Search Results (20,063)

Immune checkpoint inhibitors targeting the PD-1 (Programmed Cell Death Protein 1)/PD-L1 (Programmed Death-Ligand 1) axis have transformed cancer therapeutics, yet their efficacy in gynecologic malignancies particularly high-grade serous ovarian carcinoma remains disappointingly limited. This therapeutic resistance stems from a highly orchestrated, multidimensional immunosuppressive tumor microenvironment (TME) characterized by the convergent actions of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and an inhibitory cytokine network (IL-10, TGF-β, VEGF). Emerging evidence positions TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) as a master checkpoint integrator that coordinately regulates CD8+ T-cell exhaustion, NK-cell dysfunction, and Treg-mediated suppression. Dual blockade of PD-1 and TIGIT represents a mechanistically rational strategy to dismantle this immunosuppressive fortress. This review synthesizes current understanding of the gynecologic TME architecture, delineates the molecular and cellular basis for TIGIT/PD-1 synergy, critically evaluates ongoing clinical translation efforts, and proposes an integrative framework leveraging spatial transcriptomics, single-cell resolution immunoprofiling, and patient-derived experimental models to accelerate biomarker-driven therapeutic development. Full article

Triethylamine (TEA), a widely used volatile organic compound (VOC), poses severe threats to environmental safety and human health upon accidental leakage, making the development of high-performance TEA detection techniques urgently needed. Herein, we report a Sn-based metal–organic framework (Sn-MOF) constructed from 4,5-dichloroimidazole ligands synthesized via a solvothermal approach. The resulting MOF-derived SnO₂ materials were obtained by calcination at 400–600 °C, yielding SnO₂ with tunable specific surface area and surface defect-site density. Structural and surface characterizations revealed that the materials consist of primary nanoparticles in the range of 10–50 nm, forming aggregated particles of 1–2 µm. The gas sensing performance toward TEA was systematically evaluated. The SnO₂-400 °C sensor exhibited the highest response (S = 85.0) to 100 ppm TEA at 190 °C, with a low detection limit of 1 ppm, superior selectivity, good repeatability, and excellent long-term stability. The observed performance variation was attributed to the combined effects of specific surface area, abundant defect-associated surface sites, and suitable mesoporous structure. This work not only provides a high-performance TEA sensor for industrial and food safety monitoring but also offers a rational strategy for designing MOF-derived metal oxide gas sensors with tailored microstructures and surface defect chemistry. Full article

A pyranochromene-based ligand, 2-amino-4-(4-chlorophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (ACLPh-PC-3-CN), was employed as a chelating modifier for the electrochemical determination of Cd(II) in water samples. ACLPh-PC-3-CN was co-immobilized with Nafion on a glassy carbon electrode to form a stable ACLPh-PC-3-CN/Nafion film that combines ligand-based coordination with cation-exchange-assisted preconcentration of Cd²⁺ at the electrode surface. The Cd(II) response at the modified electrode was characterized by cyclic voltammetry and differential pulse anodic stripping voltammetry, and the data support a predominantly 1:1 Cd(II)–ligand interaction at the interface under the selected conditions. At an optimized pH of 6.0, the sensor provided a linear calibration range from 16.21 to 56.72 μM, with a detection limit of 0.60 μM and a quantification limit of 2.0 μM, and showed good precision (repeatability 2.3% RSD, reproducibility 3.1% RSD) and short-term stability (94% of the initial response after 14 days). The ACLPh-PC-3-CN/Nafion-modified electrode tolerated common inorganic ions and surfactant species (≤5% signal change) and was successfully applied to the determination of Cd(II) in tap water and Red Sea water, affording recoveries between 98.7% and 101%. While the current detection limit is higher than typical guideline values for Cd in drinking water, the proposed sensor compares favorably with several reported electrochemical Cd(II) sensors in terms of simplicity, precision, and matrix tolerance, and represents a useful platform for coordination-based electrochemical sensing of cadmium in environmental water samples. Full article

