Search Results (3,454)

Background: Gold (Au) complexes have emerged as promising anticancer candidates due to their distinct coordination chemistry and ability to modulate thiol-dependent and redox-regulated cellular pathways, particularly thioredoxin reductase (TrxR). In recent years, structurally diverse Au(I) and Au(III) complexes have been reported with potent in vitro anticancer activity; however, cross-study comparability and design principles remain unclear. Aim: This systematic review critically evaluates anticancer Au(I/III) complexes reported since 2016, with the specific aim of identifying how oxidation state, coordination geometry, and ligand class influence in vitro potency, selectivity, and translational potential. Methods: A PRISMA-guided literature search was performed in Scopus, Web of Science, PubMed, and ScienceDirect for studies published between January 2016 and March 2025. Two independent reviewers screened titles/abstracts and full texts according to predefined inclusion criteria. Only original studies reporting anticancer activity of structurally characterized Au(I/III) complexes in human cancer models were included. After the removal of duplicates, 1100 records were screened at the title and abstract level. Of these, 240 articles were assessed in full text for eligibility. Ultimately, 128 studies reporting anticancer activity of structurally characterized Au(I/III) complexes met the inclusion criteria and were included in the qualitative synthesis. Biological potency data were harmonized to μM units where applicable, and results were synthesized qualitatively due to heterogeneity in experimental design. Results: A total of 128 studies met the inclusion criteria. Au(I) complexes—particularly phosphine- and N-heterocyclic carbene (NHC)-based compounds—consistently showed sub-micromolar cytotoxicity in TrxR-dependent cancer cell lines, whereas Au(III) complexes displayed greater structural diversity but variable stability and redox behavior. In vivo efficacy was reported for a limited subset of compounds and was frequently constrained by solubility, systemic toxicity, or metabolic instability. Conclusions: The available evidence indicates that anticancer activity of gold complexes is strongly dependent on oxidation state, ligand environment, and redox stability. While Au(I) scaffolds show more reproducible in vitro potency, successful translation to in vivo models remains limited. This review defines structure–activity and structure–liability relationships that can guide the rational design of next-generation gold-based anticancer agents. Full article

Lanthanide coordination polymers have been developed at a fast rate during the past two decades due to their appealing applications in the modern field of materials science and emerging technologies like luminescence, magnetism, sensing, gas adsorption, and catalysis. The role of lanthanides in imparting specific properties to the coordination polymers has been fully documented in extensive studies carried out by numerous research groups. It has been shown that because lanthanide(III) ions possess a variable coordination number, they readily build two-dimensional and three-dimensional architectures with definite channels, permanent pores, and distinct surface areas. Due to their strong oxophilic propensity and hard Lewis acid character, lanthanides favor the construction of stable coordination polymers and MOF configurations by strongly binding the coordinating groups of the organic linkers. Associated with palladium complexes, the lanthanide ions provide synergistic effects with Lewis acid sites, beneficial to the catalytic activity. These attractive characteristics of lanthanides enabled them to be fruitfully applied in Pd-Ln coordination polymers with catalytic properties. This review covers an array of Pd-Ln coordination polymers applied as heterogeneous catalysts in Suzuki–Miyaura C(sp²)-C(sp²) cross-coupling reactions. The activity and chemoselectivity of Pd(II) ions and Pd nanoparticles associated in coordination polymers with different lanthanides from a selected array of rare earth elements (Eu, Sm, Eu, Gd, Pr, Nd, Ce, La, or Tb) is discussed. High yields (>99%) are attained under optimized reaction conditions. The specific role of lanthanides and organic ligands in creating sustainable and recyclable heterogeneous Pd catalysts is evidenced. Mechanistic aspects of the C(sp²)-C(sp²) cross-coupling reactions are considered. The synergistic interaction between lanthanides and palladium as well as with the organic ligands is highlighted. Full article

Perioperative pain remains a major clinical challenge, with many surgical patients experiencing inadequate analgesia and progression to chronic postsurgical pain. Conventional opioid-centered strategies are limited by narrow therapeutic windows, systemic toxicity, tolerance, opioid-induced hyperalgesia, and poor efficacy in neuroimmune-driven pain states. Advances in molecular neuroscience and biomedical engineering have catalyzed the development of nonpharmacologic analgesic technologies that modulate pain pathways through biophysical rather than receptor–ligand mechanisms. This narrative review synthesizes emerging nonpharmacologic analgesic platforms relevant to anesthesiology, integrating molecular, cellular, and systems-level mechanisms with clinical evidence. It examines how peripheral sensitization, spinal dorsal horn plasticity, glial and neuroimmune activation, and supraspinal network dysfunction create ideal targets for device-based interventions. Electrical neuromodulation strategies, including peripheral and central techniques, are discussed alongside temperature-based, photonic, and focused-energy modalities. These include cryoneurolysis, radiofrequency techniques, photobiomodulation, and low-intensity focused ultrasound. Clinical integration within enhanced recovery pathways, patient selection, workflow considerations, and limitations of the current human evidence base are reviewed. While many of these technologies are established in chronic pain management, this review emphasizes available human perioperative data and discusses how chronic pain evidence informs perioperative translation within opioid-sparing multimodal anesthesia care. Collectively, these technologies support a mechanism-based, systems-level approach to pain modulation, with perioperative relevance varying by modality and strength of available human evidence. Full article

