Search Results (4,383)

Melittin, a cytolytic peptide derived from honeybee venom, has demonstrated potent anticancer activity through mechanisms such as membrane disruption, apoptosis induction, and modulation of key signaling pathways. Melittin exerts its anticancer activity by interacting with key molecular targets, including downregulation of the PI3K/Akt and NF-κB signaling pathways, and by inducing mitochondrial apoptosis through reactive oxygen species generation and cytochrome c release. However, its clinical application is hindered by its systemic and hemolytic toxicity, rapid degradation in plasma, poor pharmacokinetics, and immunogenicity, necessitating the development of targeted delivery strategies to enable safe and effective treatment. Nanoparticle-based delivery systems have emerged as a promising strategy for overcoming these challenges, offering improved tumor targeting, reduced off-target effects, and enhanced stability. This review provides a comprehensive overview of the mechanisms through which melittin exerts its anticancer effects and evaluates the development of various melittin-loaded nanocarriers, including liposomes, polymeric nanoparticles, dendrimers, micelles, and inorganic systems. It also summarizes the preclinical evidence for melittin nanotherapy across a wide range of cancer types, highlighting both its cytotoxic and immunomodulatory effects. The potential of melittin nanoparticles to overcome multidrug resistance and synergize with chemotherapy, immunotherapy, photothermal therapy, and radiotherapy is discussed. Despite promising in vitro and in vivo findings, its clinical translation remains limited. Key barriers include toxicity, manufacturing scalability, regulatory approval, and the need for more extensive in vivo validation. A key future direction is the application of computational tools, such as physiologically based pharmacokinetic modeling and artificial-intelligence-based modeling, to streamline development and guide its clinical translation. Addressing these challenges through focused research and interdisciplinary collaboration will be essential to realizing the full therapeutic potential of melittin-based nanomedicines in oncology. Overall, this review synthesizes the findings from over 100 peer-reviewed studies published between 2008 and 2025, providing an up-to-date assessment of melittin-based nanomedicine strategies across diverse cancer types. Full article

Foodborne illness caused by bacterial pathogens is a global health concern and results in millions of infections annually. Therefore, food products typically undergo several processing stages, including sanitation steps, before being distributed in an attempt to remove pathogens. However, many sanitation methods have compounding effects on the color, texture, flavor, and nutritional quality of the product or do not effectively reduce the pathogens that food can be exposed to. Some bacterial pathogens particularly possess traits and tactics that make them even more difficult to mitigate such as biofilm formation. Non-thermal plasma sanitation techniques, including plasma-treated water (PTW), have proven to be promising methods that significantly reduce pathogenic bacteria that food is exposed to. Published work reveals that PTW can effectively mitigate both gram-positive and gram-negative bacterial biofilms. This study presents a novel analysis of the differences in antimicrobial effects of PTW treatment between biofilm-forming gram-positive bacteria, commonly associated with foodborne illness, that are sporulating (Bacillus cereus) and non-sporulating (Listeria monocytogenes). After treatment with PTW, the results suggest the following hypotheses: (1) that the non-sporulating species experiences less membrane damage but a greater reduction in metabolic activity, leading to a possible viable but non-culturable (VBNC) state, and (2) that the sporulating species undergoes spore formation, which may subsequently convert into vegetative cells over time. PTW treatment on gram-positive bacterial biofilms that persist in food processing environments proves to be effective in reducing the proliferating abilities of the bacteria. However, the variance in PTW’s effects on metabolic activity and cell vitality between sporulating and non-sporulating species suggest that other survival tactics might be induced. This analysis further informs the application of PTW in food processing as an effective sanitation method. Full article

Insulin-regulated glucose uptake is a central mechanism in maintaining systemic glucose homeostasis, primarily occurring in skeletal muscle and adipose tissue. This process relies on the insulin-stimulated translocation of the glucose transporter, GLUT4, from specialized intracellular compartments, known as GLUT4 storage vesicles (GSVs), to the plasma membrane. Disruption of this pathway is a hallmark of insulin resistance and a key contributor to the pathogenesis of type 2 diabetes. Recent advances have provided critical insights into both the insulin signalling cascades and the complex biogenesis, as well as the trafficking and fusion dynamics of GSVs. This review synthesizes the current understanding of the molecular mechanisms governing GSV mobilization and membrane fusion, highlighting key regulatory nodes that may become dysfunctional in metabolic disease. By elucidating these pathways, we propose new therapeutic avenues targeting GSV trafficking to improve insulin sensitivity and combat type 2 diabetes. Full article