Diabetic neuropathy is typically diagnosed with distal sensory and nerve conduction abnormalities. These symptoms may reflect earlier disturbances of axonal maintenance. This review examines axonal transport and cytoskeletal failure as convergent cellular mechanisms of diabetic axonopathy. Long peripheral axons are particularly vulnerable to damage because their integrity depends on continuous communication between the neuronal soma and distal terminals. This process involves the continuous renewal of cytoskeletal and functional proteins and the involvement of organelles such as mitochondria. Diabetes in experimental models disrupts this system at several levels. It slows cargo transport. The supply of neurofilaments, tubulin and retrograde signaling is reduced, and regenerative growth after injury is weakened. Carbonyl stress and AGEs cause modifications of neural proteins, the extracellular matrix, vascular barriers, and the excitability of sensory neurons. RAGE ligands, including AGEs and the proteins HMGB1 and S100, link the diabetic tissue environment to redox and inflammatory signaling. This occurs in neural and glial compartments, as well as in vascular tissue and the immune system. RAGE interacts with DIAPH1 to activate GTPase signaling and remodel the cytoskeleton. The RAGE–DIAPH1 interaction provides a plausible route from diabetic ligand accumulation to cytoskeletal remodeling. These observations provide a mechanistic context for axonal transport, although not all represent direct measurements of cargo movement. Direct evidence for transport impairment comes mainly from experimental studies showing altered slow cytoskeletal transport, impaired retrograde signaling, and weakened regenerative responses. This work highlights the possibility of developing therapies that go beyond symptomatic relief. Verifying the effectiveness of interventions in protecting axonal transport and nerve fiber integrity in diabetic neuropathy may be therapeutically beneficial. Full article

Chronic low-grade inflammation is a hallmark of aging and a major driver of metabolic and degenerative diseases. While systemic immune dysfunction has been widely investigated, the contribution of barrier tissues to persistent inflammatory signaling remains incompletely defined. The oral mucosa represents a uniquely exposed barrier, continuously challenged by microbial, mechanical, and metabolic stressors and characterized by a specialized immune architecture. Here, we synthesize current evidence supporting the oral barrier as an active immunometabolic interface linking local immune activation to systemic inflammatory tone. Spatially organized epithelial, neutrophil, and antigen-presenting cell (APC) compartments coordinate immune responses tightly coupled to metabolic reprogramming, including hypoxia-inducible factor-1α (HIF-1α)-dependent glycolysis and mitochondrial reactive oxygen species (mtROS) production. In parallel, the oral microbiota provides ligands and metabolites such as lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), and succinate, which activate pattern-recognition receptors (PRRs), including toll-like receptors (TLRs) and the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, thereby sustaining nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-mediated inflammatory signaling. Barrier disruption and dysbiosis promote microbial translocation and persistent innate immune activation, while saliva and gingival crevicular fluid facilitate systemic dissemination of inflammatory mediators. Overall, sustained immunometabolic engagement at the oral barrier emerges as a key driver of chronic low-grade systemic inflammation and a potential therapeutic target in inflammaging. Full article

Background/Objectives: Microtubule-targeting agents represent a pillar of cancer chemotherapy; however, their clinical utility is constrained by significant toxicity, pharmacokinetic instability, and susceptibility to multidrug resistance transporters. This study aimed to explore the impact of replacing substituted phenyl rings with a naphthalene moiety in sulfonamide-based colchicine-site ligands, with the goal of identifying new antiproliferative candidates with improved profiles. Methods: We designed, synthesized, and evaluated a library of 35 naphthalene sulfonamides bearing varied aryl groups and sulfonamide nitrogen substituents. We assessed the antiproliferative activity against multiple cancer cell lines. Mechanistic studies, including fluorescence microscopy, cell cycle analysis, and cell death assays, were performed to evaluate the effect of these compounds on microtubule polymerization dynamics and cell fate. Molecular docking and in silico pharmacokinetic profiling were carried out to support the proposed binding mode at the colchicine site and to assess drug-likeness. Results: Exclusively, compounds bearing a trimethoxyphenyl group showed antiproliferative activity in the submicromolar range, thus identifying it as a structural requirement. The most potent compound (2) reached double-digit nanomolar IC₅₀ values (67–104 nM) across multiple cancer cell lines. Microscopy confirmed intracellular disruption of microtubule polymerization. Unlike colchicine, these compounds did not induce canonical mitotic arrest but instead triggered apoptotic cell death. In silico analyses supported binding at the colchicine site and revealed favorable predicted pharmacokinetic properties. Conclusions: The naphthalene sulfonamides described herein demonstrate potent antiproliferative activity through a distinct mechanism compared to colchicine, and their favorable in silico profiles position them as promising candidates for further development as antitumor agents. Full article

