/MS Analysis

by
Xingxin Yang
1,†,
Jiaoli Cheng
2,†,
Xunqing Yin
1,
Ting Ao
1,
Xudong He
1,
Yaqin Yang
3,*,
Yuping Lin
1,* and
Zhen Chen
2,*
1
College of Pharmaceutical Science, Yunnan University of Chinese Medicine, Kunming 650500, China
2
Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming 650500, China
3
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311403, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2024, 29(11), 2410; https://doi.org/10.3390/molecules29112410
Submission received: 16 March 2024 / Revised: 26 April 2024 / Accepted: 17 May 2024 / Published: 21 May 2024
Browse Figures
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Abstract

:
Psoriasis is a common chronic immune-mediated inflammatory skin disorder. Sophora flavescens Alt. (S. flavescens) has been widely acknowledged in the prevention and treatment of psoriasis. Kushenol F (KSCF) is a natural isopentenyl flavonoid extracted from the root of S. flavescens. We aimed to investigate the effect and mechanism of KSCF on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. A mouse model of psoriasis was induced with 5% IMQ for 5 days, and the mice were given KSCF dermally for 5 days. Changes in skin morphology, the psoriasis area, the severity index (PASI), and inflammatory factors of psoriasis-like skin lesions were evaluated. Metabolites in the psoriasis-like skin lesions were analyzed with ultra-high-performance liquid chromatography/mass spectrometry followed by a multivariate statistical analysis to identify the differential metabolites and metabolic pathway. The results of the present study confirmed that KSCF significantly reduced PASI scores, epidermal thickening, and epidermal cell proliferation and differentiation. KSCF also reduced the levels of interleukin (IL)-1β, IL-6, IL-8, IL-17A, IL-22, IL-23, and tumor necrosis factor (TNF)-α in the injured skin tissues while increasing IL-10 content. KSCF significantly regulated metabolites in the skin samples, and a total of 161 significant metabolites were identified. These differential metabolites involved sphingolipid and linoleic acid metabolism and steroid hormone biosynthesis. Collectively, KSCF inhibited the inflammatory response to prevent IMQ-induced psoriasis-like skin lesions in mice by call-backing the levels of 161 endogenous metabolites and affecting their related metabolic pathways. KSCF has the potential to be developed as a topical drug for treating psoriasis symptoms.

1. Introduction

Psoriasis is a chronic and systemic immune-mediated disease. The underlying pathomechanisms involve an interplay between the innate and adaptive immune systems [1,2]. Recently, psoriasis presents many challenges, including high prevalence, chronicity, and associated comorbidity [3]. As a representative inflammatory skin disease occupied by large surface involvement, the occurrence and development of psoriasis is reported to be related to the disorder of many inflammation markers, such as IL-17A, IL-23, and TNF-α. Biologics targeting IL-17A, IL-23, and TNF-α have been developed and approved for the treatment of psoriasis [4]. The progression of psoriasis has also been confirmed to be related to immunity [5,6,7].
Common treatments for psoriasis include topical agents, systemic therapy, and ultraviolet light therapy. Topical agents mainly include calcipotriol (CVD), corticosteroids, and salicylic acid. Methotrexate, cyclosporine, and acitretin are commonly used as systemic therapy for psoriasis [8,9]. Although the therapeutic effects of these drugs have been widely recognized, adverse reactions still largely limit their clinical utilization [10]. Hence, complementary and alternative medicine may offer options for some patients.
Sophora flavescens Alt. (S. flavescens) is widely used in the clinic, can clear dampness-heat, kill insects, and dispel wind evil, which originates from the teachings of traditional Chinese medicine [11]. S. flavescens has been clinically used in numerous countries to treat skin diseases [12,13]. Kushenol F (KSCF) is a natural isopentenyl flavonoid extracted from the root of S. flavescens. It has been reported to have anti-inflammatory and anti-bacterial properties [14,15,16]. A previous study demonstrated that KSCF oral treatment could be an important therapeutic for treating atopic dermatitis. Although various studies have reported the biological effects of KSCF, the effect and mechanism of KSCF on psoriasis are unclear.
Metabolomics can reveal the specific changes in physiological and biochemical states related to phenotypes in biological systems. The application of skin metabonomics is suitable for revealing the potential functional changes in a variety of metabolic pathways and signal networks in psoriasis-like organisms, which has become a significant approach to evaluate the efficacy and mechanism of drugs [17]. The present study investigated the effects of KSCF on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice using conventional pharmacology and metabolomics. The potential biomarkers and complex mechanisms of KSCF involved in psoriasis treatment are also discussed. The results demonstrated that KSCF inhibited the inflammatory response to prevent IMQ-induced psoriasis-like skin lesions in mice by call-backing the levels of 161 endogenous metabolites and affecting their related metabolic pathways. Thus, KSCF has the potential to be developed as a topical drug for treating psoriasis symptoms.

2. Results and Discussion

2.1. KSCF Mitigated the Psoriatic Dermatitis Induced by IMQ

Psoriasis is a skin disease with characteristics of well-demarcated, erythematous, raised lesions with silvery-white dry scales. As depicted in Figure 1, after 5 days of IMQ treatment, erythema and silvery-white dry scales were observed on the dorsal skin, and the PASI was significantly increased (p < 0.001). However, after treatment with CVD and KSCF, the thickness and size of the scales on the dorsal skin were decreased. Erythema and PASI were also significantly decreased (p < 0.001). These results indicate that KSCF effectively relieved IMQ-induced psoriasis symptoms.

