作者: Matsopoulos, George K ; Zareifi, Danae Stella ; Vezakis, Antonis ; Sofotasiou, Maria ; Alexopoulos, Leonidas G ; Meimetis, Nikos ; Chala, Nafsika ; Chaliotis, Odysseas ; Fragulidis, Georgios ; Zeakis, Konstantinos ; Pantiora, Eirini

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver pathologies, however, none approved condition-specific therapy yet exists. The present study introduces a drug repositioning (DR) approach that combines in vitro steatosis models with a network-based computational platform, constructed upon genomic data from diseased liver biopsies and compound-treated cell lines, to propose effectively repositioned therapeutic compounds. The introduced in silico approach screened 20'000 compounds, while complementary in vitro and proteomic assays were developed to test the efficacy of the 46 in silico predictions. This approach successfully identified six compounds, including the known anti-steatogenic drugs resveratrol and sirolimus. In short, gallamine triethiotide, diflorasone, fenoterol, and pralidoxime ameliorate steatosis similarly to resveratrol/sirolimus. The implementation holds great potential in reducing screening time in the early drug discovery stages and in delivering promising compounds for in vivo testing.

2014-07-01·Mitochondrion3区 · 生物学

High-throughput screening of FDA-approved drugs using oxygen biosensor plates reveals secondary mitofunctional effects

3区 · 生物学

Article

作者: Tomilov, Alexey ; Sahdeo, Sunil ; Hagerman, Paul ; Iwahashi, Christine ; Datta, Sandipan ; Komachi, Kelly ; Cortopassi, Gino ; Hughes, Owen

Repurposing of FDA-approved drugs with effects on mitochondrial function might shorten the critical path to mitochondrial disease drug development. We improved a biosensor-based assay of mitochondrial O2 consumption, and identified mitofunctional defects in cell models of LHON and FXTAS. Using this platform, we screened a 1600-compound library of clinically used drugs. The assay identified drugs known to affect mitochondrial function, such as metformin and decoquinate. We also identified several drugs not previously known to affect mitochondrial respiration including acarbose, metaraminol, gallamine triethiodide, and acamprosate. These previously unknown 'mitoactives' represent novel links to targets for mitochondrial regulation and potentially therapy, for mitochondrial disease.

2013-10-21·Investigative Opthalmology & Visual Science2区 · 医学

Episcleral Venous Pressure and IOP Responses to Central Electrical Stimulation in the Rat

2区 · 医学

ArticleOA

作者: Reitsamer, Herbert A. ; Kiel, Jeffrey W. ; Strohmaier, Clemens A.

PURPOSEHistological evidence suggests a role for the central nervous system in controlling episcleral venous pressure (EVP). Based on prior studies that identified candidate regions in the brain stem, the present study assessed the effect of electrical stimulation at the location of the superior salivatory nucleus (SSN) on EVP in rats.METHODSMale Sprague-Dawley rats (n = 11) were anesthetized using pentobarbital sodium (50 mg/kg intraperitoneally initially, supplemented intravenously [IV] as needed) and paralyzed with gallamine triethiodide (1 mg/kg, IV). The animals were artificially ventilated and the femoral artery and vein were cannulated for blood pressure measurement and drug administration. Carotid blood flow was measured with an ultrasound flow probe and heart rate with a cardiotachometer. IOP was measured through a cannula in the vitreous compartment and EVP was measured through a micropipette in episcleral veins using the servonull technique. After a craniotomy was performed, a unipolar stainless steel electrode was inserted into the brainstem at the coordinates of the SSN using a stereotactic instrument. Stimulations were performed at 20Hz, 9 μA, 1 ms pulse duration, and 200 pulses.RESULTSStimulation at the SSN coordinates increased IOP from 10.6 ± 0.4 to 11.8 ± 0.6 mm Hg (P < 0.01) and EVP from 7.8 ± 1.3 to 10.7 ± 1.1 mm Hg (P < 0.01). Mean arterial pressure, carotid blood flow, and heart rate remained unaltered.CONCLUSIONSThe present study indicates that the SSN may participate in regulating EVP.

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