Search Results (2,921)

Circadian rhythms impose temporal organization on immune function, shaping host responses to infection, injury, and chronic disease. While transcriptional control by core clock components such as CLOCK and BMAL1 has been extensively characterized, this paradigm alone cannot explain the rapid and dynamic nature of immune signaling. Emerging evidence identifies post-translational modifications (PTMs)—including phosphorylation, ubiquitination, and acetylation—as critical regulators that confer speed, reversibility, and specificity to inflammatory pathways. Here, we propose the concept of a “Chrono-PTM axis,” in which circadian timing and PTM-dependent signaling are functionally integrated to govern immune activation thresholds. We discuss how PTMs not only regulate core clock machinery but also temporally gate key innate immune pathways, including NF-κB signaling and inflammasome activation, thereby controlling cytokine production at multiple levels. Furthermore, we highlight the role of immunometabolism in supplying essential cofactors that couple cellular energetic states to PTM dynamics, linking metabolic oscillations to inflammatory outputs. Disruption of this axis contributes to the pathogenesis of autoimmune diseases, cancer, and tissue-specific inflammatory disorders. Finally, we outline emerging therapeutic opportunities targeting the Chrono-PTM axis, including chronotherapy and PTM-directed interventions, and identify critical gaps in temporal proteomics and translational studies. Elucidating the integration of circadian and post-translational regulation will provide a unifying framework for understanding immune homeostasis and may enable time-informed precision immunotherapy. Full article

Nanostructured catalysts have become a core component of energy conversion in electrocatalysis and photocatalysis; however, successfully translating their performance from laboratory scale to industrial applications remains a long-standing challenge. This paper provides a critical assessment of the field, systematically tracing the entire development trajectory from catalyst design to practical application. We focus on five major classes of catalysts—monometallic catalysts, bimetallic/multimetallic alloy catalysts, metal compound catalysts, carbon-based composite catalysts, and single-atom catalysts—and explore synthetic strategies for achieving precise structural control, including hydrothermal/solvothermal methods, electrodeposition, template-assisted and MOF-derived syntheses, high-temperature pyrolysis, and post-treatment defect engineering. This paper delves into the mechanisms and performance descriptors governing the hydrogen evolution reaction (HER), oxygen evolution reaction (OER), oxygen reduction reaction (ORR), urea oxidation, photocatalytic water splitting, and CO₂ reduction. Based on the above analysis, this paper lays the mechanistic foundation for five core strategies to improve catalyst performance: morphology control, elemental doping, heterostructure and interface engineering, defect and vacancy engineering, and support modification. Furthermore, this paper provides an in-depth evaluation of the applications of these catalysts in water splitting, CO₂ valorization, fuel cells, metal–air batteries, and energy-saving electrolysis, with a particular focus on earth-abundant alternatives to precious metals. We argue that in many well-studied reactions, intrinsic activity may no longer be the primary bottleneck restricting their development; instead, the core challenge now lies in maintaining excellent catalytic performance under harsh and industrially relevant conditions, especially under high-current densities, impurity-containing feed systems, and long-term operating conditions. In response to this shift in research focus, this paper clearly identifies the key obstacles hindering the industrial application of catalysts and proposes practical directions for future research. Full article

Post-translational modification (PTM) neoantigens have emerged as key drivers of autoimmune inflammation. However, standardized protocols for MHC Class II tetramer preparation for the detection of such antigen-specific T cells remain limited, hindering the broader application of this important discovery. This study systematically engineered an HLA-DR4 (HLA-DRB1*04:02 and HLA-DRA*01:01) tetramer platform based on carboxyethyl-modified neoantigen ITGA2B peptide (ITG-CE), a PTM associated with autoimmune diseases (AUIDs) such as Ankylosing Spondylitis (AS). The platform provides a major histocompatibility complex (MHC) Class II tetramer associated with the PTM neoantigen and integrates modular protein construct, a controllable PTM peptide exchange strategy, and a specific T cell receptor (TCR) validation model. It can be employed to investigate PTM neoantigen presentation and CD4⁺ T cell auto-reactivity, providing extensive application value for future research into the mechanisms of PTM-induced AUIDs and immune monitoring. Full article

Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated “redox-dead” DRP1-C631A knock-in mutant (Drp1^C/A) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1-like macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1^C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD. Full article

Regenerative medicine integrates interdisciplinary approaches towards restoring the function of diseased organs. This study examined alterations that occurred in the liver under a high-fat diet (HFD) with the development of obesity and fatty liver, and changes in metabolic homeostasis and glucose levels, in mice. HFD nutrition causes hyperglycemia, leading to the formation and accumulation of advanced glycation end-products (AGEs) promoting protein post-translational modifications (PTMs) and introducing crosslinking in the extracellular matrix (ECM). Using histological and gene expression analyses, we detected an increase in adiposity, as well as in ECM protein deposition in the liver. Further, decellularization of the liver yielded the isolated ECM organ scaffold, allowing us to analyze the chemical modification in proteins by various imaging methods combined with spectroscopy. The measurements of intrinsic protein fluorescence are consistent with increased AGE-associated levels. SEM allows for the visualization of ECM fiber thickening as a result of protein crosslinking. Using cathodoluminescence, a label-free imaging method, we confirmed the protein modifications. The combination of innovative technologies highlights the ECM structural alterations associated with impaired glucose regulation and liver adiposity. These findings provide novel views on liver-scaffold ECM structure under metabolic diseases that will play a significant role in accelerating the understanding of effective regenerative therapies. Full article

Background/Objectives: Telewellness programs can expand access to exercise and social opportunities for older adults, especially those with mobility disabilities. The TechSAge Tele Tai Chi clinical trial assessed whether the Tai Chi for Arthritis and Fall Prevention program was feasible and acceptable when delivered in a virtual format for adults aging with mobility disabilities, and examined pre-to-post changes in two primary outcomes: physical activity and social connectedness. Methods: The TechSAge Tele Tai Chi study was a single-arm clinical trial. Sixty community-dwelling adults (60–77 years of age; M = 69.2, SD = 4.8) with self-identified long-term mobility disability (≥10 years) joined the virtual classes from home twice a week for 8 weeks. Participants exercised along with pre-recorded video lessons and engaged in guided social discussion. Assessments at baseline, post-intervention, and 1-month follow-up were analyzed with linear mixed models. Results: Leisure physical activity (PASIPD) increased significantly, with back-transformed marginal means rising from 14.2 MET h/wk at baseline to 28.7 MET h/wk post-intervention (p < 0.001). The Social Participation subscale of social connectedness also increased from baseline to post-intervention (p = 0.014); the overall social-connectedness composite did not change significantly. The virtual translation was feasible with high intervention fidelity and adherence, and participants reported high acceptability, satisfaction, enjoyment, and intention to continue. Conclusions: Adults aging with mobility disabilities can safely and successfully participate in virtual group tai chi with appropriate modifications and technology support. Full article

Dengue is an arboviral disease of global significance caused by Orthoflavivirus denguei (DENV), which has four antigenically distinct serotypes. The envelope (E) protein plays a critical role in viral entry and eliciting immune responses. This study aimed to compare the biochemical and immunological properties of the E protein across the four DENV serotypes using in silico approaches. E protein reference sequences were retrieved from RefSeq and analyzed with various bioinformatics tools. Sequence alignment revealed identities ranging from 63.08% to 77.69%. Biochemical analysis showed minimal variation in molecular weight and isoelectric point; however, the net charge of DENV-3 E protein was notably lower. Secondary structure predictions indicated a predominance of alpha-helices in DENVs-1/2, while DENVs-3/4 featured more beta-sheets. Post-translational modification analysis revealed mostly casein kinase II phosphorylation sites across all serotypes, with DENV-4 uniquely presenting also tyrosine kinase sites. Amino acids W231/D341 in DENV-1, Q86 in DENVs-2/4, and D87/D339 in DENV-3 showed maximum antigenicity scores in B cell recognition, while the human leukocyte antigen (HLA) alleles B*08:01/B*39:01 and DRB4*01:01, recognized by T cells, presented the highest number of predicted epitopes for the different DENV serotypes. Conservation analysis showed that the major antigenic regions highlighted in this study are highly conserved among contemporary DENV isolates despite the genetic variability observed within each serotype. These findings suggest that subtle structural differences in the E protein may contribute to distinct immunogenic profiles, highlighting candidate regions for future investigation. Full article