Pyrrolidinyl-substituted silacyclopentane (CH₂)₄Si(Pyr)₂ and α-amino isobutyric acid (H₂Aib) react with the release of one equivalent pyrrolidine (HPyr) and the formation of the pentacoordinate silicon bis-chelate (Aib)Si(CH₂)₄(HPyr), which features the di-anion of the amino acid as an (O,N)-chelator and one equivalent of pyrrolidine as an additional lone-pair donor. Crystallographic analyses of the chloroform solvate (Aib)Si(CH₂)₄(HPyr)·(CHCl₃), which undergoes a phase transition at 200 K, and a solvent-free modification (Aib)Si(CH₂)₄(HPyr), which features two crystallographically independent molecules of the complex, revealed that the N atom of the HPyr ligand, as well as the carboxylate of Aib, occupy the axial positions in the trigonal bipyramidal Si coordination sphere; the Si–C bonds of the silacyclopentane rest on equatorial sites. For the isolated molecule in a solvent environment, computational analyses revealed that the energy difference between this configuration and the related isomer with an equatorial HPyr and equatorial–axial positioning of the silacyclopentane motif is marginal. In DMSO solution, the adduct (Aib)Si(CH₂)₄(HPyr) decomposed, forming the hexacoordinate Si complex (HAib)₂Si(CH₂)₄ as one of the decomposition products. In a deliberate manner, this compound was accessible from the diethylamino-substituted silacyclopentane (CH₂)₄Si(NEt₂)₂ and H₂Aib with the liberation of diethylamine. (HAib)₂Si(CH₂)₄ features two mono-anions of the α-amino acid as (O,N)-chelators, their carboxylate O atoms are trans-disposed to silacyclopentane, and their NH₂ groups are mutually trans. Full article

The selective detection of small, highly hydrophilic metabolites differing only in stereochemistry represents a major challenge in biosensor development. Here, we present a computational investigation to elucidate the molecular basis of the experimentally observed selectivity of a protein-based electrochemical biosensor toward myo-inositol over D-chiro-inositol. Although the two stereoisomers differ only in the orientation of a single hydroxyl group, they induce distinct dynamic effects on the protein recognition element. Molecular docking revealed comparable binding regions and similar affinity scores, indicating that selectivity does not arise from differences in binding site or docking energy. To investigate dynamic contributions, all-atom molecular dynamics simulations were performed in triplicate (3 × 100 ns) using the AMBER99SB force field and explicit TIP3P water. Trajectory analyses showed that myo-inositol forms a more persistent hydrogen bond network, resulting in reduced residue-level flexibility, more stable ligand–protein interactions, and enhanced local structural stabilization. Overall, these findings support a dynamic model of stereoselective recognition in which ligand-induced modulation of protein conformational ensembles, rather than static affinity, governs biosensor performance. This work highlights the value of molecular dynamics simulations in the rational design of biosensors targeting structurally similar analytes. Full article

La-MOFs exhibit strong affinity toward anions such as F⁻ and phosphate. However, conventional La-MOFs show limited regeneration performance when used as CDI electrodes, posing a major challenge for practical applications. In this study, a high-performance sulfur and nitrogen co-doped La-BDC-140-derived carbon electrode (La-CNS₃) was fabricated via a coupled carbonization and doping strategy. The optimized La-CNS₃ electrode possessed abundant defects, a mesoporous structure, favorable hydrophilicity, and rapid charge-transfer capability, which collectively enhanced fluoride electrosorption. At 1.4 V, La-CNS₃ achieved a fluoride removal capacity of 31.86 mg·g⁻¹ for 10 mg·L⁻¹ F⁻ solution and up to 195 mg·g⁻¹ at an initial F⁻ concentration of 100 mg·L⁻¹. More importantly, partial fluoride desorption was realized solely under reverse voltage, and the electrode maintained favorable defluoridation performance over 50 adsorption–desorption cycles. In actual groundwater treatment, the effluent fluoride concentration decreased to below 1.0 mg·L⁻¹ after 120 min. XPS analysis and DFT calculations revealed that fluoride removal was mainly governed by La-F coordination, surface hydroxyl/water ligand exchange, and interfacial charge redistribution. The La₂O₂S/g-C₃N₄ structure provided a favorable balance between fluoride adsorption strength and desorption reversibility. This work offers a promising strategy for designing efficient, selective, and electrically regenerable rare-earth-based CDI electrodes for fluoride-contaminated water treatment. Full article

