ABSTRACT
As drug development is extremely expensive, the identification of novel indications for in-market drugs is financially attractive. Multiple algorithms are used to support such drug repurposing, but highly reliable methods combining simulation of intracellular networks and machine learning are currently not available. We developed an algorithm that simulates drug effects on the flow of information through protein-protein interaction networks, and used support vector machine to identify potentially effective drugs in our model disease, psoriasis. Using this method, we screened about 1,500 marketed and investigational substances, identified 51 drugs that were potentially effective, and selected three of them for experimental confirmation. All drugs inhibited tumor necrosis factor alpha-induced nuclear factor kappa B activity in vitro, suggesting they might be effective for treating psoriasis in humans. Additionally, these drugs significantly inhibited imiquimod-induced ear thickening and inflammation in the mouse model of the disease. All results suggest high prediction performance for the algorithm.
Subject(s)
Drug Repositioning/methods , Gene Regulatory Networks/genetics , Protein Interaction Domains and Motifs , Protein Interaction Maps , Algorithms , Animals , Cell Line , Computer Simulation , Dermatitis/drug therapy , Drug Evaluation, Preclinical , Ear, External/pathology , Humans , Imiquimod , Machine Learning , Mice , Mice, Inbred BALB C , NF-kappa B/drug effects , Psoriasis/chemically induced , Psoriasis/drug therapy , RNA/biosynthesis , RNA/genetics , Support Vector Machine , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
BACKGROUND: Glycerol is known to possess anti-irritant and hydrating properties and previous studies suggested that xylitol may also have similar effects. OBJECTIVE: Our aim was to study whether different concentrations of these polyols restore skin barrier function and soothe inflammation in sodium lauryl sulphate (SLS)-induced acute irritation. METHODS: The experiments were performed on male SKH-1 hairless mice. The skin of the dorsal region was exposed to SLS (5%) for 3 h alone or together with 5% or 10% of glycerol respectively. Further two groups received xylitol solutions (8.26% and 16.52% respectively) using the same osmolarities, which were equivalent to those of the glycerol treatments. The control group was treated with purified water. Transepidermal water loss (TEWL) and skin hydration were determined. Microcirculatory parameters of inflammation were observed by means of intravital videomicroscopy (IVM). Furthermore, accumulation of neutrophil granulocytes and lymphocytes, the expression of inflammatory cytokines and SLS penetration were assessed, as well. RESULTS: Treatment with the 10% of glycerol and both concentrations of xylitol inhibited the SLS-induced elevation of TEWL and moderated the irritant-induced increase in dermal blood flow and in the number of leucocyte-endothelial interactions. All concentrations of the applied polyols improved hydration and prevented the accumulation of lymphocytes near the treatment site. At the mRNA level, neither glycerol nor xylitol influenced the expression of interleukin-1 alpha. However, expression of interleukin-1 beta was significantly decreased by the 10% glycerol treatment, while expression of tumour necrosis factor-alpha decreased upon the same treatment, as well as in response to xylitol. Higher polyol treatments decreased the SLS penetration to the deeper layers of the stratum corneum. CONCLUSION: Both of the analysed polyols exert considerable anti-irritant and anti-inflammatory properties, but the effective concentration of xylitol is lower than that of glycerol.
Subject(s)
Dermatitis, Irritant/drug therapy , Emollients/therapeutic use , Glycerol/therapeutic use , Skin Physiological Phenomena/drug effects , Skin/metabolism , Xylitol/therapeutic use , Animals , Dermatitis, Irritant/etiology , Dermatitis, Irritant/pathology , Emollients/pharmacology , Gene Expression/drug effects , Glycerol/pharmacology , Interleukin-1alpha/genetics , Interleukin-1beta/genetics , Intravital Microscopy , Male , Mice , Mice, Hairless , Permeability/drug effects , Regional Blood Flow/drug effects , Skin/blood supply , Skin/chemistry , Sodium Dodecyl Sulfate/pharmacokinetics , Tumor Necrosis Factor-alpha/genetics , Water/analysis , Water Loss, Insensible/drug effects , Xylitol/pharmacologyABSTRACT
BACKGROUND/AIMS: Phosphatidylcholine (PC)-derived choline exhibits anti-inflammatory properties in stress conditions. Phosphatidylethanolamine (PE) and N-acylphosphatidylethanolamines (NAPEs) are endogenous bioactive phospholipids linked to the PC and endocannabinoid metabolisms. We hypothesized that an increased dietary input of PC, PE and NAPE may interfere with leukocyte reactions and thus decreases the inflammatory activation. METHODS: CFLP mice were fed with a control diet or with a diet supplemented with 1% PC, 0.4% PE and 0.1% NAPE for 7 days before the induction of pleurisy with carrageenan. Pleural leukocyte migration, pulmonary mast cell degranulation (Alcian blue-safranin O staining), and the activities of inducible nitric oxide synthase, xanthine oxidoreductase and myeloperoxidase were determined in lung tissue biopsies. RESULTS: The carrageenan-induced inflammatory response was characterized by pulmonary leukocyte infiltration, mast cell degranulation and significantly increased inducible nitric oxide synthase and xanthine oxidoreductase activities (by 82 and 60%, respectively). Treatment of mice with acetylsalicylic acid or with dietary PC + PE + NAPE supplementation significantly decreased the leukocyte reaction, and suppressed the activity of the pulmonary proinflammatory enzymes. CONCLUSION: This study confirms a potential for dietary PC + PE + NAPE supplementation to influence events crucial for the remission of acute inflammation. PC + PE + NAPE administration could possibly be a novel preventive or pharmacotherapeutic option in inflammatory pathologies.