Search Results (5,707)

Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and failure of cellular antioxidant defenses. Increasing evidence indicates that ferroptosis contributes to the biological effects of radiotherapy and influences both tumor radiosensitivity and normal tissue injury. Because radiotherapy is a central treatment modality for many head and neck cancers, understanding how ferroptosis interacts with radiation responses has important translational implications. Ionizing radiation can induce ferroptosis through reactive oxygen species generation, disruption of glutathione metabolism, suppression of the SLC7A11–GSH–GPX4 antioxidant axis, and remodeling of membrane lipid composition. Conversely, tumor cells frequently develop radioresistance by reinforcing ferroptosis-suppressive pathways, including enhanced cystine transport, lipid desaturation, and metabolic adaptation. In head and neck cancers such as head and neck squamous cell carcinoma, nasopharyngeal carcinoma, oral squamous cell carcinoma, and thyroid malignancies, experimental studies show that modulation of ferroptosis significantly alters radiation response. Strategies that promote ferroptosis—including inhibition of antioxidant defenses, targeting of lipid metabolism, and modulation of iron homeostasis—have demonstrated radiosensitizing effects in preclinical models. However, ferroptosis may also contribute to radiation-induced normal tissue injury, particularly in oxidative stress-sensitive organs such as the salivary glands. This review summarizes the molecular basis of ferroptosis in radiotherapy, examines its role in radiosensitivity and radioresistance in head and neck cancers, and discusses therapeutic strategies to exploit ferroptosis while minimizing normal tissue toxicity. Full article

The ATP-dependent inhibition of cytochrome c oxidase (CytOx, complex IV of the electron transport chain) is the second mechanism of respiratory control adjusting mitochondrial respiration in order to prevent excessive electron flow and reactive oxygen species (ROS) production. Here, we investigate how tricarboxylic acid (TCA) cycle metabolites and the subsequent complex I or complex II activities influence this regulatory mechanism. Therefore, CytOx activity was assessed by the oxygen consumption rate after cytochrome c (Cyt c) titration to stimulate complex IV activity in isolated rat heart mitochondria (RHM) and permeabilized AC16 cells. Mitochondrial membrane potential (Δψm) and ROS formation were analysed by flow cytometry. Our results show that TCA cycle intermediates differed in their impact on CytOx activity and subsequent ROS formation. NADH-linked substrates such as α-ketoglutarate, glutamate and malate increased respiratory capacity, but preserved ATP-dependent control of CytOx, indicating that elevated electron supply alone does not necessarily abolish ATP sensitivity. In contrast, succinate, which feeds electrons directly into complex II, strongly increased respiration causing the loss of ATP-dependent respiratory control in both model systems. Despite this strong respiratory effect, succinate induced only modest changes in mitochondrial membrane potential in isolated mitochondria, whereas permeabilized cardiomyocytes exhibited reduced polarization accompanied by increased superoxide formation. Together, these findings demonstrate that the effectiveness of ATP-dependent CytOx inhibition is influenced by TCA cycle activity and depends on the site of electron entry into the respiratory chain. Thus, substrate-dependent modulation of respiratory control links metabolite availability to mitochondrial redox regulation in cardiac cells. Full article

