Lipid Membranes Research Articles

Enhancing the cultivation of Salicornia fruticosa with agroindustrial compost leachates in a cascade cropping system: evaluating the impact of melatonin application.

Cascade cropping systems (CCS) utilize leachate from a primary crop to grow secondary crops and enhance the efficient use of water and fertilizers in areas with scarce water resources. A preliminary study investigated the effect of melatonin in a cascade cropping system to potentially improve plant tolerance to abiotic stresses. This study aimed to cultivate Salicornia fruticosa in this cropping system to reduce nutrient discharge and assess the impact of exogenous melatonin on Salicornia growth and quality. The CCS included a primary crop of Salicornia grown in an agro-industrial compost or peat. Leachates from these media were used to cultivate the same plant once again in a floating system under four treatments: compost leachate (T1), peat leachate (T2), 100% nutrient solution (NS) (T3), 50% NS (T4) strength. Four concentrations of exogenous melatonin were applied in foliar spray: 0, 100, 200, and 400 µM. Melatonin application increased yield, with the highest values observed when plants were grown in T1. Water use efficiency was also maximized in T1 and with both 200 and 400 µM melatonin applications. The highest nitrogen use efficiency was achieved in plants grown in peat leachate. The lipid membrane damage was assessed revealing that plants grown in compost leachate exhibited the lowest MDA values regardless of melatonin concentrations. The accumulation of some antinutritional compounds (nitrate, oxalate, and sodium) were the highest in those plants grown in compost leachate. Overall, shoots grown in peat leachate exhibited the best phytochemical profile (total phenol content, total flavonoids, and antioxidant capacity), with peak values in plants treated with 200 µM melatonin. These findings suggest that S. fruticosa can be effectively cultivated using leachate from a previous crop in a floating system and that exogenous melatonin application enhances the yield and nutritional quality of Salicornia shoots.

Caveolin assemblies displace one bilayer leaflet to organize and bend membranes.

Caveolin is a monotopic integral membrane protein, widely expressed in metazoa and responsible for constructing enigmatic membrane invaginations known as caveolae. Recently, the high-resolution structure of a purified human caveolin assembly, the CAV1-8S complex, revealed a unique organization of 11 protomers arranged in a tightly packed, radially symmetric spiral disc. One face and the outer rim of this disc are highly hydrophobic, suggesting that the complex incorporates into membranes by displacing hundreds of lipids from one leaflet. The feasibility of this unique molecular architecture and its biophysical and functional consequences are currently unknown. Using Langmuir film balance measurements, we find that CAV1-8S is highly surface active and intercalates into lipid monolayers. Molecular simulations of biomimetic bilayers support this 'leaflet replacement' model and reveal that while CAV1-8S effectively displaces phospholipids from one bilayer leaflet, it accumulates 40-70 cholesterol molecules into a disordered monolayer between the complex and its distal lipid leaflet. We find that CAV1-8S preferentially associates with positively curved membrane surfaces due to its influence on the conformations of distal leaflet lipids, and that these effects laterally sort lipids of the distal leaflet. Large-scale simulations of multiple caveolin assemblies confirmed their association with large, positively curved membrane morphologies, consistent with the shape of caveolae. Further, association with curved membranes regulates the exposure of caveolin residues implicated in protein-protein interactions. Altogether, the unique structure of CAV1-8S imparts unusual modes of membrane interaction with implications for membrane organization, morphology, and physiology.

Ferroptosis and oral squamous cell carcinoma: connecting the dots to move forward.

