Search Results (1,160)

Chemoresistance remains a major barrier to effective colorectal cancer (CRC) therapy, yet its metabolic underpinnings are poorly defined. Here, we integrate lipidomic profiling, enzymatic analysis, and functional perturbation approaches to elucidate the contribution of phosphatidylcholine (PC) metabolism and its biosynthetic regulator Choline Phosphotransferase 1 (CHPT1) to drug response. Comparative analysis of chemosensitive and chemoresistant CRC cell lines revealed that resistant HT29 cells exhibited significantly higher PC content and altered PC/lysophosphatidylcholine (LPC)ratios relative to sensitive counterparts. Importantly, functional perturbation confirmed causality: CHPT1 overexpression in SW620 cells was sufficient to promote PC accumulation and confer a chemoresistant phenotype. These findings identify CHPT1 as a metabolic gatekeeper of chemoresistance. Consistently, Human Protein Atlas survival analyses further support its clinical relevance, as elevated CHPT1 expression correlates with poor patient outcomes in CRC. Mechanistically, CHPT1-driven PC enrichment may sustain pro-survival signaling, while reducing lysophospholipid-mediated stress pathways. To therapeutically target this vulnerability, we investigated edelfosine (Edel), an alkyl-lysophospholipid that disrupts lipid rafts and inhibits PC biosynthesis upstream of CHPT1. Notably, edelfosine-mediated disruption of the Kennedy pathway enhances chemosensitivity in the resistant CRC model. Collectively, our study identifies CHPT1 and PC metabolism as central determinants of CRC drug response and proposes edelfosine-based metabolic reprogramming as a promising strategy to overcome resistance. Full article

Durable responses to cancer immunotherapy remain restricted to a subset of patients, highlighting persistent gaps in understanding immune failure mechanisms. Dendritic cells (DCs) serve as the critical bridge between antigen recognition and adaptive immune activation, yet conventional molecular models centered on discrete components fail to fully explain heterogeneous therapeutic outcomes. This integrative mechanistic synthesis proposes that DC-mediated antitumor immunity is governed by higher-order structural determinants, including membrane microdomain organization, spatial compartmentalization of signaling, and temporal integration of antigenic and co-stimulatory cues. These features determine whether antigen presentation leads to effective T-cell priming or dysfunctional states such as exhaustion or anergy within the tumor microenvironment. By reanalyzing our validated 2025 experimental pipeline alongside high-impact contextual literature, we identify emergent properties of immune competence that transcend linear molecular interactions. The resulting framework distinguishes structurally mediated failure modes from classical resistance paradigms, providing a coherent non-reductionist explanation for variability in immunotherapy efficacy. Membrane raft repair is positioned as a key promising structural condition for effective immune integration, with direct relevance to translational and regulatory contexts involving non-pharmacodynamic platforms and New Approach Methodologies (NAM)-aligned evaluation strategies. This work proposes an integrative mechanistic framework to guide future hypothesis-driven studies and clinical advancement of DC-based approaches. Full article

This review critically examines how cyclodextrins modulate regulated cell death pathways and the implications for immunometabolism and therapeutic translation. Increasing evidence, however, indicates that cyclodextrins exert intrinsic biological activity by modulating cellular lipid homeostasis, membrane organization, and intracellular trafficking. In recent years, these properties have positioned cyclodextrins as unexpected regulators of regulated cell death (RCD) pathways, with broad implications for immunometabolism and therapeutic innovation. This review provides a comprehensive overview of the mechanisms by which native and chemically modified cyclodextrins influence major forms of regulated cell death, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, and necroptosis. Particular attention is given to cholesterol sequestration, lipid raft disruption, lysosomal cholesterol mobilization, and transcriptional reprogramming via pathways such as TFEB (transcription factor EB) and AMPK (AMP-activated protein kinase), which collectively shape cell fate decisions. We further examine how cyclodextrin-mediated modulation of RCD intersects with immune metabolism, especially macrophage polarization and inflammasome activity, thereby influencing inflammatory responses and disease progression. Translational implications are discussed across diverse pathological contexts, including cancer, cardiovascular diseases, neurodegenerative disorders, inflammatory and autoimmune conditions, infectious diseases, and lysosomal storage disorders. Finally, emerging cyclodextrin-based delivery platforms, ranging from inclusion complexes to nanoparticles and polymeric systems, are evaluated with respect to their ability to achieve targeted modulation of cell death while minimizing off-target toxicity. Importantly, we critically discuss dose-dependent cytotoxicity, sterol depletion–related adverse effects, and formulation-dependent variability, which currently limit the clinical translation of cyclodextrin-mediated cell death modulation. By integrating mechanistic insights with pharmaceutical formulation strategies, this review delineates key challenges and opportunities for the rational design of cyclodextrin-based therapeutics. Overall, this review highlights cyclodextrins as bioactive modulators rather than inert carriers, underscoring their potential to inspire novel pharmacological strategies that integrate drug delivery, immunometabolism, and regulated cell death. Full article

