Search Results (1,293)

Nanomedicine has yielded clinically useful platforms, including liposomes, albumin-bound nanoparticles, and lipid nanoparticles; yet, many systems translate poorly because of nonspecific biodistribution, limited target-site accumulation, inefficient cellular uptake and intracellular delivery, immune clearance, and off-target toxicity. These bottlenecks are often shaped at cell membrane interfaces, where therapeutic materials are recognized, retained, internalized, or cleared and may elicit unsafe responses. Here, we frame cell membrane biophysics as a therapeutic interface for nanomedicine. We examine how lipid organization and fluidity, mechanics, electrochemical state, glycocalyx architecture, and membrane protein identity shape recognition, adhesion, endocytosis, fusion, trafficking, immune responses, and drug release. We assess how disease-associated membrane remodeling can create candidate therapeutic entry points and delivery barriers across cancer, neurodegeneration, inflammation, infection, and vascular disease. We then analyze receptor-mediated targeting, lipid-domain-associated uptake, membrane-coated nanocarriers, engineered extracellular vesicles, and hybrid platforms, with explicit context-of-use definitions and design boundaries. Finally, we propose translational qualification through function-linked critical quality attributes, mechanism-relevant potency assays, context-matched models, in vivo pharmacology and immune safety, scalable manufacturing, and regulatory evaluation. Progress will depend less on descriptive membrane mimicry than on measurable, reproducible, and qualified membrane-dependent functions. Full article

The increasing prevalence of antimicrobial resistance in bacteria highlights the need for alternative membrane-active compounds with favorable safety profiles. β-Caryophyllene (BCP), a bicyclic sesquiterpene, has demonstrated antimicrobial effects; however, its biological responses in Gram-negative bacteria and associated membrane interactions remain insufficiently characterized. In this study, the growth inhibitory effect of BCP against E. coli ATCC 25922 was evaluated through OD595 growth kinetics, while hemocompatibility was assessed using sheep erythrocytes, and cannabidiol (CBD) was included as a comparative control. To investigate membrane-associated effects, differential scanning calorimetry (DSC) was performed using DPPE/DPPG (8:2) bilayers as a simplified phospholipid membrane model. BCP inhibited bacterial growth with an IC₅₀ of 0.83 mg/mL and exhibited low hemolytic activity (2.92% at 1 mg/mL). DSC analyses revealed concentration-dependent shifts in phase transition temperature and reductions in transition enthalpy (ΔH kJ/mol) 36% and 82% for BCP-5 and CBD-10 according to the control, indicating alterations in lipid organization and membrane thermotropic behavior. In contrast, CBD showed greater growth inhibitory potency (IC₅₀ of 0.042 mg/mL) but more pronounced disruption of membrane organization. Overall, these findings suggest that BCP exhibits moderate growth inhibition associated with membrane related effects and low hemolytic activity, providing insights into the relationship between physicochemical properties, membrane interactions, and biological responses. Full article

Synovitis is an inflammatory disorder in horses that contributes to cartilage degradation and osteoarthritis. This study evaluated the effects of intra-articular administration of high-molecular-weight (HMW), linear (non-cross-linked) hyaluronic acid (HA) in an equine model of lipopolysaccharide (LPS)-induced acute synovitis. In this randomized blinded study, acute synovitis was induced in radiocarpal joints of 16 adult horses using LPS (0.25 ng). After 12 h, joints were treated intra-articularly with either 2 mL of phosphate-buffered saline (PBS; control group) or 2 mL of HMW-HA (20 mg/mL; 2280 kDa; treatment group). Horses underwent orthopedic, ultrasonographic, and synovial fluid evaluations. Horses treated with HMW-HA exhibited lower synovial membrane thickening and reduced lameness scores compared with controls. Synovial fluid analysis demonstrated increased concentrations of HMW-HA during the acute inflammatory phase in treated joints. Reduced chondroitin sulfate release was also detected following HMW-HA administration. Lower lipid peroxidation levels (TBARS) were observed in the treated group at 24 h and 14 days. Intra-articular administration of high-molecular-weight linear hyaluronic acid was associated with increased synovial availability of HMW-HA during the acute inflammatory phase, attenuation of pain-related clinical signs and synovial membrane thickening, and modulation of the redox environment. These findings support a modulatory role of linear HMW-HA in the intra-articular environment. Full article

