Hub genes, diagnostic model, and predicted drugs in systemic sclerosis by integrated bioinformatics analysis.
作者: Yue-Mei Yan ; Meng-Zhu Jin ; Sheng-Hua Li ; Yun Wu ; Qiang Wang ; Fei-Fei Hu ; Chen Shen ; Wen-Hao Yin
Background: Systemic sclerosis (scleroderma; SSc), a rare and heterogeneous connective tissue disease, remains unclear in terms of its underlying causative genes and effective therapeutic approaches. The purpose of the present study was to identify hub genes, diagnostic markers and explore potential small-molecule drugs of SSc. Methods: The cohorts of data used in this study were downloaded from the Gene Expression Complex (GEO) database. Integrated bioinformatic tools were utilized for exploration, including Weighted Gene Co-Expression Network Analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) regression, gene set enrichment analysis (GSEA), Connectivity Map (CMap) analysis, molecular docking, and pharmacokinetic/toxicity properties exploration. Results: Seven hub genes (THY1, SULF1, PRSS23, COL5A2, NNMT, SLCO2B1, and TIMP1) were obtained in the merged gene expression profiles of GSE45485 and GSE76885. GSEA results have shown that they are associated with autoimmune diseases, microorganism infections, inflammatory related pathways, immune responses, and fibrosis process. Among them, THY1 and SULF1 were identified as diagnostic markers and validated in skin samples from GSE32413, GSE95065, GSE58095 and GSE125362. Finally, ten small-molecule drugs with potential therapeutic effects were identified, mainly including phosphodiesterase (PDE) inhibitors (BRL-50481, dipyridamole), TGF-β receptor inhibitor (SB-525334), and so on. Conclusion: This study provides new sights into a deeper understanding the molecular mechanisms in the pathogenesis of SSc. More importantly, the results may offer promising clues for further experimental studies and novel treatment strategies.
2022-02-27·The Journal of pharmacology and experimental therapeutics3区 · 医学
PK/PD Assessment of Selective Phosphodiesterase Inhibitors in a Mouse Model of Autoimmune Hepatitis.
3区 · 医学
作者: Artur Świerczek ; Bartosz Pomierny ; Elżbieta Wyska ; William J Jusko
Autoimmune hepatitis (AIH) is a life-threatening disorder currently treated with non-specific immunosuppressive drugs. It is postulated that phosphodiesterase (PDE) inhibitors, as agents exerting anti-inflammatory and immunomodulatory activities, may constitute a possible treatment for autoimmune disorders. This study develops a PK/PD model to assess the effects of PDE-selective inhibitors, namely, cilostazol (PDE3), , rolipram (PDE4), and BRL-50481 (PDE7), in a mouse model of AIH. The pharmacokinetics of the PDE inhibitors (PDEi) were assessed in male BALB/c mice following IP administration. In pharmacodynamic studies, mice received PDEi and AIH was induced in these animals by IV injection of concanavalin A (ConA). Serum drug concentrations, TNFα, IL-17, and aminotransferase activities were quantified. The PK/PD analysis was performed using ADAPT5 software. The PK/PD model assumes inhibition of cAMP hydrolysis in T-cells by PDEi, ConA-triggered formation of TNFα and IL-17, suppression of TNFα and IL-17 production by cAMP, and stimulatory effects of TNFα and IL-17 on the hepatic release of aminotransferases. Selective blockage of PDE4 leads to the highest inhibition of cAMP degradation in T-cells and amelioration of disease outcomes. However, inhibition of both PDE3 and PDE7 also contribute to this effect. The proposed PK/PD model may be used to assess and predict the activities of novel PDEi and their combinations in ConA-induced hepatitis. A balanced suppression of different types of PDE appears to be a promising treatment option for AIH; however, this hypothesis warrants testing in humans based on translation of the PK/PD model into clinical settings. Significance Statement A novel PK/PD model of PDE inhibitor effects in mice with ConA-induced autoimmune hepatitis was developed involving a mechanistic component describing changes in cAMP concentrations in mouse T-cells. According to model predictions, inhibition of PDE4 in T cells causes the highest cAMP elevation in T cells, but suppression of PDE3 and PDE7 also contribute to this effect. A balanced inhibition of PDE3, PDE4 and PDE7 appears to be a promising treatment strategy for AIH.
2022-01-04·Archives of pharmacal research3区 · 医学
The effects of BRL-50481 on ovalbumin-induced asthmatic lung inflammation exacerbated by co-exposure to Asian sand dust in the murine model.
3区 · 医学
作者: Hong Jo Kim ; Jin Yong Song ; Tae Il Park ; Won Seok Choi ; Jong Heon Kim ; Oh Seong Kwon ; Ji-Yun Lee
Asian sand dust (ASD), which mainly originates in China and Mongolia in the spring and blows into Korea, can exacerbate respiratory and immunological diseases. This study aims to observe effects of co-exposure to ASD on ovalbumin (OVA)-induced asthmatic lung inflammation and of treatment with a phosphodiesterase 7 (PDE7) inhibitor in a mouse model. The challenge with OVA increased airway hyperresponsiveness (AHR) and inflammatory cell infiltration into the lung tissue. Interleukin (IL)-13, tumor necrosis factor-alpha, monocyte-protein-1, mucin, and antigen-specific IgE and IgG1 production increased in mouse serum. The co-exposure of ASD significantly exacerbated these effects in this asthma model. Notably, the administration of a PDE7 inhibitor, BRL-50481 (BRL), significantly reduced AHR, infiltration of inflammatory cells into the lungs, and the levels of type 2 T helper cell-related cytokines, antigen-specific immunoglobulins, and mucin. Thus, the administration of BRL ameliorated OVA-induced allergic asthmatic responses exacerbated by co-exposure to ASD. This study suggests that PDE7 inhibition can be a therapeutic strategy for inflammatory lung diseases and asthma via the regulation of T lymphocytes and reduction of IL-13, and, consequently, mucin production.