2.2. Effect of KSCF on Inflammatory Reactions in Psoriasis-like Mice

Psoriasis is a chronic inflammatory skin disease characterized by lymphocyte and neutrophil infiltration and the excessive keratinization and proliferation of keratinocytes [18,19]. The agents capable of attenuating keratinocyte hyperproliferation and excessive inflammatory responses are considered to be potentially useful for psoriasis treatment [20,21]. IMQ-induced psoriasis is usually accompanied by cellular inflammatory factor disorders in the dorsal skin. As shown in Figure 2A, IMQ induced massive inflammatory cell infiltration in the dorsal skin, which was reduced by CVD and KSCF treatment. As shown in Figure 2B, after 5 days of IMQ treatment, the levels of IL-1β, IL-6, IL-8, IL-17A, IL-22, IL-23, and TNF-α significantly increased in the dorsal skin (p < 0.05), whereas IL-10 levels significantly decreased (p < 0.0001). After treatment with CVD and KSCF, the levels of IL-1β, IL-6, IL-8, IL-17A, IL-22, IL-23, and TNF-α significantly decreased (p < 0.05) and IL-10 levels significantly increased (p < 0.0001). These results indicated that KSCF might stimulate the secretion of anti-inflammatory cytokines while inhibiting the release of pro-inflammatory cytokines, thereby alleviating IMQ-induced psoriasis.

2.3. Effect of KSCF on Metabolites in the Injured Skin of Psoriasis-like Mice

The data of skin samples were collected with ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS), and the metabolic profiles of each group were obtained. As depicted in Supplementary Figure S1, the peak number and intensity significantly varied in the total ion current profiles of the control, model, CVD, and KSCF groups, indicating significant differences among the metabolic state of each group and endogenous metabolites. Thus, the endogenous metabolites of skin changed significantly after IMQ induction and administration. In this study, PCA and OPLS-DA were used to analyze metabolome differences in the dorsal skin between the control, model, and KSCF groups using an unsupervised statistical method. The metabolic state of the control and model groups was different (Figure 3 and Figure 4A). The KSCF group was far from the model group. The results demonstrated that KSCF effectively reversed the pathological changes triggered by IMQ treatment in psoriasis-like mice.
Two hundred iteration permutation tests were performed on OPLS-DA in the positive and negative ion modes to further illustrate the reliability of the OPLS-DA model. The Q2 values were less than 0.05, further confirming the accuracy of the multivariate statistical analysis (Figure 4B).

2.4. Identification of Differential Metabolites

Changes in the metabolites can reflect the physiological and pathological states of the human body and might serve as an objective index to determine the efficacy and mechanism of drugs during disease intervention [22]. The complete metabolic information was collected, and the mechanism of KSCF against IMQ-induced psoriasis, which involved the regulation of endogenous metabolites, was revealed using the UHPLC/MS technique. S-plot diagrams based on OPLS-DA analysis were plotted to obtain information on differential metabolites between the model group and the KSCF group. Substances with a VIP of >1 and p-value of <0.05 were selected as biomarkers (Figure 5). A total of 161 potential biomarkers were detected in the dorsal skin, of which 102 metabolites were up-regulated, and 59 metabolites were down-regulated (Table 1; their chemical structures are shown in Supplementary Figure S2). These results suggested that KSCF might regulate these differential metabolites to relieve IMQ-induced psoriasis.

2.5. Metabolic Pathway Analysis

The differential metabolites were subjected to a pathway enrichment analysis to explore the potential metabolic pathways of KSCF exerting medicinal effects. Figure 6 shows the path influence diagrams of the metabolic pathway analysis. Pathways with a p-value of <0.05 were considered KSCF-involved pathways. The difference between the model and KSCF groups was clearly reflected in three pathways (Table 2), which are mainly related to lipid metabolism and steroidogenic activity.
Sphingolipids have structural and biological functions in the human epidermis, are importantly involved in the maintenance of the skin barrier, and regulate cellular processes, such as the proliferation, differentiation, and apoptosis of keratinocytes [23,24]. In this study, 3-O-sulfogalactosylceramide (d18:1/18:1(9Z)) and sphingosine 1-phosphate were identified as metabolites with significant differences after modeling and drug administration, suggesting that these key metabolites could be targets for KSCF against IMQ-induced psoriasis. Therefore, it was inferred that KSCF improved IMQ-induced psoriasis by regulating sphingolipid metabolism pathways.
Abnormal linoleic acid metabolism has been shown to be a key pathway in psoriasis. The combination of a moisturizer containing a linoleic acid–ceramide complex and glucocorticoids was shown to significantly improve the therapeutic efficacy of psoriasis and delay recurrence [25]. Our results confirmed that the levels of PC (14:1(9Z)/18:0) and PC (18:0/22:4(7Z,10Z,13Z,16Z)) were close to the normal group after KSCF administration. These results suggested that KSCF improved IMQ-induced psoriasis by regulating the linoleic acid metabolism pathways.
The skin has an endogenous steroidogenic capacity, and modulating local steroidogenic activity may be a new approach to treating inflammatory skin diseases [26,27]. In this study, 5α-Pregnan-20α-ol-3-one and 21-Hydroxy-5b-pregnane-3,11,20-trione were identified as metabolites with significant differences after modeling and drug administration. After KSCF administration, steroid hormone biosynthesis was similar to the normal group, suggesting that KSCF treatment affected steroid hormone biosynthesis to relieve IMQ-induced psoriasis.
Our results indicated that KSCF inhibited the inflammatory response to prevent IMQ-induced psoriasis-like skin lesions in mice by call-backing the levels of endogenous metabolites and affecting their related metabolic pathways (Figure 7). It is very likely that the flavonoid extract from S. flavescens also shows the therapeutic effects on psoriasis because it contains many active compounds, such as KSCF, which is worthy of further study. The deep molecular mechanism of KSCF regulating endogenous metabolites in three key pathways is also worthy to be further explored by detecting the key proteins in the pathways. It is reported that another flavonoid (kurarinone) and alkaloids (matrine and oxymarine) isolated from S. flavescens regulated the inflammatory response to intervene in psoriasis [7,28,29]. However, the differences in the efficacy and mechanism of these compounds in the psoriasis treatment and the relationship between the chemical structures of them and their anti-psoriasis activity are still unclear, which is worthy of further study.