Mitochondria are central hubs of antiviral immunity and cellular metabolism, yet the links between SARS-CoV-2–induced mitochondrial remodeling, antiviral gene regulation, and post-translational control remain incompletely understood. Here, we investigated mitochondrial–immune remodeling in SARS-CoV-2–infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion/biogenesis markers and partial ISG15–MFN2 colocalization, indicating a spatial association between ISG15-related antiviral/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-α2 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial–immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection. Full article

Dynamin-related protein 1 (Drp1) is essential for mitochondrial dynamics in skeletal muscle, particularly in regulating fission, mitophagy, and maintaining mitochondrial function. Exercise is crucial for sustaining muscle function, promoting mitochondrial adaptations that enhance energy metabolism and oxidative capacity in skeletal muscle. In this Review, we discuss the role of Drp1 in exercise-induced mitochondrial adaptations and its potential implications for skeletal muscle health. We first address the evidence that Drp1 activity must be maintained within a narrow physiological range. Both Drp1 deficiency and overabundance provoke muscle atrophy and dysfunction, establishing a Goldilocks principle for mitochondrial fission. We then examine the multi-layered post-translational modification code that governs Drp1 activity, including canonical phosphorylation, redox-sensing modifications, and the receptor selectivity model that may specify distinct fission programs. A three-stage model of exercise-induced mitochondrial adaptation is presented, describing how Drp1 activity is temporally orchestrated from acute fragmentation through short-term remodeling to long-term network optimization, and how these morphological transitions govern substrate metabolism and determine exercise performance. The pathological consequences of Drp1 dysregulation are examined in metabolic disease, where Drp1 is chronically hyperactivated, and in aging, where Drp1 activity is deficient. Finally, we analyze the ROS-Drp1 signaling axis as the mechanistic basis for the bidirectional regulation of Drp1 by exercise. Moderate exercise-induced ROS production activates Nrf2 and AMPK signaling, which suppress excessive fission in metabolic disease while restoring insufficient fission in aging, thereby moving Drp1 activity toward the physiological Goldilocks zone in both contexts. This context-dependent, bidirectional regulation distinguishes exercise from pharmacological inhibitors and identifies the ROS-Drp1 axis as a therapeutic target for conditions at opposite ends of the Drp1 activity continuum, such as sarcopenia and type 2 diabetes. Full article

Glioblastoma (GB) remains one of the most therapy-resistant solid tumors, characterized by profound metabolic plasticity, intratumoral heterogeneity, and a highly immunosuppressive microenvironment. While immunotherapies such as chimeric antigen receptor T (CAR-T) cells have shown promise in hematological malignancies, their efficacy in GB has been limited. Emerging evidence suggests that tumor-specific metabolic dependencies and post-translational modifications (PTMs) may represent exploitable vulnerabilities. This review discusses disulfidptosis, a recently described form of regulated cell death driven by disulfide stress under conditions of limited reducing capacity, as a context-dependent metabolic–redox vulnerability in GB. We further discuss how altered protein glycosylation and glycocalyx architecture in glioblastoma regulate cell survival, death signaling, and immune recognition. Particular emphasis is placed on the glycosylation of surface antigens targeted by CAR-T cells, including EGFR/EGFRvIII, IL-13Rα2, mesothelin, B7-H3, HER2, and GD2, and on how glycan-dependent epitope accessibility may limit therapeutic efficacy. Finally, we distinguish disulfidptosis, whose direct relevance to CAR-T-cell responses remains to be established, from glycosylation and glycocalyx remodeling as more direct determinants of target–antigen accessibility and immune recognition. Therapeutic strategies addressing these vulnerabilities may provide rational opportunities to improve CAR-T-based and combinatorial therapies for GB. Full article