Oral squamous cell carcinoma (OSCC) is an aggressive disease whose incomplete biological comprehension contributes to the inappropriate clinical management and poor prognosis. Thus, the identification of new promising molecular targets to treat OSCC is of paramount importance. Ferroptosis is a regulated cell death caused by the iron-dependent accumulation of reactive oxygen species and the consequent oxidative damage of lipid membranes. Over the last five years, a growing number of studies has reported that OSCC is sensitive to ferroptosis induction and that ferroptosis inducers exert a remarkable antitumor effect in OSCC, even in those displaying low response to common approaches, such as chemotherapy and radiotherapy. In addition, as ferroptosis is considered an immunogenic cell death, it may modulate the immune response against OSCC. In this review, we summarize the so far identified ferroptosis regulatory mechanisms and prognostic models based on ferroptosis-related genes in OSCC. In addition, we discuss the perspective of inducing ferroptosis as a novel strategy to directly treat OSCC or, alternatively, to improve sensitivity to other approaches. Finally, we integrate data emerging from the research studies, reviewed here, through in silico analysis and we provide a novel personal perspective on the potential interconnection between ferroptosis and autophagy in OSCC.

Molecular Dynamics Simulations Show That Short Peptides Can Drive Synthetic Cell Division by Binding to the Inner Membrane Leaflet.

An important functionality of lifelike "synthetic cells" is to mimic cell division. Currently, specialized proteins that induce membrane fission in living cells are the primary candidates for dividing synthetic cells. However, interactions between lipid membranes and proteins that are not found in living cells may also be suitable. Here, we discuss the potential of short membrane-anchored peptides to induce cell division. Specifically, we used the coarse-grained MARTINI model to investigate the interaction between short membrane-anchored peptides and a lipid bilayer patch. The simulation revealed that the anchored peptide induces significant spontaneous curvature and suggests that the lipid-peptide complex can be considered as a conically shaped "bulky headgroup" lipid. By systematically increasing the electrostatic charge of the peptide, we find that membrane-anchored peptides may generate sufficiently large constriction forces even at dilute coverages. Finally, we show that when the peptide has an opposite charge to the membrane, the peptide may induce division by binding the inner membrane leaflet of a synthetic cell, that is, cell division from within.

Folding of N-terminally acetylated α-synuclein upon interaction with lipid membranes

α-Synuclein (α-syn) is an abundant presynaptic neuronal protein whose aggregation is strongly associated with Parkinson’s disease. It has been proposed that lipid membranes significantly affect α-syn’s aggregation process. Extensive studies have been conducted to understand the interactions between α-syn and lipid membranes and have demonstrated that the N-terminus plays a critical role. However, the dynamics of the interactions and the conformational transitions of the N-terminus of α-syn at the atomistic scale details are still highly desired. In this study, we performed extensive enhanced sampling molecular dynamics simulations to quantify the folding and interactions of wild-type and N-terminally acetylated α-syn when interacting with lipid structures. We found that N-terminal acetylation significantly increases the helicity of the first few residues in solution or when interacting with lipid membranes. The observations in simulations showed that the binding of α-syn with lipid membranes mainly follows the induced-fit model, where the disordered α-syn binds with the lipid membrane through the electrostatic interactions and hydrophobic contacts with the packing defects; after stable insertion, N-terminal acetylation promotes the helical folding of the N-terminus to enhance the anchoring, thus increasing the binding affinity. We have shown the critical role of the first N-terminal residue methionine for recognition and anchoring to the negatively charged membrane. Although N-terminal acetylation neutralizes the positive charge of Met1 that may affect the electrostatic interactions of α-syn with membranes, the increase in helicity of the N-terminus should compensate for the binding affinity. This study provides detailed insight into the folding dynamics of α-syn’s N-terminus with or without acetylation in solution and upon interaction with lipids, which clarifies how the N-terminal acetylation regulates the affinity of α-syn binding to lipid membranes. It also shows how packing defects and electrostatic effects coregulate the N-terminus of α-syn folding and its interaction with membranes.

Deciphering Molecular Mechanisms of Carbon Tetrachloride- Induced Hepatotoxicity: A Brief Systematic Review.