Fever-range hyperthermia (38–41 °C) is a typical physiological response to infection, inflammation, and systemic stress. Although increased temperatures are known to affect blood rheology and erythrocyte activity, their comprehensive impact on red blood cell (RBC) structure, mechanics, and lifespan remains incompletely understood. This review summarizes current understanding of how moderate hyperthermia affects RBC membrane structure, internal behavior, mechanical properties, and clearance cues. Evidence shows that brief exposure to febrile temperatures primarily induces reversible biophysical modifications, including heightened membrane fluidity, increased membrane fluctuations, changes in hemoglobin–water interactions, and short-term improvements in deformability. These changes reflect adaptive adjustments within the membrane–cytosol–cytoskeleton system, potentially temporarily boosting microcirculatory flow. On the other hand, prolonged or repeated heat stress causes oxidative damage, hemoglobin auto-oxidation, accumulation of membrane-bound hemoglobin, band 3 clustering, cytoskeletal restructuring, calcium imbalance, and disruption of membrane lipid asymmetry. These effects weaken membrane stability and lead to vesiculation, shape changes, increased cell fragility, altered aggregation, enhanced adhesion, and activation of clearance mechanisms. A primary focus is the transition from reversible membrane softening to permanent structural damage over time. The research supports a model in which temperature affects RBC mechanics and related membrane, cytosolic, and signaling processes that influence RBC viability. We propose interpreting febrile hyperthermia as a dynamic factor that shifts RBCs from an adaptive phase to accelerated aging and removal during prolonged heat exposure. This perspective enhances our understanding of RBC behavior during fever and systemic inflammation and underscores the role of temperature in shaping erythrocyte function and lifespan. Full article

Environmental temperature is a major ecological factor shaping physiological and molecular evolution in mammals. Fatty acid desaturase genes (FADS1 and FADS2) play essential roles in the biosynthesis of long-chain polyunsaturated fatty acids (PUFAs), which are critical for membrane structure and metabolic regulation. However, their evolutionary responses to climatic variation in wild mammals remain poorly understood. In this study, we analyzed 27 rodent species distributed across diverse climatic regions to investigate the relationship between environmental temperature and the evolutionary rates of the FADS1 and FADS2 genes. Phylogenetic comparative methods, including phylogenetic ANOVA, phylogenetic generalized least squares (PGLS), and branch model analyses, were applied to estimate ω (dN/dS) ratios and assess selection patterns. Branch-site model analyses were further performed to test for episodic positive selection acting on specific codons in low-temperature-associated lineages. Our results showed that species inhabiting lower-temperature environments exhibited significantly higher ω values for both FADS genes compared with those in warmer environments. PGLS analyses revealed consistent negative associations between temperature variables and evolutionary rates, particularly for BIO5, and branch model analyses further indicated elevated ω values in low-temperature-associated lineages relative to background branches. Branch-site analyses detected significant signatures of episodic positive selection in Spermophilus dauricus and Microtus oregoni, with candidate positively selected codons identified in both lineages. Similar temperature-associated evolutionary rate patterns were also observed in expanded mammalian datasets, suggesting a broader cross-taxa trend. Overall, these findings indicate that environmental temperature is associated with heterogeneous evolutionary rate patterns in FADS genes and suggest that lipid metabolism genes may be recurrently influenced by cold-related selective pressures across mammals. Full article