Transfer RNAs (tRNAs) are chemically matured decoding molecules that are central to protein synthesis. Their post-transcriptional modifications, especially those in the anticodon stem-loop (ASL), shape local RNA structure, codon recognition and translational fidelity at the tRNA-mRNA decoding interface. 2′-O-methylation (Nm) is a conserved ribose modification installed at selected ASL positions, particularly positions 32 and 34, by the modular Trm7/FTSJ1 methyltransferase system. Rather than directly changing base-pairing identity, these marks help prepare the decoder for efficient translation and function within an interconnected 32–34–37 modification network, best illustrated by tRNA^Phe. Loss of Trm7/FTSJ1-mediated Nm may impair selected codon–tRNA decoding pairs; in yeast, Trm7 deficiency is additionally associated with GAAC activation and phenotypes consistent with reduced functional tRNA^Phe availability. In humans, mutations in FTSJ1 are associated with nonsyndromic X-linked intellectual disability (NSXLID), suggesting that disruption of tRNA chemical maturation can affect neuronal translation programs. In this review, we integrate anticodon-loop modifications at positions 32, 34, and 37 into a decoder-centered framework and compare the conserved enzymatic logic of yeast Trm7 and human FTSJ1 with their divergent substrate repertoires. By synthesizing structural, biochemical, genetic, and translational evidence, we distinguish established mechanisms from working models and unresolved questions concerning tRNA modification hierarchies and neuronal vulnerability. Full article

Lactylation is an emerging lactate-derived post-translational modification that may link tumour metabolic reprogramming, epigenetic regulation and DNA damage repair. Enhanced glycolysis and lactate accumulation are common in many tumours, and lactate has been reported to induce histone and non-histone lactylation in specific experimental contexts. Recent studies suggest that lactylation is associated with several DNA repair pathways, including base excision repair/single-strand break repair, nucleotide excision repair, homologous recombination and non-homologous end joining, and may contribute to therapy resistance in selected cancer models. Specifically, XRCC1 lactylation has been reported to promote nuclear translocation and repair activity in glioblastoma models; H4K12 lactylation has been linked to PARP inhibitor resistance through RAD23A activation in ovarian cancer models; and BLM lactylation has been associated with enhanced homologous recombination repair in bladder cancer models. Lactylation of NBS1, RAD51 and XLF has also been implicated in DNA repair regulation in specific experimental systems, although some mechanistic links are inferred from pathway activation or functional rescue experiments rather than directly demonstrated across multiple tumour types. These findings suggest that lactylation may modulate DNA repair and therapeutic response in a context-dependent manner. Targeting lactate metabolism, transport and lactylation regulators, including LDHA, MCT1/4, ACAT1, AARS1 and GCN5, or using site-specific lactylation-inhibiting peptides may improve chemotherapy and PARP inhibitor efficacy, but clinical translation remains limited by heterogeneity, metabolic plasticity, toxicity and insufficient validation. Full article