This study presents the successful expression, purification, and functional characterization of the human TRPM8 ion channel, a key player in temperature sensing and pain modulation. Using a modified bacterial expression protocol and DDM-based solubilization, TRPM8 was purified via HPLC-SEC and analyzed for its membrane-binding properties. FRET-based assays with synthetic lipid rafts revealed a strong and selective affinity of TRPM8 for cholesterol-containing membranes, suggesting cholesterol’s role in modulating TRPM8 localization and activity. These findings provide quantitative in vitro evidence of TRPM8–cholesterol interactions and establish a robust model system for future structural and functional studies of membrane-associated proteins. Full article

The spontaneous emergence of macroscopic dissipative structures in systems driven by generalized chemical potentials is well established in non-equilibrium thermodynamics. Examples include atmospheric/oceanic currents, hurricanes and tornadoes, Rayleigh–Bénard convection cells and reaction–diffusion patterns. Less well recognized, however, are microscopic dissipative structures that form when the driving potential excites internal molecular degrees of freedom (electronic states and nuclear coordinates), typically via high-energy photons or coupling with ATP. Examples include dynamic nanoscale lipid rafts, kinesin or dynein motors along microtubules, and spatiotemporal Ca²⁺ signaling waves propagating through the cytoplasm. The thermodynamic dissipation theory of the origin of life asserts that the core biomolecules of all three domains of life originated as self-organized molecular dissipative structures—chromophores or pigments—that proliferated on the Archean ocean surface to absorb and dissipate the intense “soft” UV-C (205–280 nm) and UV-B (280–315 nm) solar flux into heat. Thermodynamic coupling to ancillary antenna and surface-anchoring molecules subsequently increased photon dissipation and enabled more complex dissipative processes, including photosynthesis, to dissipate lower-energy but higher-intensity UV-A and visible light. Further thermodynamic coupling to abiotic geophysical cycles (e.g., the water cycle, winds, and ocean currents) ultimately led to today’s biosphere, efficiently dissipating the incident solar spectrum well into the infrared. This paper reviews historical considerations of UV light in life’s origin and our proposal of UV-C molecular dissipative structuring of three classes of fundamental biomolecules: nucleobases, fatty acids, and pigments. Increases in structural complexity and assembly into larger complexes are shown to be driven by the thermodynamic imperative of enhancing solar photon dissipation. We conclude that thermodynamic selection of dissipative structures, rather than Darwinian natural selection, is the fundamental creative force in biology at all levels of hierarchy. Full article

Background/Objective: Human papillomavirus (HPV) represents the most widespread sexually transmitted infection globally, with high-risk strains such as HPV16 driving a rising incidence of oropharyngeal squamous cell carcinoma (OPSCC), particularly in developed countries like the United States and United Kingdom. In the U.S., HPV16-associated OPSCC has surpassed cervical cancer as the most common HPV-related malignancy. Despite the availability of preventive vaccines, uptake remains suboptimal among adolescents and shifting sexual behaviors have contributed to increased disease burden. Early detection remains a major clinical challenge due to the absence of defined precursor lesions and the extended latency between viral exposure and disease onset. Most patients present with advanced-stage disease and no prior clinical history of pre-malignancy, limiting access to early-stage samples and hindering biomarker discovery. Methods: To address these limitations, we developed an in vitro HPV16 oral cancer model, using the three-dimensional organotypic raft culture system that simulates the progression of HPV16-transfected oral epithelium from precancerous states to malignant phenotypes. Results: Using HPV16-transfected human tonsil keratinocytes, we generated stratified and differentiated epithelia that mimic the biochemical and structural changes observed in vivo. This system enables detailed monitoring of epithelial differentiation, biochemical shifts, viral genome status, and key oncogenic and metabolic markers associated with HPV16-driven OPSCC. By aligning expression profiles with clinical datasets, we validated the model through the measurement of virologic markers linked to infection and progression, as well as tissue markers indicative of carcinogenic transformation. Conclusions: This model offers a promising tool for refining early detection strategies and evaluating potential clinical biomarkers, ultimately aiming to improve diagnostic precision and therapeutic outcomes in HPV-associated OPSCC. Full article

