Search Results (433)

Serotonergic signaling is traditionally conceived as a transient, vesicle-mediated process restricted to the synaptic cleft. Here, we propose an expanded model in which serotonin can also be inserted into the plasma membrane of neurons and glial cells, forming a stable, membrane-associated reservoir that prolongs its availability beyond classical synaptic timescales. In this framework, the synapse emerges not as a simple neurotransmitter–receptor interface but as a dynamic, multiscale medium where membrane order, hydration, and quantum-level processes jointly govern information flow. Two temporal “tunnels” appear to regulate serotonin bioavailability: its aggregation in synaptic vesicles during exocytosis, and its cholesterol-dependent insertion into neuronal and glial membranes at the tripartite synapse. Lipid raft microdomains enriched in cholesterol and gangliosides thus act as active regulators of a continuum between transient and constitutive serotonin signaling. This extended serotonergic persistence prompts a reconsideration of current pharmacological models and the action of antidepressants such as fluoxetine, which not only inhibits the serotonin transporter (SERT) but also accumulates in lipid rafts, perturbs raft organization, and alters serotonin–cholesterol equilibria, contributing to SERT-independent effects. Grounded in the recently established fundamental parameters of biological systems, this model invites a broader, quantum-informed rethinking of synaptic transmission. Full article

Severe acute respiratory syndrome coronavirus (SARS-CoV) assembles and buds from the Golgi apparatus or the ER membrane, but the specific membrane microdomains utilized during this process remain underexplored. Here, we show that co-expression of the SARS-CoV structural proteins S, M, and N in HEK-293T cells is sufficient to generate genome-free SARS-CoV-like virus-like particles (VLPs), which preferentially bud from glycolipid-enriched membrane lipid raft microdomains. Immunofluorescence microscopy using raft-selective dyes (DiIC16) and spike-specific antibodies revealed strong co-localization of VLPs with lipid rafts. Detergent-resistant membrane analysis and sucrose gradient centrifugation further confirmed the presence of S protein in buoyant, raft-associated fractions alongside the raft marker CD44. Importantly, pharmacological disruption of rafts with methyl-β-cyclodextrin reduced VLP budding and S protein partitioning into raft domains, underscoring the requirement for intact lipid rafts in assembly. Additionally, our data support lipid raft-associated proteins’ (e.g., FNRA, VIM, CD59, RHOA) roles in modulating cellular responses conducive to viral replication and assembly. These findings highlight lipid rafts as crucial platforms for SARS-CoV morphogenesis and suggest new avenues for vaccine and antiviral development using VLPs and raft-targeting therapeutics. Full article

Lipid raft-associated gangliosides facilitate the early stages of SARS-CoV-2 entry by triggering the exposure of the receptor-binding domain (RBD) within the trimeric spike protein, which is initially sequestered. A broad range of in silico, cryoelectron microscopy and physicochemical approaches indicate that the RBD becomes accessible after a ganglioside-induced conformational rearrangement originating in the N-terminal domain (NTD) of one protomer and propagating to the neighboring RBD. We previously identified a triad of amino acids, Q134-F135-N137, as a strictly conserved element on the NTD. In the present review, we integrate a series of structural and experimental data revealing that this triad may act as a conformational transducer connected to a chain of residues that are capable of transmitting an internal conformational wave within the NTD. This wave is generated at the triad level after physical interactions with lipid raft gangliosides of the host cell membrane. It propagates inside the NTD and collides with the RBD of a neighboring protomer, triggering its unmasking. We also identify a chain of aromatic residues that are capable of controlling electron transfer through the NTD, leading us to hypothesize the existence of a dual conformational/quantum wave. In conclusion, the complete conservation of the Q134-F135-N137 triad despite six years of extensive NTD remodeling underscores its critical role in the viral life cycle. This triad represents a potential Achilles’ heel within the hyper-variable NTD, offering a stable target for therapeutic or vaccinal interventions to disrupt the conformational wave and prevent infection. These possibilities are discussed. Full article

