Search Results (48,162)

Ferroptosis is a recently discovered form of cell death, driven by membrane lipid peroxidation with the contribution of intracellular iron. In recent years, many researchers have discovered the involvement of ferroptotic mechanisms in the etiology of various diseases, including several forms of cancer. Different points in the ferroptotic pathway can be crucial for arising or sustained pathologies, given the contribution of numerous molecular mechanisms concerning membrane channels, several proteins, enzymes, and also kinases. The latter, in particular, seems to be very important in the control of ferroptosis in different manners depending on the pathology. Therefore, many articles in recent years have described how the pathways that involve kinases can determine, control, or alter the physiological ferroptotic contribution. Interestingly, in a tumoral context, oncogenes and tumor suppressor activity affect the correct ferroptotic process directly or indirectly promoted by abnormal kinase activity. Expanding the understanding of how kinases contribute to tumorigenesis by altering ferroptosis mechanisms may provide important insights to improve current anticancer therapies. Furthermore, new data have indicated how kinase-dependent ferroptotic activity may influence the efficacy of immunotherapy. Since one of the major obstacles to this promising anticancer therapy concerns the resistance induced by cancer cells, finding new targets, such as kinases, to improve ferroptosis in tumor cells could open an intriguing door to enhancing immunotherapy and overcoming the current obstacle. Full article

Background: Valproic acid (VPA) poisoning has a dynamic clinical course and may require extracorporeal toxin removal (ECTR) in severe cases. Intermittent hemodialysis is the preferred ECTR technique; however, clinical experience with expanded hemodialysis (HDx) using medium cut-off (MCO) membranes in acute VPA intoxication is scarce. We describe a case of severe VPA poisoning managed with intermittent HDx and outline the clinical rationale and kinetic response. Case Report: A 54-year-old woman presented to the emergency department after accidental presumably ingesting approximately 4 g of VPA, with depressed consciousness (Glasgow Coma Scale 7) and metabolic acidosis (pH 7.10, HCO₃⁻ 13 mmol/L, PCO₂ 50 mmHg, lactate 2.8 mmol/L, ionized calcium 0.8 mmol/L, elevated anion gap). Initial plasma VPA was 262.99 µg/mL, ammonia was 14 µmol/L, and cranial computed tomography showed no acute abnormalities. ECTR was initiated in the intensive care unit as intermittent HDx using an MCO dialyzer for 4 h. Serial VPA concentrations were obtained before treatment, at 2 h, and at the end of the session to guide real-time prescription adjustment, with an increase in blood flow from 200 to 230 mL/min. Results: VPA decreased from 262.99 µg/mL pre-HD to 141.48 µg/mL at 2 h (46.2% reduction) and 97.81 µg/mL at 4 h (62.8% reduction), with clear improvement in the level of consciousness. A mild post-dialysis rebound was observed (100.07 µg/mL at 14 h). The patient recovered without additional ECTR and was discharged with normalized VPA levels on follow-up. Conclusions: In this patient, intermittent HDx with an MCO membrane was feasible, well tolerated, and associated with rapid VPA clearance and neurological recovery. Serial drug monitoring enabled bedside optimization of the dialysis prescription and post-treatment evaluation. A single HDx session was sufficient, and VPA therapy was safely reintroduced under close monitoring. Full article

Pituitary neuroendocrine tumors (PitNETs) are usually benign intracranial neoplasms that may exhibit invasion of the cavernous sinus, complicating surgery and increasing the risk of recurrence. This study aimed to investigate membranous E-cadherin (mE-cad) expression across PitNET subtypes and transcription factor (TF) lineages, including Pit-1 (pituitary-specific positive transcription factor 1), SF-1 (Steroidogenic Factor 1), and TPIT (T-box pituitary transcription factor), and its association with tumor invasiveness in sixty-nine patients. mE-cad expression was evaluated as the percentage of positive cells (0%, 1–10%, >10%) and by immunoreactive score (IRS). Staining intensity was scored as: 0, no staining; 1, weak; 2, moderate; 3, strong. The proportion of positive cells was scored as: 0, none; 1, <10%; 2, 10–50%; 3, 51–80%; 4, >80%. Mean mE-cad expression was 5.2% in gonadotroph, 3.2% in corticotroph, 0.5% in lactotroph, and 17.5% in plurihormonal PitNETs. By TF lineage, the mean expression was 5.3% for Pit-1, 3.2% for TPIT, and 5.1% for SF-1. Low mE-cad expression (IRS 1–2) was associated with higher odds of cavernous sinus invasion compared with IRS 3–6 (adjusted OR = 6.0, 95% CI 1.08–33.4, p = 0.04), independent of tumor volume (adjusted OR = 4.0, 95% CI 1.50–10.7, p = 0.01). After restricting the analysis to the gonadotroph PitNET group, tumors with an IRS of 1–2 showed significantly higher invasiveness compared with those with an IRS of 3–6 (p = 0.012). These findings suggest that mE-cad may serve as a biomarker of PitNET invasiveness, with expression varying according to TF lineage and tumor subtype. Full article