Solid-contact ion-selective electrodes (SC-ISEs) are typically constructed using ion-selective membrane (ISM)-based configurations. However, such structures often suffer from water-layer formation and the weak mechanical stability of the ISM. Herein, we report an ISM-free K⁺-SC-ISE based on a Prussian blue analogue transducer, KMnFe(CN)₆, eliminating the need for a conventional ionophore-based ISM layer. KMnFe(CN)₆ was synthesized via a one-step citrate-assisted co-precipitation method. The material functions as a bifunctional transducer, in which the open framework structure with ion-transport channels enables selective K⁺ recognition, while the redox-active Mn centers facilitate ion-to-electron transduction. The fabricated KMnFe(CN)₆-based K⁺ sensor exhibits a near-Nernstian response with a sensitivity of 52.3 ± 1.0 mV dec⁻¹ and a rapid response time of 25 s. The linear range and limit of detection were determined to 10⁻⁴ to 10⁻¹ M and 5.8 × 10⁻⁵ M, respectively. The sensor also demonstrates selectivity to representative interfering ions, with log K_ij of −2.39 ± 0.12 (Na⁺), −2.86 ± 0.09 (Li⁺), −3.06 ± 0.09 (Ca²⁺), −2.74 ± 0.12 (Mg²⁺) and −0.95 ± 0.08 (NH₄⁺). By eliminating the ISM layer, the water-layer effect is effectively avoided, resulting in excellent long-term stability with a potential drift of 57.2 ± 6.1 μV h⁻¹ over 7 days. The sensor was further applied to the analysis of K⁺ in real lake water samples, where the measured concentration showed good agreement with ion chromatography results. This work provides an ISM-free SC-ISE strategy for ion analysis in water environments. Full article

Metabolic dysfunction, a hallmark of diet-induced obesity (DIO), is increasingly attributed to alterations in intestinal nutrient and electrolyte transport. Yet the mechanisms that drive obesity-associated functional alterations of intestinal transporters remain incompletely understood. In this context, the effects of a high-fat diet (HFD) induced obesity on sodium-dependent glucose co-transporter 1 (SGLT1), Na⁺/H⁺ exchanger 3 (NHE3), and Cl⁻/HCO₃⁻ exchangers (DRA/PAT1), the primary glucose, sodium, and chloride absorptive pathways in mice small intestinal villus cells, were investigated. SGLT1 activity significantly increased in intact villus cells and brush border membrane vesicles (BBMV) from HFD-fed mice. Kinetic analysis demonstrated reduced Km without a change in Vmax, indicating enhanced transporter affinity. Notably, SGLT1 mRNA and protein expression, including BBM localization, were unchanged. Basolateral Na⁺/K⁺-ATPase activity was decreased, excluding enhanced Na⁺ gradient generation as the mechanism for SGLT1 stimulation. In contrast, DRA/PAT1 activity was significantly increased in HFD-fed mice, and kinetic studies revealed elevated Vmax without a change in Km, indicating increased transport capacity. DRA/PAT1 mRNA, total protein, and BBM expression were all significantly elevated. NHE3 activity and expression remained unchanged. These findings demonstrate that DIO enhances intestinal glucose absorption by increasing SGLT1 affinity and chloride absorption by upregulating DRA/PAT1 transcription. These transporter-specific alterations may amplify nutrient absorption and contribute to metabolic dysregulation in obesity. Full article

Background/Objectives: The escalating crisis of antibiotic resistance and the inherent limitations of conventional antibiotics necessitate the development of innovative therapeutic strategies. Targeted drug delivery (TDD) offers a powerful approach to enhance efficacy, minimize systemic toxicity, and circumvent bacterial resistance. This systematic review aims to evaluate the potential of unique bacterial transport systems (BTSs), surface specific receptors and intracellular enzymes as platforms for TDD via the “Trojan Horse” strategy (THS). Methods: A comprehensive literature review was conducted, focusing on studies that investigated the specificity and mechanisms of BTSs responsible for the uptake of metabolites that are essential for and unique to bacteria. This includes an analysis of transport systems for siderophores, bacteria-specific sugars, cell wall components, D-amino acids, and vitamins. We assessed preclinical and clinical examples of drug conjugates utilizing these pathways, as well as emerging platforms such as bacteriophage-derived proteins, antibody–antibiotic conjugates, and bacterial extracellular vesicles (EVs). Results: BTSs demonstrate high specificity for their cognate substrates, providing effective molecular gateways for TDD of drugs photosensitizers and diagnostic probes in form of conjugates. The siderophore–cephalosporin conjugate cefiderocol represents a clinically validated example, having received FDA approval. Preclinical studies further reveal that conjugates utilizing sugars (e.g., maltose, trehalose) and vitamins (e.g., B12) can significantly enhance antibiotic uptake and activity against both Gram-positive and Gram-negative pathogens, including drug-resistant strains. Emerging platforms like bacteriophage endolysins and engineered EVs show promise for overcoming biological barriers such as bacterial outer membranes and intracellular host niches. Conclusions: The THS leveraging BTSs represents a clinically viable and promising avenue for next-generation antibacterial therapies. Advantages of BTS include overcoming bacterial resistance, such as reduced membrane permeability and efflux pumps, enabling the “revival” of antibiotics that are poorly permeable or toxic, increasing their local concentration at the target site and reducing side effects on host cells. While significant progress has been made, a striking disconnect persists between the hundreds of conjugates demonstrating potent in vitro activity and the limited agent that has achieved clinical use. This in vitro–in vivo gap reflects, in large part, the early stage of this field rather than a fundamental failure. Further research is critically needed not only to identify novel BTSs and optimize drug-linker chemistry, but also to systematically address the translational barriers—including poor pharmacokinetics, immunogenicity, and unexpected toxicity—that have prevented most promising candidates from advancing beyond preclinical evaluation. Full article

