Baptista, M. d. S. | bioRxiv Science

bioRxiv2024

Comparative study of Ergosterol and 7-dehydrocholesterol and their Endoperoxides: Generation, Identification and Impact in Phospholipid Membranes and Melanoma Cells

Melanoma is an aggressive cancer that has attracted attention in recent years due to its high mortality rate of 80%. Damage caused by oxidative stress generated by radical (type I reaction) and singlet oxygen, 1O2 (type II reaction) oxidative reactions may induce cancer. Thus, studies that aim to unveil the mechanism that drives these oxidative damage processes become relevant. Ergosterol, an analogue of 7-dehydrocholesterol, important in the structure of cell membranes, is widely explored in cancer treatment. However, to date little is known about the impact of different oxidative reactions on these sterols in melanoma treatment, and conflicting results about their effectiveness complicates the understanding of their role in oxidative damage. Our results highlight differences among ergosterol, 7-dehydrocholesterol (7-DHC) and cholesterol in membrane properties when subjected to distinct oxidative reactions. Furthermore, we conducted a comparative study exploring the mechanisms of cell damage by photodynamic treatment in A375 melanoma. Notably, endoperoxides from ergosterol and 7-DHC generated by 1O2 showed superior efficacy in reducing the viability of A375 cells compared to their precursor molecules. We also describe a step-by-step process to produce and identify endoperoxides derived from ergosterol and 7-DHC. While further studies are needed, this work provides new insights for understanding cancer cell death induced by different oxidative reactions in the presence of biologically relevant sterols.

biochemistry↗

bioRxiv2023

Analytical solutions for the short-term plasticity

Synaptic dynamics plays a key role in neuronal communication. Due to its high-dimensionality, the main fundamental mechanisms triggering different synaptic dynamics and its relation with the neurotransmitters release regimes (facilitation, biphasic, and depression) are still elusive. For a general set of parameters, and by means of an approximated solution for a set of differential equations associated with a synaptic model, we obtain a discrete map that provides analytical solutions that shed light into the dynamics of synapses. Assuming that the presynaptic neuron perturbing the neuron whose synapse is being modelled is spiking periodically, we derive the stable equilibria and the maximal values for the release regimes as a function of the percentage of neurotransmitter released and the mean frequency of the presynaptic spiking neuron. Assuming that the presynaptic neuron is spiking stochastically following a Poisson distribution, we demonstrate that the equations for the time average of the trajectory are the same as the map under the periodic presynaptic stimulus, admitting the same equilibrium points. Thus, the synapses under stochastic presynaptic spikes, emulating the spiking behaviour produced by a complex neural network, wander around the equilibrium points of the synapses under periodic stimulus, which can be fully analytically calculated. Author summaryBased on the model proposed by Tsodyks et al., we obtained a map approximation to study analytically the dynamics of short-term synaptic plasticity. We identified the synaptic regimes named facilitation, depression, and biphasic in the parameters space, and determined the maximal and equilibrium points of active neurotransmitters for presynaptic neurons spiking periodically and stochastically following a Poisson process. Besides that, we verify that the time average of the variables for the synaptic dynamics driven by presynaptic neurons spiking following a Poisson distribution presents the equilibrium points obtained for the synaptic driven by periodic presynaptic neurons, spiking with a frequency that is the mean frequency of the Poisson distribution. These results shed analytical light into the understanding of synaptic dynamics.

neuroscience↗