3. Materials and Methods

3.1. Chemicals, Reagents, and Materials

KSCF was provided from Chengdu Pufei De Biotech Co., Ltd. (Chengdu, China). CVD was purchased from A&M Pharmaceuticals (Hong Kong, China). Hematoxylin stain was obtained from Wuhan Google Biotechnology Co., Ltd. (Wuhan, China). Vaseline for medical use was purchased from Shandong Lircon Medical Technology Co., Ltd. (Dezhou, China). IMQ was acquired from Sichuan MED-SHINE Pharmaceutical Co., Ltd. (Chengdu, China). Four percent paraformaldehyde solution was provided from Beijing lanjieke Technology Co., Ltd. (Beijing, China). IL-6, IL-8, IL-1β, IL-10, IL-22, IL-23, IL-17A, and TNF-α ELISA Kits were purchased from Jiangsu Meimian Industrial Co., Ltd. (Yancheng, China). The reference substance of KSCF (purity > 98%) was purchased from Chengdu Pufei De Biotech Co., Ltd. (Chengdu, China). High purity deionized water was purified using a Milli-Q system (Millipore, Bedford, MA, USA). HPLC-grade formic acid, methyl alcohol, and acetonitrile were acquired from Fischer Control Equipment International Co., Ltd. (Hong Kong, China). H&E Staining kits were purchased from Beijing Solarbio Science&Technology Co., Ltd. (Beijing, China). Seventy-five percent ethanol was purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). All other reagents used were of analytical reagent grade or higher.

3.2. Animals and Experimental Protocol

All experimental procedures in this study complied with the National Guidelines for the Care and Use of Laboratory Animals and were approved by the Animal Ethics Committee of Yunnan University of Chinese Medicine, with ethics number R062021158.
Healthy male BALB/c mice (20 ± 2 g), aged 6–8 weeks, were obtained from Sipeifu Biotechnology Co., Ltd. (Beijing, China). The mice were kept in the Laboratory of Yunnan University of Traditional Chinese Medicine (Kunming, China), following standard housing conditions. All mice were adaptively fed for one week. The mice were randomized into six groups (n = 6 mice per group), including control group (75% ethanol), model group (75% ethanol), positive group (CVD, 62.5 mg/kg), low-dose KSCF group (L-KSCF, 200 mg/kg), medium-dose KSCF group (M-KSCF, 400 mg/kg), and high-dose KSCF group (H-KSCF, 600 mg/kg). Except for the control group, mice were topically treated with 5% IMQ cream at a daily dose of 62.5 mg for a duration of 5 days on their dorsal region. KSCF and CVD were dissolved in 75% ethanol. Starting from the day of modeling, the corresponding drugs were sprayed continuously for 5 days (0.3 mL/day/mouse) in the administration group. Seventy-five percent ethanol (0.3 mL/day/mouse) was sprayed for the control group and the model group.

3.3. Psoriasis Area and Severity Index (PASI) Assessment

According to clinical PASI score standard, the severity of the skin inflammation was evaluated once daily, including the measurements for skin erythema, scaling, and thickening. Erythema, scaling, and thickening were scored independently on a scale from 0 to 4: 0, none; 1, slight; 2, moderate; 3, marked; 4, very marked. The cumulative score (erythema plus scaling plus thickening) served as a measure of the severity of inflammation (scale 0–12) [30].

3.4. Image Acquisition and Skin Sample Collection

After euthanizing the mice through carbon dioxide asphyxiation, images were captured on the dorsal side of each mouse group. Then, the dorsal skin of the mice was carefully excised using surgical scissors and divided into two sections. One section was immediately immersed in liquid nitrogen for cryopreservation, while the other section was fixed in 4% paraformaldehyde universal tissue fixative.

3.5. Histopathology Analyses

The dorsal skin of mice was fixed in 4% paraformaldehyde universal tissue fixative for 24 h, washed with PBS, dehydrated with gradient ethanol and transparentized with xylene, and embedded in paraffin. After hematoxylin and eosin staining, histological parameters were observed under a light microscope, and images were taken at 200× magnification.

