Search Results (2,981)

Reactive oxygen species (ROS), inevitable by-products of aerobic metabolism, act both as regulators of signaling pathways and as mediators of oxidative stress and aging-related damage. Protein oxidative post-translational modifications (Ox-PTMs) are recognized hallmarks of aging and metabolic decline, yet the persistence of protein oxidation under different physiological conditions, such as age and diet, remains unclear. Here, we applied proteomics to mitochondrial and membrane-enriched fractions of male Fischer 344 rat cerebrum and heart, comparing Ox-PTMs across young and aged animals subjected to ad libitum nutrition (AL) or calorie restriction (CR). We identified 139 mitochondrial and membrane-associated proteins consistently exhibiting high levels of oxidation, including tricarboxylic acid (TCA) cycle enzymes, respiratory chain subunits, ATP synthase components, cytoskeletal proteins, and synaptic vesicle regulators. Functional enrichment and network analyses revealed that oxidized proteins clustered in modules related to mitochondrial energy metabolism, membrane transport, and excitation–contraction coupling. Notably, many proteins remained persistently oxidized, predominantly as mono-oxidation, without significant changes during aging or CR. Moreover, the enzymatic activity of mitochondrial complexes was not only preserved but significantly enhanced in specific contexts, and the structural integrity of the respiratory chain was maintained. These findings indicate a dual strategy for coping with oxidative stress: CR reduces ROS production to limit oxidative burden, while protein and network robustness enable functional adaptation to persistent oxidation, collectively shaping mitochondrial function and cellular homeostasis under differing physiological conditions. Full article

Thigmomorphogenesis denotes a suite of anatomical, physiological, biochemical, biophysical, and molecular responses of plants to mechanical stimulation. This phenomenon is evolutionarily conserved among diverse plant lineages; however, the magnitude and character of the response are strongly determined by both the frequency and intensity of the applied stimulus. In angiosperms, thigmomorphogenetic reactions typically occur gradually, reflecting a complex interplay of morphological alterations, biochemical adjustments, and genetic reprogramming. In dicotyledonous plants, thigmomorphogenesis is commonly expressed as a reduction in leaf blade surface area, shortening of petioles, decreased plant height, radial thickening of stems, and modifications in root system architecture. In monocotyledons, in turn, mechanical stress frequently results in stem rupture below the inflorescence, with concomitant shortening and increased flexibility of younger internodes. These specific traits can be explained by structural features of monocot secondary walls as well as by the absence of vascular cambium and lateral meristems. Mechanical stimulation has been shown to initiate a cascade of responses across multiple levels of plant organization. The earliest events involve activation of mechanoresponsive genes (e.g., TCH family), followed by enzymatic activation, biochemical shifts, and downstream physiological and molecular adjustments. Importantly, recent findings indicate that prolonged mechanical stress may significantly suppress auxin biosynthesis, while leaving auxin transport processes unaffected. Moreover, strong interdependencies have been identified between thigmostimulation, gibberellin biosynthesis, and flowering intensity, as well as between mechanical stress and signaling pathways of other phytohormones, including abscisic acid, jasmonic acid, and ethylene. At the molecular scale, studies have demonstrated a robust correlation between the expression of specific calmodulin isoforms and the GH3.1 gene, suggesting a mechanistic link between mechanosensing, hormone homeostasis, and regulatory feedback loops. The present study consolidates current knowledge and integrates novel findings, emphasizing both morphological and cellular dimensions of thigmomorphogenesis. In particular, it provides evidence that mechanical stress constitutes a critical modulator of hormonal balance, thereby shaping plant growth, development, and adaptive potential. Full article

Skin hydration is fundamental for maintaining epidermal barrier integrity and overall skin homeostasis. Beyond traditional moisturizing agents, recent research has highlighted the role of aquaporins (AQPs), transmembrane water channels, in regulating epidermal hydration, barrier function, and cellular signalling. Among them, aquaporin-3 (AQP3), predominantly expressed in keratinocytes, has attracted particular attention due to its involvement in water and glycerol transport. Dysregulation of AQP expression has been associated with impaired barrier function, inflammatory skin disorders, and ageing. Growing evidence suggests that specific cosmetic ingredients and bioactive compounds, including glycerol, glyceryl glucoside, isosorbide dicaprylate, urea, retinoids, bakuchiol, peptides, plant extracts, and bacterial ferments, can modulate AQP3 expression, thereby improving skin hydration and resilience. Despite promising in vitro data, clinical evidence remains limited, mainly due to methodological and ethical constraints associated with assessing aquaporin expression in vivo. Nonetheless, aquaporins represent promising molecular targets for innovative cosmetic strategies aimed at enhancing hydration, promoting regeneration, and counteracting photoageing. Furthermore, AQP modulation may improve dermal delivery of active substances, providing new perspectives for advanced skincare formulation design. While the available evidence supports their cosmetic potential, emerging discussions on the safety of long-term AQP upregulation highlight the need for continued research and careful evaluation of such ingredients. Future studies should focus on elucidating the molecular mechanisms underlying AQP regulation and validating these findings in human clinical models. Full article

