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. 2021 Sep 17:12:748772.
doi: 10.3389/fphar.2021.748772. eCollection 2021.

Pithecellobium clypearia: Amelioration Effect on Imiquimod-Induced Psoriasis in Mice Based on a Tissue Metabonomic Analysis

Ying Li  1 , Jiaxin Zong  1 , Wenjun Ye  1   2 , Yuanfeng Fu  1 , Xinyi Gu  1 , Weisong Pan  3 , Li Yang  1 , Ting Zhang  1 , Mingmei Zhou  1
Affiliations

Pithecellobium clypearia: Amelioration Effect on Imiquimod-Induced Psoriasis in Mice Based on a Tissue Metabonomic Analysis

Ying Li et al. Front Pharmacol. .

Abstract

Pithecellobium clypearia Benth. (accepted name: Archidendron clypearia (Jack) I.C.Nielsen; Mimosaceae), a popular traditional Chinese medicine, has a significant anti-inflammatory effect. The crude water extract of the aerial part of P. clypearia has been clinically applied to treat upper respiratory tract infections, acute gastroenteritis, laryngitis, and pharyngitis. However, the therapeutic mechanism of ethanol fraction of water extract (ESW) of P. clypearia to treat psoriasis should be complemented. The aim of our research was to clarify the protective effects of ESW from P. clypearia against psoriasis-like skin inflammation induced by imiquimod (IMQ) in mice with efficacy indexes and target tissue (spleen and serum) metabolomics. The ingredient of ESW was analyzed by ultrahigh-performance liquid chromatography combined with tandem mass spectrometry (UHPLC-MS/MS) method. The imiquimod-induced psoriatic mouse model was employed to investigate the effect of ESW against psoriasis, where the treatment method was implemented for 6 days both topically (Gel at 5%) and orally (at 2.4 g/kg p.o.). Traditional pharmacodynamic indicators (phenotypic characteristics, psoriasis area and severity index (PASI) score, H&E staining, immunohistochemical staining, the thickness of epidermis, body weight change, and spleen index) were conducted to appraise the efficacy of ESW. Furthermore, a gas chromatography-mass spectrometer (GC-MS) coupled with multivariate analysis was integrated and applied to obtain serum and spleen metabolic profiles for clarifying metabolic regulatory mechanisms of ESW. The current study illustrated that ESW is composed mainly of gallic acid, ethyl gallate, quercitin, 7-O-galloyltricetiflavan, quercetin, and myricetin by UHPLC-MS/MS analysis. ESW could distinctly improve IMQ-induced psoriasis in mouse through reducing PASI score, alleviating tissue damage, restoring spleen index, and inhibiting proliferating cell nuclear antigen (PCNA) expression in psoriasis-like skin tissue. From the metabolomics study, 23 markers with significant changes are involved in eight main pathways in spleen and serum samples, including linoleic acid metabolism and glycine, serine, and threonine metabolism. The current study showed that ESW had obvious antipsoriasis effects on IMQ-induced psoriasis in mice, which might be attributed to regulating the dysfunction of differential biomarkers and related pathways. In summary, ESW of P. clypearia showed a favourable therapeutic effect on IMQ-induced psoriasis, and metabolomics provided insights into the mechanisms of ESW to the treatment of psoriasis.

Keywords: Pithecellobium clypearia Benth. (Archidendron clypearia (Jack) I.C.Nielsen); imiquimod; mechanisms; metabolomics; psoriasis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The TICs of the six analytes in mixed standard (A) and sample (B) by UHPLC-MS/MS in positive and negative ion mode. Alphabets corresponded to the compounds as follows: a, gallic acid; b, ethyl gallate; c, quercitin; d, 7-O-galloyltricetiflavan; e, quercetin; f, myricetin.
FIGURE 2
FIGURE 2
ESW alleviated the severity of IMQ-induced psoriasis-like skin inflammation. (A) Representative photos of the lesional skin of mice from each group. (B) The PASI scores of erythema score, scaled score, thickness score, and average score in each group from day 1 to day 7. All data were expressed as mean ± SD (n = 8).
FIGURE 3
FIGURE 3
(A) Histological evaluation of skin lesions (H&E staining, magnification ×200); △: microlimb swelling; ×: parakeratosis; ◇: acanthosis; ☆: lymphocyte infiltration; ○: hair follicles and sebaceous glands. (B) Immunohistochemical staining (×200) for proliferating cell nuclear antigen (PCNA) (brown) in mouse back skin. (C,D) Thickness of epidermal and PCNA+ cells of the skin sections of mice from each group on day 7. (E) Histogram of the spleen index of each group. (F) Body weight change in each group from day 1 to day 7. Results were shown as the mean ± SD. **p < 0.01 or ***p < 0.001 vs. IMQ group.
FIGURE 4
FIGURE 4
PCA and PLS-DA scores plots of mouse spleen data in Con group, IMQ group, and ESW group. (A) Dynamic mean-centered PCA 2D score plot of mouse spleen data. (B) Dynamic mean-centered PLS-DA 2D score plot of mouse spleen data. (C) Dynamic mean-centered PCA 3D score plot of mouse spleen data. (D) Dynamic mean-centered PLS-DA 3D score plot of mouse spleen data.
FIGURE 5
FIGURE 5
PCA and PLS-DA scores plots of mouse serum data in Con group, IMQ group, and ESW group. (A) Dynamic mean-centered PCA 2D score plot of mouse serum data. (B) Dynamic mean-centered PLS-DA 2D score plot of mouse serum data. (C) Dynamic mean-centered PCA 3D score plot of mouse serum data. (D) Dynamic mean-centered PLS-DA 3D score plot of mouse serum data.
FIGURE 6
FIGURE 6
The OPLS-DA data of the spleen tissue. (A,B) OPLS-DA score plots comparisons between the Con and IMQ groups as well as the IMQ and ESW groups, respectively. (C,D) S-plots of the OPLS-DA model for the Con and IMQ groups as well as for the IMQ and ESW groups, respectively. (E,F) The 100-permutation test of the OPLS-DA model was for the Con and IMQ groups as well as for the IMQ and ESW groups, respectively.
FIGURE 7
FIGURE 7
The OPLS-DA data of the serum. (A,B) OPLS-DA score plots comparisons between the Con and IMQ groups as well as the IMQ and ESW groups. (C,D) S-plots of the OPLS-DA model for the Con and IMQ groups as well as for the IMQ and ESW groups. (E,F) The 100-permutation test of the OPLS-DA model was for the Con and IMQ groups as well as for the IMQ and ESW groups.
FIGURE 8
FIGURE 8
Venn diagram of the significant differential metabolites and heatmap of differential metabolites in the spleen (A,B) and serum (C,D).
FIGURE 9
FIGURE 9
(A) Summary of pathway analysis in the spleen. (a) Linoleic acid metabolism, (b) phenylalanine, tyrosine, and tryptophan biosynthesis, (c) phenylalanine metabolism, (d) starch and sucrose metabolism, (e) glycine, serine and threonine metabolism, and (f) glyoxylate and dicarboxylate metabolism. (B) Summary of pathway analysis in the serum. (a) Starch and sucrose metabolism, (b) inositol phosphate metabolism, and (c) galactose metabolism.
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