3.6. Measurement of Skin Inflammatory Factors

Approximately 50 mg of injured skin from the dorsal region of each mouse were weighed and placed on ice. The surface blood stains on the skin samples were rinsed with pre-cooled normal saline solution. After air-drying the filter paper, the skin samples were promptly sectioned into pieces and transferred into a covered 2 mL centrifuge tube. The tube was then subjected to centrifugation (Centrifuge 5430R, Eppendorf, Germany) at 1500× g for 15 min, and subsequently, the supernatant of the homogenized tissue was collected for further utilization. The levels of cytokines IL-1β, IL-6, IL-8, IL-10, IL-17A, IL-22, IL-23, and TNF-α in the dorsal skin lesions of all groups of mice were detected according to the kit manufacturer’s instructions. The values were determined by measuring the absorbance value (OD) at 450 nm using a microplate reader (Rayto Life and Analytical Sciences Co., Ltd., Shenzhen, China).

3.7. Metabolomic Analysis

3.7.1. Sample Pre-Treatment

Skin samples: 50 mg skin sample and a 6 mm diameter grinding bead was added to a 2 mL centrifuge tube. An amount of 400 μL of extraction solution (methanol: water = 4:1 (v:v)) was used for metabolite extraction. Samples were ground with Wonbio-96c frozen tissue grinder (Shanghai Wanbo Biotechnology Co., Ltd., Shanghai, China) for 6 min (−10 °C, 50 Hz) followed by low-temperature ultrasonic extraction for 30 min (5 °C, 40 kHz). Then, the sample was allowed to stand for 30 min at −20 °C and centrifuged for 15 min (4 °C, 3500× g). The supernatant was transferred to a clean tube and dried gently with nitrogen. The residues were redissolved in 200 µL of methanol for UHPLC/MS analysis.
Quality control sample: A random injection sequence was employed to detect signal fluctuation. An amount of 2 μL of skin samples were taken and thoroughly mixed. Then, the mixture was centrifuged at 3500× g for 15 min at 4 °C. The supernatant was collected to perform UHPLC/MS analysis.

3.7.2. UHPLC/MS Analysis

UHPLC analyses were performed using Ultimate 3000 Ultra High Performance Liquid Chromatography (Thermo Fisher Scientific, San Jose, CA, USA) equipped with a Thermo Scientific Hypersil GOLD column (50 mm × 2.1 mm, 1.9 μm). The column temperature was maintained at 40 °C to obtain better sample separation. The mobile phases consisted of water containing 0.1% formic acid (A) and acetonitrile (B) at a 0.4 mL/min of flow rate. The gradient program was set as follows: 0–3.5 min, 0% B → 24.5% B; 3.5–5 min, 24.5% B → 65% B; 5–7.4 min, 65% B → 100% B; 7.4–7.6 min, 100% B → 51.5% B; 7.6–10 min, 51.5% B → 0% B.
The MS data were collected using a Thermo Scientific Q-Exactive TM hybrid quadrupole-orbitrap mass spectrometer with a heated electrospray ionization probe (Thermo Fisher Scientific, San Jose, CA, USA). MS conditions were as follows: CUR, 15 psi; Gas1 and Gas2, 50 psi; IS, 5500 V; gas temperature, 500 °C.

3.8. Statistical Analysis

All UHPLC/MS raw files were exported in comma-separated value (CSV) format using the Progenesis QI (Waters Corporation, Milford, CT, USA) software. All data were uploaded to XCMS online for peak alignment, normalization, and retrieval. The data were analyzed with principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) using the SIMCA-P 14.1 software (Sweden, Umeå, Umetrics). The potential biomarkers were selected according to the parameters of variable importance in the projection (VIP > 1 and p < 0.05) from OPLS-DA. The structural information of the metabolites was identified using the HMDB databases. Finally, the metabolic pathways were searched using Kyoto Encyclopedia of Genes and Genomes (KEGG) through MetaboAnalyst 5.0 online, and the pathways with an impact value greater than 0.1 were considered KSCF-involved pathways.
All experimental data were presented as means ± S.D. Each experiment was performed in triplicate. The overall significance of the results was examined with one-way ANOVA using GraphPad Prism 5.0 (GraphPad Software, La Jolla, CA, USA). Kolmogorov–Smirnov test was used for the pre-test of the analysis of ANOVA to ensure the rationality of the statistical analysis. Student’s t-test delivered the p-values shown. The differences between the compared groups were considered statistically significant at p < 0.05, p < 0.01, p < 0.001, p < 0.0001.

4. Conclusions

KSCF inhibited the inflammatory response to prevent IMQ-induced psoriasis-like skin lesions in mice by call-backing the levels of 161 endogenous metabolites and affecting the three related metabolic pathways, including sphingolipid and linoleic acid metabolism and steroid hormone biosynthesis. Thus, KSCF has the potential to be developed as a topical drug for treating psoriasis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29112410/s1, Figure S1: Representative total ion current profiles of the skin samples in the negative and positive ion mode; Figure S2: The chemical structures of 161 potential biomarkers.

Author Contributions

Z.C. and J.C. wrote the manuscript. J.C., X.Y. (Xunqing Yin) and T.A. performed the experiments. Z.C., Y.Y. and X.H. provided technical support and helpful discussions. Y.Y. and X.Y. (Xingxin Yang) wrote and modified the manuscript. X.Y. (Xingxin Yang) and Y.L. designed the study. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant numbers 82174037, 82060707, 82104381, and 81960710) and the Application and Basis Research Project of Yunnan China (Grant numbers 202001AV070007, 202001AZ070001-006, 202201AW070016, 2019IB009 and 202101AY070001-077).