High-density lipoprotein (HDL) metabolism depends on several key factors, including ATP-binding cassette (ABC) transporters such as ABCA1 and ABCG1. These transporters are essential for maintaining cholesterol homeostasis by mediating the efflux of cellular lipids and promoting HDL formation and maturation. Dysfunction in these pathways compromises HDL biogenesis, leading to lipid accumulation in macrophages and peripheral cells. Together with oxidized low-density lipoproteins (LDLs), these alterations promote foam cell formation, atherosclerotic plaque development, and the progression of cardiovascular and metabolic diseases. Oxidative stress plays a central role in disturbing lipid balance and impairing ABC transporter activity. Unlike previous reviews that have mainly summarized mechanisms of oxidative regulation, this work integrates recent molecular findings to propose a unifying framework in which oxidative stress sequentially disrupts ABCA1 and ABCG1 function, thereby altering HDL metabolism. Moreover, it highlights emerging pharmacological strategies aimed at restoring cholesterol homeostasis and mitigating oxidative damage, contributing to the prevention of cardiovascular and metabolic disorders. Full article

The non-antibacterial effects of the tetracycline antibiotic minocycline on human erythrocytes are currently under investigation. Our data indicate alterations in the surface structure of erythrocytes; the antibiotic promotes the redistribution of cellular transformational forms during preliminary in vitro incubation (1 h and 24 h) with the modifier. The degree of surface relief changes increases over time, leading to the formation of erythrocytes displaying outgrowths and ridges, spherulation, and “deflated ball”-shaped cells (after 1 day). These alterations are largely reversible, as washing the erythrocyte suspensions with a 1% bovine serum albumin solution reduces the number of echinocytes and irreversibly transformed spherocytes with spikes. Spectrophotometric analysis has shown that minocycline stabilizes the spatial organization of hemoprotein molecules, as it does not lead to increased methemoglobin formation in the samples over time. The antibiotic appears to bind primarily to amino acid residues within heme pockets, as confirmed by molecular docking. Our findings suggest a potential risk of reduced oxygen transport function in red blood cells when taking this antibiotic, highlighting the need to consider potential erythrocyte-related side effects during long-term minocycline therapy. Full article

Peptides are emerging as versatile platforms in medicine, serving as therapeutic agents, diagnostic probes, and drug delivery vehicles. Their physical state—in a form of monomeric cell-penetrating peptides (CPPs), liquid-like coacervates, or solid amyloid fibrils—critically determines their interaction with cell surfaces and subsequent intracellular trafficking pathways. While the transport of CPPs has been extensively studied, the mechanisms governing the cellular uptake of peptide-based coacervates and fibrils are less understood. This review summarizes the current understanding of the intracellular transport mechanisms of all three distinct peptide states and their complexes or conjugates with cargo molecules. We examine a range of pathways, including direct membrane translocation, several endocytosis subtypes, and phagocytosis-like transport. Particular attention is given to unique aspects observed exclusively for CPPs, coacervates, or fibrils. Further verification and detailed characterization of internalization mechanisms are crucial for the rational design of next-generation peptide-based carriers that allow for precise cargo delivery and therapeutic efficacy. Full article

The proliferation of drones across precision agriculture, disaster response operations, and delivery services has accentuated the critical need for secure communication frameworks. Due to the limited computational capabilities of drones and the fragility of real-time wireless communication networks, the cellular connected drones confront mounting cybersecurity threats. Traditional authentication mechanisms, such as public-key infrastructure-based authentication, and identity-based authentication, are centralized and have high computational costs, which may result in single point of failure. To address these issues, this paper proposes a blockchain-enabled authentication and key agreement scheme for cellular-connected drones. Leveraging identity-based cryptography (IBC) and the Message Queuing Telemetry Transport (MQTT), the scheme flow is optimized to reduce the communication rounds in the authentication. By integrating MQTT brokers with the blockchain, it enables drones to authenticate through any network node, thereby enhancing system scalability and availability. Additionally, cryptographic performance is optimized via precompiled smart contracts, enabling efficient execution of complex operations. Comprehensive experimental evaluations validate the performance, scalability, robustness, and resource efficiency of the proposed scheme, and show that the system delivers near-linear scalability and accelerated on-chain verification. Full article

