A computational model of cell membrane bioelectric polarization and depolarization, connected with cell proliferation, in different tissue geometries.

A reliable theory of biological tissues growth and organization, a fundamental tool for a comprehensive interpretation of experimental observations and a guide to progress in life sciences, is definitively missing. This would support the advancement of knowledge for both normal and pathological expansion and regulation of tissues and organisms. In this work is presented a computational model of cell culture that describes its growth and organization using cell proliferation as its default state, constrained by contact inhibition, closely connected to the cell bioelectric state. The model results describe in a correct way the reported experimental results, involving contact inhibition due to the presence of other cells, and gap junctions for signaling, molecules exchange and extracellular environment sensing. Starting from depolarized cells (in this model considered tantamount to proliferative), the cell culture grows until it fills the available domain and, due to the contact inhibition constraint, it turns into quiescence (a consequence of cell polarization), except on the periphery. Using drugs or via protein expression manipulation, it is possible to change the final tissue state, to fully polarized or depolarized. Other experimental tests are proposed and the expected results simulated. This model can be extended to pathological events, such as carcinogenesis, with cells homeostasis perturbed by a cell depolarizing (carcinogenic) event and express its default proliferative state without adequate control. This simplified model of tissue organization, regulated by the cell's bioelectric state and their interaction with vicinity, is an alternative to the description of the experimental results by mechanical stress, and can be further tested and extended in dedicated experiments.

Inhibition of severe acute respiratory syndrome coronavirus 2 replication by hypertonic saline solution in lung and kidney epithelial cells

An unprecedented global health crisis has been caused by a new virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We performed experiments to test if a hypertonic saline solution was capable of inhibiting virus replication. Our data show that 1.2% NaCl inhibited virus replication by 90%, achieving 100% of inhibition at 1.5% in the nonhuman primate kidney cell line Vero, and 1.1% of NaCl was sufficient to inhibit the virus replication by 88% in human epithelial lung cell line Calu-3. Furthermore, our results indicate that the inhibition is due to an intracellular mechanism and not to the dissociation of the spike SARS-CoV-2 protein and its human receptor. NaCl depolarizes the plasma membrane causing a low energy state (high ADP/ATP concentration ratio) without impairing mitochondrial function, supposedly associated with the inhibition of the SARS-CoV-2 life cycle. Membrane depolarization and intracellular energy deprivation are possible mechanisms by which the hypertonic saline solution efficiently prevents virus replication in vitro assays.

Stable gastric pentadecapeptide BPC 157 and bupivacaine.

Bupivacaine toxicity following accidental overdose still lacks therapeutic solution. However, there are major arguments for testing BPC 157 against bupivacaine toxicity in vivo in rats, in particular, and then finally, in vitro. These are: the lack of any known BPC 157 toxicity, a lifesaving effect via the mitigation of arrhythmias in rats underwent hyperkalemia or digitalis toxicity, the elimination of hyperkalemia and arrhythmias in rats underwent succinylcholine toxicity and finally, the reduction of potassium-induced depolarization in vitro (in HEK293 cells) in severe hyperkalemia. Most importantly, BPC 157 successfully prevents and counteracts bupivacaine cardiotoxicity; BPC 157 is effective even against the worst outcomes such as a severely prolonged QRS complex. Here, rats injected with bupivacaine (100mg/kg IP) exhibited bradycardia, AV-block, ventricular ectopies, ventricular tachycardia, T-wave elevation and asystole. All of the fatalities had developed T-wave elevation, high-degree AV-block, respiratory arrest and asystole. These were largely counteracted by BPC 157 administration (50µg/kg, 10µg/kg, 10ng/kg, or 10pg/kg IP) given 30min before or 1min after the bupivacaine injection. When BPC 157 was given 6min after bupivacaine administration, and after the development of prolonged QRS intervals (20ms), the fatal outcome was markedly postponed. Additionally, the effect of bupivacaine on cell membrane depolarization was explored by measuring membrane voltages (Vm) in HEK293 cells. Bupivacaine (1mM) alone caused depolarization of the cells, while in combination with BPC 157 (1µm), the bupivacaine-induced depolarization was inhibited. Together, these findings suggest that the stable gastric pentadecapeptide BPC 157 should be a potential antidote for bupivacaine cardiotoxicity.