Background Plasma membrane proteins (PMPs) play key roles in cell signalling, adhesion, and trafficking, and are attractive therapeutic targets in cancer due to their surface accessibility. However, their typically low abundance limits detection by conventional proteomic approaches. Methods: To improve PMP detection, we employed a surface proteomics workflow combining cell surface biotinylation and affinity purification prior to LC-MS/MS analysis in cervical (SiHa) and bladder (UMUC3) cancer cell lines cultured under normoxic (21% O₂) or hypoxic (0.1% O₂) conditions. Results: In SiHa cells, 43 hypoxia-upregulated proteins were identified exclusively in the biotin-enriched fraction, including ITGB2, ITGA7, AXL, MET, JAG2, and CAV1/CAV2. In UMUC3 cells, 32 unique upregulated PMPs were detected, including CD55, ADGRB1, SLC9A1, NECTIN3, and ACTG1. These proteins were not observed in corresponding whole-cell lysates and are associated with extracellular matrix remodelling, immune modulation, and ion transport. Biotinylation enhanced the detection of membrane-associated pathways such as ECM organisation, integrin signalling, and PI3K–Akt activation. Protein–protein interaction analysis revealed links between membrane receptors and intracellular stress regulators, including mitochondrial proteins. Conclusions: These findings demonstrate that surface biotinylation improves the sensitivity and selectivity of plasma membrane proteomics under hypoxia, revealing hypoxia-responsive proteins and pathways not captured by standard whole-cell analysis. Full article

One major challenge in cellular neuroscience is to elucidate how the accurate alignment of presynaptic release sites with postsynaptic densely clustered ligand-gated ion channels at chemical synapses is achieved upon synapse assembly. The clustering of neurotransmitter receptors at postsynaptic sites is a key moment of synaptogenesis and determinant for effective synaptic transmission. The number of the ionotropic neurotransmitter receptors at these postsynaptic sites of both excitatory and inhibitory synapses is variable and is regulated by different mechanisms, thus allowing the modulation of synaptic strength, which is essential to tune neuronal network activity. Several well-regulated processes seem to be involved, including lateral diffusion within the plasma membrane and local anchoring as well as receptor endocytosis and recycling. The molecular mechanisms implicated are numerous and were reviewed recently in great detail. The role of pre-synaptically released neurotransmitters within the complex regulatory apparatus organizing the postsynaptic site underneath presynaptic terminals is not completely understood, even less for inhibitory synapses. In this mini review article, we focus on this aspect of synapse formation, summarizing and contrasting findings on the functional role of the neurotransmitters glycine and γ-aminobutyric acid (GABA) for initiation of postsynaptic receptor clustering and regulation of Cl⁻ channel receptor numbers at inhibitory synapses gathered over the last two decades. Full article

Staphylococcus aureus is a Gram-positive bacterium that causes significant human morbidity and mortality. The capacity of S. aureus to cause disease is primarily attributed to an array of virulence factors produced by this pathogen that collectively overcome immune defenses and promote survival in a variety of host tissues. These include an arsenal of different cytotoxins that compromise plasma membrane integrity, with the specificity of each dependent upon the host organism and cell type. S. aureus encounters a variety of peripheral blood cell types during infection that play important roles in maintaining homeostasis and defending against microbial invasion, namely erythrocytes, thrombocytes, and leukocytes. S. aureus targets each of these cell types with specific cytotoxins to successfully establish disease. This review summarizes our current understanding of the susceptibility of different human peripheral blood cell types to each of these cytotoxins. Full article

