Formononetin attenuates psoriasiform inflammation by regulating interferon signaling pathway.

BACKGROUND: Psoriasis is a long-lasting, inflammatory, continuous illness caused through T cells and characterized mainly by abnormal growth and division of keratinocytes. Currently, corticosteroids are the preferred option. However, prolonged use of traditional topical medication can lead to adverse reactions and relapse, presenting a significant therapeutic obstacle. Improved alternative treatment options are urgently required. Formononetin (FMN) is a representative component of isoflavones in Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.]. It possesses properties that reduce inflammation, combat oxidation, inhibit tumor growth, and mimic estrogen. Although FMN has been shown to ameliorate skin barrier devastation via regulating keratinocyte apoptosis and proliferation, there are no reports of its effectiveness in treating psoriasis. OBJECTIVE: Through transcriptomics clues and experimental investigation, we aimed to elucidate the fundamental mechanisms underlying FMN's action on psoriasis. MATERIALS AND METHODS: Cell viability was examined using CCK8 assay in this study. The results of analysis of differentially expressed genes (DEGs) between FMN-treated HaCaT cells and normal HaCaT cells using RNA-sequencing (RNA-seq) were presented on volcano plots and heatmap. Enrichment analysis was conducted on DEGs using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), and results were validated through RT-qPCR verification. After 12 days of FMN treatment in psoriasis mouse model, we gauged the PASI score and epidermis thickness. A variety of techniques were used to assess FMN's effectiveness on inhibiting inflammation and proliferation related to psoriasis, including RT-qPCR, HE staining, western blot, and immunohistochemistry (IHC). RESULTS: The findings indicated that FMN could suppress the growth of HaCaT cells using CCK8 assay (with IC50 = 40.64 uM) and 20 uM FMN could reduce the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to the greatest extent. FMN-treated HaCaT cells exhibited 985 up-regulated and 855 down-regulated DEGs compared to normal HaCaT cells. GO analysis revealed that DEGs were linked to interferon (IFN) signaling pathway. Furthermore, FMN improved pathological features, which encompassed decreased erythema, scale, and thickness scores of skin lesions in psoriasis mouse model. In vivo experiments confirmed that FMN down-regulated expression of IFN-α, IFN-ß, IFN-γ, decreased secretion of TNF-α and IL-17 inflammatory factors, inhibited expression of IFN-related chemokines included Cxcl9, Cxcl10, Cxcl11 and Cxcr3 and reduced expression of transcription factors p-STAT1, p-STAT3 and IFN regulatory factor 1 (IRF1) in the imiquimod (IMQ) group. CONCLUSIONS: In summary, these results suggested that FMN played an anti-inflammatory and anti-proliferative role in alleviating psoriasis by inhibiting IFN signaling pathway, and FMN could be used as a potential therapeutic agent.

Qinzhuliangxue mixture ameliorates psoriasis by restraining apoptosis in psoriasis via downregulating the MDA-5 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is characterized by hyperkeratosis that produces the classic silvery scales, and the pathogenesis of psoriasis involves abnormal proliferation of keratinocytes. Emerging evidence supports that apoptosis regulates keratinocyte proliferation and formation of stratum corneum, which maintains the homeostasis of the skin. Qinzhuliangxue mixture (QZLX) is a representative formula for the treatment of psoriasis, which was earliest recorded in the classic Chinese medicine book Xia's Surgery. In our previous clinical studies, QZLX demonstrated 83.33% efficacy with few side effects in the treatment of psoriasis. Furthermore, our published basic research has also proved that the QZLX mixture effectively inhibits the hyperproliferation of keratinocytes, thus exerting therapeutic effects on psoriasis. However, whether QZLX mixture can regulate keratinocytes apoptosis requires further clarification. OBJECTIVE OF THE STUDY: To investigate the mechanism of QZLX in the treatment of psoriasis from the perspective of keratinocyte apoptosis. MATERIALS AND METHODS: First, psoriasis-like mice with imiquimod (IMQ)-induced were given QZLX intragastric administration and Psoriasis Area Severity Index (PASI) scores were recored for 11 consecutive days to appraise the efficacy. Then, tissue samples were collected for transcriptome analysis. The DEseq2 method detected significantly differentially expressed genes (DEGs), Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway databases were used to analyze the functions and pathway enrichment of DEGs. After that, the therapeutic mechanisms of QZLX in intervening with psoriasis were explored using TUNEL, immunohistochemical staining, and western blotting. RESULTS: QZLX ameliorated the symptoms and pathological characteristics of IMQ-induced psoriasis in mice. The epidermal cell hyperplasia in the skin was inhibited, in accordance with the suppressed expression of PCNA and Ki67 after treatment. Transcriptome sequencing showed that melanoma differentiation associated gene-5 (MDA-5) was downregulated. GO and KEGG enrichment analysis of the signaling pathways indicated that the differentially expressed genes were significantly enriched in apoptosis pathways. Besides, QZLX treatment decreased the apoptosis of keratinocyte as shown by reduced TUNEL-positive cells. As MDA-5 protein levels decreased, so did the expression of the downstream protein Caspase-8, which indicates that the apoptotic pathway was triggered. Furthermore, QZLX therapy might also help to balance the apoptotic Bcl-2 family expression. CONCLUSION: QZLX restrains the apoptosis of keratinocyte in psoriasis-like mice by downregulating the MDA-5 pathway. The restoration of the balance between cell apoptosis and proliferation in the skin may lead to considerable psoriasis relief. Our study reveals the possible molecular processes behind the effects of QZLX therapy on the skin lesions of psoriasis, and lends support to its clinical efficacy.