The balance of alveolar macrophage (AM) polarization is severely disrupted in chronic inflammatory diseases like bronchiectasis, where a persistent pro-inflammatory (M1) phenotype perpetuates inflammation. To address this, we developed a high-throughput platform using a series of synthetic glycoligands (L1-L5) on a polyethyleneimine (PEI) scaffold. These ligands, which have varying affinities for macrophage lectin-like receptors, were used for phenotypic “fingerprinting” of AM subpopulations from pediatric bronchiectasis patients and a healthy control. Analysis of bronchoalveolar lavage fluid (BALF) revealed a pathogenic, M1-dominant profile (55% M1) in patients, confirming a state of chronic inflammation, which starkly contrasted with the quiescent, M0-dominant profile in the healthy control. We then leveraged this platform for targeted immunomodulation, using a drug-ligand conjugate to steer the dysregulated macrophage population toward a healthy state. The most potent conjugate, Dox-L5, dramatically suppressed the pathogenic M1 population (from 55% to 16%). This M1 suppression was accompanied by a significant shift toward the M2a (tissue-repair) phenotype and the emergence of a quiescent M0-like population, effectively remodeling the AM profile. This work validates a glycan-based platform for both diagnosing and correcting pathological macrophage imbalances. Our targeted approach offers a precise strategy to resolve chronic inflammation in bronchiectasis by suppressing M1 macrophages and promoting a pro-resolving M0/M2 phenotype, thereby restoring lung homeostasis. Full article

The clinical durability of SARS-CoV-2 main protease (M^pro) inhibitors depends on their resilience to emerging resistance mutations. Recent genomic surveillance and functional reports have highlighted substitutions at positions 49, 165, and 301, raising questions about the robustness of the noncovalent inhibitor WU-04 in variant backgrounds. Here, we combined μs-scale, triplicate molecular dynamics simulations with end-state binding free energy estimates and a network-rewiring inference (NRI) framework that maps long-range dynamical communication across the full protease dimer. We evaluated wild type (WT), single mutants M49K, M165V, S301P, and selected double mutants (M49K & M165V, M49K & S301P). Relative to WT, single substitutions produced reductions in computed binding affinity of up to ~12kcal/mol, accompanied by loss or reshaping of the S2 subsite and altered ligand burial. Notably, the M49K/S301P double mutant partially restored WU-04 engagement, narrowing the ΔΔG_restore gap to within ΔΔG_restore of WT and re-establishing key hydrophobic and hydrogen-bond contacts. NRI analysis revealed that distal residue 301 participates in a communication corridor linking the C-terminal helical domain to the active-site cleft; its substitution rewires inter-domain coupling that can compensate for local disruptions at residue 49. Together, these results identify structural hotspots and network pathways that may inform the design of next-generation M^pro inhibitors with improved mutation tolerance—specifically by strengthening interactions that do not rely solely on the mutable S2 pocket and by engaging conserved backbone features near the 165–166 region. Full article

Glioblastoma (GB) is one of the most aggressive and invasive cancers. Current treatment protocols for GB include surgical resection, radiotherapy, and chemotherapy with temozolomide. However, despite these treatments, physicians still struggle to effectively image, diagnose, and treat GB. As such, patients frequently experience recurrence of GB, demanding innovative strategies for early detection and effective therapy. Bioconjugated quantum dots (QDs) have emerged as powerful nanoplatforms for precision imaging and targeted drug delivery due to their unique optical properties, tunable size, and surface versatility. Due to their extremely small size, QDs can cross the blood–brain barrier and be used for precision imaging of GB. This review explores the integration of QDs with click chemistry for robust bioconjugation, focusing on artificial intelligence (AI) to advance GB therapy, mechanistic insights into cellular uptake and signaling, and strategies for mitigating toxicity. Click chemistry enables site-specific and stable conjugation of targeting ligands, peptides, and therapeutic agents to QDs, enhancing selectivity and functionalization. Algorithms driven by AI may facilitate predictive modeling, image reconstruction, and personalized treatment planning, optimizing QD design and therapeutic outcomes. We discuss molecular mechanisms underlying interactions of QDs with GB, including receptor-mediated endocytosis and intracellular trafficking, which influence biodistribution and therapeutic efficacy. Use of QDs in photodynamic therapy, which uses reactive oxygen species to induce apoptotic cell death in GB cells, is an innovative therapy that is covered in this review. Finally, this review addresses concerns associated with the toxicity of metal-based QDs and highlights how QDs can be coupled with AI to develop new methods for precision imaging for detecting and treating GB for induction of apoptosis. By converging nanotechnology and computational intelligence, bioconjugated QDs represent a transformative platform for paving a safer path to smarter and more effective clinical interventions of GB. Full article