Neuronal development relies on cell-surface glycoconjugates that function as complex bioinformational codes. Recently, altered glycosylation has emerged as a central mechanistic theme in the pathophysiology of autism spectrum disorder (ASD). Critically, the brain maintains a distinctively restricted glycan profile through strict biosynthetic regulation, creating a specialized landscape highly susceptible to homeostatic perturbation. This “membrane-centric vulnerability” spans both glycoproteins and glycolipids; however, evidence remains fragmented, obscuring their pathogenic interplay. To bridge this gap, this review synthesizes evidence for these two primary classes of membrane glycoconjugates into a unified framework. We examine how defects in key glycoproteins (such as NCAM1 and neuroligins) directly impair synaptic signaling, trafficking, and plasticity. We then demonstrate how these defects are functionally coupled to the glycolipid (ganglioside) environment, which organizes the lipid raft platforms essential for glycoprotein function. We propose that these two systems are not independent but represent a final common pathway for diverse etiological drivers. Genetic variants (e.g., MAN2A2), environmental factors (e.g., valproic acid), and epigenetic dysregulation (e.g., miRNAs) all converge on this mechanism of impaired glycan maturation. This model elucidates how distinct upstream causes can produce a common downstream synaptic pathology by compromising the integrity of the membrane signaling platform. Full article

The cellular prion protein (PrP^C) displays a functional repertoire that extends well beyond its classical link to transmissible spongiform encephalopathies. Abundant in the nervous system and localized within lipid raft microdomains, PrP^C has emerged as a multifunctional signaling platform that regulates cell differentiation, neurogenesis, neuroprotection, and synaptic plasticity. Recent evidence highlights its dynamic expression in stem cell populations, where it participates in multimolecular complexes that control lineage commitment, particularly during neuronal differentiation. PrP^C expression tightly correlates with stem cell status, making it a promising biomarker of stemness and developmental progression. Through interactions with growth factors, extracellular matrix components, and synaptic proteins, PrP^C functions as a molecular integrator of signals essential for tissue repair and regeneration. Preclinical studies demonstrate that recombinant PrP^C can stimulate neurogenesis and tissue repair, while monoclonal antibodies modulate its physiological and pathological functions. Likewise, cell-based therapies leveraging PrP^C-enriched stem cells or PrP^C-dependent signaling profiles have shown promise in models of neurodegeneration and ischemia. Conversely, dysregulated PrP^C expression has also been observed in solid tumors, where it contributes to cancer cell survival, proliferation, metastasis, and therapy resistance, reinforcing its role as a regulator of cell fate and an oncological target. This review integrates stem cell biology, tissue regeneration, and oncology into a unified framework, offering a novel perspective in which PrP^C emerges as a shared molecular hub governing both physiological repair and pathological tumor behavior, opening previously unrecognized conceptual and translational opportunities. Full article

Pollen tube growth entails complex molecular interactions between the cytoskeletal apparatus and membrane trafficking. Tip growth involves polarized distribution of proteins and lipids along the plasma membrane, including liquid-ordered microdomains, rich in sterols and sphingolipids (lipid rafts), in the apical/subapical region of tobacco pollen tubes. Intriguingly, biochemical characterization of detergent-insoluble membranes purified from tobacco pollen tubes revealed the presence of both actin and tubulin. Here, we report that inhibition of sterol biosynthesis altered lipid rafts and lowered the association of tubulin with detergent-insoluble membranes. Our results showed that sterol depletion increased the number of microtubules in the subapical region, altered microtubule distribution and affected microtubule bundling activity. Oryzalin washout experiments also suggested that lipid-ordered domains could play a role in regulating microtubule nucleation/regrowth. Full article

