Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Background: Pathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/-, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients. Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening

Experimental and theoretical study of quercetin complexes formed on pure silica and Zn-modified mesoporous MCM-41 and SBA-16 materials

SBA-16 and MCM-41 silica materials were synthesized and modified by post-synthesis method with different amounts of Zn (2 and 4 wt.%). Quercetin, a flavonol compound, was loaded by incipient wetness impregnation method on the pure silica and Zn-modified mesoporous MCM-41 and SBA-16 supports. The parent and drug loaded formulations were characterized by powder XRD, N2 physisorption, thermal analysis, TEM, UV Vis and FT-IR spectroscopies. The formation of Zn:quercetin complex was studied by FT-IR spectroscopy and quantum-chemical calculations. Loading of quercetin on mesoporous carriers made the sustained delivery of the bioactive compound possible in a buffer with pH ¼ 5.5, typical of dermal formulations. The results from the release experiments are in good accordance with the interaction energy between the bioactive molecule and non-modified and Zn-modified mesoporous materials, predicted by the quantum-chemical calculations. For the first time the formation of the most stable Zn quercetin complexes loaded on the mesoporous silica materials were determined. The obtained mesoporous delivery systems with Zn-quercetin complex are promising as dermal formulations

50 години Катедра „Социална медицина и организация на здравеопазването`

22 Май 201