Search Results (4,489)

High-mobility group box 1 (HMGB1) is a multifunctional protein that operates both within the nucleus and as an extracellular signaling molecule. Its extracellular activity has been increasingly associated with cancer progression. Emerging evidence suggests that structural modifications of HMGB1, including C-terminal truncation, may alter its biological activity, though the underlying mechanisms remain largely unexplored. Here, we show that HMGB1, which lacks the entire C-terminal acidic tail, is associated with increased cellular plasticity and invasive potential through distinct signaling pathways not strictly dependent on RAGE (Receptor for Advanced Glycation End-product) under the tested conditions. Functional analyses indicate that this truncated form promotes epithelial–mesenchymal transition-related behaviors and activates downstream inflammatory signaling in a context-dependent manner. Notably, pharmacological intervention with metformin effectively suppressed responses to the full-length protein but was less effective against the tail-less variant, underscoring potential therapeutic challenges. These findings suggest an underappreciated regulatory role of the HMGB1 C-terminal domain in tumor aggressiveness. Full article

Triple-negative breast cancer (TNBC) is characterized by prominent neutrophil infiltration; however, its significance remains controversial. Here, we investigated the role of neutrophil chemoattractant receptors in TNBC progression and metastasis. In contrast to wild-type (WT), Fpr^-/-, and Fpr2^-/- mice, neutrophils were almost completely absent in 4T1 tumors from Cxcr2^⁻/⁻ mice, indicating a dominant role for CXCR2 in the recruitment of tumor-associated neutrophils, leading us to use Cxcr2^-/- mice for further studies. Primary tumor growth was comparable between WT and Cxcr2^-/- mice, whereas lung metastasis was significantly increased in Cxcr2^-/- mice, with reduced expression of inflammatory cytokines, chemokines and cytotoxic molecules, including granzyme B and perforin, in primary tumors and metastatic lungs of Cxcr2^-/- mice. In vitro, WT, but not Cxcr2^-/-, neutrophils enhanced CD8⁺ T cell activation, partly via ICAM-1, and directly induced tumor cell death, supporting their anti-tumor function. To assess clinical relevance, transcriptomic data were analyzed. High neutrophil infiltration combined with elevated CXCR2 expression, and to a lesser extent CXCR1 expression, was associated with improved prognosis in patients with basal-like BC that largely overlaps with TNBC. Collectively, these findings suggest that CXCR2-mediated neutrophil recruitment exerts protective, anti-tumor effects and may represent a new prognostic marker for TNBC patients. Full article

To date, Lyme vaccine development has largely overlooked the vaccinee’s human leukocyte antigen (HLA) genetic makeup on which antibody production critically depends. Here, we evaluated in silico the predicted binding affinities of 192 HLA-II alleles with all 15-mer peptide sequences of five Borrelia burgdorferi proteins to identify peptides with strong binding affinity, as they would be the best candidates for antibody production in response to vaccination. We found the following: (a) 226 of the 1067 peptides tested (21.2%) were found to bind strongly to HLA-II molecules; (b) decorin-binding protein A had the greatest number of strongly binding peptides; and (c) 69 HLA-II alleles (primarily of the DRB1 gene) bound with strong affinity to peptides from Borrelia burgdorferi proteins. Finally, we tested for possible susceptibility to autoimmunity by any one of the 226 peptides above by searching for their occurrence in ~84,000 proteins of the human proteome and found overlap with only two 8-mer peptide sequences (embedded within the 226 15-mer peptides), neither of which was characterized by strong binding to HLA-I, suggesting a reduced likelihood of autoimmunity. These findings emphasize the importance of a personalized vaccine approach based on the vaccinee’s human leukocyte antigen genetic makeup and offer specific vaccine-candidate peptides that are predicted to maximize vaccine effectiveness and safety. The results of this computational study provide novel directions for future development of Lyme vaccines. Full article

Adenosine triphosphate (ATP) serves as a central energy currency and signaling molecule in cellular processes, with ATP-binding sites in proteins playing critical roles in enzymatic catalysis, signal transduction, and gene regulation. The accurate identification of ATP-binding sites is essential for understanding protein function mechanisms and facilitating drug discovery, enzyme engineering, and disease pathway analysis. In this study, we present a novel hybrid deep learning framework that synergizes heterogeneous learning paradigms based on protein sequence information for accurate ATP-binding site prediction. Our approach integrates two complementary base classifiers. One is a Transformer-based model, which leverages high-level contextual embeddings generated by Evolutionary Scale Modeling 2 (ESM-2), a state-of-the-art protein language model, combined with a local–global dual-attention mechanism that enables the model to simultaneously characterize short-segment and long-range contextual dependencies across the entire protein sequence. The other is a deep Q-network (DQN)-inspired classifier that achieves residue-level prediction as a sequential decision-making process. The final predictions are generated using a weighted ensemble strategy, where optimal weights are determined via cross-validations to leverage the strengths of both models. The prediction results on benchmark independent testing sets indicate that our method achieves satisfactory performance on key metrics. Beyond predictive efficacy, this work uncovers the intrinsic biological mechanisms underlying protein–ATP interactions, including the synergistic roles of local structural motifs and global conformational constraints, as well as family-specific binding patterns, endowing the research with substantial biological significance. The research in this work offers a deeper understanding of the protein–ligand recognition mechanisms and supportive efforts on large-scale functional annotations that are critical for system biology and drug target discovery. Full article