Background/Objectives: Myasthenia gravis (MG) is an immune-mediated neuromuscular disorder for which antibody-based assays have limited sensitivity, particularly in double-seronegative MG (dsNMG), highlighting the need for complementary biomarkers. Given their roles in immune regulation, membrane integrity, and metabolic stress responses, lipids represent promising candidates for biomarker discovery. Methods: We designed a prospective case–control study and systematically stratified 68 patients with myasthenia gravis (MG) according to clinical classification and autoantibody status. Using LC–MS/MS, we quantified 824 lipids in 136 serum samples collected from these patients and 68 healthy controls. The analyzed subtypes included ocular MG (OMG), generalized MG (GMG), acetylcholine receptor antibody-positive MG (AChR-MG), and dsNMG. Differential lipid analysis, correlation network construction, KEGG pathway enrichment, and multivariable logistic regression were performed. Diagnostic and subtype prediction models were developed using LASSO with 10 × 10 repeated cross-validation and interpreted using Shapley Additive exPlanations (SHAP) analysis. A longitudinal follow-up analysis was conducted to assess dynamic associations between lipid signatures and disease activity. Results: In total, 240 lipids were significantly altered in MG compared with controls. Lipids distinguishing GMG from OMG were enriched in ether lipid metabolism, necroptosis, and sphingolipid signaling pathways. AChR-MG and dsNMG shared lipid networks related to membrane remodeling and signaling regulation, whereas dsNMG exhibited marked elevations in acylcarnitines and bile acid-related metabolites, potentially reflecting a distinct phenotype characterized by altered energy metabolism. The lipid-based model achieved an AUC of 0.917 for distinguishing MG from controls, and AUCs of 0.77 and 0.71 for differentiating AChR-MG from dsNMG and GMG from OMG, respectively. Longitudinal analyses showed that SM(d18:1/23:0) and Cer(d24:1/18:0(2OH)) displayed dynamic changes consistent with disease activity. Conclusions: Serum lipidomics revealed subtype-specific metabolic features of MG, with stable disease-associated remodeling and dynamic sphingolipid changes potentially reflecting disease activity. By integrating systematic clinical and antibody-based subtype stratification with longitudinal follow-up, this study supports lipidomics as a complementary tool for precision diagnosis and disease stratification, particularly in antibody-negative dsNMG. Full article

This paper proposes that the origin of life may be understood as a cascade of dynamical integration events governed by Painlevé transcendental equations—a class of nonlinear differential equations arising widely in physics, from quantum mechanics to general relativity. Four prebiotic subsystems (mineral catalysts, information polymers, free-energy transducers, and lipid membranes) undergo progressive coupling, tracing a stepwise cascade ($\mathrm{PVI}\to \mathrm{PV}\to {\mathrm{PIII}}^{D_6}\to {\mathrm{PIII}}^{D_7}\to {\mathrm{PIII}}^{D_8}$) along the Chekhov confluence diagram, culminating in the LUCA (Last Universal Common Ancestor). Each step corresponds to a specific biochemical integration event. The Painlevé framework is explicitly phenomenological: it classifies dynamical regimes of subsystem coupling rather than deriving biochemical mechanisms from first principles. A central quantitative feature is a characteristic separation parameter (${\Delta }_{\min }\approx 0.15$) between effective subsystem rates ($r_i={\tau }_i^{-1}$), with oscillation frequencies scaling as $\omega \propto r^{1/2}{\Delta }^{-1/2}$. Several prospective test systems are identified, including the Belousov–Zhabotinsky reaction, the formose reaction, and chemically monitored extreme environments. Existing literature is used to define operational protocols, but no retrospective dataset is treated here as an independent validation of the proposed value of ${\Delta }_{\min }\approx 0.15$. In particular, the formose calculation below is explicitly an illustrative model calculation whose parameters remain to be measured. The framework offers a potential unification of the RNA World, Metabolism-First, and Protocell theories as sequential stages of a single cascade; provides an indicative timeline (4.4–3.5 Ga) anchored to geological constraints; and makes quantitative, falsifiable predictions. A dedicated Scope and Limitations section discusses what the approach does and does not claim. Full article

Sperm cryopreservation is essential for fertility preservation and assisted reproduction; however, post-thaw sperm quality varies markedly between individuals despite standardized protocols. This exploratory study investigated whether good and poor freezers differ in cellular, sub-cellular, and molecular features associated with cryoresistance. One ejaculate from each of 100 normozoospermic donors was assessed before cryopreservation and after thawing. Samples were classified after thawing as good freezers (GFs; n = 50) or poor freezers (PFs; n = 50) according to post-thaw motility performance, using total motility ≥ 42% and progressive motility ≥ 30% as thresholds. Sperm quality was evaluated using computer-assisted sperm analysis, membrane and acrosome integrity assays, mitochondrial membrane potential, capacitation-associated patterns, membrane lipid disorder and DNA/chromatin integrity tests. Post-thaw thermoresistance was assessed at 37 °C for 60 and 120 min. An exploratory Western blot panel was performed only on fresh pre-freeze samples from a selected subset of 4 GF and 4 PF samples. Cryopreservation reduced sperm quality in both groups; however, PF samples showed significantly greater declines in total and progressive motility, sperm viability, membrane and acrosome integrity, mitochondrial membrane potential and thermoresistance. Exploratory Western blot data showed GF-favoring patterns for proAKAP4, SPAG6, proACR and the proACR/ACR ratio, whereas PF samples showed relatively higher ACR abundance; these molecular findings require validation in larger cohorts. Our data indicate that human sperm cryoresistance is a coordinated multi-level phenomenon involving membrane, mitochondrial, acrosomal, chromatin and flagellar resilience. This study identifies candidate functional and molecular indicators associated with cryoresistance and supports future development of pre-freeze screening strategies rather than providing a validated predictive model or clinical cut-off values. Full article