Advances in multimodal therapy for high-risk neuroblastomas (NBs) have plateaued, prompting therapeutic initiatives to harness the immune system. NBs, however, are immunologically “cold” and a significant challenge to immunotherapy. Here, in a Jurkat lymphocyte cytotoxicity model, we describe an antigen-independent, cell-mediated mechanism for eliminating NB cells, first detected in PMA-activated low pcDNA-SH-SY5Y and high TrkAIII-SH-SY5Y TrkAIII-expressing cells, which are resistant to Jurkat elimination under normal conditions. Characterization of this mechanism through live cell imaging, adhesion assays, RT-PCR, Western blotting and indirect IF, employing a variety of inhibitors, indicates that it initiates with PMA-induced NB cell CCL2 expression. This results in CCL2 promotion of Jurkat CCR2b expression, CCL2/CCR2b-mediated Jurkat LFA-1 activation and the formation of cytotoxic lipid-raft LFA1/ICAM-1 immune synapses, through which Jurkat m-TRAIL combines with PMA-enhanced NB cell DR5/TRAIL-R2 expression to induce NB cell apoptosis. This mechanism is enhanced by the NB-associated oncoprotein TrkAIII through Shp/Src-regulated c-FLIP sequester and is PD-L1/PD-1-independent and resistant to osteoprotegerin. It eliminates both non-MYCN-amplified (SH-SY5Y and SK-N-SH) and MYCN-amplified (SMS-KCNR) NB cells that exhibit PMA-inducible CCL2 expression but not MYCN-amplified NB cells (IMR-32 and NB-1) that exhibit CCL2 repression, and is offset by reciprocal NB cell-induced Fas-mediated Jurkat cell apoptosis. These findings form a solid foundation for further pre-clinical development aimed at identifying clinically relevant physiological immune cell equivalents and alternative PKC activators, with the ultimate goal of translating this mechanism into an effective immune-therapeutic approach for the treatment of high-risk non-immunogenic NBs, especially NBs that exhibit CCL2 and TrkAIII expression. Full article

China has assumed a leadership position in global kelp cultivation and export. However, the kelp harvesting process in China still relies primarily on manual labor, with only limited adoption of semi-mechanized devices. This dependence results in suboptimal efficiency and elevated labor intensity. The industry now faces an acute labor shortage driven by an aging workforce and rising labor costs, highlighting the urgent need for a fully mechanized harvesting solution. This paper comprehensively reviews current research on mechanized kelp harvesting devices for raft cultivation systems in China. It compares domestic and international practices in kelp seedling cultivation, cultivation models, and harvesting devices, with particular emphasis on the technical challenges hindering harvesting device development in China. Based on this analysis, we propose several recommendations, including the simultaneous advancement of cultivation model optimization and harvesting device innovation, the development of harvesting technologies aligned with specific downstream processing requirements, and the design of modular and multifunctional kelp harvesting vessels. Looking ahead, future research should prioritize integrating automation and intelligent systems, reflecting evolving trends in China’s marine aquaculture. Furthermore, to support China’s “dual carbon” goals, future harvesting systems should incorporate carbon-reduction features. Full article