The liver plays a critical role in metabolic processes, making it vulnerable to injury. Researchers often study carbon tetrachloride (CCl4)-induced hepatotoxicity in model organisms because it closely resembles human liver damage. This toxicity occurs due to the activation of various cytochromes, including CYP2E1, CYP2B1, CYP2B2, and possibly CYP3A, which produce the trichloromethyl radical (CCl3*). CCl3* can attach to biological molecules such as lipids, proteins, and nucleic acids, impairing lipid metabolism and leading to fatty degeneration. It can also combine with DNA to initiate hepatic carcinogenesis. When exposed to oxygen, CCl3* generates more reactive CCl3OO*, which leads to lipid peroxidation and membrane damage. At the molecular level, CCl4 induces the release of several inflammatory cytokines, including TNF-α and NO, which can either help or harm hepatotoxicity through cellular apoptosis. TGF-β contributes to fibrogenesis, while IL-6 and IL-10 aid in recovery by minimizing anti-apoptotic activity and directing cells toward regeneration. To prevent liver damage, different interventions can be employed, such as antioxidants, mitogenic agents, and the maintenance of calcium sequestration. Drugs that prevent CCl4- induced cytotoxicity and proliferation or enhance CYP450 activity may offer a protective response against hepatic carcinoma.

Thrombin Generation Is Associated With Extracellular Vesicle and Leukocyte Lipid Membranes in Atherosclerotic Cardiovascular Disease.

Clotting, leading to thrombosis, requires interactions of coagulation factors with the membrane aminophospholipids (aPLs) phosphatidylserine and phosphatidylethanolamine. Atherosclerotic cardiovascular disease (ASCVD) is associated with elevated thrombotic risk, which is not fully preventable using current therapies. Currently, the contribution of aPL to thrombotic risk in ASCVD is not known. Here, the aPL composition of circulating membranes in ASCVD of varying severity will be characterized along with the contribution of external facing aPL to plasma thrombin generation in patient samples. Thrombin generation was measured using a purified factor assay on platelet, leukocyte, and extracellular vesicles (EVs) from patients with acute coronary syndrome (n=24), stable coronary artery disease (n=18), and positive risk factor (n=23) and compared with healthy controls (n=24). aPL composition of resting/activated platelet and leukocytes and EV membranes was determined using lipidomics. External facing aPLs were detected on EVs, platelets, and leukocytes, elevating significantly following cell activation. Thrombin generation was higher on the surface of EVs from patients with acute coronary syndrome than healthy controls, along with increased circulating EV counts. Thrombin generation correlated significantly with externalized EV phosphatidylserine, plasma EV counts, and total EV membrane surface area. In contrast, aPL levels and thrombin generation from leukocytes and platelets were not impacted by disease, although circulating leukocyte counts were higher in patients. The aPL membrane of EV supports an elevated level of thrombin generation in patient plasma in ASCVD. Leukocytes may also play a role although the platelet membrane did not seem to contribute. Targeting EV formation/clearance and developing strategies to prevent the aPL surface of EV interacting with coagulation factors represents a novel antithrombotic target in ASCVD.

Can calmodulin bind to lipids of the cytosolic leaflet of plasma membranes?

Calmodulin (CaM) is a ubiquitous calcium-sensitive messenger in eukaryotic cells. It was previously shown that CaM possesses an affinity for diverse lipid moieties, including those found on CaM-binding proteins. These facts, together with our observation that CaM accumulates in membrane-rich protrusions of HeLa cells upon increased cytosolic calcium, motivated us to perform a systematic search for unmediated CaM interactions with model lipid membranes mimicking the cytosolic leaflet of plasma membranes. A range of experimental techniques and molecular dynamics simulations prove unambiguously that CaM interacts with lipid bilayers in the presence of calcium ions. The lipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) hold the key to CaM-membrane interactions. Calcium induces an essential conformational rearrangement of CaM, but calcium binding to the headgroup of PS also neutralizes the membrane negative surface charge. More intriguingly, PE plays a dual role-it not only forms hydrogen bonds with CaM, but also destabilizes the lipid bilayer increasing the exposure of hydrophobic acyl chains to the interacting proteins. Our findings suggest that upon increased intracellular calcium concentration, CaM and the cytosolic leaflet of cellular membranes can be functionally connected.

