Background: The imiquimod (IMQ)-induced psoriasis mouse model has been used as a model for pathogenic mechanism research, and methotrexate (MTX) is widely employed to treat various clinical manifestations of psoriasis. We explored the underlying pathogenesis of psoriasis and the treatment mechanism of the conventional drugs from the metabolic perspective of the psoriasis mouse model. Methods: Male BALB/c mice were smeared IMQ for 7 days to induce treatment-resistant psoriasis and intragastrically administered 1 mg/kg MTX. We evaluated inflammation of psoriasis-like lesions and therapeutic effects of MTX based on histological changes and immunohistochemistry. Based on gas chromatography-mass spectrometer detection of serum samples, a comprehensive metabolomics analysis was carried out to identify alterations of metabolites. Results: It was found that MTX ameliorated psoriatic lesions (representative erythema, scaling, and thickening) by inhibiting proliferation and differentiation of keratinocytes. Using multivariate statistical analysis to process metabolomics data, the results displayed alterations in serum metabolites among mice of the control group, IMQ group, and MTX group. Compared with group, psoriasis mice had the higher level of d-galactose and lower expression of myo-inositol, 9,12-octadecadienoic acid, and cholesterol. In contrast with the model set, serum levels of glycine, pyrrolidone carboxylic acid, d-galactose, and d-mannose were significantly decreased in the MTX group. Conclusion: The differential metabolites, reflecting the perturbation in the pathways of inositol phosphate metabolism; galactose metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and glutathione metabolism, may lead to the pathogenesis of psoriasis, and they are also related to the pharmacological treatment effect of MTX on psoriasis. This study established the foundation for further research on the mechanism and therapeutic targets of psoriasis.

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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.

Background insulin receptor substrate-1 (IRS-1) rs956115 is associated with vascular risk in patients with coronary artery disease (CAD) and concomitant diabetes. CYP2C19 rs4244285 modulates clopidogrel responsiveness and predicts outcome of CAD. We designed this study to explore the association between IRS-1 rs956115, CYP2C19 rs4244285, and platelet reactivity as well as 1-year outcome in patients with CAD undergoing percutaneous coronary intervention (PCI).Methods IRS-1 rs956115, CYP2C19 rs4244285 genotypes and platelet reactivity were assessed in 1611 post-PCI patients. Major adverse cardiovascular events (MACE) which were defined as a composite of cardiovascular death, myocardial infarction and ischemic stroke over 1-year were evaluated. One-way ANOVA was used to compare the platelet reactivity among different genotypes of rs956115 and rs4244285. Multivariable Cox proportional hazard model analysis was used to estimate the association between genotypes of rs956115 and rs4244285 and risk of MACE.Results At 1 month, patients with rs956115 CG genotype had significantly lower level of residual ADP-induced platelet aggregation (PLADP) than those with CC genotype. PLADP significantly increased with the number of rs4244285 A alleles. Patients with rs956115 CG or GG genotype had a 2.09-fold higher risk of MACE than those with CC genotype (adjusted HR=2.09; 95%CI:1.04-4.19; P=0.0376), and those with rs4244285 GA genotype had a 2.19-fold higher risk than GG homozygotes (adjusted HR=2.19; 95%CI:1.13-4.24; P=0.0200). There was no significant difference in risk between AA and GG homozygotes. No interaction between rs956115 and rs4244285 was observed. Conclusions In post-PCI patients, rs956115 GG/CG and rs4244285 GA genotypes were associated with 2.09- and 2.19-fold cardiovascular risks respectively at 1-year follow-up. The effect of rs956115 appeared to be independent of known clinical predictors, while that of rs4244285 GA could be mediated by lower clopidogrel response. Trial registration: Pharmacogenetic and Pharmacokinetic Study of Clopidogrel (PPSC), NCT01968499. Registered October 17, 2013 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01968499?term=NCT01968499&draw=1&rank=1