Background: Cardiolipin (CL) is a phospholipid composed of a glycerol linked with two phosphatidate moieties that constitutes an integral part of the human inner mitochondrial membrane under physiological conditions. It is also vital for bacterial membrane transport and key bacterial functions associated with cell division and infection. CL is released in the cytosol or into the extracellular milieu upon cell death and during inflammation. We therefore tested the ability of CL to activate and expand tumor infiltrating lymphocytes (TIL) from patients with epithelial cancer. Methods: TIL were isolated from gastrointestinal tumor tissues and expanded in vitro in the presence of CL. The role of the NLRP3 inflammasome was evaluated using the specific inhibitor MCC950 and siRNA-mediated silencing of NLRP3. Phenotypic changes and T-cell potency were assessed via CXCL9/10 expression levels. To characterize the immune repertoire, deep TCR sequencing was performed to compare the TCR Vα and Vβ CDR3 regions between TIL and the corresponding tumor tissue. Recognition of autologous tumor cells and tumor-specific mutations, including mutations in KRAS and mitochondrial UQCRFS1 (D145V), was assessed using MHC class I and II restriction assays. Results: CL-expanded TIL exhibited increased CXCL9/10 expression, which is associated with increased potency of tissue invasion. CL-TIL exhibited broader recognition of frequently occurring KRAS mutations, and this effect could be blocked with an inhibitor (MCC950) of the NLRP3 pathway, a multiprotein inflammatory complex associated with danger signaling. TIL exhibited an enriched TCR Vα and Vβ CDR3 repertoire compared to tumor tissue, as defined by deep TCR sequencing. TCR αβ+ TIL recognized autologous tumor tissue in an MHC class I– and class II–restricted fashion, including the mutant HLA-DP–restricted mitochondrial protein associated with the electron respiratory chain complex III (UQCRFS1 D145V) presented by autologous tumor cells. Conclusions: CL activates the NLRP3 inflammasome pathway in TIL from patients with GI cancer and increases CXCL9/CXCL10 expression in TIL, resulting in enhanced recognition of mutant cancer–associated target epitopes, including a mitochondrial protein. CL may provide a danger signal: that facilitates TIL expansion via CL-activated pathways. Full article