Background/Objectives: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor prognosis. The neddylation inhibitor MLN4924 has demonstrated potent anti-leukemic activity in preclinical models, yet its clinical translation faces significant challenges. The aim of this study was to explore combination therapy strategies that could further enhance MLN4924’s anti-leukemia potential. Methods: AML cell lines used in this study were Kasumi-1 and MOLM-13. Cell viability was assessed using CCK-8 assays. mRNA and protein expression levels were determined through RT-qPCR and Western blot, respectively. Flow cytometry was employed to analyze surface markers (SLC1A5, CD11b, CD14, CD16), mitochondrial membrane potential (JC-1), and apoptosis (Annexin V-FITC/PI). In vivo efficacy was validated using an NCG mouse xenograft model. Transcriptomic profiling was performed to explore the potential mechanism by which MLN4924 in combination with V9302 inhibits leukemia. Results: Treatment with MLN4924 significantly upregulated key glutamine metabolic proteins, GLUL and the glutamine transporter SLC1A5, in AML cells. Knockdown of SLC1A5 significantly enhanced AML cell sensitivity to MLN4924. The combination of MLN4924 and the SLC1A5 inhibitor V9302 synergistically inhibited AML cell proliferation, induced monocytic differentiation, and promoted apoptosis. Transcriptomic analysis revealed that this combination therapy prominently suppressed the tricarboxylic acid (TCA) cycle. Conclusions: Neddylation inhibition induces compensatory upregulation of glutamine metabolism in AML. Co-targeting neddylation and glutamine transporter SLC1A5 synergistically exerts anti-leukemic effects, at least in part through disruption of the TCA cycle. This combination represents a novel and effective therapeutic strategy against AML. Full article

This study evaluated Apis mellifera brood fat extracts as a sustainable alternative to beeswax for anti-inflammatory topical delivery, including their formulation into nanostructured lipid carriers (NLCs). Brood fat was extracted using acetone, ethyl acetate (EA), and hexane, and the resulting extracts were characterized for fatty acid composition and physicochemical properties. Safety was assessed using the hen’s egg chorioallantoic membrane test and cytotoxicity testing in RAW 264.7 macrophages. Anti-inflammatory activity was assessed by inhibition of lipopolysaccharide-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) production. The most suitable extract was formulated into NLCs using sugar squalane as liquid lipid, and the effects of lipid ratio and preparation method were investigated. The results showed that the ethyl acetate extract had the highest yield. Compared with beeswax, all fat extracts exhibited a favorable oleic acid–rich fatty acid profile with comparable crystallinity and thermal behavior, while showing significantly enhanced anti-inflammatory activity (p < 0.05). All extracts and their NLCs were non-irritating and non-cytotoxic. Ethyl acetate extract-based NLCs exhibited favorable particle sizes (72.1 ± 0.3 nm) and narrow polydispersity (0.14 ± 0.00), with high-pressure homogenization producing smaller particles compared to probe sonication without affecting IL-6 or TNF-α inhibition. Therefore, A. mellifera brood fat extract is a sustainable anti-inflammatory lipid source with strong potential as an alternative to beeswax in topical nano-formulations. Full article