The emergence of biological membranes was a critical step in the origin of cellular life because compartmentalization enabled molecular concentration, selective interactions, and increasingly complex chemical evolution. While fatty acids are widely considered the primary constituents of primitive membranes, the origin of the hydrophilic molecular scaffolds required for more stable amphiphilic systems remains unresolved. In this review, we propose a new conceptual framework in which low-molecular-weight polyols—including ethylene glycol, glycerol, tetritols, and related sugar alcohols—served as key molecular intermediates linking abiotic carbohydrate chemistry with the emergence of proto-lipids and protomembranes during a pre-phosphate stage of Earth history. Experimental and theoretical studies indicate that abiotic carbon chemistry can generate abundant polyols capable of esterification, etherification, hydrogen bonding, and reversible complexation with borate species. We hypothesize that borate-mediated stabilization of sugars and polyols promoted molecular selection, while sulfur-rich geochemical environments supplied chemically diverse amphiphiles and redox-active reaction networks. Building upon these observations, we propose a pH-dependent evolutionary model in which acidic sulfur-rich environments favored sulfo-protolipids, near-neutral environments promoted mixed polyol–fatty acid membranes, and alkaline boron-rich systems facilitated borate-associated amphiphiles and dynamic supramolecular membrane organization. We further suggest that borate-cross-linked polyol hydrogels acted as transitional soft-matter systems connecting molecular synthesis, membrane self-assembly, compartmentalization, and the emergence of proto-informational assemblies. Modern glycolipids, sulfolipids, archaeal ether lipids, and calditol-containing tetraether membranes are discussed as structural analogues, rather than direct evolutionary descendants, supporting the chemical versatility of polyol-based membrane architectures. Although the proposed evolutionary framework remains hypothetical, it integrates current knowledge from prebiotic organic chemistry, membrane biophysics, boron coordination chemistry, sulfur geochemistry, and systems chemistry into a unified and experimentally testable model for the evolution of proto-lipids, protomembranes, and early protocellular organization. Full article

Nursery-plant grading relies on morphological traits, but leaf metabolic variation associated with nursery-plant grade remains unclear. In this study, untargeted HPLC-QTOF-MS metabolomics was applied to mature and young leaves of Grade I, II, and III apple nursery plants to explore grade-associated metabolic variation and its relationship with growth performance. After quality filtering, 198 positive-ion features were retained from mature leaves, while 259 positive-ion and 8 negative-ion features were retained from young leaves. Multivariate analysis showed clear grade-associated separation in both leaf types, with stronger discrimination in young leaves. A combination of orthogonal partial least squares (OPLS) modeling and trend analysis identified 20 and 28 differential features in mature and young leaves, respectively. Cross-model prioritization further highlighted key metabolites putatively annotated as methyl nicotinate and 1-palmitoyl-sn-glycero-3-phosphocholine in mature leaves, and methyl nicotinate, nicotinamide riboside, cis-jasmone, and methyl (9Z,14Z)-12,13,16-trihydroxyoctadeca-9,14-dienoate in young leaves. These key metabolites were potentially associated with NAD precursor metabolism, membrane lipid remodeling, and oxylipin-related signaling. Correlation analysis showed that they were associated with both initial grading traits and post-transplant growth performance. These metabolites represent candidate molecular correlates of grade-associated physiological variation and growth performance in apple nursery plants. Full article