Extracellular vesicles (EVs), as key mediators of intercellular communication, play multifaceted roles in the pathogenesis, treatment, drug resistance, and monitoring of B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). EVs derived from lymphoma cells or tumor microenvironment cells carry diverse cargoes such as proteins, microRNAs (miRNAs), and viral oncoproteins, which regulate tumor progression by modulating signaling pathways related to cell proliferation, invasion, apoptosis, autophagy, and immune suppression. In terms of treatment, accumulating evidence suggests that EVs may be associated with the efficacy of classical regimens such as R-CHOP, and they also hold potential as therapeutic targets and drug delivery vehicles for B-NHL. They contribute to drug resistance by altering the expression of key molecules or reshaping the tumor niche. Additionally, EV-derived biomarkers enable non-invasive diagnosis and monitoring of treatment response and prognosis. This review summarizes the latest research progress on the roles of EVs in major B-NHL subtypes, aiming to provide new insights for the development of innovative diagnostic and therapeutic strategies for B-NHL. Full article

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

Charge transport underpins essential biological processes, including cellular respiration, photosynthesis, and enzymatic catalysis. Advances in molecular electronics have enabled single-molecule measurements that unequivocally establish redox-active proteins as efficient electron conductors, with their metal cofactors serving as intrinsic redox relays. By contrast, ubiquitous non-redox proteins lacking such redox centers have long been considered poor conductors. However, recent research has challenged this view, demonstrating that efficient charge transport in non-redox proteins can be mediated through polypeptide backbones, aromatic side-chain arrays, and hydrogen bond networks. This review surveys progress in understanding the single-molecule conductance of non-redox proteins. Firstly, we elucidate the fundamental transport mechanisms, highlighting the interplay between coherent tunneling and thermally activated hopping. We then provide an overview of state-of-the-art experimental techniques for single-molecule characterization. Through analysis of diverse systems spanning short peptides to large enzymes, we illustrate how aromatic amino acid networks and dynamic conformational fluctuations govern conductance, enabling emerging applications in label-free biosensing and single-molecule protein/DNA sequencing. Finally, we discuss persistent challenges and outline future opportunities for integrating protein-based conductors into bioelectronic devices. This review aims to stimulate further research and pave the way for novel applications harnessing protein conductance. Full article

Nanoemulsions are pivotal carriers which are increasingly adopted as carriers for poorly soluble active molecules. This review provides a critical overview of ‘green’ nanoemulsions, which are systems based on renewable, biodegradable, and non-toxic components and/or using sustainable production techniques. We here focus on the role of food-grade oils (including poly-unsaturated fatty acid-rich sources) and green excipients, with special attention on the interfacial properties of biosurfactants such as proteins, polysaccharides, and small-molecule surfactants. This review provides a critical overview of the formulation principles, interfacial phenomena, and physicochemical stability of green nanoemulsions, with reference to topical and pharmaceutical applications. The performance of nanoemulsions as delivery systems for bioactive lipids, essential oils, vitamins, carotenoids, phenolic compounds, and conventional drugs is examined through representative case studies. Known limitations, including oxidative instability, compositional variability, and difficulties in large scale production, are analyzed along with future opportunities in multifunctional formulations and sustainable processing. Overall, green nanoemulsions emerge as promising next-generation platforms for safe, effective, and environmentally friendly drug delivery. Full article

