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The effect of carbon dots (CDs) on a model blayer membrane was studied as a means of comprehending their ability to affect cell membranes. Initially, the interaction of N-doped carbon dots with a biophysical liposomal cell membrane model was investigated by dynamic light scattering, z-potential, temperature-modulated differential scanning calorimetry, and membrane permeability. CDs with a slightly positive charge interacted with the surface of the negative-charged liposomes and evidence indicated that the association of CDs with the membrane affects the structural and thermodynamic properties of the bilayer; most importantly, it enhances the bilayer's permeability against doxorubicin, a well-known anticancer drug. The results, like those of similar studies that surveyed the interaction of proteins with lipid membranes, suggest that carbon dots are partially embedded in the bilayer. In vitro experiments employing breast cancer cell lines and human healthy dermal cells corroborated the findings, as it was shown that the presence of CDs in the culture medium selectively enhanced cell internalization of doxorubicin and, subsequently, increased its cytotoxicity, acting as a drug sensitizer. [ABSTRACT FROM AUTHOR]

Hydrogen peroxide (H2O2) not only is an oxidant but also is an important signaling molecule in vascular biology, mediating several physiological functions. Red blood cells (RBCs) have been proposed to be the primary sink of H2O2 in the vasculature because they are the main cellular component of blood with a robust antioxidant defense and a high membrane permeability. However, the exact permeability of human RBC to H2O2 is neither known nor is it known if the mechanism of permeation involves the lipid fraction or protein channels. To gain insight into the permeability process, we measured the partition constant of H2O2 between water and octanol or hexadecane using a novel double-partition method. Our results indicated that there is a large thermodynamic barrier to H2O2 permeation. The permeability coefficient of H2O2 through phospholipid membranes containing cholesterol with saturated or unsaturated acyl chains was determined to be 4 x 10-4 and 5 x 10-3 cm s-1, respectively, at 37 °C. The permeability coefficient of human RBC membranes to H2O2 at 37 °C, on the other hand, was 1.6 x 10-3 cm s-1. Different aquaporin-1 and aquaporin-3 inhibitors proved to have no effect on the permeation of H2O2. Moreover, human RBCs devoid of either aquaporin-1 or aquaporin-3 were equally permeable to H2O2 as normal human RBCs. Therefore, these results indicate that H2O2 does not diffuse into RBCs through aquaporins but rather through the lipid fraction or a still unidentified membrane protein. [ABSTRACT FROM AUTHOR]

The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage, cells express peroxidases, which are antioxidant enzymes that catalyze the reduction of oxidized biomolecules. Glutathione peroxidase 4 (GPX4) is the major hydroperoxidase specifically responsible for reducing lipid peroxides; this homeostatic mechanism is essential, and its inhibition causes a unique type of lytic cell death, ferroptosis. The mechanism(s) that lead to cell lysis in ferroptosis, however, are unclear. We report that the lipid peroxides formed during ferroptosis accumulate preferentially at the plasma membrane. Oxidation of surface membrane lipids increased tension on the plasma membrane and led to the activation of Piezo1 and TRP channels. Oxidized membranes thus became permeable to cations, ultimately leading to the gain of cellular Na+ and Ca2+ concomitant with loss of K+. These effects were reduced by deletion of Piezo1 and completely inhibited by blocking cation channel conductance with ruthenium red or 2-aminoethoxydiphenyl borate (2-APB). We also found that the oxidation of lipids depressed the activity of the Na+/K+-ATPase, exacerbating the dissipation of monovalent cation gradients. Preventing the changes in cation content attenuated ferroptosis. Altogether, our study establishes that increased membrane permeability to cations is a critical step in the execution of ferroptosis and identifies Piezo1, TRP channels, and the Na+/K+-ATPase as targets/effectors of this type of cell death. [Display omitted] • Lipid peroxidation increases plasma membrane tension and opens Piezo1 • Piezo1 and TRP channels cooperatively promote ferroptosis by facilitating cation flux • Collapse of transmembrane cation gradients is magnified by Na+/K+-ATPase inhibition • Blocking sodium influx and/or potassium efflux suppresses ferroptosis Hirata et al. report that peroxidation of lipids increases plasma membrane tension and leads to the activation of mechanosensitive cation channels including Piezo1. Gating of these channels induces loss of K+ and gain of Na+ that promote ferroptosis. These findings demonstrate key roles of mechanosensing channels in the execution of ferroptosis. [ABSTRACT FROM AUTHOR]

Human cell membranes consist of various lipids that are essential for their structure and function. It typically comprises phosphatidylcholine (POPC), phosphatidylethanolamine (POPE), phosphatidylserine (POPS), sphingomyelin (PSM), and cholesterol (CHL). Several experimental and computational techniques have been employed to characterize the composition of human cell membranes, however, CHL enriched membrane is still not clearly understood through these techniques. Molecular dynamics simulation results illustrated the biophysical properties of heterogeneous membranes based on the lipid composition as well as the concentration of lipids, exclusively for CHL and PSM. Herein, we have investigated the structure-function relationships of lipids comparatively to delineate the effect of heterogeneity on the biophysical properties of different membranes. It has been observed that the significant fraction of CHL (i.e., ~33% in ternary, ~25% in quaternary, and ~16% in senary type bilayers) in combination with other lipids introduced compactness, and increased the thickness of the membrane. The analysis of lipid mass density stated that the density of lipid head group, phosphate , and glycerol-ester in presence of CHL with or without PSM is an underlying reason for membrane ordering. Results also revealed that the presence of POPI and POPS are the reasons for an adequate drop in the ordering of lipid chain, particularly on POPE chain. The self-interaction of CHL, PSM, POPE and the interaction of CHL and POPC with POPE seem to determine the structure and function of the heterogeneous membrane. Our findings provide a qualitative understanding of the effect of membrane heterogeneity on the physiological properties of membranes. The structures inspected in this study would help to select the heterogeneous bilayer model to mimic the human cell membranes to analyse or characterize the membrane-associated phenomena. [Display omitted] • Structure-function relationship of lipids to delineate the effect of heterogeneity on the biophysical properties of membranes. • The membrane ordering depends on the density of lipid head group, phosphate, and glycerol-ester in presence of CHL with or without PSM. • Results also revealed the POPI and POPS are the reasons for an adequate drop in the ordering of lipid chain particularly of POPE chain. [ABSTRACT FROM AUTHOR]

Benzimidazole derivatives have gained attention recently due to their wide pharmacological activity acting as anti-inflammatory, hypotensive, analgesic, and anti-aggregatory agents. They are also common ligands in transition metal coordination chemistry, forming complex compounds with enhanced biological properties, especially in targeted cancer therapy. A key issue to understand anti-tumour effects is drug permeability through cellular membranes, as poor permeability outcomes can avert further futile drug development. In this work, we conducted atomistic molecular dynamics (MD) simulations and biased MD simulations to explore the interactions of 2-benzimidazolyl-urea with a phospholipid bilayer (dipalmitoylphosphatidylcholine, DPPC) together with a previously synthesized copper(II) complex compound. The aim was to study the permeability of these compounds by assessing their free energy profile along the bilayer normal. The simulations indicated that both the ligand (2-benzimidazolyl-urea, BZIMU) and the complex show a similar behaviour, yielding high energy barriers for the permeation process. However, with increasing concentration of BZIMU, the molecules tend to aggregate and form a cluster, leading to the formation of a pore. Clustering and pore formation can possibly explain the previously observed cytotoxicity of the BZIMU molecule via membrane damage. [ABSTRACT FROM AUTHOR]