Recurrent massive strandings of pelagic Sargassum have severely impacted Caribbean and Gulf of Mexico coastlines over the past decade, generating major environmental, sanitary, and socioeconomic consequences. Accurate monitoring of Sargassum dynamics in nearshore waters remains challenging, as most existing satellite products rely on moderate-resolution sensors that inadequately resolve coastal processes. Here, we present a high-spatial- and -temporal-resolution Sargassum detection dataset derived from the VENµS (Vegetation and Environment New Micro-Satellite) mission, providing daily observations at 4 m resolution for five coastal zones in Guadeloupe, Martinique, and the Yucatán Peninsula over the 2022–2024 period. VENµS imagery consists of 12 multispectral bands, and the analysis specifically uses the red, the red-edge/near-infrared and the short-wave infrared bands. Detection is based on the Alternative Floating Algae Index (AFAI), combined with land and cloud masking, background estimation, and adaptive thresholding. We demonstrate the capability of this dataset to resolve fine-scale Sargassum raft dynamics, characterize the seasonal influx of Sargassum along the coastline, and assess exposure across different coastal typologies. By offering the highest combined spatial and temporal resolution currently available for these regions, this dataset provides a novel resource for coastal impact assessment, nearshore drift analysis, and validation of Sargassum transport and stranding models. Full article

Mitochondrial transfer in mammals has been proven to occur both under physiological conditions and during pathological conditions. It has been shown that neighboring cells can exchange mitochondria via nanotunnel tubes. However, there is evidence that free mitochondria, as well as whole mitochondria and individual mitochondrial fragments, can be transported between cells within extracellular vesicles (EVs). This review discusses the methodological aspects of isolation and a minimal set of methods for characterizing mitochondria-rich EVs (mitoEVs), as well as methodological approaches for studying the nucleic acid, protein, and lipid composition. It has been shown that mitoEVs, as well as extracellular mitochondria, contain a characteristic set of nucleic acids of mitochondrial origin. First and foremost, the dominant fraction of mitochondrial nucleic acids is mitochondrial DNA (mtDNA), a circular double-stranded molecule approximately 16.6 thousand base pairs in length. The mechanisms involved in EV internalization include clathrin-dependent endocytosis, caveolin-dependent endocytosis, raft-mediated endocytosis, and macropinocytosis. Mitochondrial-enriched autologous and xenogeneic EVs are thought to be internalized by similar mechanisms. The review also presents the main sources (stem cells, platelet concentrate, peripheral blood mononuclear cells) for obtaining mitochondria-rich EVs for therapeutic purposes. Full article

Ion channels are fundamental membrane proteins that mediate selective ion flow across biological membranes and thereby govern excitability, signaling, and homeostasis in virtually all cell types. Although channel function is determined by intrinsic structural features, the surrounding lipid milieu is now recognized as a decisive regulatory layer. Lipids tune ion channel activity through complementary mechanisms: they can bind directly to channel proteins, reshape bilayer physical properties, or act as signaling messengers that couple extracellular cues to channel gating. In addition, the organization of membranes into lipid microdomains such as rafts and caveolae can cluster channels with receptors and scaffolds, enhancing signaling specificity and efficiency. Recent advances in cryo-electron microscopy and molecular simulations have expanded our understanding of these lipid–channel interactions, revealing lipids as active modulators rather than passive structural components. This review provides a comprehensive overview of the principles by which lipids regulate ion channel function and highlights the biological and potential clinical significance of this fundamental interplay. Full article

Background/Objectives: Alginate-based rafts are typically used for antacids and provide a floating, gastric-retaining gel in the stomach that acts as a barrier to the entrance of stomach acid into the esophagus. Various technologies have been developed to enhance the sustained release of drugs and bioactive components and overcome challenges associated with gastric retention. Modern methods, such as the alginate raft, not only function as an antacid in gastroesophageal reflux disease but also can serve as a delivery system that extends the drug release time in gastric medium. This study assessed the effects of biocompatible natural polymers, such as Plantago major mucilage (PMM), on raft formation instead of synthetic polymers, such as Carbomer. Methods: PMM was substituted in the raft formulation at concentrations of 0.5% and 1%. The formed rafts were analyzed for their physicochemical, mechanical, and structural properties. To evaluate the sustained release potential of the optimized raft formulation, the aqueous extract of Artemisia annua L. was incorporated into coconut protein nanoparticles and loaded into the optimized raft at three different concentrations of 1%, 2%, and 3%. Results: The rafts formulated with PMM 0.5% revealed excellent stability of the suspension, as well as improved physicochemical properties of the developed rafts compared to the raft that included Carbomer. The results illustrated that the inclusion of PMM in the raft system enhances antacid capacity, swelling percentage, resilience time, strength, and a stiffer gel with a higher G′. Conclusions: The optimized PMM raft was able to prolong the in vitro release of phenolic extracts and reach the cumulative release of less than 30% after 6 h. Full article