Simulating carbohydrate digestion in physiologically relevant ways remains a challenge for in vitro models. In this study, the Dynamic In vitro Human Stomach (DIVHS) system was applied to investigate cereal digestion and subsequent intestinal cellular responses. Rice, millet, and corn were digested under dynamic and static conditions. Compared with the static model, the dynamic system generated smaller grain fragments, a larger chyme–enzyme contact area (451.2 ± 4.4 cm² vs. 160.4 ± 6.0 cm²), and higher average intragastric pressure (25.0 ± 1.2 kPa vs. 7.2 ± 0.7 kPa). Salivary amylase activity also declined more gradually in the dynamic system. An empirical approach for predicting the glycemic index (eGI) was proposed, which showed improved agreement with reported human GI values compared with earlier in vitro methods. Exposure of Caco-2 cells to digested products significantly altered transcriptional profiles, including protein binding, ATP binding, and glucose transporter activity. Notably, products from the dynamic model induced stronger transcriptional responses than those from the static model, including 421 genes up-regulated and 138 down-regulated. Functional enrichment highlighted pathways related to glucose transport, energy metabolism, and cellular regulation. Overall, this study demonstrates the advantages of dynamic digestion models in replicating gastrointestinal conditions, improving GI prediction, and providing mechanistic insights into intestinal cellular responses to digested carbohydrates. Full article

Microbial metabolism is intricately governed by thermodynamic constraints that dictate energetic efficiency, growth dynamics, and metabolic pathway selection. Previous research has primarily examined these principles under carbon-limited conditions, demonstrating how microbes optimize their proteomic resources to balance metabolic efficiency and growth rates. This study extends this thermodynamic framework to explore microbial metabolism under various non-carbon nutrient limitations (e.g., nitrogen, phosphorus, sulfur). By integrating literature data from a range of species, it is shown that growth under anabolic nutrient limitations consistently yields more negative Gibbs free energy ($\Delta G$) values for the net catabolic reaction (NCR) per unit of biomass than carbon-limited scenarios. The findings suggest three potentially complementary hypotheses: (1) proteome allocation hypothesis: microbes favor faster enzymes to reduce the proteome fraction used for catabolism, thus freeing proteome resources for additional nutrient transporters; (2) coupled transport contribution hypothesis: the more negative $\Delta G$ of the NCR may in part stem from the increased reliance on ATP-coupled or energetically driven transport mechanisms for nutrient uptake under limitation; (3) bioenergetic efficiency hypothesis: microbes prefer pathways with a more negative $\Delta G$ to enhance the cellular energy status, such as membrane potentials or the ATP/ADP ratio, to support nutrient uptake under anabolic limitations. This integrative thermodynamic analysis broadens the understanding of microbial adaptation strategies and offers valuable insights for biotechnological applications in metabolic engineering and microbial process optimization. Full article

Background/Objectives: Predicting whether a compound is subject to active transport is crucial in drug development. We propose a simple threshold for passive membrane permeability (P_m), derived from the cell’s energy limitation, to identify compounds unlikely to be actively effluxed. Results: By considering fundamental cellular energy constraints, our approach provides a mechanistic rationale for why compounds with very high passive permeability in combination with low applied concentration will not undergo active efflux. This moves beyond the empirical observation (such as in previous systems that associate fast-permeating, poorly soluble compounds with low transporter activity) by grounding the prediction in the cell’s energetic limitations. For MDCK (Madin–Darby canine kidney) cells, this threshold—normalized to the applied compound concentration (C_ext)—was determined to be P_m×C_ext = 10^−1.7 cm/s×µM. Methods: To derive this threshold, we conducted an extensive analysis of literature-reported efflux ratios (ERs) in MDCKII cells overexpressing efflux transporters (MDR1, BCRP, MRP2; 294 datapoints across 136 unique compounds). Concentration-dependent measurements for Amprenavir, Eletriptan, Loperamide, and Quinidine—chosen because these borderline compounds exhibited the highest P_m×C_ext while still being actively effluxed—enabled the most accurate determination of the threshold. Literature ER values were re-evaluated through the experimental determination of reliable P_m values, as well as newly measured ER values with MDCK efflux assays. Conclusions: The results of these assays and the re-evaluation allowed us to reclassify all but three outliers (compounds with ER > 2.5 and log(P_m×C_ext) > −1.7). In contrast, more than 60% of the compounds analyzed without significant ER values (123 compounds) fell above the threshold, in strong agreement with our theory of an energy limitation to active transport. This permeability threshold thus provides a simple and broadly applicable criterion to identify compounds for which active efflux is energetically not feasible and may serve as a practical tool for early drug discovery and optimization, pending further validation in practical applications. Full article

