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#BSCH: vak: wiskunde (algebra, meetkunde) --- Schoolbooks - Didactic material

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Cardiac arrhythmias can pose a major threat to a patient’s health and are difficult to treat. An import class of arrhythmias are related to a defective calcium homeostasis in the cardiomyocytes. This can occur during ischemia or can be caused by genetic mutations in the regulators of calcium homeostasis in cardiomyocytes. Extrasystolic increases in cytosolic calcium concentration lead to delayed afterdepolarizations (DADs) and triggered activity, resulting in the arrhythmias. Contributors to DADs are Ca2+-activated depolarizing currents. This group might include Transient Receptor Potential Melastatin 4 protein (TRPM4), a Ca2+-activated non-selective monovalent cation channel. Mutations in TRPM4 were previously associated with occurrence of familial conduction disorders, like Brugada syndrome and Progressive Familial Heart Block type 1 (PFHB1). Recent studies also found an increased and decreased susceptibility to cardiac arrhythmias in mice overexpressing TRPM4 and TRPM4-/- mice, respectively. These studies were bound to genetically modified mouse strains to study the physiological role of TRPM4 due to a lack of suitable in vivo inhibitors. Recently, meclofenamate has been discovered as a selective and potent inhibitor of TRPM4 in vitro. We aimed to investigate the role of TRPM4 in the development of cardiac arrhythmias via in vivo inhibition of TRPM4 with meclofenamate, and the potential of meclofenamate to prevent and suppress arrhythmias in freely moving mice. We induced arrhythmias with caffeine (75 mg/kg) in RyRR4496C/R4496C mice, an established disease model for catecholaminergic polymorphic ventricular tachycardia (CPVT). To test the role of TRPM4 in these events, we applied meclofenamate (30 mg/kg) before (pre-treatment) or after (post-treatment) administration of caffeine. Evaluation of meclofenamate’s effect on cardiac arrhythmias was performed by recording the ECG signals of freely moving mice via implanted telemetry devices (Data Sciences InternationalTM). The occurrence of ventricular arrhythmias (single ventricular ectopic beats (VEBs) and bidirectional ventricular tachycardia (biVT)) and conduction disturbances (CDs) was evaluated. We found that caffeine at a concentration of 75 mg/kg was an efficient inducer of cardiac arrhythmias in RyRR4496C/R4496C mice. We observed a dose-dependent effect of meclofenamate on the number of arrhythmic events. Both pre- and post-treatment with 30 mg/kg meclofenamate resulted in a substantial reduction of the amount of single VEBs and episodes and duration of biVT in RyRR4496C/R4496C mice. Post-treatment with meclofenamate elicited a stronger reducing effect on ventricular arrhythmias (near- complete suppression) than pre-treatment. We observed no apparent effect of meclofenamate on conduction disturbances in RyRR4496C/R4496C mice. Based on our results we can conclude that TRPM4 plays an important role in the development of ventricular arrhythmias. Meclofenamate at a concentration of 30 mg/kg proved to be a potent suppressor of ventricular arrhythmias in RyRR4496C/R4496C mice, which makes it an interesting compound in the research and development on new antiarrhythmic drugs. Furthermore, this model is suitable for in vivo studies on ventricular arrhythmias, but it appeared not to be efficient for research on conduction disturbances.

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Recently, steviol, stevioside and rebaudioside A were shown to potentiate mTRPM5, a Ca2+-activated monovalent cation channel expressed in the type II TRC and the β-cell, enhancing glucose-induced insulin secretion. This work highlights TRPM5 as a possible drug target and stevioside as lead-compound for the development of new antidiabetics. In Ca2+ imaging experiments with murine pancreatic islets, stevioside was shown to increase Ca2+ oscillations in a dose-dependent way (EC50 = 0.690 µM) in the range of free circulating steviol plasma concentrations (0.369 µM) of mice having access to stevioside-supplemented water. Stevioside was shown to act in a GLP-R1-independent way, as it increased glucose-induced Ca2+ oscillations in the presence of both GLP-1R agonist and antagonist. We validated an in-house developed lick-O-meter drinking test. Using this test it was shown that stevioside enhances the taste of quinine in Tas1r2,Tas1r3(-/-)2 mice, illustrating that steviol glycosides potentiate TRPM5 in a way independent of the taste receptor. Using a thallium-based screening assay a top five of TRPM5-potentiating stevioside analogues were identified, which were confirmed with Ca2+ imaging. Using this screening assay, the sulfonylurea glimepiride was shown to positively modulate TRPM5. Glimepiride induced Ca2+ oscillations at lower concentrations in WT than Trpm5-/- islets, illustrating TRPM5 is already targeted. Future work can investigate the interactions of TRPM5 and steviol analogues in more detail with the use of patch clamp and mutational studies. Furthermore, the impact can be broadened by investigating the role of TRPM5 in human islets and setting-up clinical trials to translate this research into practice.

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Autosomal dominant polycystic kidney disease (ADPKD), as most common monogenetic inherited kidney disease, shows many similarities with cancer. There is a noticeable difference of disease severity and progression both inter- and intrafamilial. These differences are not only caused by genetic and allelic differences. True understanding of what causes these alternations is yet to be discovered. Due to recent research, it has become more likely that the cyst microenvironment (CME) plays an important role in the development of disease severity. To support this finding, researchers have taken great interest in the parallels that can be drawn between cancer and ADPKD. In both diseases, the immune system, both innate and adaptive, take upon a primary role in development and progression. Furthermore, conventional treatments in the cancer field like immune checkpoint inhibition (e.g. anti-PD-1 and anti-CTLA-4) and JAK/STATS interfering agents are also tested in pre-clinical and clinical studies in ADPKD. Dual checkpoint inhibition has shown to slow down disease progression in an orthologous adult-onset PKD mouse model. Based on the excessive amount of data that support the role of immune cells in disease progression of ADPKD, it is very likely that upcoming treatment options will be immune-based therapies. In this review article, we provide an overview of the current evidence of the role of inflammation in ADPKD, in analogue with the immune response in cancer.