Water electrolysis is a key technology for sustainable hydrogen production and a cornerstone of future low-carbon energy systems. However, large-scale deployment is constrained not only by efficiency and cost, but increasingly by the sustainability and availability of materials used in electrocatalysts and membranes. This review provides a materials-centric assessment of state-of-the-art and emerging electrocatalysts for alkaline (AEL), proton exchange membrane (PEM), and solid oxide electrolysis (SOEC) technologies, emphasizing the interdependence of performance, durability, cost, and sustainability. Electrocatalyst activity and stability are linked to cell- and stack-level efficiency, energy demand, and the levelized cost of hydrogen. Life cycle assessment (LCA) and resource criticality analyses are integrated to quantify environmental impacts, supply risks, and recycling potential of key materials, including platinum group metals, nickel, rare earth elements, and ceramic oxides. Particular attention is given to recycling and circularity strategies, which are essential for mitigating material scarcity and reducing upstream emissions, especially in PEM electrolyzers. Emerging catalyst concepts such as single-atom catalysts, high-entropy alloys, and noble-metal-free systems are discussed as promising pathways to reduce critical material dependence. The review concludes by highlighting the need for integrated material–technology–system approaches to enable efficient, scalable, and truly sustainable hydrogen production. Full article

Staphylococcus aureus is a major cause of skin and soft tissue infections, necessitating the development of new topical agents with rapid bactericidal activity and low resistance potential. Here, we evaluated the antibacterial activity of a pyrazolone copper complex (P-FAH-Cu-phen) against S. aureus, investigated its in vitro mode of action, and its assessed therapeutic efficacy in a murine model of S. aureus-infected skin trauma. P-FAH-Cu-phen exhibited potent bactericidal activity (minimum inhibitory concentration [MIC] 1.4 μg/mL; minimum bactericidal concentration [MBC] 2.8 μg/mL) and rapid killing (>91% eradication within 2.5 min), with no detectable MIC increase under the tested serial passaging conditions. Cell-envelope dysfunction was evidenced by increased supernatant alkaline phosphatase activity, elevated leakage of nucleic acids and proteins, and reduced membrane-associated Na⁺/K⁺- and Ca²⁺/Mg²⁺-ATPase activities. At sub-inhibitory concentrations, P-FAH-Cu-phen reduced haemolytic and coagulase activities, modulated virulence gene expression (sea, hla, agrA), and inhibited biofilm formation and biofilm-associated metabolic activity. In vivo, topical treatment accelerated wound closure and histopathological repair, increased hydroxyproline content, reduced bacterial burden, and lowered TNF-α and IL-10 levels in wound tissues. Collectively, P-FAH-Cu-phen shows multi-faceted anti-infective activity and exhibits further development as a topical candidate for S. aureus-infected skin wounds. Full article

Canine coronavirus (CCoV), an alphacoronavirus belonging to the Coronaviridae family, is primarily associated with enteric infections in dogs. The ongoing evolution of coronaviruses through genetic recombination and mutation leads to the emergence of novel strains with increased pathogenicity, thereby raising the risk of cross-species transmission and spillover events. In this context, viral entry inhibitors represent a promising strategy, as they can serve as pivotal tools to prevent initial infection and subsequent viral replication. The S2 subunit of the spike (S) glycoprotein contains two heptad repeat regions (HRN and HRC), which play essential roles in the conformational changes required for viral fusion. In this study, we describe the design, synthesis, and functional evaluation of a peptide derived from the HRC domain of the CCoV S glycoprotein. First, we assessed the cytotoxicity of the CCoV-HRC peptide in two cell lines, HE293T and A72, and determined CC₅₀ values > 100 μM. At non-toxic concentrations, the peptide effectively blocked membrane fusion mediated by the CCoV S glycoprotein and significantly reduced viral infection, as demonstrated both in cell–cell fusion assays and in live virus experiments. These findings were supported by in silico docking and molecular dynamics simulations, which provided structural insight into the interaction between CCoV-HRC and the S fusion core. Then, molecular analyses were conducted to evaluate the expression of the gene encoding the viral S protein, confirming the antiviral potential of CCoV-HRC peptide. Overall, these findings provide a solid foundation for the development of peptide-based therapeutics to treat or prevent CCoV infections. Full article