Microfluidic measurement of the size and shape of lipid-anchored proteins

The surface of a cell is crowded with membrane proteins. The size, shape, density, and mobility of extracellular surface proteins mediate cell surface accessibility to external molecules, viral particles, and other cells. However, predicting these qualities is not always straightforward, even when protein structures are known. We previously developed an experimental method for measuring flow-driven lateral transport of neutravidin bound to biotinylated lipids in supported lipid bilayers. Here, we use this method to detect hydrodynamic force applied to a series of lipid-anchored proteins with increasing size. We find that the measured force reflects both protein size and shape, making it possible to distinguish these features of intact, folded proteins in their undisturbed orientation and proximity to the lipid membrane. In addition, our results demonstrate that individual proteins are transported large distances by flow forces on the order of femtoNewtons, similar in magnitude to the shear forces resulting from blood circulation or from the swimming motion of microorganisms. Similar protein transport across living cells by hydrodynamic force may contribute to biological flow sensing.

Tumor cell membrane biomimetic liposomes-coated oncolytic viruses to target the homotypic tumor and augment the antitumor efficacy

Though oncolytic viruses (OVs) hold significant potential for comprehensive treatment of malignant tumors, their systemic administration faces substantial challenges such as insufficient circulation time, inadequate tumor targeting, and spontaneous antiviral immune response of the body, which seriously limits the clinical application of OVs. Herein, we proposed a tumor targeting strategy of tumor cell membrane biomimetic liposomes to encapsulate OVs for intravenous delivery, which enables OVs to target the homotypic tumor lesions and exert their oncolytic effect. On the one hand, this cell membrane biomimetic carrier enhanced the encapsulation of OVs by the hybrid lipid membranes, concealed the viral capsid proteins, and diminished the neutralization and clearance of the virions from the bloodstream. On the other hand, enhanced tumor targeted delivery can be achieved through the utilization of homologous adhesion molecules on the surface of tumor cell membrane. In addition, this strategy also promoted the tumor infiltration of CD4+, CD8+ T cells mediated by the oncolytic effect of OVs and increased the levels of inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the tumor, thereby effectively enhancing the anti-tumor effect of intravenous administration of OVs. The findings of our study demonstrate that T-L@Ad11 offers a handy and efficient approach for targeting tumors, thereby enhancing the antitumor efficacy of intravenous administration of OVs.

Oxidation of lipid membrane cholesterol by cholesterol oxidase and its effects on raft model membrane structure

The effects of a peripheral protein – cholesterol oxidase (3β-hydroxysteroid oxidase, ChOx) on the characteristics of model lipid membranes composed of cholesterol, cholesterol:sphingomyelin (1:1), and the raft model composed of DOPC:Chol:SM (1:1:1) were investigated using two membrane model systems: the flat monolayer prepared by the Langmuir technique and the curved model consisting of liposome of the same lipids. The planar monolayers and liposomes were employed to follow membrane cholesterol oxidation to cholestenone catalyzed by ChOx and changes in the lipid membrane structure accompanying this reaction. Changes in the structure of liposomes in the presence of the enzyme were reflected in the changes of hydrodynamic diameter and fluorescence microscopy images, while changes of surface properties of planar membranes were evaluated by grazing incidence X-ray diffraction (GIXD) and Brewster angle microscopy. UV-Vis absorbance measurements confirmed the activity of the enzyme in the tested systems. A better understanding of the interactions between the enzyme and the cell membrane may help in finding alternative ways to decrease excessive cholesterol levels than the common approach of treating hypercholesterolemia with statins, which are not free from undesirable side effects, repeatedly reported in the literature and observed by the patients.