Huntingtin (HTT) is a large, ubiquitously expressed scaffold protein that participates in multiple cellular processes, including vesicular transport, transcriptional regulation, and energy metabolism. The mutant form of HTT (mHTT), characterized by an abnormal polyglutamine (polyQ) expansion in its N-terminal region, is the causative agent of Huntington’s disease (HD), a progressive neurodegenerative disorder. Current therapeutic efforts for HD have primarily focused on lowering HTT levels through gene silencing or promoting mHTT degradation. However, accumulating evidence suggests that post-translational modifications (PTMs) of HTT—such as phosphorylation, ubiquitination, acetylation, and SUMOylation—play pivotal roles in modulating HTT’s conformation, aggregation propensity, subcellular localization, and degradation pathways. These modifications regulate the balance between HTT’s physiological functions and pathological toxicity. Importantly, dysregulation of PTMs has been linked to mHTT accumulation and selective neuronal vulnerability, highlighting their relevance as potential therapeutic targets. A deeper understanding of how individual PTMs and their crosstalk regulate HTT homeostasis may not only provide mechanistic insights into HD pathogenesis but also uncover novel, more specific strategies for intervention. In this review, we summarize recent understanding on HTT PTMs, discuss their implications for disease modification, and outline critical knowledge gaps that remain to be addressed. Full article

Low-complexity domains (LCDs) are protein regions characterized by a simple amino acid composition and low sequence complexity, as they are typically composed of repeats or a limited set of a few amino acids. Historically dismissed as “garbage sequences”, these regions are now acknowledged as critical functional elements. This review systematically explores the structural characteristics, biological functions, pathological roles, and research methodologies associated with LCDs. Structurally, LCDs are marked by intrinsic disorder and conformational dynamics, with their amino acid composition (e.g., G/Y-rich, Q-rich, S/R-rich, P-rich) dictating structural tendencies (e.g., β-sheet formation, phase separation ability). Functionally, LCDs mediate protein–protein interactions, drive liquid–liquid phase separation (LLPS) to form biomolecular condensates, and play roles in signal transduction, transcriptional regulation, cytoskeletal organization, and nuclear pore transportation. Pathologically, LCD dysfunction—such as aberrant phase separation or aggregation—is implicated in neurodegenerative diseases (e.g., ALS, AD), cancer (e.g., Ewing sarcoma), and prion diseases. We also summarize the methodological advances in LCD research, including biochemical (CD, NMR), structural (cryo-EM, HDX-MS), cellular (fluorescence microscopy), and computational (MD simulations, AI prediction) approaches. Finally, we highlight current challenges (e.g., structural heterogeneity, causal ambiguity of phase separation) and future directions (e.g., single-molecule techniques, AI-driven LCD design, targeted therapies). This review provides a comprehensive perspective on LCDs, illuminating their pivotal roles in cellular physiology and disease, and offering insights for future research and therapeutic development. Full article

Ischemic stroke remains one of the most catastrophic diseases in neurology, in which, due to a disturbance in the cerebral blood flow, the brain is acutely deprived of its oxygen and glucose oligomer, which in turn rapidly leads to energetic collapse and progressive cellular death. There is now increasing evidence that this type of stroke is not simply a type of ‘oxidative stress’ but rather a programmable loss-of-redox homeostasis, within which electron flow and the balance of oxidants/reductants are cumulatively displaced at the level of the single molecule and at the level of the cellular area. The advances being made in cryo-electron microscopy, lipidomics, and spatial omics are coupled with the introduction of a redox code produced by the interaction of the couples NADH/NAD⁺, NADPH/NADP⁺, GSH/GSSG, BH₄/BH₂, and NO/SNO, which determine the end results of the fates of the neurons, glia, endothelium, and pericytes. Within the mitochondria, pathophysiological events, including reverse electron transport, succinate overflow, and permeability transition, are found to be the first events after reperfusion, while signals intercommunicating via ER–mitochondria contact, peroxisomes, and nanotunnels control injury propagation. At the level of the tissue, events such as the constriction of the pericytes, the degradation of the glycocalyx, and the formation of neutrophil extracellular traps underlie microvascular failure (at least), despite the effective recanalization of the vessels. Systemic influences such as microbiome products, oxidized lipids, and free mitochondrial DNA in cells determine the redox imbalance, but this generally occurs outside the brain. We aim to synthesize how the progressive stages of ischemic injury evolve from the cessation of flow to the collapse of the cell structure. Within seconds of injury, there is reverse electron transport (RET) through mitochondrial complex I, with bursts of superoxide (O₂•⁻) and hydrogen peroxide (H₂O₂) being produced, which depletes the stores of superoxide dismutase, catalase, and glutathione peroxidase. Accumulated succinate and iron-induced lipid peroxidation trigger ferroptosis, while xanthine oxidase and NOX2/NOX4, as well as uncoupled eNOS/nNOS, lead to oxidative and nitrosative stress. These cascades compromise the function of neuronal mitochondria, the glial antioxidant capacity, and endothelial–pericyte integrity, leading to the degradation of the glycocalyx with microvascular constriction. Stroke, therefore, represents a continuum of redox disequilibrium, a coordinated biochemical failure linking the mitochondrial metabolism with membrane integrity and vascular homeostasis. Full article