To achieve efficient development of medium-depth and shallow high-rank coalbed methane in the Qinshui Basin of Shanxi Province, the authors focused on the microscopic methane release mechanism. Through scanning electron microscopy, nuclear magnetic resonance, and isothermal adsorption experiments, the pore structure, distribution patterns, and influence of hydration effects in this type of coal were revealed. It was clarified that the ineffective utilization of “bound-state” methane within nanopores is the key factor leading to low productivity and efficiency in coalbed methane development. Further, based on molecular simulations, the competitive adsorption characteristics between water and methane molecules were quantified, indicating that about 78% of the methane in the internal pores of 4 nm coal molecular clusters cannot be desorbed through pressure reduction. Meanwhile, the production enhancement mechanism of hydraulic fracturing on coal seam depressurization, permeability enhancement, reduction in low-speed diffusion distance, and enhancement of high-speed linear flow was clarified. Through large-scale pad water injection and stepwise slow production increase, the coal seam can be fully communicated, the reservoir effectively stimulated, and the adsorbed methane sufficiently released. This paper establishes a “channeled” fracturing concept and its supporting technological system for medium-depth and shallow high-rank coal, which has been successfully applied in field operations. The pilot well group achieved stable daily production exceeding 50,000 cubic meters per day, laying a solid foundation for the continuous and stable production increase in medium-depth and shallow high-rank coalbed methane in the Qinshui Basin. Full article

The fluorescence properties of organic molecules are largely determined by molecular architecture, π-conjugation, and electronic substituent effects. In this study, three novel pyrene-chromone Schiff base derivatives were designed and synthesized to investigate substituent-driven modulation of photophysical behavior. The compounds were obtained via condensation of 1-aminopyrene with three different chromone-based aldehydes and fully characterized by FT-IR, ¹H-NMR, and mass spectrometry. The molecular design involves a donor-π-acceptor architecture: pyrene donates electrons, while the chromene moiety accepts them, enabling charge transfer upon excitation. UV-Vis and fluorescence spectroscopy revealed intense absorption in the 430–440 nm range and tunable emission in the 540–565 nm region, corresponding to large Stokes shifts (107–125 nm). Substituent effects significantly influenced optical band gaps and emission intensities, with the nitro-substituted derivative exhibiting a reduced band gap and pronounced fluorescence quenching due to enhanced intramolecular charge transfer. Concentration-dependent absorption studies demonstrated linear Beer–Lambert behavior, indicating the absence of aggregation within the investigated range. These results establish clear structure–property relationships in pyrene-chromene Schiff bases and highlight their potential as promising candidates for optoelectronic and fluorescence-based sensing applications. Full article

The global prevalence of obesity continues to rise, posing serious risks to human health largely because obesity itself leads to metabolic disorders of carbohydrate and lipids. Currently, effective and healthy interventions for lowering blood glucose, reducing blood lipids, and promoting weight loss remain limited due to the complexity of obesity development. Lactobacillus plantarum (GDMCC 1.140) was shown to promote catabolic processes and reduce hepatic lipid accumulation in largemouth bass fed with high-starch feed (HSF) in our previous study; however, molecular mechanisms underlying the function of this probiotic remain unclear. Here, we evaluated the effects of L-carnosine, one of metabolites produced by Lactobacillus plantarum, on carbohydrate and lipid metabolisms in an obesity model of zebrafish, which was induced by HSF. Histopathological analyses of livers from different groups indicated that a dietary supplement with L-carnosine can alleviate hepatic impairment and reduce lipid accumulation in the hepatocytes of obese zebrafish. Transcriptomic analyses revealed that L-carnosine supplementation can reverse the expression of about 70 HSF-induced genes, mainly gene-specific transcription regulators and metabolite interconversion enzymes. Furthermore, approximately 250 HSF-inhibited genes were found to be up-regulated by L-carnosine, reaching levels comparable to those in normal-starch feed (NSF) zebrafish. These genes, targeted by L-carnosine and inhibited by HSF, are highly enriched in GO terms such as lipid metabolic process, small molecule metabolic process, and cellular response to chemical stimulus, with monocarboxylic acid metabolic process, modified amino acid metabolic process and aldehyde metabolic process following, and in KEGG pathways of carbohydrate, lipid and amino acid metabolisms, such as pentose and glucuronate interconversions, glycolysis/gluconeogenesis, glycerolipid metabolism, pentose phosphate pathways, fatty acid degradation, beta-alanine metabolism and arginine and proline metabolism. These findings provide functional and molecular evidence that L-carnosine can ameliorate HSF-induced disorders of carbohydrate and lipid metabolisms. Full article

Terpenoids represent a large class of bioactive natural compounds with promising pharmacological properties, including anti-inflammatory, antimicrobial, and anticancer activities. However, their clinical application is often limited by poor aqueous solubility, low membrane permeability, and suboptimal bioavailability. Phytosomal delivery systems have emerged as a promising strategy to enhance the pharmacokinetic performance of plant-derived compounds by forming molecular complexes between bioactive molecules and phospholipids. This review critically examines the structural principles, preparation methods, physicochemical characterization, and biological performance of terpenoid phytosomes. Particular attention is given to the molecular interactions between terpenoids and phospholipids that govern complex formation and vesicular assembly. The review also summarizes current analytical techniques used to confirm phytosome formation and discusses the influence of formulation parameters, including phospholipid composition and molar ratios, on stability and biological activity. In addition, emerging insights from molecular modeling and membrane interaction studies are considered to better understand the mechanisms underlying improved drug delivery. Finally, challenges related to safety assessment, manufacturing scalability, and clinical translation of phytosomal systems are discussed. Overall, terpenoid phytosomes represent a promising nanodelivery platform capable of improving the pharmacokinetic profile and therapeutic potential of terpenoid compounds. Full article