Extracellular vesicles (EVs), naturally secreted by cells as nanoscale lipid bilayer structures, have become a research hotspot in biomedicine owing to their excellent biocompatibility, low immunogenicity, and inherent ability to cross biological barriers. This review systematically summarizes recent advances in EVs as natural nanomaterials. The biogenesis mechanisms of EVs are outlined, followed by a comparative analysis of the advantages and limitations of mainstream isolation and purification methods, including ultracentrifugation, size-exclusion chromatography, and microfluidic technologies. The core guiding role of the MISEV 2023 guidelines in standardizing EV characterization is highlighted. Engineering strategies to enhance EV therapeutic efficacy—including parental cell modification, post-isolation physicochemical tailoring, and hybrid vesicle construction—are then reviewed, followed by a comparative analysis of mainstream isolation technologies, emphasizing the trade-offs between purity and yield. Distinct from conventional descriptive reviews, this article establishes a strong biomimetic framework to scrutinize engineering strategies, including parental cell genetic modification, post-isolation physicochemical tailoring, and the fabrication of hybrid bio-synthetic vesicles. The design principles governing targeted delivery, drug-loading physics, and in vivo pharmacokinetic stability are critically evaluated through the lens of biomimetic nanotechnology. Furthermore, we identify critical research gaps and technical bottlenecks impeding clinical translation, offering a forward-looking perspective on the evolution of EVs from natural messengers into standardized precision medicine platforms. Full article

Regulated cell death is essential for tissue homeostasis, immune defense, and disease progression, yet the lipid-based regulatory mechanisms that coordinate cell death signaling remain incompletely understood. Protein palmitoylation is a dynamic and reversible lipid post-translational modification that controls protein membrane association, trafficking, stability, and signaling complex assembly. This review summarizes the regulatory roles of palmitoylation and depalmitoylation in major forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-related cell death. Particular attention is given to representative palmitoylated substrates, including Fas cell surface death receptor (Fas), receptor-interacting protein kinase 1 (RIPK1), NLR family pyrin domain containing 3 (NLRP3), gasdermin D (GSDMD), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), autophagy-related 16 like 1 (ATG16L1), and Beclin1. These substrates illustrate how palmitoylation links membrane organization, metabolic status, inflammatory signaling, and cell fate decisions. Disease-oriented evidence further indicates that dysregulated palmitoylation contributes to cancer, neurodegenerative diseases, and inflammatory or immune-related disorders by modulating cell death resistance, inflammatory amplification, immune evasion, or impaired proteostasis. Current challenges include limited quantitative information on palmitoylation dynamics, incomplete evidence for some enzyme–substrate relationships, and insufficient distinction between disease-driving and secondary palmitoylation events. Targeting zinc finger Asp-His-His-Cys (zDHHC) palmitoyl acyltransferases, depalmitoylating enzymes, or specific palmitoylated substrates may provide new therapeutic opportunities. Overall, this review positions protein palmitoylation as a dynamic molecular switch linking lipid metabolism, membrane signaling, regulated cell death, and disease remodeling. Full article

The integration of artificial intelligence (AI) into the life sciences has accelerated significantly between 2022 and 2026, accompanied by global investment exceeding USD 100 billion and widespread expectations of a transformative impact in drug discovery. Despite these advances, the extent to which AI has improved clinical outcomes remains unclear. This study presents a structured narrative review evaluating the economic, technical, clinical, and regulatory dimensions of AI adoption in drug discovery. Current evidence indicates that clinical attrition rates remain high, with approximately 90% of drug candidates entering clinical development failing to achieve regulatory approval. Although AI systems such as AlphaFold have achieved high structural prediction accuracy, with predicted local distance difference test (pLDDT) scores exceeding 90 for well-structured proteins and root mean square deviation (RMSD) values comparable to experimental methods, limitations persist in modelling protein dynamics, post-translational modifications, and protein–ligand interactions. Clinical case studies demonstrate that while AI can accelerate early-stage discovery timelines, these advantages do not consistently translate into improved late-stage success rates. Furthermore, reproducibility challenges, limited data transparency, and regulatory gaps continue to constrain reliable implementation. These findings suggest that AI in drug discovery is currently in a transitional phase characterised by high investment but limited validated clinical impact. Future progress will depend on strengthening validation frameworks, improving data sharing practices, and aligning regulatory standards with real-world clinical performance. Full article