Biotic stresses (pest feeding, pathogenic fungal/bacterial/viral infection) and diverse abiotic stresses (extreme temperature, drought, waterlogging, saline–alkali soil, heavy metal pollution, nutrient deficiency, UV-B, ozone) severely restrict crop growth and global agricultural yield. Lipids act as core membrane structural constituents and vital secondary signaling messengers, executing multi-layered adaptive balancing functions during cell-type interactive stress acclimation, rather than uniform whole-plant lipid responses. They sustain membrane structural integrity across distinct cell populations, serve as synthetic precursors of bioactive signaling molecules, and trigger cascaded transcriptional and metabolic reprogramming upon environmental stimuli to rebalance physiological status among different cell types. This review systematically summarizes cell-type interactive lipid-mediated plant defense and acclimation balance mechanisms across biotic and abiotic stress contexts. We elaborate the biological functions of fatty acids, phospholipids, galactolipids, sphingolipids and their derivatives (jasmonate, salicylic acid, phosphatidic acid, oxylipin) in stress signal transduction and antioxidant defense and strictly distinguish two categories of lipid changes under all stress types: active adaptive lipid remodeling and passive stress-induced lipid oxidative damage. Key contents include stress-triggered cell-type-specific membrane lipid remodeling, the hierarchical transcriptional regulatory network mediated by WRI1, LEC1, PHR, MADS and other transcription factors governing oil metabolism, as well as crosstalk between lipid metabolism and compartmentalized reactive oxygen species (reactive oxygen species (ROS)) signaling. We further compare conserved lipid-regulatory modules and species-specific divergent responses across model plants and economic oilseed crops, integrating state-of-the-art targeted/untargeted lipidomics, single-cell spatial lipidomics and multi-omics joint breeding strategies to improve multi-stress tolerance in oilseed crops. By consolidating global research progress up to 2025, including the two latest 2026 cross-species meta-analysis reviews, this review provides systematic theoretical support and operable multi-level technical frameworks for genetic engineering targeting conserved lipid pathways to breed stress-resilient high-oil crop germplasm, and highlights reliable lipid stress biomarker screening as a promising translational research direction. Full article

Background: Despite extensive development of liposomal antibiotics, the structural determinants governing their stability, release, and biological activity remain poorly understood. This study investigated how the cholesterol content and drug-to-lipid ratio affect membrane organization and thereby determine the physicochemical and biological properties of linezolid-loaded liposomes. Methods: Nine liposomal formulations, varying in their cholesterol content (10–30 wt%) and drug-to-lipid ratios (1–5%), were prepared by thin-film hydration. Membrane organization was analyzed by ATR-FTIR spectroscopy and principal component analysis. Liposomes were further characterized by particle size, ζ-potential, encapsulation efficiency, storage stability, in vitro release in phosphate buffer with and without bovine serum albumin, antibacterial activity against B. subtilis, and antimycobacterial activity in an ex vivo PBMC-derived Mycobacterium tuberculosis granuloma model. Results: The cholesterol content and drug-to-lipid ratio markedly altered membrane interfacial organization, particularly the hydration of the carbonyl and phosphate regions. These structural changes correlated with differences in storage stability, protein-responsive release, and antibacterial activity. Functional behavior was non-monotonic, as 30-L showed the highest overall storage stability, while the apparent release depended jointly on the cholesterol content, drug loading, and medium. BSA altered the composition-dependent release pattern instead of producing a uniform effect. In the exploratory granuloma model, the formulations 10-S, 10-L, and 30-M reduced M. tuberculosis CFU by >99%, whereas free linezolid produced approximately 60% inhibition. Conclusions: Membrane interfacial organization is a key determinant of the functional performance of liposomal linezolid, establishing a structure–property–function relationship that provides a mechanistic basis for the rational design of liposomal antibiotic delivery systems for tuberculosis therapy. Full article