ABC transporters (ATP-binding cassette transporters) constitute one of the largest known protein families and are widely distributed in plants. Their primary function involves utilizing energy derived from ATP hydrolysis to transport substrates across membranes against concentration gradients. These transporters play crucial roles in the translocation and accumulation of metabolites, stress tolerance, disease resistance, and plant defense. Lotus is an important traditional Chinese medicinal herb and contains active ingredients primarily composed of secondary metabolites, whose transport and accumulation require the involvement of ABC transporters. However, the function of these ABC transporters remains unexplored in lotus. In this study, 122 ABC transporter genes were predicted within the lotus genome. We identified 1~15 conserved motifs among the NnABC proteins and most of them were stable proteins predominantly located on the plasma membrane with ExPASy-ProtParam, ProComp and WoLF PSORT analysis. Phylogenetic tree analysis revealed that the lotus ABC transporter gene family could be divided into eight subfamilies, from ABCA to ABCI, and the evolution was predominantly driven by purifying selection. Comparative transcriptome analysis between the cultivar ‘Yindu Zhimi’ with orange-reddish stamen and ‘Weishan Hong’ with yellowish stamen, along with quantitative real-time PCR results, showed that the NnABCG25 gene is highly specifically expressed in the orange-reddish stamen. Molecular docking demonstrated that NnABCG25 has a stable affinity for lycopene, β-carotene and β-apocarotenal, suggesting its potential involvement in the transport of carotenoids in the stamen. These findings expand our understanding of the role of ABC transporters in the transport and accumulation of carotenoids, as well as providing a valuable reference for research on the ABC transporter gene family in other plants. Full article

Conventional drug delivery systems often suffer from problems such as limited targeting specificity, short half-lives, poor biocompatibility, and systemic toxicity, which significantly limit their therapeutic efficacy against major diseases like cancer. Blood cells, as native components of the human circulatory system, offer distinct advantages including low immunogenicity, long circulation times, remarkable mechanical flexibility, and innate ability to home to disease sites. These attributes make blood cells a promising platform for next-generation targeted drug carriers. In this review, we examine the biological and mechanical properties of red blood cells, white blood cells, platelets, and cell-derived membrane vesicles. We highlight recent advances in how these cells are engineered and loaded with drugs, and their application in tumor-targeted therapy, while also considering their potential in other diseases. We also discuss current technical challenges and outline future directions for clinical translation, offering a practical perspective on advancing blood cell-based delivery technologies. Full article

Oxidative stress in intestinal epithelial cells has been increasingly recognized as a key factor in various intestinal disorders. Gastrodia elata polysaccharide-2 (GEP-2), a water-soluble polysaccharide known for its antioxidant properties, has shown potential against intestinal injury. However, its effects on intestinal epithelial cells and the molecular mechanisms involved are not yet fully understood. In this study, we established a hydrogen peroxide (H₂O₂)-induced oxidative stress model using human colonic epithelial cells (NCM460) to evaluate the protective effects of GEP-2. We assessed cell viability, antioxidant enzyme activities, reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP). The results demonstrated that GEP-2 pretreatment significantly improved the viability of NCM460 cells subjected to H₂O₂ damage. Additionally, it could enhance the antioxidant defense, reduce the levels of ROS, malondialdehyde (MDA), and maintain the MMP. Transcriptomic analysis identified 169 differentially expressed genes upregulated in the glutathione metabolism. JAK-STAT pathway and downregulated in inflammation. Furthermore, it was shown that GEP-2 treatment activated the Nuclear factor erythroid 2-related factor 2 (Nrf2)/quinone oxidoreductase 1 (NQO1)-mediated antioxidant response and promoted the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Therefore, GEP-2 exerts multi-targeted cell protection by coordinating the Nrf2/NQO1 antioxidant axis and the JAK/STAT survival signaling pathway, providing a theoretical basis for the development of novel antioxidants. Full article

This study aimed to design a multi-epitope vaccine (MEV) against Pasteurella multocida (Pm) using immunoinformatics approaches. Based on four conserved outer membrane proteins (OmpA; OmpH; PlpEand LolA), 15 immunodominant epitopes were identified, including 8 CTL epitopes, 3 HTL epitopes, and 4 B-cell epitopes. A vaccine construct was developed by incorporating RGD and PADRE adjuvant sequences. Computational analyses indicated that the vaccine possesses favorable physicochemical properties and structural stability. The molecular docking and normal mode analyses reveal a potential binding interface between the basis and TLR2/TLR4, with a computed binding energy of −10.1 kcal/mol for TLR4, suggesting a possible preferential interaction. Immune simulation predicted the vaccine could effectively elicit responses from B cells, T cells, and key cytokines such as IFN-γ. Additionally, the vaccine sequence was successfully cloned into the pET-28a (+) expression vector, facilitating future recombinant expression. This study provides a theoretical foundation for developing a safe and effective subunit vaccine against Pm. Full article