Precise control of transmembrane current via regulating bionic lipid membrane composition.

The transport of ions through biological ion channels is regulated not only by their structural characteristics but also by the composition of the phospholipid membrane, which serves as a carrier for nanochannels. Inspired by the modulation of ion currents by lipid membrane composition, exemplified by the activation of the K+ channel of Streptomyces A by anionic lipids, we present a biomimetic nanochannel system based on combining DNA nanotechnology with two-dimensional graphene oxide (GO) nanosheets. By designing multibranched DNA nanowires, we assemble programmable DNA scaffold networks (DSNs) on the GO surface to precisely control membrane composition. Modulating the DSN layers from one to five enhances DNA composition, yielding a maximum 12-fold enhancement in ion current, primarily due to charge effects. Incorporating DNAzymes facilitates reversible modulation of membrane composition, enabling cyclic conversion of ion current. This approach offers a pathway for creating devices with highly efficient, tunable ion transport, applicable in diverse fields like mass transport, environmental protection, biomimetic channels, and biosensors.

HIV-1 Gag Polyprotein Affinity to the Lipid Membrane Is Independent of Its Surface Charge.

The binding of the HIV-1 Gag polyprotein to the plasma membrane is a critical step in viral replication. The association with membranes depends on the lipid composition, but its mechanisms remain unclear. Here, we report the binding of non-myristoylated Gag to lipid membranes of different lipid compositions to dissect the influence of each component. We tested the contribution of phosphatidylserine, PI(4,5)P2, and cholesterol to membrane charge density and Gag affinity to membranes. Taking into account the influence of the membrane surface potential, we quantitatively characterized the adsorption of the protein onto model lipid membranes. The obtained Gag binding constants appeared to be the same regardless of the membrane charge. Furthermore, Gag adsorbed on uncharged membranes, suggesting a contribution of hydrophobic forces to the protein-lipid interaction. Charge-charge interactions resulted in an increase in protein concentration near the membrane surface. Lipid-specific interactions were observed in the presence of cholesterol, resulting in a two-fold increase in binding constants. The combination of cholesterol with PI(4,5)P2 showed cooperative effects on protein adsorption. Thus, we suggest that the affinity of Gag to lipid membranes results from a combination of electrostatic attraction to acidic lipids, providing different protein concentrations near the membrane surface, and specific hydrophobic interactions.

Clinical Spectrum, Diagnosis, and Management of TANGO2 Deficiency Disorder: A Comprehensive Review

TANGO2 deficiency disorder is an autosomal recessive disease caused by biallelic pathogenic variants in the TANGO2 gene. First described in 2016, the disorder is characterized by acute metabolic crises, neurological dysfunctions, developmental delays, and intellectual disabilities. Laboratory findings indicate a mitochondrial fatty acid oxidation defect, with metabolic crises often triggered by stressors such as illness or fasting. The TANGO2 protein, implicated in lipid metabolism, membrane trafficking, and cellular homeostasis, is critical for maintaining lipid droplets, regulating phospholipid levels, and facilitating protein and lipid transport between cellular compartments. Symptoms of TANGO2 deficiency are diverse, including psychomotor delays, intellectual impairments, seizures, ataxia, and episodic neurological symptoms known as TANGO2 spells. Diagnosis involves genetic testing, with several pathogenic variants identified. During metabolic crises, patients may experience severe cardiac and metabolic disturbances. No curative treatment exists; management includes B-vitamin supplementation, antiepileptic drugs, and interventions for spasticity, dystonia, thyroid dysfunction, and arrhythmias. TANGO2 deficiency disorder can co-occur with DiGeorge syndrome, complicating diagnosis due to overlapping symptoms. Improved awareness and diagnostic strategies are crucial for effective management of this underrecognized condition.

Prewetting couples membrane and protein phase transitions to greatly enhance coexistence in models and cells.

