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Tetrahydroquinoline/4,5-dihydroisoxazoline derivatives counteract multidrug resistance in cancer cells by inhibiting P-glycoprotein (ABCB1)-mediated transport
No full textCancer treatment is challenged by the emergence of multidrug resistance (MDR). MDR is often caused by the overexpression of certain ABC transporters, such as P-glycoprotein (P-gp, ABCB1) in the plasma membrane of tumor cells and tumor stem cells. Inhibition of ABC transporter-mediated efflux of anticancer drugs might be a plausible approach to overcome MDR. Here, we studied the interaction of 16 tetrahydroquinoline/4,5-dihydroisoxazole derivatives (A1 - D4) with human P-gp to identify and characterize new P-gp inhibitors. We found that compounds C1 and D1 inhibited the P-gp-mediated efflux of rhodamine 123 (R123), with IC50 values of 41.5 and 6.6 μM, respectively. Both compounds showed low cytotoxicity on NIH3T3 and NIH3T3-ABCB1 cells over a broad concentration range. Interestingly, C1 and D1 increased the ATPase activity of P-gp at sub-micromolar concentrations, showing EC50 values of 0.17 and 0.62 μM, respectively. However, thermal inactivation and UIC2 reactivity assays supported that, similar to potent P-gp inhibitors, C1 and D1 can hinder the dimerization of the nucleotide binding domains (NBDs), when applied at higher concentrations (≥10 μM). In addition, docking studies showed that D1 preferentially interacts with the central substrate binding cavity of P-gp. Finally, D1 chemosensitized drug-resistant KB-V1 cells overexpressing P-gp. In view of our previous findings that C1 and D1 also inhibit ABCG2 and MRP1, they can be considered as novel pan-ABC transporter inhibitors offering potential for treating chemotherapy-resistant tumors
”Tämmöiset ei ole ollenkaan itsestään selviä, vaan niitä ihan oikeasti opetellaan”: Ensimmäisen luokan opettajien näkemyksiä koululaistaidoista ja niiden opettamisesta
No full textMeasuring tongue contours from ultrasound images in certain Finnish language speech sounds
No full text"On muistissani tapaus Aunuksen kansannousun ajoilta" Aunuksen sotaretken osallistujien kuvaukset Karjalan ja Aunuksen kansasta
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Evolving trends in application of low-cost air quality sensor networks: challenges and future directions
No full textLow-cost air quality sensors (LCS) are increasingly used to complement traditional air quality monitoring yet concerns about their accuracy and fitness-for-purpose persist. This scoping review investigates topics, methods, and technologies in the application of LCS networks in recent years that are gaining momentum, focusing on LCS networks (LCSN) operation, drone-based and mobile monitoring, data fusion/assimilation, and community engagement. We identify several key challenges remaining. A major limitation is the absence of unified performance metrics and cross-validation methods to compare different LCSN calibration and imputation techniques and meta-analyses. LCSN still face challenges in effectively sharing and interpreting data due to a lack of common protocols and standardized definitions, which can hinder collaboration and data integration across different systems. In mobile monitoring, LCS siting, orientation, and platform speed are challenges to data consistency of different LCS types and limit the transferability of static calibration models to mobile settings. For drone-based monitoring, rotor downwash, LCS placement, flight pattern, and environmental variability complicate accurate measurements. In integrating LCS data with air quality models or data assimilation, realistic uncertainty quantification, ideally at the individual measurement level, remains a major obstacle. Finally, citizen science initiatives often encounter motivational, technological, economic, societal, and regulatory barriers that hinder their scalability and long-term impact
Muistisairauksien patogeneesi tarkentuu
No full text• Viimeaikaiset geneettiset sekä solutason tutkimukset ovat merkittävästi lisänneet tietoutta mikrogliasolujen tärkeästä roolista Alzheimerin taudin etenemisessä.
• Otsalohkodementian patogeneesiin liittyvät muun muassa RNA:n säätelyyn, immunologiseen signalointiin ja proteiinien epänormaaliin kertymiseen liittyvät mekanismit.
• Lewyn kappale -tauti on monitekijäinen sairaus, jonka tautimekanismien ymmärtäminen vaatii vielä tutkimusta