As the global population continues to rise, sustainable agricultural systems such as aquaponics have gained attention for their potential to maximize food production while minimizing resource use. This study evaluated the growth performance, yield, and mineral composition of okra (Abelmoschus esculentus) grown in a coupled aquaponic system with Nile tilapia (Oreochromis niloticus), comparing two production methods: floating raft and flooded media bed. Okra was cultivated at two planting densities (32 and 48 plants/m²) over a 12-week period, and multiple plant growth parameters and tissue mineral compositions were assessed at harvest. Results showed that plant production method significantly (p < 0.05) influenced okra growth and yield, while planting density had limited impact. Okra grown in media beds exhibited greater (p < 0.05) stem length, stem and root weights, number of leaves, and okra (fruit) production compared to those grown on floating rafts. Although root length was longer (p < 0.05) in raft-grown plants, root biomass was notably higher (p < 0.05) in plants grown in media beds. Mineral composition of plant tissues also varied with production method and density. Media-grown okra generally had higher (p < 0.05) concentrations of calcium, phosphorus, and copper in leaves and stems, whereas raft-grown plants showed elevated levels of sodium and zinc in several tissues. Plant density affected a few specific mineral concentrations, particularly in roots and fruit, though effects were inconsistent. While fish growth was not high, possibly due to some water quality parameters (such as alkalinity and hardness) not being optimal, plant performance in media beds without supplemental nutrient inputs highlights the viability of fired clay media in aquaponic okra production. These findings suggest that media beds offer agronomic advantages over floating rafts for okra cultivation in aquaponic systems, with implications for optimizing nutrient delivery and plant health in sustainable food production systems. Full article

Cell–cell signaling through a network of cytokine receptors is pivotal for normal immune development and function, with disruptions of these signaling pathways being implicated in a variety of immune cell diseases. Signaling via the interleukin-7 receptor (IL-7R) facilitates the development and homeostasis of various T-cell, B-cell and other immune-cell populations. This is reflected in the raft of mutants and variants of IL-7R components and downstream signaling molecules that have been identified in the context of immunodeficiencies, autoimmune disorders and lymphoid malignancies, but also through the use of pathway modulators as therapeutics. This review provides an overview of IL-7R biology, the role of mutations and variants affecting IL-7R signaling pathway components in the etiology of immune cell diseases and the specific therapies related to this pathway. Full article

Biological membranes are dynamic, information-rich platforms whose structural and functional properties are dictated by lipid composition rather than acting as passive barriers. Recent advances in lipidomics have revealed that variations in lipid headgroups, acyl-chain length and saturation, sn-positional architecture, and oxidative modifications profoundly influence membrane mechanics, lateral organization, and protein–lipid interactions. These features collectively regulate fundamental cellular processes, including signaling, trafficking, curvature generation, and transbilayer asymmetry. In parallel, a wide range of pathological conditions—including cancer, metabolic disorders, neurodegeneration, and inflammatory diseases—are increasingly associated with coordinated lipid remodeling that reshapes membrane material properties and electrostatic landscapes. In this review, we integrate biophysical principles with lipidomics-based evidence to elucidate how lipid chemical diversity translates into membrane-level behavior. We discuss the roles of major membrane lipid classes, the functional consequences of acyl-chain and sn-positional remodeling, and the biological significance of lipid asymmetry and lateral heterogeneity. Particular attention is given to disease-associated lipid reprogramming and extracellular vesicle lipidomes as functional extensions of cellular membranes. Finally, we examine key analytical barriers in modern lipidomics and outline strategies required to connect lipid structural information with biological function. Together, this framework highlights membrane lipid architecture as a central determinant of cellular physiology and a promising axis for mechanistic insight and translational biomarker discovery. Full article