Dopamine transporter (DAT) mutations are associated with neurological and psychiatric diseases, and DAT gene knockout in rats (DAT-KO) provides an opportunity to evaluate the DAT role in pathological conditions. We analyzed DAT expression and co-expression with other genes in the substantia nigra and striatum in public transcriptomic data represented in the GEO repository and then estimated the identified DAT co-expression pattern in DAT-KO rats by RT-PCR. In silico analysis confirmed DAT expression in the substantia nigra and absence of DAT mRNA in the striatum. Also, DAT is co-expressed with genes involved in dopamine signaling, but these associations are disrupted in dopamine neuron-damaging conditions. To estimate this co-expression pattern when DAT expression is lost, we evaluate it in the substantia nigra of DAT-KO rats. However, in DAT-KO rats the associations between genes involved in dopamine signaling were not disturbed compared to wild-type littermates, and tyrosine hydroxylase expression upregulation in the substantia nigra of these animals may be considered as compensation for the loss of dopamine reuptake. Further studies of expression regulation in dopamine neurons of DAT-KO rats may provide valuable information for compensatory mechanisms in substantia nigra dopaminergic neurons. Full article

The Golgi of goblet cells represents a specialized machine for mucin glycosylation. This process occurs in a specialized form of the secretory pathway, which remains poorly examined. Here, using high-resolution three-dimensional electron microscopy (EM), EM tomography, serial block face scanning EM (SBF-SEM) and immune EM we analyzed the secretory pathway in goblet cells and revealed that COPII-coated buds on the endoplasmic reticulum (ER) are extremely rare. The ERES vesicles with dimensions typical for the COPII-dependent vesicles were not found. The Golgi is formed by a single cisterna organized in a spiral with characteristics of the cycloid surface. This ribbon has a shape of a cup with irregular perforations. The Golgi cup is filled with secretory granules (SGs) containing glycosylated mucins. Their diameter is close to 1 µm. The cup is connected with ER exit sites (ERESs) with temporal bead-like connections, which are observed mostly near the craters observed at the externally located cis surface of the cup. The craters represent conus-like cavities formed by aligned holes of gradually decreasing diameters through the first three Golgi cisternae. These craters are localized directly opposite the ERES. Clusters of the 52 nm vesicles are visible between Golgi cisternae and between SGs. The accumulation of mucin, started in the fourth cisternal layer, induces distensions of the cisternal lumen. The thickness of these distensions gradually increases in size through the next cisternal layers. The spherical distensions are observed at the edges of the Golgi cup, where they fuse with SGs and detach from the cisternae. After the fusion of SGs located just below the apical plasma membrane (APM) with APM, mucus is secreted. The content of this SG becomes less osmiophilic and the excessive surface area of the APM is formed. This membrane is eliminated through the detachment of bubbles filled with another SG and surrounded with a double membrane or by collapse of the empty SG and transformation of the double membrane lacking a visible lumen into multilayered organelles, which move to the cell basis and are secreted into the intercellular space where the processes of dendritic cells are localized. These data are evaluated from the point of view of existing models of intracellular transport. Full article

Background/Objectives: Nutraceuticals containing milk fat globule membranes (MFGMs) and extracellular vesicles (EVs) are purported to abate age-related metabolic dysfunction due to their richness in milk sphingolipids. As such, nutraceuticals offer a compelling strategy to improve metabolic health through dietary means, especially for elderly persons who are unable to adhere to common therapeutic interventions. To address this, we examined the effects of supplementing aged sedentary rats with an MFGM/EV-rich concentrate. Methods/Results: In a 25-week study, 89-week-old male rats received either a milk sphingolipid-rich MFGM/EV concentrate or a control supplement. Analysis of metabolic health using a battery of tests, including MS^ALL lipidomics of plasma, liver, and other peripheral tissues, revealed that MFGM/EV supplementation promotes accretion of unique sphingolipid signatures, ameliorates ceramide biomarkers predictive of cardiovascular death, and has a general lipid-lowering effect. At the functional level, we find that these health-promoting effects are linked to increased lipoprotein particle turnover, showcased by reduced levels of triglyceride-rich particles, as well as a metabolically healthier liver, assessed using whole-body lipidomic flux analysis. Conclusions: Altogether, our work unveils that MFGM/EV-containing food holds a potential for ameliorating age-related metabolic dysfunction in elderly individuals. Full article