Background/Objectives: Giardia lamblia is an intestinal protozoan responsible for giardiasis, a globally prevalent parasitic disease. Current therapeutic options, including nitroimidazoles and benzimidazoles, have increasing treatment failures due to resistance, adverse reactions, and patient non-compliance. Drug repositioning offers a cost-effective strategy for identifying new antigiardial agents. This study aimed to evaluate the in vitro antiparasitic effects and possible mechanisms of action of the tricyclic antidepressant imipramine against G. lamblia trophozoites. Methods: Trophozoites were exposed to increasing concentrations of imipramine (25–125 µM). Growth inhibition and adhesion capacity were quantified using cell counts. Apoptosis- or necrosis-like death was evaluated through Annexin V/PI staining. The expression and distribution of α-tubulin and lipid rafts were analyzed by immunofluorescence microscopy. Finally, the effect of the drug on encystment efficiency was assessed in vitro. Results: Imipramine inhibited G. lamblia trophozoite growth in a concentration-dependent manner, with an IC₅₀ of 42.31 µM at 48 h. The drug significantly reduced adhesion capacity (>90% at 125 µM) and induced apoptosis-like cell death, as evidenced by Annexin V positivity. Immunofluorescence revealed disruption of α-tubulin distribution and lipid raft organization, accompanied by morphological rounding. Moreover, encystment efficiency decreased in a concentration-dependent mode, suggesting interference in the differentiation process. Conclusions: This investigation describes, for the first time, the antigiardial potential of imipramine, which alters cytoskeletal organization, membrane microdomains, and differentiation pathways, ultimately leading to apoptosis-like cell death. These findings position this compound as a promising lead structure and support further exploration of tricyclic antidepressants as scaffolds for the development and optimization of new antiparasitic agents, as well as future studies on their molecular targets and in vivo efficacy. Full article

Immunotherapy has demonstrated significant efficacy in colorectal cancer (CRC), but its therapeutic effects remain limited in microsatellite stable (MSS) patients, indicating the critical role of the tumor immune microenvironment (TIME) in regulating immune responses. Lipid rafts, dynamic membrane microdomains enriched in cholesterol and sphingolipids, have emerged as potential targets for TIME remodeling through their integration of immune signal transduction, enrichment of cell death receptors, and regulation of immune cell functionality. This review outlines the pivotal mediating roles of lipid rafts in cellular survival, death, and tumor progression. Specifically, MSS-type CRC exhibits lipid raft structural remodeling driven by dysregulated lipid metabolism, which fosters multiple immune escape mechanisms through exosome-mediated immunosuppressive signaling, promotion of tumor-associated macrophage (TAM) M2 polarization, enhanced infiltration of regulatory T cells (Tregs), and functional exhaustion of effector cells, such as CD8⁺ T cells and NK cells. Finally, we discuss targeted therapeutic strategies based on lipid raft characteristics and CRC molecular profiles, proposing an innovative multidimensional treatment framework combining immune checkpoint inhibitors with lipid raft-targeted interventions and chemoradiotherapy. This approach provides theoretical and strategic support for overcoming CRC immunotherapy resistance and advancing clinical translation. Full article

Nanogels provide unique opportunities for stabilizing fragile enzymes through soft, hydrated polymer networks. Here, we report the development of a glutathione peroxidase (GPx)-loaded nanogel (GPxNG) engineered via a mild “grafting-to” epoxy–amine coupling strategy to enhance enzyme stability and antioxidant function. An amphiphilic copolymer composed of methacrylated 2,2,6,6-tetramethyl-4-piperidyl (PMA) and glycidyl methacrylate (GMA) was synthesized by controlled reversible addition–fragmentation chain-transfer (RAFT) polymerization using a poly(ethylene glycol) (PEG) macro-chain transfer agent (macro-CTA), yielding well-defined polymer chains with reactive epoxy groups. Covalent conjugation between polymer epoxides and GPx enzyme surface amines generated soft, PEGylated nanogels with high coupling efficiency, uniform particle sizes, and excellent colloidal stability. The engineered nanogels exhibited shear-thinning injectability, robust storage stability, and non-cytotoxic behavior in RAW 264.7 macrophages. Compared with native GPx enzyme, GPxNGs demonstrated significantly enhanced reactive oxygen species (ROS) scavenging activity, including strong inhibition of lipid peroxidation and copper-induced low-density lipoprotein (LDL) oxidation. Importantly, the nanogels preserved GPx enzyme activity after extended storage, freeze–thaw cycles, and repeated catalytic use, whereas the free enzyme rapidly lost function. This protective effect arises from the nanoscale confinement of the GPx enzyme within the flexible PEG-based network, which limits unfolding and aggregation. Overall, this work introduces a simple and biocompatible “grafting-to” nanogel platform capable of stabilizing redox-active enzymes without harsh conditions. The GPx nanogels combine high enzymatic preservation, potent antioxidant activity, and excellent handling properties, highlighting their potential as a therapeutic nanoplatform for mitigating oxidative stress-associated disorders such as atherosclerosis. Full article

