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Browsing by Subject "jänniteherkkä natriumkanava"

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  • Leino, Teppo (2013)
    Voltage-gated sodium channels play an essential role in the function of the nervous system as they are responsible for producing action potentials. Abnormal activity of sodium channels is in connection to several diseases such as epilepsy and chronic pain. Voltage-gated sodium channel blockers which are selective towards a specific isoform could provide more efficient and better tolerated drugs to treat these diseases when compared to the drugs used today. Clathrodin is an alkaloid isolated from Caribbean sea sponge Agelas clathrodes. Bioactivity studies have shown that clathrodin changes the function of voltage-gated sodium channels. The aim of this study was to synthesize two kinds of structure analogs of clathrodin and study their structure-activity relationship towards different isoforms of voltage-gated sodium channels. The study is part of the MAREX project (Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications) funded by the European Union. Intention of the project is to find new bioactive compounds in marine organisms. A four-step route was developed for synthesizing 2-aminobenzothiazole analogs. A three-step route was developed as well but the last step seemed to be problematic for some of the compounds. The three-step route provided new compounds as intermediates and some of them were sent to tests for activity. Synthesis of 1H-pyrrole-2-carboxamide analogs of clathrodin failed. 4,5-dihydrooxazole was recognized as a problem as it was formed as a result of a cyclization reaction when bromination was tried on the intermediate. The formed structure was used in synthesizing 2-(1H-pyrrol-2-yl)-4,5-dihydrooxazole analogs of clathrodin. These reactions failed to give any final products which could have been tested for activity. Eight synthesized compounds were sent to tests for activity. Results were received from two of them and they showed no activity towards the voltage-gated sodium channels in 10 µM concentrations. Discussion about structure-activity relationship is not possible based on two compounds only.
  • Kari-Koskinen, Julia (2021)
    Left ventricular noncompaction cardiomyopathy (LVNC) is a unique form of cardiomyopathy, which is believed to arise from arrest in the compaction process during cardiac development. Dysfunctions in cell cycle regulation and increased or decreased proliferation of cardiomyocytes during cardiac development are likely to contribute to the development of LVNC. SCN5A gene encoding the α-subunit of cardiac voltage gated sodium channel Nav1.5 has associated with LVNC- phenotype in a Finnish family. The direct correlation of SCN5A gene mutation and LVNC has not been studied before. There is strong evidence that Nav1.5 channel has an essential role in cardiac development and cardiomyocyte proliferation, therefore perturbed function of the channel might also contribute to the development of LVNC. We used patient-specific human induced pluripotent stem cell -derived cardiomyocytes (hiPSC-CMs), reprogrammed from fibroblasts obtained from LVNC patient carrying SCN5A to study the phenotype of the cells. We utilized immunofluorescent staining in combination with high content analysis (HCA) to investigate the proliferation and Nav1.5 cellular localization. Proliferation potential was assessed at multiple timepoints from three to six weeks. We also investigated the stress response of patient-specific hiPSC-CMs by exposing the cells to mechanical stretch, a hypertrophy inducer, followed by quantitative reverse transcription PCR to study changes in stress biomarker levels. According to our results, the patient-specific hiPSC-CMs have prolonged proliferation compared to control cells as the proliferation peaks towards the last timepoint, whereas in control cells it decreases. Differences were also observed in the hypertrophic gene expression after 24-hour mechanical stretching. An increase in NPPB expression levels caused by stretching was threefold in patient-specific cells to control cells. These results implicate that SCN5A gene has as an important role on cardiomyocyte proliferation. Mutations in SCN5A could correspond to increased proliferation in trabeculations during cardiac development, which might be preventing the compaction process and lead to the development of LVNC. Our results emphasizes that SCN5A has an important role in cardiomyocyte physiology unrelated solely to electrical activity.