Institutional Review Board Statement

All experimental procedures in this study complied with the National Guidelines for the Care and Use of Laboratory Animals and were approved by the Animal Ethics Committee of Yunnan University of Chinese Medicine, with ethics number R062021158.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are available upon request.

Conflicts of Interest

The authors declare that they have no competing interests.

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Molecules 29 02410 g001
Figure 1. Effect of KSCF on psoriatic dermatitis induced by IMQ. KSCF mitigated skin lesions on the back (A) and decreased PASI values (B) in IMQ-induced mice. CVD, calcipotriol; H-KSCF, high-dose KSCF group; M-KSCF, medium-dose KSCF group; L-KSCF, low-dose KSCF group. # vs. control group; * vs. model group; ### p < 0.001; ***p < 0.001.
Figure 1. Effect of KSCF on psoriatic dermatitis induced by IMQ. KSCF mitigated skin lesions on the back (A) and decreased PASI values (B) in IMQ-induced mice. CVD, calcipotriol; H-KSCF, high-dose KSCF group; M-KSCF, medium-dose KSCF group; L-KSCF, low-dose KSCF group. # vs. control group; * vs. model group; ### p < 0.001; ***p < 0.001.
Molecules 29 02410 g001
Molecules 29 02410 g002
Figure 2. Effect of KSCF on inflammatory reactions in psoriasis−like skin lesions in mice. KSCF reduced inflammatory cell infiltration in the dorsal skin (A) and regulated the secretion of inflammatory cytokines (B). CVD, calcipotriol group; H-KSCF, high-dose KSCF group; M-KSCF, medium-dose KSCF group; L-KSCF, low-dose KSCF group. # vs. control group; * vs. model group; #### p < 0.0001, ### p < 0.001, ## p < 0.01; **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05.
Figure 2. Effect of KSCF on inflammatory reactions in psoriasis−like skin lesions in mice. KSCF reduced inflammatory cell infiltration in the dorsal skin (A) and regulated the secretion of inflammatory cytokines (B). CVD, calcipotriol group; H-KSCF, high-dose KSCF group; M-KSCF, medium-dose KSCF group; L-KSCF, low-dose KSCF group. # vs. control group; * vs. model group; #### p < 0.0001, ### p < 0.001, ## p < 0.01; **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05.
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Figure 3. PCA score plots of psoriasis−like skin lesions in mice. I, positive ion mode; II, negative ion mode; KSCF, Kushenol F.
Figure 3. PCA score plots of psoriasis−like skin lesions in mice. I, positive ion mode; II, negative ion mode; KSCF, Kushenol F.
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Figure 4. OPLS−DA score plots of psoriasis−like skin lesion samples. (A) OPLS−DA score plots. (B) Permutation test plot. I, positive ion mode; II, negative ion mode; KSCF, Kushenol F.
Figure 4. OPLS−DA score plots of psoriasis−like skin lesion samples. (A) OPLS−DA score plots. (B) Permutation test plot. I, positive ion mode; II, negative ion mode; KSCF, Kushenol F.
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Figure 5. S−Plot of the model and KSCF administration group. I, positive ion mode; II: negative ion mode; red, VIP ≥ 1; green, VIP < 1.
Figure 5. S−Plot of the model and KSCF administration group. I, positive ion mode; II: negative ion mode; red, VIP ≥ 1; green, VIP < 1.
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Figure 6. Pathway analysis of KSCF treatment.
Figure 6. Pathway analysis of KSCF treatment.
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Figure 7. KSCF regulated endogenous metabolites in three key pathways against IMQ-induced psoriasis. 1, steroid hormone biosynthesis; 2, sphingolipid metabolism; 3, linoleic acid metabolism. Red, up.
