Browsing by Subject "PLASMA-MEMBRANES"

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  • Hellinen, Laura; Hongisto, Heidi; Ramsay, Eva; Kaarniranta, Kai; Vellonen, Kati-Sisko; Skottman, Heli; Ruponen, Marika (2020)
    The retinal pigment epithelial (RPE) cell monolayer forms the outer blood-retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We compared the barrier properties of several RPE secondary cell lines (ARPE19, ARPE19mel, and LEPI) and both primary (hfRPE) and stem-cell derived RPE (hESC-RPE) cells by investigating the permeability of nine drugs (aztreonam, ciprofloxacin, dexamethasone, fluconazole, ganciclovir, ketorolac, methotrexate, voriconazole, and quinidine) across cell monolayers. ARPE19, ARPE19mel, and hfRPE cells displayed a narrow P-app value range, with relatively high permeation rates (5.2-26 x 10(-6) cm/s. In contrast, hESC-RPE and LEPI cells efficiently restricted the drug flux, and displayed even lower P-app values than those reported for bovine RPE-choroid, with the range of 0.4-32 cm(-6)/s (hESC-RPE cells) and 0.4-29 x 10(-6) cm/s, (LEPI cells). Therefore, ARPE19, ARPE19mel, and hfRPE cells failed to form a tight barrier, whereas hESC-RPE and LEPI cells restricted the drug flux to a similar extent as bovine RPE-choroid. Therefore, LEPI and hESC-RPE cells are valuable tools in ocular drug discovery.
  • Postila, Pekka A.; Vattulainen, Ilpo; Rog, Tomasz Jakub (2016)
    Atomistic molecular dynamics simulations were performed with 13 non-peptidic neurotransmitters (NTs) in three different membrane environments. The results provide compelling evidence that NTs are divided into membrane-binding and membrane-nonbinding molecules. NTs adhere to the postsynaptic membrane surface whenever the ligand-binding sites of their synaptic receptors are buried in the lipid bilayer. In contrast, NTs that have extracellular ligand-binding sites do not have a similar tendency to adhere to the membrane surface. This finding is a seemingly simple yet important addition to the paradigm of neurotransmission, essentially dividing it into membrane-independent and membrane-dependent mechanisms. Moreover, the simulations also indicate that the lipid composition especially in terms of charged lipids can affect the membrane partitioning of NTs. The revised paradigm, highlighting the importance of cell membrane and specific lipids for neurotransmission, should to be of interest to neuroscientists, drug industry and the general public alike.
  • Mysore, Yashavanthi; del Amo, Eva M.; Loukovaara, Sirpa; Hagström, Marja; Urtti, Arto; Kauppinen, Anu (2021)
    Proliferative vitreoretinopathy (PVR) with rhegmatogenous retinal detachment (RRD) is a complex inflammatory ocular disease. Statins are widely used cholesterol-lowering drugs with putative anti-inflammatory properties. In this study, we have explored their efficacy in controlling post-surgical PVR formation. Simvastatin (SIM), atorvastatin (ATV), or rosuvastatin (RSV) were added to cultures of human retinal pigment epithelial cells (ARPE-19) prior to exposure with the bacterial lipopolysaccharide (LPS), and the production of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) was examined using an enzyme-linked immunosorbent assay. In addition, the concentrations of simvastatin, atorvastatin, rosuvastatin, and their metabolites were measured from the vitreal samples of 20 patients undergoing vitrectomy (16 of them receiving oral statin therapy) using an ultra-performance liquid chromatography-tandem mass spectrometer technique. All statins alleviated LPS-induced inflammation at 5 µM concentration in the ARPE-19 cell cultures. Statin levels in the vitreous samples ranged from 6 to 316 pg/mL (ca. 0.1–7 M−10). Vitreal statin concentrations were similar to the typical steady-state unbound statin concentrations in plasma, indicating that only the unbound drug distributes from the blood circulation into the vitreous. Pharmacokinetic simulations of the intravitreal delivery of statins indicate that the measured clinical statin concentrations could be maintained with existing drug delivery technologies for months. Our results suggest that intravitreal statin therapy may have the potential in alleviating the risk of post-surgical PVR.