Drug Repurposing by Simulating Flow Through Protein-Protein Interaction Networks.

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.

Abnormal regulation of fibronectin production by fibroblasts in psoriasis.

BACKGROUND: Data indicate that in psoriasis, abnormalities are already present in nonlesional skin. Transforming growth factor-ß and keratinocyte growth factor (KGF), together with fibronectin and α5ß1 integrin, were suggested to play a crucial role in the pathogenesis of psoriasis by influencing inflammation and keratinocyte hyperproliferation. OBJECTIVES: To investigate the expression of KGF, fibroblast growth factor receptor (FGFR)2, fibronectin (FN) and extra domain A (EDA)-positive FN in healthy and nonlesional psoriatic skin, and to study the effect of KGF on the regulation of FN and EDA(+) FN production by fibroblasts. METHODS: Healthy, nonlesional psoriatic skin and lesional psoriatic skin were immunostained for α5 integrin, KGF, FGFR2, EDA(+) FN and signal transducer and activator of transcription (STAT)1. KGF-treated cell cultures were analysed for FN and EDA(+) FN mRNA and protein by real-time reverse-transcriptase polymerase chain reaction and flow cytometry, respectively. The major downstream signalling of KGF was investigated by blocking experiments using inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK1), AKT1/2, STAT1 and STAT3. RESULTS: The expression of α5 integrin, EDA(+) FN, KGF and its receptor FGFR2 is elevated in psoriatic nonlesional skin compared with healthy skin. KGF mildly induced EDA(+) FN, but not FN expression in healthy fibroblasts through MAPK signalling. Fibroblasts express the FGFR2-IIIc splice variant. STAT1 negatively regulates both FN and EDA(+) FN expression in healthy fibroblasts, and this regulation is compromised in fibroblasts derived from nonlesional psoriatic dermis. We detected active STAT1 in healthy and lesional skin, similarly to a previous report. However, in the nonlesional skin STAT1 activation was absent in tissues far away from lesions. CONCLUSIONS: The production of FN and EDA(+) FN by fibroblasts and the signalling of STAT1 are abnormally regulated in psoriatic nonlesional skin.

Secretin attenuates the hereditary repetitive hyperactive movements in a mouse model.

It was previously demonstrated that secretin influenced the behavior of rats investigated by open-field test. In the present experiment, we have compared the effect of intracerebroventricular administration of 2 µg of secretin on the behavior of CFLP white and Japanese waltzing mice. These latter animals exhibit stereotypic circular movements. The effect of secretin on the horizontal (ambulation) and vertical movements (rearing and jumping) was investigated in open-field test. The ambulation time and distance were shorter, and the number of rearing and jumping were much lower in Japanese waltzing mice than in CFLP white mice during 30 min-experimental period. In white mice, 2 µg of secretin had no effect on the above-mentioned parameters; however, in Japanese waltzing mice, secretin enhanced the ambulation time and distance to the level of CFLP white mice, but did not influence the rearing and jumping. On the basis of the results, it was concluded that intracerebroventricularly administered secretin attenuated the stereotypic (circulating) movement and improved the horizontal movement indicated by the normalization of the ambulation time and distance; however, it did not influence the explorative behavior (rearing and jumping) in our special animal model.