Receptor tyrosine kinases (RTKs), a class of membrane proteins involved in several physiological processes such as growth, survival, angiogenesis, and differentiation, are profoundly influenced by the microenvironment, particularly by surrounding lipids. Lipids coordinate RTK life cycle at multiple steps. First, receptor lipidation is a key post-translational modification for receptor-targeting localization. Then, RTK dimerization and activation are regulated by membrane-enriched lipids like phosphatidylserine and phosphoinositides, gangliosides, and Cholesterol, which directly engage RTK juxtamembrane domain or cytoplasmic tail. Eventually, lipids spatially organize RTK signaling within Cholesterol- and sphingolipid-enriched membrane microdomains. These membrane rafts act as dynamic “signalosomes” coordinating receptor clustering, endocytosis, and recycling. Perturbations in lipid composition remodel raft architecture and alter RTK behavior, contributing to pathological conditions such as cancer, metabolic, and neurodegenerative disorders. Emerging lipid-targeted therapies offer a promising way to enhance RTK-directed therapies. This review aims to explore how specific lipid species and membrane domains modulate RTK activation, clustering, and endocytic recycling. By bridging biochemical and pathological perspectives, we discuss how membrane lipid composition reshapes RTK signaling in physiology and pathology, pointing to emerging opportunities for lipid-focused therapeutic modulation. Full article

Background/Objectives: Breast cancer is the most prevalent malignancy among women, and paclitaxel (PTX) is a first-line chemotherapeutic, but chemoresistance driven by ATP-binding cassette (ABC) transporters limits its efficacy. Single-target ABC inhibitors fail due to toxicity and cooperative transporter activity, creating an urgent need for safe multi-target strategies. Membrane cholesterol-rich lipid rafts support ABC transporter function, making cholesterol a key chemoresistance target. This study explored a cholesterol-targeted approach for overcoming PTX resistance. Methods: A PTX-resistant breast cancer line (MCF-7/PTX) showing ABCB1/ABCC3 co-upregulation and enriched cholesterol rafts was established. The effects of Polyphyllin H (PPH), a steroidal saponin from Paris polyphylla, were compared with lovastatin, a biosynthetic cholesterol inhibitor. In vitro and in vivo assays investigated Polyphyllin H’s cholesterol binding and effects on transporters, PTX accumulation, and tumor growth. Results: PPH directly binds membrane cholesterol, disrupting lipid rafts, downregulating ABCB1/ABCC3, reducing drug efflux, and increasing intracellular PTX to restore sensitivity. PPH showed superior cholesterol-binding and resistance-reversal efficacy than lovastatin, with faster, stronger PTX-enhanced cytotoxicity and tumor suppression. Conclusions: PPH reverses PTX resistance by targeting cholesterol-lipid rafts to inhibit multiple ABC transporters. This offers a safer adjuvant for PTX-based breast cancer therapy and a translational framework for other drug-resistant malignancies. Full article

Major depressive disorder (MDD) is a complex, multifactorial condition involving dysregulation across immune, neural, and metabolic systems. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have emerged as promising adjunctive interventions, with evidence supporting their efficacy in alleviating depressive symptoms. Here, we synthesize current knowledge on the interconnected biological pathways through which n-3 PUFAs may exert antidepressant effects. A growing body of evidence implicates the gut–brain axis as a central pathway through which n-3 PUFAs may exert antidepressant effects. By shaping microbiota composition and metabolite production, n-3 PUFAs influence intestinal permeability, immune activation, and vagal signaling, thereby contributing to both immunomodulatory and neurochemical effects. In combination, n-3 PUFAs modulate peripheral and central inflammation by promoting specialized pro-resolving mediators, downregulating pro-inflammatory cytokines, and influencing microglial activation. Parallel actions on neuronal membrane composition and lipid raft integrity affect neurotransmitter signaling, synaptic plasticity, and neurogenesis, with downstream effects on neural function. Additional pathways, including hypothalamic–pituitary–adrenal axis regulation and oxidative stress reduction, further integrate n-3 PUFA actions across multiple systems. Collectively, these mechanisms suggest that n-3 PUFAs act as network modulators, supporting recovery in depression. Translational research highlights the importance of EPA-predominant formulations, optimal dosing, and patient stratification. By framing n-3 PUFAs activity within a multi-level systems biology perspective, this review provides a comprehensive mechanistic understanding and underscores their potential as targeted adjunctive strategies for MDD. Full article