Identification of ligands targeting essential enzymes in Mycobacterium species remains an important strategy for anti-tuberculosis drug discovery. Here, a native mass spectrometry approach was employed using pooled 100-compound mixtures, enabling the direct detection of intact HPPK–ligand complexes in solution. Dual-mode MS acquisitions (low collision energy for complex detection and high collision energy for ligand confirmation), combined with an automated data analysis workflow, ensured robust identification of binding events from these complex samples. This strategy led to the identification of several HPPK-binding small molecules, all belonging to the dammarane triterpene glycoside (ginsenoside) class. Subsequent analysis of the hits revealed clear structure–affinity relationships, highlighting how specific aglycone modifications and glycosylation patterns influence binding to HPPK. Our findings expand the known chemical space of HPPK ligands and demonstrate the utility of native MS-based screening coupled with automated data analysis to uncover new ligand scaffolds for challenging enzyme targets. Full article

Melanoma treatment has been transformed by immune checkpoint blockade, yet many patients still experience primary resistance, limited durability of response, or acquired resistance. These limitations underscore the need for additional targets that reflect melanoma biology while enabling new therapeutic strategies, particularly in biologically defined settings of immune escape such as checkpoint-resistant, HLA-low, dedifferentiated, or stress-adapted melanoma. The B7-H6/NKp30 axis has gained attention as a link between tumor cell stress, immune recognition, and therapy-related adaptation. B7-H6 (NCR3LG1), an inducible ligand for NKp30, has been detected in melanoma cell lines and tumor specimens, and soluble B7-H6 has been identified in a subset of patients. Membrane-bound B7-H6 may support NK-cell activation, whereas ligand shedding and accumulation of soluble B7-H6 may reduce effective antitumor recognition and promote immune evasion. Emerging evidence further suggests that B7-H6 expression may be linked to tumor-intrinsic programs relevant to melanoma cell survival, migration, and adaptation to therapeutic stress. However, B7-H6 is not yet a validated predictive biomarker or an established therapeutic target in melanoma, and current evidence remains limited by small melanoma-specific datasets, incomplete information on spatial and temporal heterogeneity, and the absence of melanoma-focused clinical validation. In this review, we examine the role of the B7-H6/NKp30 axis in immune surveillance, tumor escape, biomarker development, and therapeutic targeting, and discuss its translational potential in melanoma as an emerging but incompletely validated pathway that warrants focused investigation in melanoma states where conventional immune control is limited. Full article

Imaging of infections has the potential to improve clinical outcomes, but pathogen-specific imaging strategies are currently unavailable. Given their target specificity, antimicrobials may be useful as molecular imaging ligands to target infections. Despite substantial development efforts, no antimicrobial-based ligands are approved for clinical use. This scoping review comprehensively surveys radiolabeled antimicrobials across antibacterial, antimycobacterial, antiviral, and antifungal drug classes, examining their progression through the translational pipeline. The review utilized PubMed and Google Scholar databases (1970–2025), following PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. Two reviewers independently screened titles, abstracts, and full-text articles; data were extracted, and content duplicates were removed. In total, 143 preclinical and 25 clinical articles met the selection criteria. In clinical studies, most tracers showed suboptimal specificity for infections, while some proved useful for pharmacokinetic characterization. Among preclinical studies, radiolabeled plazomicin and echinocandins (caspofungin and anidulafungin) exhibited the greatest number of preferred characteristics. In conclusion, ideal antimicrobial pharmacologic properties can be counterproductive for imaging, where rapid background clearance and a high target-to-non-target ratio (T/NT) are essential. Many radioligands demonstrate good tissue penetration but suboptimal washout, limiting their diagnostic value. In vivo pharmacokinetic applications during active infections are promising, though significant challenges remain for infection imaging. Full article