Figure 7. KSCF regulated endogenous metabolites in three key pathways against IMQ-induced psoriasis. 1, steroid hormone biosynthesis; 2, sphingolipid metabolism; 3, linoleic acid metabolism. Red, up.
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Table 1. Differential metabolites identified from psoriatic skin lesion samples.
Table 1. Differential metabolites identified from psoriatic skin lesion samples.
Retention Time (min)Molecular
Weight (Da)		VIPPotential BiomarkerFormulaChange Trend
ESI−
4.843308.1242.604GlutaminyltyrosineC14H19N3O5DOWN
6.468453.2022.0542-Hydroxy-imipramine glucuronideC25H32N2O7UP
6.183581.3002.676SerylarginineC9H19N5O4UP
2.626263.0761.4783,4,5-trihydroxy-6-[(2-methylpropanoyl)oxy]oxane-2-carboxylic acidC10H16O8DOWN
2.821374.0952.0807-HydroxygliclazideC15H21N3O4SDOWN
2.829299.0701.075Methionyl-GlutamateC10H18N2O5SDOWN
4.270315.1632.0053-[8-hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-chromen-5-yl]propanoic acidC19H24O4DOWN
4.791165.0591.3013-Mercapto-2-methyl-1-butanolC5H12OSDOWN
6.240480.2492.770Dynorphin A (6–8)C18H37N9O4UP
6.278457.1972.666DeoxypyridinolineC18H28N4O7UP
6.308469.1612.372Melleolide BC24H32O7UP
6.308667.1711.090HydroxychlorpromazineC17H19ClN2OSUP
6.347455.1812.248ArmillaneC23H32O7UP
6.378437.1702.123NevskinC24H32O5UP
6.431177.0231.6563,3′-Thiobispropanoic acidC6H10O4SUP
6.442295.0312.518Cis,trans-5′-HydroxythalidomideC13H10N2O5UP
6.456421.1752.033Euglobal IIbC23H30O5UP
6.462465.2021.909HomofukinolideC25H34O6UP
6.493486.1871.5334-HydroxyvalsartanC24H29N5O4UP
5.583451.1851.0717-[(2,6-dihydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl)methoxy]-6-hydroxy-2H-chromen-2-oneC24H32O6UP
6.601467.2172.471Colupdox aC25H36O6UP
6.630553.2971.078Phytolaccinic acidC31H48O6DOWN
6.969492.1172.5752-amino-4-({1-[(carboxymethyl)-C-hydroxycarbonimidoyl]-2-[(2,3-dihydroxy-1-phenylpropyl)sulfanyl]ethyl}-C-hydroxycarbonimidoyl)butanoic acidC19H27N3O8SUP
7.023609.3611.208Lactapiperanol CC16H26O4DOWN
7.434810.5831.023PE(18:0/20:0)C43H86NO8PDOWN
7.480606.5002.0481,1′-(1,4-Dihydro-4-nonyl-3,5-pyridinediyl)bis[1-dodecanone]C38H69NO2DOWN
8.936453.2021.579Colupox aC25H36O5UP
8.915701.4211.880PG(a-13:0/a-15:0)C34H67O10PUP
8.846465.3141.130(2β,3α,9α,24R)-Ergosta-7,22-diene-2,3,9-triolC28H46O3DOWN
7.712865.5221.182PG(18:1(11Z)/22:6(4Z,7Z,10Z,13Z,16Z,19Z))C46H77O10PDOWN
7.365820.5891.091PE(18:1(11Z)/22:1(13Z))C45H86NO8PDOWN
7.157463.2932.768Palmitoyl glucuronideC22H42O7DOWN
7.057361.1740.993PerindoprilatC17H28N2O5DOWN
6.541379.2182.1673′-HydroxystanozololC21H32N2O2DOWN
6.475439.1852.144Lucidone AC24H34O5UP
6.456423.1542.4635,7-dihydroxy-4-(1-hydroxypropyl)-6-(3-methylbut-2-en-1-yl)-8-(2-methylbutanoyl)-2H-chromen-2-oneC22H28O6UP
6.451455.2172.656Cavipetin DC25H38O5UP
6.431475.1632.153α-CEHC glucuronideC22H30O10UP
6.378500.1672.3302-amino-4-({1-[(carboxymethyl)-C-hydroxycarbonimidoyl]-2-{[4-(2,6-dihydroxyphenyl)-3-hydroxy-2-methylbutan-2-yl]sulfanyl}ethyl}-C-hydroxycarbonimidoyl)butanoic acidC21H31N3O9SUP
6.371453.1652.610Diosbulbin HC23H30O7UP
6.354439.1861.9451α-O-MethylquassinC23H32O6UP
6.347507.1742.465L-NicotianineC10H12N2O4UP
6.284520.1932.082HydroxynefazodoneC25H32ClN5O3UP
6.240452.2181.926Chondroitin sulfate E (GalNAc4,6diS-GlcA), precursor 5aC7H9N3OUP
6.222369.2111.2483-keto-DigoxigeninC23H32O5DOWN
6.218476.2791.123LysoPE(0:0/18:2(9Z,12Z))C23H44NO7PDOWN
6.134457.1601.105ValechlorinC22H31ClO8UP
5.718371.2262.685DigoxigeninC23H34O5DOWN
5.114348.1561.934(+)-O-MethylarmepavineC20H25NO3DOWN
5.065329.1792.31312,20-Dioxo-leukotriene B4C20H28O5DOWN
4.974357.2111.89617-Hydroxy-E4-neuroprostaneC22H32O5DOWN
4.589357.2221.037Kinetensin 1-3C15H30N6O4UP
2.829365.1431.110Valproic acid glucuronideC14H24O8DOWN