Psoriasis is a complex inflammatory disease related to cardiometabolic disorders (CMDs). Galectin-4 (gal-4) is involved in biological processes such as lipid raft stabilization, intestinal inflammation and tumorigenesis. Charcot-Leyden crystals (CLCs), inter alia, Charcot-Leyden crystal/galectin-10 (CLC/gal-10), are involved in eosinophil-derived diseases. To date, neither of these galectins has been investigated in the context of psoriasis. The study aimed to evaluate serum galectin-4 and -10 levels in psoriatic patients and explore potential relationships with disease activity, metabolic or inflammatory indices. Blood samples were collected from 60 patients with plaque-type psoriasis and 30 healthy volunteers and evaluated using an Enzyme-Linked Immunosorbent Assay (ELISA). Morphological and biochemical indices were measured using routine laboratory techniques. Plasma gal-4 and gal-10 concentrations were significantly higher in patients with psoriasis than in the control group (p < 0.05). Galectins did not correlate with the Psoriasis Area Severity Index (PASI) nor age (p > 0.5); however, gal-4 showed a significant positive correlation with Body Mass Index (BMI), psoriasis duration (p = 0.03), and transaminase activity. Both proteins were the highest in obese psoriatics (p < 0.05). The results indicate that galectin-4 and galectin-10 may be involved in the pathophysiological mechanisms underlying CMDs in psoriatics. These galectins represent promising candidates for biomarkers of metabolically driven inflammation, with galectin-4, in particular, emerging as a potential indicator of hepatic dysfunction in psoriatic patients. Full article

Cyclodextrins (CDs) have traditionally been recognized as excipients that enhance solubility and stability of drugs. However, growing evidence shows that CDs themselves can act as active therapeutic agents. Their unique supramolecular properties enable them to interact with biological membranes, mobilize cholesterol, and modulate immune responses. This review highlights four therapeutic areas where CDs demonstrate particular promise. First, in gene and mRNA therapy, cationic CD derivatives form nanoparticles that protect nucleic acids, promote endosomal escape, and achieve targeted delivery. Second, in neurodegenerative disorders such as Niemann–Pick type C and Alzheimer’s disease, hydroxypropyl-β-CD facilitates cholesterol clearance and reduces pathological lipid accumulation. Third, in detoxification, the γ-CD derivative sugammadex exemplifies a clinically approved agent that encapsulates neuromuscular blockers to reverse anesthesia. Finally, CDs have emerged as safe vaccine adjuvants, inducing robust systemic and mucosal immunity with reduced IgE responses compared to alum. Together, these examples illustrate a paradigm shift: CDs are not only versatile excipients but also active molecules with direct therapeutic effects. Future translation will require careful optimization of safety, scalability, and regulatory compliance, but CDs are poised to contribute meaningfully to next-generation medicines. Full article

Microviscosity and lipid order are the main parameters characterizing the phase states of the membrane. Variations in microviscosity and lipid composition in a living cell may indicate serious disturbances, including various kinds of stress. In this work, the effect of hyperosmotic stress on the microviscosity of mitochondrial membranes was investigated, using potato (Solanum tuberosum L.) tuber mitochondria. The microviscosity of mitochondrial membranes isolated from check and stressed (9 days at 34–36 °C) tubers was estimated by determining the generalized polarization (GP) values using a Laurdan fluorescent probe in confocal microscopy studies. It was revealed that the GP distribution in mitochondria isolated from stressed tubers contained new component-characterizing membrane domains with an increased lipid order compared to the rest of the membrane. We have mapped the microviscosity of mitochondrial membranes for the first time and observed the dynamics of the membrane microviscosity of an individual mitochondrion. The hyperosmotic stress significantly influences the functional state of potato mitochondria, decreasing the substrate oxidation rate and respiratory control coefficient but increasing MitoTracker Orange fluorescence. Under hyperosmotic stress, the microviscosity of mitochondrial membranes changes, and membrane domains with increased lipid order are formed. The revealed changes open up prospects for further research on the participation of raft-like microdomains of mitochondria in plant resistance to stress factors. Full article