Background: GDF15 (growth/differentiation factor-15) is part of the transforming growth factor-beta family and represents a cellular stress-induced gene. It might have a role in metaflammation and adipoflammation. We aimed to investigate the effects of Toll-like receptor (TLR) activation and hypoxia-related pathways together with metabolic factors on GDF15 regulation in adipocytes and adipose tissue (AT). Methods: GDF15 mRNA quantities in the human adipocyte cell line SGBS, in visceral (VAT) and subcutaneous adipose tissue (SAT) (resected from n = 96 obese and characterized patients), and in murine 3T3-L1 adipocytes were measured by real-time RT-PCR. GDF15 protein concentrations in cell supernatants and serum were quantified by ELISA. The following stimuli/pathways were investigated: insulin, glucose, TLR ligands (TLR2/6, TLR3, TLR4, TLR7, TLR9), bile acids, synthetic FXR/TGR5 activators, and HIF1α activators. Results: Basal GDF15 expression is low and only marginally induced in SGBS cells. In contrast, GDF15 is expressed in human SAT and VAT and correlates positively with the corresponding GDF15 protein concentration in peripheral blood serum of obese patients. Among metabolic factors, insulin and bile acids such as ursodeoxycholic acid upregulate GDF15 expression in 3T3-L1 adipocytes, the latter via FXR but not via TGR5. Among innate immune regulators, only TLR7 activation and hypoxic mediators upregulate whereas STAT3 signaling downregulates GDF15. Conclusion: GDF15 expression in human SAT and VAT is correlated to peripheral blood GDF15 concentrations and is regulated by metabolic and innate immune response pathways involved in AT inflammation and metaflammation. Full article

This study aimed to compare the chemical composition and antimicrobial activity of essential oils obtained from the rhizomes and leaves of Conamomum pierreanum (Zingiberaceae), and to evaluate interactions of selected constituents with microbial targets using molecular docking and molecular dynamics simulations. Gas chromatography–mass spectrometry (GC-MS) identified 21 compounds in the rhizome essential oil (EO) and 10 in the leaf EO of C. pierreanum, with 1,8-cineole (54.44% and 75.73%, respectively) as the predominant constituent. Notably, the rhizome EO was uniquely characterized by epi-γ-eudesmol (3.47%) and isobornyl acetate (3.39%), which were absent in the leaf oil. In vitro assays revealed that the rhizome EO possessed stronger antibacterial and antifungal activities (MIC = MBC = MFC = 0.4%) compared to the leaf EO (0.8%) against Staphylococcus aureus and Candida albicans. Molecular docking identified epi-γ-eudesmol as the most potential ligand, exhibiting remarkably high binding affinities for S. aureus DHFR (−8.1 kcal/mol) and C. albicans CYP51 (−8.5 kcal/mol), significantly outperforming the major constituents. A total of 100 ns molecular dynamics simulations and MM-PBSA analysis further confirmed the structural stability and energetically favorable binding of these complexes, with epi-γ-eudesmol maintaining a low average RMSD (<1.2 Å) throughout the simulation. The enhanced efficacy of the rhizome oil is attributed to the synergistic contribution of these high-affinity minor constituents. These findings suggest that C. pierreanum rhizome EO may serve as a potential source of bioactive compounds for antimicrobial applications, warranting further investigation. Full article

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of ALL characterized by unfavorable clinical outcomes. Despite significant progress in deciphering the genetic and epigenetic landscapes of T-ALL, the underlying molecular mechanisms, particularly in non-early T-cell precursor (non-ETP) T-ALL, remain incompletely understood. In this study, functional assays were performed using three well-characterized non-ETP T-ALL cell lines. In vivo therapeutic efficacy was evaluated using non-ETP T-ALL xenograft models. Transcriptomic profiling was performed by RNA sequencing (RNA-seq) followed by bioinformatic analysis. Publicly available clinical datasets from T-ALL patients were mined to analyze survival outcomes. We found that activation of CD40 ligand (CD40LG) or CD28 accelerates cell-cycle progression and enhances the migratory capacity of non-ETP T-ALL cells, with CD40LG uniquely upregulating CXCR4 to mediate bone marrow tropism. Further RNA-seq and functional validation identified Rho GTPase signaling, specifically RhoA/Rac1/Rac2, as a pivotal downstream effector of CD40LG/CD28, leading to therapeutic resistance to PI3K inhibition. Pharmacological blocking RhoA or Rac1 using small-molecule compounds not only induces remarkable cytotoxicity but also sensitizes resistant cells to PI3K inhibitors, both in vitro and in vivo. Clinically, elevated expression of CD40LG, CD28, RHOA, or RAC2 correlates with poor prognosis in non-ETP T-ALL patients. These findings uncover a novel CD40LG/CD28-Rho GTPase axis as a key driver of pathogenesis and a potential therapeutic vulnerability in non-ETP T-ALL, providing a new target for precision intervention and a promising strategy to overcome therapeutic resistance. Full article