Both membranes and biopolymers can individually separate into coexisting liquid phases. Here we explore biopolymer prewetting at membranes, a phase transition that emerges when these two thermodynamic systems are coupled. In reconstitution, we couple short poly-L-Lysine and poly-L-Glutamic Acid polyelectrolytes to membranes of saturated lipids, unsaturated lipids, and cholesterol, and detect coexisting prewet and dry surface phases well outside of the region of coexistence for each individual system. Notability, polyelectrolyte prewetting is highly sensitive to membrane lipid composition, occurring at 10 fold lower polymer concentration in a membrane close to its phase transition compared to one without a phase transition. In cells, protein prewetting is achieved using an optogenetic tool that enables titration of condensing proteins and tethering to the plasma membrane inner leaflet. Here we show that protein prewetting occurs for conditions well outside those where proteins condense in the cytoplasm, and that the stability of prewet domains is sensitive to perturbations of plasma membrane composition and structure. Our work presents an example of how thermodynamic phase transitions can impact cellular structure outside their individual coexistence regions, suggesting new possible roles for phase-separation-prone systems in cell biology.

Oxyplasma meridianum gen. nov., sp. nov., an extremely acidophilic organotrophic member of the order Thermoplasmatales.

A mesophilic, hyperacidophilic archaeon, strain M1T, was isolated from a rock sample from Vulcano Island, Italy. Cells of this organism were cocci with an average diameter of 1 µm. Some cells possessed filaments. The strain grew in the range of temperatures between 15 and 52 °C and pH 0.5-4.0 with growth optima at 40 °C and pH 1.0. Strain M1T was aerobic and chemoorganotrophic, growing on complex substrates, such as casamino acids, trypticase, tryptone, yeast and beef extracts. No growth at expenses of oxidation of elemental sulphur or reduced sulphur compounds, pyrite, or ferrous sulphate was observed. The core lipids were glycerol dibiphytanyl glycerol tetraether lipids (membrane spanning) with 0 to 4 cyclopentane moieties and archaeol, with trace amounts of hydroxy archaeol. The dominant quinone was MK-7 : 7. The genome size of M1T was 1.67 Mbp with a G+C content of 39.76 mol%, and both characteristics were well within the common range for Thermoplasmatales. The phylogenetic analysis based on 16S rRNA gene sequence placed the strain M1T within the order Thermoplasmatales with sequence identities of 90.9, 90.3 and 90.5% to the closest SSU rRNA gene sequences from organisms with validly published names, Thermoplasma acidophilum, Thermoplasma volcanium and Thermogymnomonas acidicola, respectively. Based on the results of our genomic, phylogenetic, physiological and chemotaxonomic studies, we propose that strain M1T (=DSM 116605T=JCM 36570T) represents a new genus and species, Oxyplasma meridianum gen. nov., sp. nov., within the order Thermoplasmatales.

Effective Inclusion of Electronic Polarization Improves the Description of Electrostatic Interactions: The prosECCo75 Biomolecular Force Field.

prosECCo75 is an optimized force field effectively incorporating electronic polarization via charge scaling. It aims to enhance the accuracy of nominally nonpolarizable molecular dynamics simulations for interactions in biologically relevant systems involving water, ions, proteins, lipids, and saccharides. Recognizing the inherent limitations of nonpolarizable force fields in precisely modeling electrostatic interactions essential for various biological processes, we mitigate these shortcomings by accounting for electronic polarizability in a physically rigorous mean-field way that does not add to computational costs. With this scaling of (both integer and partial) charges within the CHARMM36 framework, prosECCo75 addresses overbinding artifacts. This improves agreement with experimental ion binding data across a broad spectrum of systems─lipid membranes, proteins (including peptides and amino acids), and saccharides─without compromising their biomolecular structures. prosECCo75 thus emerges as a computationally efficient tool providing enhanced accuracy and broader applicability in simulating the complex interplay of interactions between ions and biomolecules, pivotal for improving our understanding of many biological processes.