Wounds caused by Vibrio vulnificus (V. vulnificus) infection often exhibit delayed healing and are prone to complications, making them a significant challenge in clinical treatment. Current conventional treatments, such as antibiotics and gauze dressings, have limited effectiveness. To address this, this study developed a multifunctional fiber membrane using electrospinning technology. Micron- or nano-sized Haliotidis Concha (HC) and eugenol (Eu) were loaded onto the membrane to promote healing in V. vulnificus-infected wounds. The prepared fiber membranes exhibited diameters of approximately 0.35 ± 0.01 μm. Membranes loaded with nano-HC demonstrated significant antibacterial efficacy, achieving a 96.2% inhibition rate against V. vulnificus, which was markedly superior to the micron-HC group (p < 0.05). Notably, the nano-HC/Eu membranes exhibited exceptionally high flexibility with an elongation at break of 878.1 ± 35.3%, while maintaining a tensile strength of approximately 2.2 MPa. Furthermore, these membranes exhibited excellent biocompatibility, with cell viability exceeding 85% for fibroblasts, and demonstrated good hemocompatibility. They also effectively promoted cell migration, indicating their potential as wound scaffold materials. In a V. vulnificus-infected skin wound model, the nano-HC/Eu fiber membrane accelerated collagen deposition and promoted wound healing, achieving a wound closure rate of 94.7 ± 1.1% on day 15. In summary, this study developed a multifunctional fiber membrane with antibacterial, antioxidant, and wound healing properties, offering a novel dressing for treating V. vulnificus infections. Full article

Leucine-rich repeat-containing 8A (LRRC8A; also known as SWELL1), the essential subunit of volume-regulated anion channels (VRACs), is amplified in multiple malignancies and has been implicated in tumor progression and therapeutic resistance. Three-dimensional (3D) cancer spheroids have been well-established as in vitro models that recapitulate characteristics of tumor stemness and intrinsic drug resistance. In the present study, spheroid formation in human breast cancer cell lines, YMB-1 and MDA-MB-468, conferred resistance to multiple anticancer drugs, including doxorubicin (DOX), gemcitabine (GEM), and 5-fluorouracil (5-FU), thereby mimicking the characteristic properties of breast cancer stem-like cells. LRRC8A expression was upregulated in 3D spheroids compared with adherent 2D monolayers, and its pharmacological inhibition induced membrane hyperpolarization accompanied by intracellular Cl⁻ accumulation. Inhibition of LRRC8A significantly sensitized spheroids to DOX, GEM, and 5-FU. Spheroid formation increased the expression of multidrug resistance-related protein 3 (MRP3) and the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4), whereas LRRC8A inhibition suppressed their expression. The transcriptional upregulation of MRP3 and CYP3A4 was mediated through the NRF2–CEBPB/D transcriptional axis. Collectively, these findings suggest that LRRC8A inhibition may represent a therapeutic strategy to overcome chemoresistance by repressing MRP3 and/or CYP3A4 expression in breast cancer stem cells. Full article

Trogocytosis is the process of engulfment of a portion of a cell’s membrane by another cell. This process is characterized by the transfer of membrane fragments and proteins between adjacent cells without their complete fusion or phagocytosis, which distinguishes it from classical cellular uptake pathways. In the immune system, the initiating signal for trogocytosis is antigen presentation or the interaction of the Fc receptor with an antibody bound to the cell. During trogocytosis, T cells transfer not only the MHC molecule with the antigenic peptide, but also the costimulatory molecules CD80, CD86, OX-40 and others. As a result of trogocytosis, cells can transfer various surface molecules, acquire new immunological properties, and modulate each other’s activity. This review examines the basic mechanisms of trogocytosis, the involvement of T2-mediated immunity components in trogocytosis, and its possible role in allergies. Full article