The therapeutic efficacy and mechanism action of Si Cao formula in the treatment of psoriasis: A pilot clinical investigation and animal validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is a chronic inflammation and relapsing disease that affected approximately 100 million individuals worldwide. In previous clinical study, it was observed that the topical application of Si Cao Formula (SCF) ameliorated psoriasis skin lesions and reduced the recurrence rate of patients over a period of three months. However, the precise mechanism remains unclear. AIM OF THE STUDY: The objective of this study was to assess the effectiveness and safety of SCF in patients diagnosed with psoriasis and explore the molecular mechanisms that contribute to SCF's therapeutic efficacy in psoriasis treatment. MATERIALS AND METHODS: A randomized, controlled, and pilot clinical study was performed. This study assessed 30 individuals diagnosed with mild to moderate plaque psoriasis. 15 of them underwent local SCF treatment, the others received calcipotriol intervention. The outcome measure focused on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and recurrence rate. In addition, IMQ-induced psoriasis-like mice model were used to assess the impact of SCF on ameliorating epidermal hyperplasia, suppressing angiogenesis, and modulating immune response. Furthermore, we performed bioinformatics analysis on transcriptome data obtained from skin lesions of mice model. This analysis allowed us to identify the targets and signaling pathways associated with the action of SCF. Subsequently, we conducted experimental validation to confirm the core targets. RESULTS: Our clinical pilot study demonstrated that SCF could ameliorate skin lesions in psoriasis patients with comparable efficacy of calcipotriol in drop of PASI and DLQI scores. SCF exhibited a significantly reduced recurrence rate within 12 weeks (33.3%). Liquid Chromatography Mass Spectrometry (LC-MS) identified 41 active constituents of SCF (26 cations and 15 anions). Animal experiments showed SCF ameliorates the skin lesions of IMQ-induced psoriasis like mice model and suppresses epidermal hyperkeratosis and angiogenesis. There were 845 up-regulated and 764 down-regulated DEGs between IMQ and IMQ + SCF groups. GO analysis revealed that DEGs were linked to keratinization, keratinocyte differentiation, organic acid transport epidermal cell differentiation, and carboxylic acid transport interferon-gamma production. KEGG pathway analysis showed that SCF may play a vital part through IL-17 and JAK/STAT signaling pathway. In addition, SCF could reduce the number of positive cells expressing PCNA, CD31, pSTAT3, CD3, and F4/80 within the epidermis of psoriatic lesions, as well as the expression of Il-17a and Stat3 in IMQ-induced psoriasis mice. CONCLUSIONS: Our research suggests that SCF serves as a reliable and efficient local approach for preventing and treating psoriasis. The discovery of plausible molecular mechanisms and therapeutic targets associated with SCF may support its broad implementation in clinical settings.

Discovering Novel Biomarkers Associated with the Pathogenesis of Psoriasis: Evidence from Bioinformatic Analysis.