Hybrid gas separation technologies combining different physicochemical mechanisms represent a promising approach for the efficient treatment of complex natural gas mixtures. In this work, a hybrid process integrating gas hydrate crystallization and membrane gas separation was investigated for the upgrading of multicomponent natural gas-containing hydrocarbons (C₁–C₄), acid gases (CO₂ and H₂S), and inert components. Polysulfone hollow-fiber membranes were fabricated, and their gas transport properties were experimentally determined using an eight-component quasi-real natural gas mixture under elevated pressure conditions. The obtained mixed-gas permeance values were used as input parameters for the development of a detailed mathematical model of a hollow-fiber membrane module implemented in the Aspen Custom Modeler. The model was applied to simulate membrane separation of both gas- and hydrate-derived streams produced by the gas hydrate crystallizer. Simulation results were analyzed in terms of hydrocarbon composition, acid gas removal efficiency, and hydrocarbon recovery as a function of the stage-cut. The modeling predictions were validated experimentally using a laboratory membrane module integrated with the gas hydrate crystallization unit. Good agreement between the experimental data and simulation results was observed for all major components. The deviation between modeled and experimental concentrations remained small, while the discrepancy in hydrocarbon recovery was higher and reached approximately 10–20%, which is attributed to the cumulative uncertainty of flow rate and composition measurements. These results confirm the adequacy of the developed model. The hybrid process demonstrates strong complementarity between the thermodynamic selectivity of hydrate formation and the transport selectivity of membrane separation, enabling efficient removal of acid gases while maintaining acceptable hydrocarbon recovery. The results indicate that the proposed gas hydrate–membrane hybrid process is a promising strategy for advanced natural gas purification and upgrading. Full article

The cornea of the dromedary camel is essential for maintaining ocular clarity and protecting the eye in dry, dusty, and thermally stressful environments. Aquaporins are membrane channels that facilitate water transport, and AQP1 has been widely implicated in corneal fluid homeostasis in several species. The present work investigated, for the first time, the regional distribution of AQP1 in the camel cornea. Corneas collected from twelve healthy adult camels after slaughter were divided into nine anatomical regions: central (C), middle dorsal (MD), middle ventral (MV), middle nasal (MN), middle temporal (MT), peripheral dorsal (PD), peripheral ventral (PV), peripheral nasal (PN), and peripheral temporal (PT). Histological examination and immunohistochemistry were combined with digital morphometry to assess corneal layer thickness and AQP1 localization. AQP1 labeling was identified in the corneal epithelium, stromal keratocytes, and endothelium. Epithelial staining differed among regions and was most pronounced in the peripheral nasal region, whereas stromal keratocytes and endothelial cells showed strong and relatively uniform immunoreactivity. These findings indicate that AQP1 is broadly expressed in the camel cornea and likely contributes to regional control of hydration and tissue maintenance in an arid-adapted species. Full article

The microporous layer (MPL) is a key functional component in proton exchange membrane fuel cells (PEMFCs), and clarifying the quantitative relationship between its microstructure and mass transport properties is essential for improving cell performance. In this study, a three-dimensional MPL model was developed using a stochastic reconstruction method, and, together with a random walk algorithm, was employed to systematically investigate the effects of porosity, carbon sphere radius, maximum overlap ratio, seed ratio, and polytetrafluoroethylene (PTFE) content on permeability, effective diffusivity, and tortuosity. The results reveal that increasing porosity reduces tortuosity from 1.7 to 1.3, while permeability and effective diffusivity increase by factors of approximately 6.5 and 1.8, respectively. As the carbon sphere radius increases, tortuosity decreases from 1.55 to 1.35, accompanied by an increase in permeability from 2 × 10⁻¹⁶ m² to 20 × 10⁻¹⁶ m². Moreover, increasing the PTFE content raises permeability from 5 × 10⁻¹⁶ m² to 22.5 × 10⁻¹⁶ m², corresponding to an enhancement by a factor of approximately 4.5. The high-accuracy fitting equations obtained from the simulation results provide theoretical guidance for the microstructural design and optimization of MPLs, which can enhance oxygen transport and water management, reduce mass transport losses, and thereby benefit high-power-density operation and the overall efficiency of PEM fuel cells. Full article

