ABSTRACT
Gap junctions (GJs) made of connexin-43 (Cx43) are necessary for the conduction of electrical impulses in the heart. Modulation of Cx43 GJ activity may be beneficial in the treatment of cardiac arrhythmias and other dysfunctions. The search for novel GJ-modulating agents using molecular docking allows for the accurate prediction of binding affinities of ligands, which, unfortunately, often poorly correlate with their potencies. The objective of this study was to demonstrate that a Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using molecular docking, QSAR, and 3D-QSAR, we evaluated 16 known Cx43 GJ inhibitors, suggested the monocyclic monoterpene d-limonene as a putative Cx43 inhibitor, and tested it experimentally in HeLa cells expressing exogenous Cx43. The predicted concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds were compared with those determined experimentally (pIC50 and eIC50, respectively). The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR and 3D-QSAR models showed a good correlation with their eIC50ies (R = 0.88 and 0.90, respectively) in contrast to pIC50ies obtained from molecular docking (R = 0.78). However, molecular docking suggests that inhibitor potency may depend on their docking conformation on Cx43. Searching for new potent, selective, and specific inhibitors of GJ channels, we propose to perform the primary screening of new putative compounds using the QSAR model, followed by the validation of the most suitable candidates by patch-clamp techniques.
ABSTRACT
Purpose: To retrospectively evaluate single-centre experience in endovascular therapy (EVT) of acute superior mesenteric artery (SMA) occlusion by assessing technical success, mortality, and its dependence on the level and aetiology of occlusion. Material and methods: Eighty patients presented with acute SMA occlusion and underwent EVT at our centre from 2018 to 2020. Clinical diagnosis was confirmed by computed tomography angiography (CTA). Based on findings of CTA and digital subtraction angiography, we classified all cases by the number of SMA large branches that remained non-occluded (ostial, proximal, distal occlusion), as well as according to aetiology (embolic, thrombotic). Technical success was evaluated according to restoration of blood flow to the SMA stem and all large branches (successful, partially successful, failure). Results: Thrombotic aetiology was identified in 25.0% and embolic in 75.0% of patients. We distinguished 3 occlusion level types: ostial occlusion (23.8%), proximal occlusion (47.5%), and distal occlusion (28.7%). 67.5% of cases were technically successful, 12.5% were partially successful, and 20.0% resulted in technical failure. The 30-day mortality rate was 55.0%. EVT technical success did not statistically depend on the aetiology or on the level of occlusion. The aetiology of occlusion had no statistical significance regarding intrahospital mortality. In the group with EVT failure, fewer non-occluded large branches meant more fatal cases, and vice versa. Conclusions: Despite EVT technical success rates being adequate, mortality rates remain extremely high. While the occlusion level appeared to have no influence over EVT technical success rates, it may be a potentially useful prognostic factor in the case of failed recanalization. Aetiology of the occlusion seemed to have no impact on technical success or mortality.