Cell-penetrating peptides offer a promising strategy for intracellular delivery; however, non-specific uptake and off-target cytotoxicity limit their clinical utility. To address these limitations, a cold atmospheric plasma-responsive delivery platform was developed in which the membrane activity of a peptide was transiently suppressed upon complexation with a DNA-based nanostructure. Upon localized plasma exposure, DNA masking was disrupted, restoring the biological functions of the peptides. Transmission electron microscopy revealed that the synthesized DNA nanoflower structures were approximately 150–250 nm in size. Structural and functional analyses confirmed that the system remained inert under physiological conditions and was rapidly activated by plasma treatment. Fluorescence recovery, cellular uptake assays, and cytotoxicity measurements demonstrated that the peptide activity could be precisely controlled in both monolayer and three-dimensional spheroid models. This externally activatable nanomaterial-based system enables the spatial and temporal regulation of peptide function without requiring biochemical triggers or permanent chemical modifications. This platform provides a modular strategy for the development of potential peptide therapeutics that require precise control of activation in complex biological environments. Full article

Background: Oral lichen planus is a chronic, potentially malignant disorder affecting the mucous membrane. As the etiology remains not fully understood, the treatment of this condition is mainly symptomatic, involving corticosteroids and other immunosuppressive agents, e.g., calcineurin inhibitors. One of the alternative therapeutic approaches includes platelet concentrates, which are autologous bioactive materials. The aim of this review was to evaluate the effects of platelet concentrates in the treatment of oral lichen planus and to compare them to other therapeutic strategies. Methods: The electronic databases PubMed/Medline, Web of Science, and Cochrane Library were searched for articles published up to 30 March 2025, describing clinical studies focused on oral lichen planus and treatment with platelet concentrates. Results: Fourteen studies describing the effects of oral lichen planus therapy with three types of platelet concentrates (injectable platelet-rich plasma, injectable platelet-rich fibrin, and platelet-rich plasma gel) were included in this review. Comparative strategies included steroids and immunosuppressive agents. The treatment duration ranged from 3 weeks to 2 months. The follow-up period varied from 4 weeks to 6 months. In most of the studies, comparable efficacy was achieved for platelet derivatives and alternative treatments. Two of the studies demonstrated more beneficial effects for platelet concentrates compared to controls, while in one of the studies, more severe adverse reactions were revealed in the platelet group compared to the controls. Conclusions: Autologous platelet concentrates showed comparable efficacy in achieving clinical improvement in patients with oral lichen planus to steroids and immunosuppressive drugs. Platelet derivatives could be considered as an alternative treatment to topical immunosuppressives, especially in steroid-refractory cases. Full article

Background: Surgical management of large full-thickness macular holes (MHs) remains challenging, particularly when aiming for both rapid visual recovery and consistent anatomical closure without inducing retinal trauma. This retrospective single-center study evaluated the efficacy of activated conditioned plasma (ACP) as an intraoperative coadjuvant supporting ILM (internal limiting membrane) peeling and air tamponade in the treatment of idiopathic MHs measuring 400–800 µm, under real-time intraoperative optical coherence tomography (i-OCT) guidance. Methods: Seventy eyes from fifty patients underwent pars plana vitrectomy with intraoperative ACP application. ACP, a leukocyte-poor autologous platelet concentrate, was used intraoperatively as a coadjuvant to ILM peeling and air tamponade. It facilitated the formation of a transparent fibrin membrane over the retinal surface, supporting edge approximation and promoting retinal healing. Results: The primary outcome was complete MH closure confirmed by OCT; the secondary outcome was improvement in BCVA on postoperative day 7 and during a 12-month follow-up. Anatomical closure was achieved in 98.6% of cases. On day 7, 78.6% of eyes showed a ≥ three-line BCVA improvement, with mean BCVA increasing from 0.25 ± 0.21 to 0.69 ± 0.20 (p < 0.001). These outcomes remained stable throughout the follow-up. No significant intraoperative or postoperative complications were observed. Conclusions: The combination of ACP and i-OCT appears to be a safe and effective strategy for anatomical foveolar reconstruction, enabling early visual recovery while minimizing inflammation and fibrotic scarring associated with conventional techniques. Full article