The hydrophilicity of the porous transport layer (PTL) critically influences the mass transport overpotential and overall efficiency of a proton exchange membrane water electrolyzer (PEMWE). In this study, titanium felts with three distinct levels of hydrophilicity are systematically characterized and evaluated electrochemically. A novel bilayer gradient hydrophilic titanium felt structure is designed, resulting in notable performance improvements: the average cell voltage decreases by 12.92%, and the overpotential is reduced by 9.94–18.03% across a current density range of 0.1–1.6 A·cm⁻². High-speed imaging reveals that the gradient hydrophilic structure effectively regulates bubble dynamics, nearly eliminating annular flow bubbles, reducing the proportion of slug flow bubbles by 40.78%, decreasing the bubble detachment diameter by 28.26%, and enhancing bubble displacement by 51.03% compared to that of untreated titanium felt. These results demonstrate that gradient hydrophilic structures can significantly enhance PEMWE performance, offering a promising strategy and a theoretical foundation for optimizing mass transfer in electrolytic systems. Full article

Access to clean water remains a critical global challenge, particularly in arid and fog-rich regions where conventional resources are limited. Fog water harvesting has emerged as a low-energy alternative; however, the performance of traditional collectors (typically 3–10 L m⁻² day⁻¹) remains constrained by inefficient droplet capture and transport. This review provides a systematic and critical analysis of recent advances in membrane-based fog harvesting technologies, focusing on material design, surface engineering, and structural optimization. The analysis shows that nanostructured and electrospun membrane systems can enhance water collection rates to ~20–60 L m⁻² day⁻¹, representing up to a 5–6 times improvement over conventional meshes. Furthermore, biomimetic and Janus wettability designs significantly improve droplet nucleation and directional transport, while hierarchical micro/nanostructures accelerate coalescence and runoff dynamics. At the structural level, optimized collector geometries (vertical harp designs) demonstrate ~3–4 times higher collection efficiency compared to traditional Raschel mesh due to reduced clogging and enhanced drainage. Despite these advances, key challenges remain, including material durability, fouling resistance, lack of standardized testing protocols, and limited large-scale validation. This review identifies critical design–performance relationships and proposes a framework linking surface wettability, morphology, and environmental parameters to harvesting efficiency. Future directions emphasize the development of durable, scalable membrane systems and the integration of fog harvesting with hybrid water supply technologies. Full article

The retromer is a highly conserved complex that mediates the trafficking of cargo proteins to the plasma membrane or the trans-Golgi network. In pathogenic microorganisms, retromer-dependent transport contributes to the delivery of virulence factors and promotes infection. The retromer consists of a sorting nexin dimer (SNX) and a cargo-selection complex (CSC), formed by Vps26, Vps35, and Vps29. In Entamoeba histolytica, the parasite that causes human amoebiasis, the retromer functions as a Rab7A GTPase effector and participates in phagocytosis and cytotoxicity. Although we previously characterized the roles of EhVps26 and EhVps35, the function of EhVps29 remained unclear. In this study, we analyzed the subcellular localization and functional role of EhVps29 in adhesion, phagocytosis, and cytopathic effect. EhVps29 localized to the plasma membrane, cytosol, vesicles, tubules, Golgi-like structures, MVBs and, for the first time, the nucleus. Immunofluorescence and Western blot assays demonstrated that EhVps29 modulates the localization of EhVps26, EhADH adhesin, and EhCP112 cysteine protease. Ehvps29 gene silencing and overexpression confirmed its involvement in virulence-associated processes. Immunoprecipitation and confocal microscopy results showed the interaction among EhVps29 and the ESCRT machinery members EhVps36 and EhADH. Our results indicate that EhVps29 is involved in parasite virulence and protein trafficking through recycling or degradation pathways. Full article