Objective: This study aimed to investigate key biomarkers and their molecular pathogenesis in psoriasis. Methods: Differentially expressed genes (DEGs) of datasets (GSE13355, GSE30999, and GSE106992) obtained from Gene Expression Omnibus (GEO) were identified using Venn diagram. Function and pathway enrichment analyses were performed. Protein-protein interaction (PPI) network and the hub genes were constructed. The correlation between normal tissue and infiltrating immune cells was analyzed by CIBERSORT. ROC analysis was performed to distinguish between skin lesion samples and skin non-lesion samples. Analyze the highest expression of single gene in the whole body within the Human Protein Atlas (HPA) database. Effect of CXCL8 expression level on proliferation, invasion, migration and apoptosis of HaCat cells was detected by qPCR. Results: A total of 239 pairs of normal and lesional skin samples were downloaded. PPI network revealed a tight interaction among 197 DEGs. The GO enrichment analysis showed that these genes were markedly enriched in the "defense response to virus", "type I interferon signaling pathway", and "cell response to type I interferon" categories. The KEGG pathway analysis showed that the DEGs were mainly in the NOD-like receptor axis, interaction between cytokine and cytokine receptor and the IL-17 axis. PPI analysis showed that CXCL8 was the novel hub gene of psoriasis and correlated to 22 types of infiltrating immune cells. 6 miRNAs were predicted to be related to CXCL8. CXCL8 was most widely distributed in lymphoid tissues and plays a role in psoriatic inflammatory lesions by promoting cell proliferation, migration, and anti-apoptosis. Conclusion: CXCL8 plays a key role in psoriasis development. This study provided new insights into the exploration of molecular mechanisms and therapeutic targets of psoriasis.

Integrated bioinformatic analysis of key biomarkers and signalling pathways in psoriasis.

BACKGROUND AND AIMS: Psoriasis is a relatively common autoimmune inflammatory skin disease with a chronic etiology. Since psoriasis is still incurable, it is necessary to identify the molecular mechanisms of psoriasis. The present study was designed to detect novel biomarkers and pathways associated with psoriasis incidence, and provide new insights into treatment of psoriasis. METHODS AND RESULTS: Differentially expressed genes (DEGs) associated with psoriasis in the Gene Expression Omnibus (GEO) database were identified, and their functional roles and interactions were then annotated and evaluated through GO, KEGG, and gene set variation (GSVA) analyses. In total 197 psoriasis-related DEGs were identified and found to primarily be associated with the NOD-like receptor, IL-17, and cytokine-cytokine receptor interaction signalling pathways. GSVA revealed significant differences between normal and lesional groups (P < 0.05), while PPI network analyses identified CXCL10 as the hub gene with the highest degree value, whereas IRF7, IFIT3, OAS1, GBP1, and ISG15 were promising candidate genes for the therapeutic treatment of psoriasis. CONCLUSION: The findings of the present integrated bioinformatics may enhance our understanding of the molecular events occurring in psoriasis, and these candidate genes and pathways together may prove to be therapeutic targets for psoriasis.

Herb Sanqi-Derived Compound K Alleviates Oxidative Stress in Cultured Human Melanocytes and Improves Oxidative-Stress-Related Leukoderma in Guinea Pigs.

Sanqi, a traditional Chinese herb, is widely used for cardiovascular diseases, and its neuroprotective effects against oxidative stress were recently discovered. The purpose of this study was to investigate whether Sanqi-derived compound K (Sanqi-CK), an active metabolite of Sanqi, could protect melanocytes from oxidative stress. Cultured human primary skin epidermal melanocytes (HEMn-MPs) were treated with hydrogen peroxide (H2O2) in the presence or absence of Sanqi-CK. Sanqi-CK exhibited protective effects against H2O2-induced cell death by reducing oxidative stress. In addition, treatment with Sanqi-CK reversed the decreased glutathione reductase activity and decreased ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) seen in H2O2-treated melanocytes. Furthermore, topical application of Sanqi-CK alleviated leukoderma in guinea pigs, a disorder characterized by melanocyte cell death resulting from rhododendrol-induced oxidative stress. Taken together, these data suggest that Sanqi-CK protects melanocytes against oxidative stress, and its protective effects are associated with modulating the redox balance between GSH and GSSG and activating glutathione reductase. Thus, Sanqi-CK may be a good candidate for preventing melanocyte loss in oxidative-stress-associated pigmentary disorders.

The first case report of kerion-type scalp mycosis caused by Aspergillus protuberus.