Tellurite (TeO₃²⁻) is a highly soluble and toxic oxyanion that inhibits the growth of Escherichia coli at concentrations as low as ~1 µg/mL. This toxicity has been primarily attributed to the generation of reactive oxygen species (ROS) during its intracellular reduction by thiol-containing molecules and NAD(P)H-dependent enzymes. However, under anaerobic conditions, E. coli exhibits significantly increased tellurite tolerance—up to 100-fold in minimal media—suggesting the involvement of additional, ROS-independent mechanisms. In this study, we combined chemical-genomic screening, untargeted metabolomics, and targeted biochemical assays to investigate the effects of tellurite under both aerobic and anaerobic conditions. Our findings reveal that tellurite perturbs amino acid and nucleotide metabolism, leading to intracellular imbalances that impair protein synthesis. Additionally, tellurite induces notable changes in membrane lipid composition, particularly in phosphatidylethanolamine derivatives, which may influence biophysical properties of the membrane, such as fluidity or curvature. This membrane remodeling could contribute to the increased resistance observed under anaerobic conditions, although direct evidence of altered membrane fluidity remains to be established. Overall, these results demonstrate that tellurite toxicity extends beyond oxidative stress, impacting central metabolic pathways and membrane-associated functions regardless of oxygen availability. Full article

Semen cryopreservation is associated with sperm vulnerability to oxidative stress and ice crystal-induced damage, adversely affecting in vitro fertilization (IVF) success. This study aimed to investigate the effects of freezing diluent supplemented with antioxidant limonin (Lim), myo-inositol (MYO), and the ice crystal formation inhibitor L-proline (LP) through sperm motility, morphological integrity, and antioxidant capacity. The Lim (150 mM), MYO (90 mM), and LP (100 mM) significantly ameliorated the quality of post-thaw sperm in Debao boar, and combined treatment of these agents significantly enhanced sperm motility, structural integrity, and antioxidant capacity compared with individual agents (p < 0.05). Notably, the combined use of these agents reduced glycerol concentration in the freezing diluent from 3% to 2%. Meanwhile, the integrity of the sperm plasma membrane, acrosome membrane, and mitochondrial membrane potential was significantly improved (p < 0.05), and the result of IVF revealed the total cell count of the blastocysts was also greater in the 2% glycerol group (p < 0.05). In conclusion, the newly developed freezing diluent for semen, by adding Lim (150 mM), MYO (90 mM), and LP (100 mM), can enhance the quality of frozen–thawed Debao boar sperm and reduce the concentration of glycerol from 3% to 2% as high concentrations of glycerol can impair the quality of thawed sperm and affect in vitro fertilization outcomes. In conclusion, the improved dilution solution formulated demonstrated efficacy in enhancing the quality of porcine spermatozoa following cryopreservation and subsequent thawing. Full article

Peanut (Arachis hypogaea L.) is a globally important oilseed cash crop, yet its limited genetic diversity and unique reproductive biology present persistent challenges for conventional crossbreeding. Traditional breeding approaches are often time-consuming and inadequate, mitigating the pace of cultivar development. Essential for double fertilization and programmed cell death (PCD), DUF679 membrane proteins (DMPs) represent a membrane protein family unique to plants. In the present study, a comprehensive analysis of the DMP gene family in peanuts was conducted, which included the identification of 21 family members. Based on phylogenetic analysis, these genes were segregated into five distinct clades (I–V), with AhDMP8A, AhDMP8B, AhDMP9A, and AhDMP9B in clade IV exhibiting high homology with known haploid induction genes. These four candidates also displayed significantly elevated expression in floral tissues compared to other organs, supporting their candidacy for haploid induction in peanuts. Subcellular localization prediction, confirmed through co-localization assays, demonstrated that AhDMPs primarily localize to the plasma membrane, consistent with their proposed roles in the reproductive signaling process. Furthermore, chromosomal mapping and synteny analyses revealed that the expansion of the AhDMP gene family is largely driven by whole-genome duplication (WGD) and segmental duplication events, reflecting the evolutionary dynamics of the tetraploid peanut genome. Collectively, these findings establish a foundational understanding of the AhDMP gene family and highlight promising targets for future applications in haploid induction-based breeding strategies in peanuts. Full article