The plasma membrane plays essential roles in cellular transport and signaling. One of its fundamental structural features is the asymmetric distribution of lipids between the inner and outer leaflets. This asymmetry is actively maintained by lipid transport systems, including flippases, floppases, and scramblases, and is critical for membrane integrity and signaling regulation. Accumulating evidence indicates that membrane lipid asymmetry is frequently altered in cancer cells, leading to the externalization of normally inner-leaflet phospholipids such as phosphatidylserine and phosphatidylethanolamine. These alterations can influence tumor signaling, immune interactions, and membrane-associated biological processes. Recent studies further suggest that metabolic reprogramming in cancer may play an important role in regulating membrane lipid asymmetry. Changes in cellular energy status, oxidative stress, calcium signaling, and lipid metabolism can modulate lipid transport systems and membrane organization. In addition, tumor metabolism generates diverse circulating metabolites, including lactate, lysophospholipids, and acylcarnitines, which may influence membrane properties and lipid redistribution. These observations raise the possibility that membrane lipid asymmetry functions as a metabolically responsive interface linking intracellular metabolic state to cell surface signaling and tumor–microenvironment interactions. In this review, we propose a conceptual framework in which cancer-associated metabolic reprogramming influences lipid transport systems and membrane organization, thereby reshaping phospholipid distribution across the plasma membrane. We discuss how metabolic perturbations—including changes in energy metabolism, redox balance, calcium signaling, and lipid remodeling—may regulate membrane lipid asymmetry and explore the implications of these processes for tumor signaling, immune interactions, and emerging membrane-targeted therapeutic strategies. Full article

Oenococcus oeni (O. oeni) can initiate and complete the malolactic fermentation (MLF) process, which significantly improves wine quality. However, stress factors commonly encountered in wine, such as acid stress and ethanol stress, can hinder this process. Overexpression of certain key functional genes using genetic recombination technology can enhance the stress tolerance of O. oeni. In this study, the large-conductance mechanosensitive channel (mscl) gene was overexpressed in O. oeni SD-2a using genetic recombination technology. The results showed that overexpression of this gene enhanced the growth rate of O. oeni under 10% ethanol stress conditions. Physiological index measurements indicated that overexpression of this gene enhanced the control of cell membrane permeability in the recombinant strain at different time points under ethanol stress and altered cell membrane fluidity at these time points. Proteomic analysis after 12 h of treatment under 10% ethanol stress revealed that mscl overexpression significantly altered the protein expression pattern of O. oeni. The most significantly affected proteins included some cell membrane transporters (for sugars, lipids, amino acids, and nucleotides) and proteins involved in cell wall synthesis. These results suggest that mscl overexpression enhances the ethanol stress tolerance of O. oeni by altering its cell membrane properties and affecting the expression levels of proteins related to cell membrane transport and cell wall synthesis. This study provides a theoretical reference for obtaining O. oeni recombinant strains with enhanced stress tolerance through genetic recombination technology. Full article

Chemotherapy-induced mucositis (CIM) is a dose-limiting toxicity of cancer therapy that is mainly associated with mitochondrial dysfunction in epithelial cells. We investigated whether GV1001, a mitochondrial protective peptide from human telomerase reverse transcriptase (hTERT), attenuates 5-fluorouracil (5-FU)-induced mucositis in a murine model. 5-FU induced notable mortality, leukopenia, and mucositis in the gastrointestinal (GI) tract, including tongue, esophagus and small intestine. It promoted epithelial–mesenchymal transition (EMT), nuclear factor kappa-B (NF-κB) activation, systemic and mucosal inflammation, DNA damage, impaired cell proliferation, and apoptosis throughout the GI tract. GV1001 blocked 5-FU–associated mortality, significantly attenuated leukopenia, and notably prevented mucositis. GV1001 also suppressed 5-FU-induced DNA damage, EMT, loss of proliferative capacity, apoptosis, and NF-κB activation in mucosal epithelium. In normal human keratinocytes, 5-FU inhibited the cell proliferation, disrupted mitochondrial function, as evidenced by reduced mitochondrial membrane potential, increased reactive oxygen species (ROS) production, impaired electron transport chain (ETC) complex integrity, decreased ATP synthesis, and cytochrome c release into the cytosol. GV1001 markedly mitigated these 5-FU-induced mitochondrial defects. Taken together, GV1001 mitigates CIM by most likely preserving mitochondrial integrity and function, supporting its potential as a strategy to prevent cancer chemotherapy-associated mucosal injury in patients. Full article