Scientific PublicationsPeer Reviewed Articles, Conference Posters, Publications on Technology
The selexipag active metabolite ACT-333679 displays strong anti-contractile and anti- remodeling effects, but low β-arrestin recruitment and desensitization potential
The Journal of Pharmacology and Experimental Therapeutics, 2017
Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular matrix synthesis. Selexipag (Uptravi®) is the first non-prostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of selexipag and the main contributor to clinical efficacy, ACT-333679 (previously known as MRE-269), behaved as full agonist in multiple PAH-relevant receptor-distal – or downstream – cellular readouts with a maximal efficacy comparable to that of the prototypic PGI2analog iloprost: In PASMC, ACT-333679 potently induced cellular relaxation (EC50=4.3 nM), inhibited cell proliferation (IC50=4.0 nM) as well as extracellular matrix synthesis (IC50=8.3 nM). In contrast, ACT-333679 displayed partial agonism in receptor-proximal – or upstream – cAMP accumulation assays (Emax=56%) when compared to iloprost (Emax=100%) and the PGI2 analogs beraprost and treprostinil. Partial agonism of ACT-333679 also resulted in limited β-arrestin recruitment (Emax=40%) and lack of sustained IP receptor internalization, whereas all tested PGI2analogs behaved as full agonists in these desensitization-related assays. In line with these in vitro findings, selexipag, but not treprostinil, displayed sustained efficacy in rat models of pulmonary and systemic hypertension. Thus, the partial agonism of ACT-333679 allows for full efficacy in amplified receptor-distal PAH-relevant readouts while causing limited activity in desensitization-related receptor-proximal readouts.
Live Single-cell Mass Spectrometry with Spatial Quantitation by Three-Dimensional Holographic and Tomographic Laser Microscopy
Analytical Sciences as Rapid Communication, 2016
The locations and volumes of the contents of a single HepG2 cell were visualized under three-dimensional (3D) holographic and tomographic (HT) laser microscopy, colored by refractive index, not staining. After trapping the specific area of a target cell in a nanospray tip, quantification was performed by live single-cell mass spectrometry. Comparison of the HepG2 cells’ before and after 3D-HT images allowed the inference of the precise volume and original location of the trapped cell contents. The total amount of a trapped molecule was estimated. The images also revealed morphological changes in the cell structure caused by the manipulation.
Tomographic Holographic Microscopy for Nano-Scale Dose Calculation and Assessing Gold Nanoparticle Uptake in Live Cells
Nanomicroscopy for Live Cell tomography
The Handbook of Nanomedicine, Third Edition, 2017
Characterising live cell behaviour: Traditional label-free and quantitative phase imaging approaches
The International Journal of Biochemistry & Cell Biology, 2017