Background/Objectives: Platelets are anucleate cells that play a crucial role in primary hemostasis and arterial thrombosis, contributing to cardiovascular diseases. Eugenol, a bioactive phenolic compound, exhibits vasodilatory, antibacterial, and anticancer properties and inhibits platelet aggregation induced by collagen and arachidonic acid (AA). AA is a critical lipid component of the platelet membrane and a precursor for potent signaling molecules that mediate platelet activation. However, the precise mechanisms through which eugenol modulates AA-stimulated platelet activation remain unclear. Methods: Human platelets were pretreated with eugenol and subsequently stimulated with AA. Platelet aggregation, ATP release, intracellular calcium mobilization, and P-selectin expression were measured. JNK, p38 MAPK, ERK, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation were analyzed by Western blotting. SP600125, SQ22536, and ODQ were used to examine the involvement of JNK and cyclic nucleotide signaling pathways. Antithrombotic effects were further evaluated in a mouse mesenteric thrombosis model. Results: Eugenol significantly suppressed AA-induced platelet aggregation, ATP release, calcium mobilization, and P-selectin expression, selectively reducing JNK phosphorylation without affecting p38 MAPK or ERK. SP600125 produced similar inhibitory effects. Neither SQ22536 nor ODQ reversed eugenol’s inhibitory effects on platelet aggregation. Furthermore, eugenol did not alter VASP phosphorylation at Ser157 or Ser239. In vivo, real-time intravital imaging showed that eugenol and SP600125 delayed thrombus formation and prolonged occlusion time. Conclusions: These findings suggest that eugenol exerts inhibitory effects that may involve modulation of JNK phosphorylation, independent of cyclic nucleotide/VASP pathways in AA-induced platelet activation, highlighting its potential as an antithrombotic agent. Full article

Background: Nose-to-brain delivery offers a noninvasive route to bypass the blood–brain barrier for the treatment of neurodegenerative diseases. AmyP53 is a first-in-class adaptive 12-mer peptide that prevents the formation of neurotoxic amyloid oligomers by competitively targeting lipid raft gangliosides on brain cell membranes, thereby blocking the shared pathological mechanism underlying both Alzheimer’s and Parkinson’s diseases. Objective: Here, we report the identification of optimal spray devices for the nose-to-brain delivery of AmyP53, ahead of a planned Phase 1 clinical trial. Method/Results: Among six devices evaluated (four commercial systems and two novel devices specifically engineered for nose-to-brain delivery), two systems were identified as optimal for further clinical development (narrower plume angles and significantly higher deposition in the olfactory region): the Neurospray™ and Neurospray™ Preservative-Free (PF). AmyP53 was quantitatively and reproducibly delivered by both Neurospray™ systems, retaining full recognition of its therapeutic target (gangliosides), as assessed by a surface pressure-based ganglioside-binding assay. In a rabbit preclinical model, intranasal administration of AmyP53 with the Neurospray™ resulted in rapid and sustained brain delivery, detectable at 10 min and persisting at 24 h post-administration, without significant systemic exposure. Conclusions: These results validate the Neurospray™ drug delivery systems as optimal drug delivery systems for the clinical development of AmyP53. Full article

Introduction: The study purpose was to identify possible key metabolites that determine the adaptation of the Endomyces magnusii yeast to long-term cultivation (four weeks) using glycerol as an “oxidative” and glucose as a “fermentative” substrate. Methods: The metabolic profile was assayed using gas chromatography combined with mass spectrometry, followed by bioinformatic analysis (PARADISe, Golm metabolome database (GMD), MassBank, UniChrom). Results: PCA and PLS-DA analyses showed that the type of carbon source contributed significantly to the overall variability of the data, and the greatest variance was observed for the groups grown on different substrates for the first cultivation week. Growth on glycerol increased the chronological lifespan of E. magnusii due to the early launch of adaptive oxidative stress, the active use of lipids as an energy source, the accumulation of membrane sterols, osmo-protective polyols, organic acids (malic, methyl glycerinic, palmitic, linoleic), and some sugars (lyxose, galactose), which increased the overall resistance and maintained high cell survival. On the contrary, cultivation using glucose provoked a sharp substrate depletion, inducing passive storage of sugars (trehalose), diauxic shock, and less effective antioxidant protection, which provided lower cell survival upon prolonged growth. Conclusions: (1) Metabolic signs associated with prolonged culturing were identified in all the compounds classes tested (polyols, fatty acids, lactones); (2) some metabolites (in particular, dulcitol), being hypothetical biomarkers of aging, are at the same time protective agents involved in the adaptation of yeast cells to the deep stationary growth stages. Our data can serve as a basis for comparative studies of aging-related metabolism in other eukaryotic models. Full article