2.814296.1061.0047-AminonitrazepamC15H13N3ODOWN
1.685295.0401.398N-Acetyldjenkolic acidC9H16N2O5S2UP
1.527183.0441.218Mevalonic acidC6H12O4UP
6.371383.1611.50121-Hydroxy-5b-pregnane-3,11,20-trioneC21H30O4DOWN
6.278581.2631.973S-(3-Methylbutanoyl)-dihydrolipoamide-EC13H25NO2S2UP
8.922689.3511.131ZeranolC18H26O5UP
ESI+
6.444453.2003.257Pro Ser Ser TyrC20H28N4O8UP
4.727828.5340.9763-O-Sulfogalactosylceramide (d18:1/18:1(9Z))C42H79NO11SDOWN
3.285404.2221.210Ser Ala Ala ArgC15H29N7O6UP
4.253317.1771.919Capillartemisin AC19H24O4DOWN
5.069331.1932.82716-Hydroxy-4-oxoretinoic acidC20H26O4DOWN
6.224371.2251.96017-phenyl trinor-13,14-dihydro Prostaglandin A2C23H30O4DOWN
6.254395.2521.328(3R, 6′Z)-3,4-Dihydro-8-hydroxy-3-(6-pentadecenyl)-1H-2-benzopyran-1-oneC24H36O3UP
6.304565.3501.002PG(22:2(13Z,16Z)/0:0)C28H53O9PUP
6.324313.0772.457Inosine-5′-carboxylateC11H12N4O7UP
7.031626.5331.139MuricatenolC37H68O6UP
6.338301.0772.967TemazepamC16H13ClN2O2UP
1.543286.1572.191Tryptophyl-ValineC16H21N3O3UP
3.194298.1501.266Histidinyl-ThreonineC10H16N4O4DOWN
3.319281.1191.1916-hydroxy-7E,9E-Octadecadiene-11,13,15,17-tetraynoic acidC18H16O3UP
4.064534.3231.347Cys Lys Lys ArgC21H43N9O5SDOWN
4.235255.1291.186Isoleucyl-ThreonineC10H20N2O4DOWN
4.305622.3771.446Tyr Arg Lys ArgC27H47N11O6DOWN
4.474277.1241.256IsobutyrylcarnitineC11H22NO4+UP
4.604386.2461.473Pseudoginsenoside RT3C41H70O13DOWN
4.654549.1721.514Myricatomentoside IC26H32O10DOWN
4.987359.2251.4757,8-epoxy-17S-HDHAC22H30O4DOWN
5.118696.4521.502PA(16:1(9Z)/15:0)C34H65O8PDOWN
5.170828.5331.338PE(MonoMe(11,3)/MonoMe(11,3))C43H74NO10PDOWN
5.994242.1340.972Lysyl-MethionineC11H23N3O3SUP
6.016548.2871.51111-Hydroxyprogesterone 11-glucuronideC27H38O9UP
6.082465.2591.132(−)-Jolkinol BC29H36O5UP
6.136502.1632.0013-(3-hydroxyphenyl)-2-(4-hydroxyphenyl)-5-[(E)-2-(3hydroxyphenyl)ethenyl]-2,3-dihydro-1 benzofuran-6-olC28H22O5UP
6.149467.2751.3161,25-Dihydroxyvitamin D3-26,23-lactoneC27H40O5UP
6.205363.2251.0975α-Pregnan-20α-ol-3-oneC21H34O2UP
6.224453.2211.813AustraligeninC27H42O4UP
6.283534.2211.608Cyclocalopin DC23H32O13UP
6.297365.2411.267Adipostatin AC21H36O2UP
6.324574.2531.565Glaucarubolone 15-O-β-d-glucopyranosideC26H36O13UP
6.360427.2761.508Asymmetric dimethylarginineC8H18N4O2UP
6.360455.1793.227Gly Glu Ser TyrC19H26N4O9UP
6.367441.2004.192Gly Thr Tyr ThrC19H28N4O8UP
6.416435.2942.760Alanyl-LysineC9H19N3O3UP
6.437527.3452.800Pro Val Arg ArgC22H42N10O5UP
6.451355.1252.024Meta-O-Dealkylated flecainideC15H19F3N2O3UP
6.472463.1822.851PA(8:0/8:0)C19H37O8PUP
6.479441.2003.151(9S,10S)-10-hydroxy-9-(phosphonooxy)octadecanoateC18H37O7PUP
6.500714.5091.058PA(18:1(9Z)/18:3(9Z,12Z,15Z))C39H69O8PUP
6.521523.4112.648Panaxydol linoleateC35H54O3DOWN
6.604411.2251.903Pro Pro Thr ProC19H30N4O6UP
6.646722.5191.386PE(18:4(6Z,9Z,12Z,15Z)/P-18:1(11Z))C41H72NO7PUP
6.660678.4921.312PE(18:4(6Z,9Z,12Z,15Z)/P-16:0)C39H70NO7PUP
6.674634.4651.471Tsugarioside BC37H60O7UP
6.856670.5231.605PE(15:0/18:0)C38H76NO8PUP
7.010904.7121.184PC(o-20:0/22:0)C50H102NO7PUP
7.066407.1531.1193b,16a-Dihydroxyandrostenone sulfateC19H28O6SUP
8.944425.2054.129O-DesmethylcarvedilolC23H24N2O4UP
9.287423.1892.131Cys Val Thr ThrC16H30N4O7SUP
8.685895.7541.939TG(18:1(11Z)/22:4(7Z,10Z,13Z,16Z)/18:3(9Z,12Z,15Z))C61H102O6DOWN
6.940539.3601.7213-methyl-4-(methylamino)-1,2-diphenylbutan-2-olC18H23NOUP
6.870626.4961.675PE(15:0/P-16:0)C36H72NO7PUP
6.870614.3531.399LysoPC(22:2(13Z,16Z))C30H58NO7PUP
6.849714.5501.546PC(14:1(9Z)/18:0)C40H78NO8PUP
6.828802.6041.578PC(18:0/22:4(7Z,10Z,13Z,16Z))C48H88NO8PUP
6.737696.4961.312CL(i-12:0/18:2(9Z,11Z)/i-18:0/i-19:0)C76H144O17P2UP
6.730740.5231.185CL(18:0/18:0/16:1(9Z)/22:6(4Z,7Z,10Z,13Z,16Z,19Z))C83H148O17P2UP