Monitoring changes in the zeta potential and the surface charge of human glioblastoma cells and phosphatidylcholine liposomes induced by curcumin as a function of pH

Curcumin (CUR) has received worldwide attention for its beneficial effects on human health. Research report possible cytotoxic activity against various cancers, including glioblastoma. So far, little attention has been given to the binding properties of CUR to lipid membranes, which influences their electrical characteristics and can provide insight into their membrane-permeation abilities. Biophysical interactions between the polyphenol and in vitro models (liposomes and LN-18 human glioblastoma cells) were investigated by monitoring zeta potential and the membrane's surface charge as a function of pH. We focused on practical measurements and undertook a theoretical analysis of interactions in the natural cell membrane. We used the MTT assay to evaluate the viability of CUR-treated cells. Measurements performed using the Electrophoretic Light Scattering method demonstrated the dose-dependent effect of CUR on both membrane surface charge and zeta potential analyzed in vitro models. We determined theoretical parameters characterizing the cell membrane based on a quantitative description of the adsorption equilibria formed due to the binding of solution ions to the membrane of glioblastoma cells. The interaction of CUR with liposomes and human cancer cells is pH-dependent.

Synergistic Toxicity of Pollutant and Ultraviolet Exposure from a Mitochondrial Perspective.

Ultraviolet (UV) exposure and atmospheric pollution are both independently implicated in skin diseases such as cancer and premature aging. UVA wavelengths, which penetrate in the deep layers of the skin dermis, exert their toxicity mainly through chromophore photosensitization reactions. Benzo[a]pyrene (BaP), the most abundant polycyclic aromatic hydrocarbon originating from the incomplete combustion of organic matter, could act as a chromophore and absorb UVA. We and other groups have previously shown that BaP and UVA synergize their toxicity in skin cells, which leads to important oxidation. Even if mitochondria alterations have been related to premature skin aging and other skin disorders, no studies have focused on the synergy between UV exposure and pollution on mitochondria. Our study aims to investigate the combined effect of UVA and BaP specifically on mitochondria in order to assess the effect on mitochondrial membranes and the consequences on mitochondrial activity. We show that BaP has a strong affinity for mitochondria and that this affinity leads to an important induction of lipid peroxidation and membrane disruption when exposed to UVA. Co-exposure to UVA and BaP synergizes their toxicity to negatively impact mitochondrial membrane potential, mitochondrial metabolism and the mitochondrial network. Altogether, our results highlight the implication of mitochondria in the synergistic toxicity of pollution and UV exposure and the potential of this toxicity on skin integrity.

Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids.

The mechanisms of action of pyrimidine nucleoside derivatives on model lipid membranes of various compositions were studied. A systematic analysis of the tested agents' effects on the membrane physicochemical properties was performed. Differential scanning microcalorimetry data indicated that the ability of nucleoside derivatives to disorder membrane lipids depended on the types of nucleoside bases and membrane-forming lipids. The 5'-norcarbocyclic uracil derivatives were found to be ineffective, while N4-alkylcytidines demonstrated the most pronounced effects, significantly decreasing the dipalmitoylphosphocholine melting temperature and cooperativity of phase transition. The elongation of hydrophobic acyl radicals potentiated the disordering action of N4-alkylcytidines, while an increase in hydrophilicity due to replacing deoxyribose with ribose inhibited this effect. The ability of compounds to form transmembrane pores was also tested. It was found that 5-alkyluridines produced single, ion-permeable pores in phosphatidylglycerol membranes, and that methoxy-mycolic acid and trehalose monooleate potentiated the pore-forming activity of alkyloxymethyldeoxyuridines. The results obtained open up perspectives for the development of innovative highly selective anti-tuberculosis agents, which may be characterized by a low risk of developing drug resistance due to the direct action on the membranes of the pathogen.