The paradigm of cellular vehicle-to-everything (C-V2X) communications assisted by unmanned aerial vehicles (UAVs) is poised to revolutionize the future of sixth-generation (6G) intelligent transportation systems, as outlined by the international mobile telecommunication (IMT)-2030 vision. This integration of UAV-assisted C-V2X communications is set to enhance mobility and connectivity, creating a smarter and reliable autonomous transportation landscape. The UAV-assisted C-V2X networks enable hyper-reliable and low-latency vehicular communications for 6G applications including augmented reality, immersive reality and virtual reality, real-time holographic mapping support, and futuristic infotainment services. This paper presents a Markov chain model to study a third-generation partnership project (3GPP)-specified C-V2X network communicating with a flying UAV for task offloading in a Federated Learning (FL) environment. We evaluate the impact of various factors such as model update frequency, queue backlog, and UAV energy consumption on different types of communication latency. Additionally, we examine the end-to-end latency in the FL environment against the latency in conventional data offloading. This is achieved by considering cooperative perception messages (CPMs) that are triggered by random events and basic safety messages (BSMs) that are periodically transmitted. Simulation results demonstrate that optimizing the transmission intervals results in a lower average delay. Also, for both scenarios, the optimal policy aims to optimize the available UAV energy consumption, minimize the cumulative queuing backlog, and maximize the UAV’s available battery power utilization. We also find that the queuing delay can be controlled by adjusting the optimal policy and the value function in the relative value iteration (RVI). Moreover, the communication latency in an FL environment is comparable to that in the gross data offloading environment based on Kullback–Leibler (KL) divergence. Full article

Background/Objectives: Semen Ziziphi Spinosae (SZS), a medicinal and edible traditional Chinese herb, has been widely used to treat insomnia. As critical regulators of the central nervous system, astrocytes play a pivotal role in maintaining sleep homeostasis. However, the mechanisms by which SZS modulates astrocytic function to improve sleep remain unclear. Methods: In this study, we employed an integrated transcriptomics and metabolomics approach to investigate the protective effects of SZS extract against lipopolysaccharide (LPS)-induced inflammatory injury and metabolic dysfunction in astrocytes. Results: Transcriptomic analysis revealed that SZS ameliorates cellular damage (including apoptosis, autophagy, and cell cycle dysregulation) through a FOXO3-centric signaling network. Concurrently, SZS restored cellular energy metabolism by increasing ATP production and reducing Ca²⁺ overload, thereby activating the AMPK signaling pathway to support normal astrocytic function. Metabolomic profiling further demonstrated that SZS-mediated restoration of energy homeostasis sustains ABC transporter activity, which in turn modulates neurotransmitter (serotonin, L-glutamic acid, adenosine), metabolic mediators (leukotrienes, palmitoylethanolamide, succinic acid), and nucleotide (uridine 5′-diphosphate). These coordinated changes normalized GABAergic synapse activity and neuroactive ligand receptor interactions, ultimately resolving neural metabolic network disturbances. Conclusions: Our findings elucidate a novel FOXO3-energy metabolism-ABC transporter axis through which SZS extract attenuates neuroinflammation and metabolic dysfunction in astrocytes and exerts sleep-promoting and neuroprotective effects. This study provides a scientific foundation for understanding the modern pharmacological mechanisms of traditional Chinese medicine in insomnia treatment, highlighting astrocytic regulation as a potential therapeutic target. Full article