| 1. |
- Hellinen, Laura, et al.
(author)
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Inhibition of prolyl oligopeptidase : A promising pathway to prevent the progression of age-related macular degeneration
- 2022
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In: Biomedicine and Pharmacotherapy. - : Elsevier. - 0753-3322 .- 1950-6007. ; 146
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Journal article (peer-reviewed)abstract
- Dry age-related macular degeneration (AMD) is a currently untreatable vision threatening disease. Impaired proteasomal clearance and autophagy in the retinal pigment epithelium (RPE) and subsequent photoreceptor damage are connected with dry AMD, but detailed pathophysiology is still unclear. In this paper, we discover inhibition of cytosolic protease, prolyl oligopeptidase (PREP), as a potential pathway to treat dry AMD. We showed that PREP inhibitor exposure induced autophagy in the RPE cells, shown by increased LC3-II levels and decreased p62 levels. PREP inhibitor treatment increased total levels of autophagic vacuoles in the RPE cells. Global proteomics was used to examine the phenotype of a commonly used cell model displaying AMD characteristics, oxidative stress and altered protein metabolism, in vitro. These RPE cells displayed induced protein aggregation and clear alterations in macromolecule metabolism, confirming the relevance of the cell model. Differences in intracellular target engagement of PREP inhibitors were observed with cellular thermal shift assay (CETSA). These differences were explained by intracellular drug exposure (the unbound cellular partition coefficient, Kpuu). Importantly, our data is in line with previous observations regarding the discrepancy between PREP's cleaving activity and outcomes in autophagy. This highlights the need to further explore PREP's role in autophagy so that more effective compounds can be designed to battle diseases in which autophagy induction is needed. The present work is the first report investigating the PREP pathway in the RPE and we predict that the PREP inhibitors can be further optimized for treatment of dry AMD.
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| 2. |
- Inkinen, Satu, et al.
(author)
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Collagen and chondrocyte concentrations control ultrasound scattering in agarose scaffolds
- 2014
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In: Ultrasound in Medicine and Biology. - : Elsevier. - 0301-5629 .- 1879-291X. ; 40:9, s. 2162-2171
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Journal article (peer-reviewed)abstract
- Ultrasound imaging has been proposed for diagnostics of osteoarthritis and cartilage injuries in vivo. However, the specific contribution of chondrocytes and collagen to ultrasound scattering in articular cartilage has not been systematically studied. We investigated the role of these tissue structures by measuring ultrasound scattering in agarose scaffolds with varying collagen and chondrocyte concentrations. Ultrasound catheters with center frequencies of 9 MHz (7.1–11.0 MHz, −6 dB) and 40 MHz (30.1–45.3 MHz, −6 dB) were applied using an intravascular ultrasound device. Ultrasound backscattering quantified in a region of interest starting right below sample surface differed significantly (p < 0.05) with the concentrations of collagen and chondrocytes. An ultrasound frequency of 40 MHz, as compared with 9 MHz, was more sensitive to variations in collagen and chondrocyte concentrations. The present findings may improve diagnostic interpretation of arthroscopic ultrasound imaging and provide information necessary for development of models describing ultrasound propagation within cartilage.
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