Ornithine decarboxylase (ODC) functions as the rate-limiting enzyme in the polyamine (PA) biosynthetic pathway. It catalyzes the decarboxylation of L-ornithine to produce putrescine, thereby initiating the biosynthesis of polyamines. Polyamines are a class of widely distributed polycationic aliphatic compounds in living organisms, including putrescine, spermidine, and spermine. They serve not only as critical regulators of cell growth, proliferation, and differentiation, but also as important signaling molecules involved in plant responses to environmental stress and key precursors in the biosynthesis of diverse secondary metabolites. Focusing on recent advances in plant ODC research, this review summarizes the characteristics and evolutionary relationships of the ODC gene family, the biochemical properties and catalytic mechanism of the enzyme, and its multiple physiological roles in growth, development, secondary metabolism, and stress adaptation. Furthermore, we discuss the complex regulatory mechanisms governing ODC activity at both transcriptional and post-translational levels, with a critical gap in understanding the post-translational regulation of ODC in plants, particularly the mechanisms governing its degradation. Unlike in animals, where antizymes mediate ODC degradation, functional analogs of antizymes have not yet been identified in plants, leaving the degradation pathway largely unexplored. Finally, we review the applications of plant genetic modification targeting ODC in enhancing the production of valuable secondary metabolites in medicinal plants and improving stress tolerance in crops, along with perspectives on future research directions. This review illustrates the diversity of ODC functions and the complexity of its regulatory mechanisms in plant growth, development, stress responses, and secondary metabolism. It also provides a theoretical foundation and insights for exploring ODC as a target for plant genetic modification, which is promising for improving the economic traits and stress resistance of horticultural plants. Full article

Two novel cocrystals of zwitterionic trimethylglycine (TMG) with 2,6-dichlorophenol [TMG•2,6-dichlorophenol] (1:1) and 2,6-dibromophenol [TMG•2,6-dibromophenol] (1:2) are synthesized and structurally characterized using single crystal X-ray diffraction. To estimate the energy of various intermolecular interactions, periodic DFT calculations were performed followed by Bader analysis of the crystalline electron density. TMG molecules form dimers in [TMG•2,6-dichlorophenol] (1:1). Its supramolecular structure is governed by the primary charge-assisted H-bonds (~60 kJ/mol) and supported by C–H∙∙∙O contacts (~12 kJ/mol). Cl/Br substitution introduces a more potent halogen-bonding donor. The Br∙∙∙O⁻ interaction (~10 kJ/mol) is strong enough to reorganize the packing into a catemeric motif. As a result, TMG molecules form infinite chains in [TMG•2,6-dibromophenol] (1:2). This illustrates that “fine tuning” is not merely about changing distances, but about shifting the entire energy hierarchy of the crystal. Two-dimensional fingerprint diagrams (2D diagrams) obtained from the Hirshfeld surface and Bader’s analysis of the crystalline electron density give significantly different values of the contributions of the H∙∙∙H contacts, 28% vs. 5% respectively. The main reason for this discrepancy is the large number of relatively short intermolecular H∙∙∙H contacts without a critical bond point in trimethylglycine cocrystals. Full article

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for more deaths than any other malignancy. Despite advances in treatment, it remains highly lethal, with 5-year survival rates showing minimal improvement over the past several decades, highlighting a critical unmet clinical need. Macrophage Migration Inhibitory Factor (MIF) is a multifunctional cytokine that contributes to inflammation and cancer, promoting tumor growth, progression, and metastasis through modulation of the tumor microenvironment, stimulation of angiogenesis, and regulation of immune responses. Polymorphisms in the promoter region of MIF, such as high-expression CATT repeats, influence MIF expression and susceptibility to a range of inflammatory, autoimmune, and malignant disorders, yet their role in lung cancer remains largely unexplored. Therapeutic strategies targeting MIF, including small-molecule inhibitors, antibodies, and peptide-based agents, have shown promise in preclinical models, although their clinical translation is still limited. This review discusses the dual role of MIF in inflammation and oncology, summarizes current therapeutic developments, and emphasizes the potential of MIF-targeted interventions in lung cancer. It discusses the significance of genetic predisposition, particularly high-expression MIF alleles, in guiding personalized treatment strategies for lung cancer and identifying patients who may derive benefit from MIF inhibition. Full article