6.646840.5781.939PG(18:0/22:4(7Z,10Z,13Z,16Z))C46H83O10PDOWN
6.604163.0761.0604-Hydroxy-2,6,6-trimethyl-3-oxo-1,4-cyclohexadiene-1-carboxaldehydeC10H12O3UP
6.590295.0661.8162-hydroxy-3-[3-(3-methylbut-2-en-1-yl)-4-(sulfooxy)phenyl]propanoic acidC14H18O7SUP
6.583459.1872.136Ser Glu Ser HisC17H26N6O9UP
6.542355.1941.101Nigakihemiacetal BC22H30O6DOWN
6.493764.5161.715CL(16:0/18:0/18:0/22:5(7Z,10Z,13Z,16Z,19Z))C83H152O17P2DOWN
6.472700.4931.413PA(15:0/18:2(9Z,12Z))C36H67O8PUP
6.472385.1363.2062′,7-Dihydroxy-4′-methoxy-8-prenylflavanC21H24O4UP
6.465351.1301.754N-RibosylhistidineC11H17N3O6UP
6.451521.3961.727Ginsenoyne A linoleateC35H52O3DOWN
6.388285.0811.654(2S)-2-hydrazinyl-3-(4-hydroxy-3-methoxyphenyl)-2-methylpropanoic acidC11H16N2O4DOWN
6.381439.1843.069Gln Glu TyrC19H26N4O8UP
6.345375.1151.271Cyclic N-Acetylserotonin glucuronideC18H20N2O8DOWN
6.338361.1352.0237-Hydroxy-6-methyl-8-ribityl lumazineC12H16N4O7UP
6.324538.2551.523Rubraflavone BC30H34O5UP
6.311618.2832.1363′-DeaminofusarochromanoneC15H19NO4UP
6.297424.2212.812Sphingosine 1-phosphateC18H38NO5PUP
6.290508.2802.746LysoPE(0:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z))C27H44NO7PUP
6.283510.2964.312LysoPE(0:0/22:5(7Z,10Z,13Z,16Z,19Z))C27H46NO7PUP
6.276583.2773.375(4E)-6-hydroxy-1,7-diphenylhept-4-en-3-oneC19H20O2UP
6.241451.2790.944PA(19:1(9Z)/0:0)C22H43O7PUP
6.231498.2593.159PE(18:3/0:0)C23H42NO7PUP
6.199437.2641.0651-Oleoyl Lysophosphatidic Acid (sodium salt)C21H41O7PUP
6.186175.1232.811α-Methyltryptamine (AMT)C11H14N2UP
6.174569.2983.37011-α-O-β-d-Glucopyranosyl-16α-O-methylneoquassinC29H44O11UP
6.075487.3591.085Lys Ile Val LysC23H46N6O5UP
6.005618.3401.903PentasineC30H49N6O10+UP
6.000349.2091.127Oryzalexin EC20H32O2UP
5.554183.0821.5262-Methyl-4-propyl-1,3-oxathianeC8H16OSUP
5.112740.4791.500PS(14:0/20:3(8Z,11Z,14Z))C40H72NO10PDOWN
5.006240.1420.993Isopropyl β-d-glucosideC9H18O6UP
4.945336.1300.976GynocardinC12H17NO8DOWN
4.897352.1611.890(+/−)-RollipyrroleC16H20N2O3DOWN
4.615338.1451.145N-Acetyl-3-hydroxyprocainamideC15H23N3O3DOWN
4.391233.0971.094L-TarginineC7H16N4O2UP
3.611402.2421.022N-Didesmethylmifepristone (RU 42848)C27H31NO2DOWN
3.396261.1501.327Methyl dihydrophaseateC16H24O5UP
3.222229.1231.660Blennin BC15H20O4UP
2.566267.1401.527(S)-17-Hydroxy-9,11,13,15-octadecatetraynoic acidC18H20O3UP
1.360217.1341.518GirgensonineC13H16N2ODOWN
0.013300.2081.0402-hydroxydesipramineC18H22N2OUP
6.800524.2831.27011-β-Hydroxyandrosterone-3-glucuronideC25H38O9UP
Table 2. Metabolic pathway of psoriatic skin lesion samples.
Table 2. Metabolic pathway of psoriatic skin lesion samples.
No.Pathwayp-ValueDetails
1Sphingolipid metabolism0.001KEGG
2Linoleic acid metabolism0.036KEGG
3Steroid hormone biosynthesis0.021KEGG
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Yang, X.; Cheng, J.; Yin, X.; Ao, T.; He, X.; Yang, Y.; Lin, Y.; Chen, Z. Metabolic Profiling for Unveiling Mechanisms of Kushenol F against Imiquimod-Induced Psoriasis with UHPLC/MS Analysis. Molecules 2024, 29, 2410. https://doi.org/10.3390/molecules29112410

AMA Style

Yang X, Cheng J, Yin X, Ao T, He X, Yang Y, Lin Y, Chen Z. Metabolic Profiling for Unveiling Mechanisms of Kushenol F against Imiquimod-Induced Psoriasis with UHPLC/MS Analysis. Molecules. 2024; 29(11):2410. https://doi.org/10.3390/molecules29112410

Chicago/Turabian Style

Yang, Xingxin, Jiaoli Cheng, Xunqing Yin, Ting Ao, Xudong He, Yaqin Yang, Yuping Lin, and Zhen Chen. 2024. "Metabolic Profiling for Unveiling Mechanisms of Kushenol F against Imiquimod-Induced Psoriasis with UHPLC/MS Analysis" Molecules 29, no. 11: 2410. https://doi.org/10.3390/molecules29112410

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