BACKGROUND: Scalp mycosis is often caused by dermatophytes and was so called tinea capitis. There is no published report caused by Aspergillus protuberus. We report a rare case of kerion-type scalp mycosis caused by A. protuberus. CASE PRESENTATION: A 5-year-old girl developed pyogenic mass with pain for 8 days and got a fever for 2 days prior to admission. Surgical incision and drainage of the mass, intravenous cefuroxime and metronidazole in the local hospital aggravated the skin lesions. Species identification was performed by observation of morphologic and biochemical characteristicsand sequencing of the internal transcribed spacer (ITS) and ß-tubulin (BT2). Treatment with oral and topical antifungal agents was effective with no relapse during the six months of clinical follow-up. CONCLUSIONS: Aspergillusis a opportunistic pathogenic fungus and its infection occurs mostly in patients with underlying conditions and immunocompromised statuses. So far no report of kerion-type scalp infection has been reported. The first case of kerion-type scalp mycosis caused by A. protuberus was described to highlight the importance of mycological examination that helps to recognize rare pathogenic fungi. Any boggy lesion with hair loss over the scalp and non-responsive to antibiotics should be suspected as resulting from fungal infection, and mycological examination should be performed, especially in children.

Total glucosides of paeony for the treatment of psoriasis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Psoriasis is a common chronic relapsing immune-mediated inflammatory disease, the prevalence of which has increased in recent years. At present, there are many treatment methods available for the condition, but the curative effect is unsatisfactory. HYPOTHESIS/PURPOSE: This study aimed to evaluate the efficacy, adverse reactions, and recurrence rates of using paeoniflorin capsules for psoriasis treatment. STUDY DESIGN: systematic review and meta-analysis. METHODS: Randomized controlled trials comparing total glycosides of paeony (TGP) with other treatments for patients with psoriasis were retrieved by searching EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials electronic databases. Cochrane bias risk tool was used to evaluate the quality of randomized controlled trial (RCT) methodology. The primary outcome measure is the effective number. Secondary outcomes included psoriasis area and severity index (PASI), adverse reactions, recurrence, and inflammatory biomarkers. RESULTS: In all, 30 RCTs with 2,802 participants were included in this meta-analysis. The studies were generally of low methodological quality. Although there was no statistically significant difference between the use of TGP capsule alone and other monotherapies in the treatment of psoriasis (RR: 0.93; 95% CI: 0.76-1.15; p = 0.50), the addition of TGP to other therapies had an advantage over monotherapy with regard to the effective number (RR: 1.31; 95% CI: 1.26-1.37; p < 0.00001), PASI (RR: -3.40; 95% CI: -4.22,-2.57; p < 0.00001), adverse reactions, recurrence rate (RR: 0.42; 95% CI: 0.24-0.74; p = 0.002), and inflammatory inhibition (RR:-12.54; 95% CI: -18.50, -6.59; p < 0.0001). CONCLUSIONS: TGP can be used to treat psoriasis with reduced adverse reactions and recurrence rates. However, the mechanism of TGP in psoriasis treatment requires to be evaluated further in high-quality, large-sample, and rigorous clinical studies.

Comparisons of gene expression in normal, lesional, and non-lesional psoriatic skin using DNA microarray techniques.

OBJECTIVES: This study was designed to explore the pathogenesis of psoriasis and to identify potential bio-targets. Genome array technology was used to analyze the gene expression profiles of lesional and non-lesional psoriatic skin samples and normal skin samples. METHODS: Gene expression profile GSE14905 was downloaded from the Gene Expression Omnibus (GEO) database. This included skin biopsy samples from normal healthy donors (n = 21), lesional skin biopsy samples from psoriasis patients (n = 33), and non-lesional skin biopsy samples from psoriasis patients (n = 28). Differentially expressed genes (DEGs) were identified using the Limma package in R language. Functions of specific DEGs were predicted by Gene Ontology (GO) enrichment analysis. A protein-protein interaction network was constructed to display the interactions among common DEGs. Finally, DAVID and WebGestalt were used to achieve a functional analysis of common DEGs. RESULTS: Totals of 1020, 562, and 643 genes, respectively, were identified as being differentially expressed in normal versus lesional, normal versus non-lesional, and lesional versus non-lesional samples. The specific DEGs in the three groups were enriched for several GO terms, including mitotic cell cycle, immune response, and response to organic matter. The 40 common DEGs in the three groups may be involved in the defense response pathway in the development of psoriasis. Furthermore, three genes (RGS1, SOCS3, and NAMPT) may play key roles in distinguishing lesional and non-lesional tissues from normal tissues, and 10 genes (PTRRC, ALDH1A3, SAMSA1, C15orf48, ZC3H12A, SOD2, IL8, LTF, RHCG, and IL7R) may play key roles in distinguishing non-lesional from normal and lesional samples. CONCLUSIONS: These genes may be considered as potential diagnostic markers and targets of therapeutics in psoriasis.