Melanoma is an aggressive skin cancer that continues to present major therapeutic difficulties. Although targeted drugs and immune checkpoint inhibitors have improved outcomes, resistance and treatment-related toxicity limit long-term benefit. In recent years, nanotechnology has been explored as a way to improve how drugs are delivered and to achieve greater tumor selectivity. Among available nanocarriers, liposomes have attracted particular interest. Built from lipid bilayers, they can carry both hydrophilic and hydrophobic molecules, and they are generally well tolerated. Importantly, their surface can be modified with polymers or targeting ligands to direct the carrier more selectively to melanoma cells. Experimental models show that liposomal drug formulations can increase concentrations in tumor tissue while limiting distribution to healthy organs. They have also been used successfully to combine different types of agents, chemotherapies, immunomodulators, and nucleic acids, within a single delivery system. These findings suggest genuine potential to address several of the shortcomings of conventional treatments. Although translation to the clinic is slowed by challenges such as formulation stability and large-scale production, liposomes represent an important step toward safer and more effective melanoma therapy within the broader field of oncologic nanotechnology. Full article

Resistance to imatinib remains a therapeutic challenge, largely driven by point mutations within the kinase domain of the BCR-ABL, among which the T315I substitution constitutes the most clinically significant barrier. Ponatinib effectively inhibits this mutant form but is limited by dose-dependent cardiovascular toxicity, prompting efforts to develop safer and more selective agents. Recent advances highlight aminopyrimidine-derived scaffolds and their evolution into thienopyrimidines, oxadiazoles, and pyrazines with improved activity against BCR-ABL^T315I. Further progress has been achieved with benzothiazole–picolinamide hybrids incorporating a urea-based pharmacophore, which benefit from strategic hinge-region substitutions and phenyl linkers that enhance potency. Parallel research into dual-mechanism inhibitors, including Aurora and p38 kinase modulators, demonstrates additional opportunities for overcoming resistance. Combination strategies, such as vorinostat with ponatinib, provide complementary therapeutic avenues. Natural-product-inspired approaches utilizing fungal metabolites provided structurally diverse scaffolds that could engage sterically constrained mutant kinases. Hybrid molecules derived from approved TKIs, including GNF-7, olverembatinib, and HG-7-85-01, exemplify rational design trends that balance efficacy with improved safety. Molecular modeling continues to deepen understanding of ligand engagement within the T315I-mutated active site, supporting the development of next-generation inhibitors. In this review, we summarized recent progress in the design, optimization, and biological evaluation of small molecules targeting the BCR-ABL^T315I mutation. Full article

Structural insights into methyl-coenzyme M reductase from Methanobrevibacter ruminantium (M. ruminantium) has implications for methane mitigation strategies. Methanogenesis in ruminants is a major contributor to global greenhouse gas emissions, primarily driven by the rumen archaeon M. ruminantium. Central to this process is methyl-coenzyme M reductase (Mcr), an enzyme that catalyzes the final step of methane production. Despite its significance as a chemogenetic target for methane mitigation, the high-resolution structure of M. ruminantium Mcr has remained elusive. Here, we employed homology modeling and CDOCKER simulations within the CHARMM force field to elucidate the structural and functional features of the M. ruminantium Mcr/ligand complexes. We characterized two distinct states: the reduced Mcr_oxi-silent state bound to HS-CoM and CoB-SH, and the oxidized Mcr_silent state bound to the heterodisulfide CoM-S-S-CoB. Alanine-scanning mutagenesis identified 71 and 62 key residues per active site for each state, respectively, revealing the fundamental determinants of structural stability and substrate selectivity on the Ni-F₄₃₀ cofactor. Furthermore, structure-based pharmacophore modeling defined essential features (AAADDNNN and AAADDNN) that drive ligand binding. These findings provide a high-resolution molecular framework for the rational design of specific Mcr inhibitors, offering a robust starting point for developing broad-spectrum strategies to suppress enteric methane emissions. Full article

Density functional theory (DFT) calculations elucidate the mechanism of diastereoselective cyclization of 2-picoline with 1,5-hexadiene catalyzed by a cationic half-sandwich scandium complex. The catalytic cycle proceeds through four key stages: formation of active species, initial alkene insertion, cis-selective cyclization, and protonation. Central to the mechanism is the dual role of 2-picoline, which initially coordinates as a supporting ligand to facilitate C–H activation and regioselective 1,2-insertion but must dissociate to enable stereocontrol. The mono(2-picoline)-coordinated complex C3 is identified as the thermodynamically favored active species. C–H activation reactivity follows the trend: ortho-C(sp²)–H (2-picoline-free) > ortho-C(sp²)–H (2-picoline-coordinated) > benzylic C(sp³)–H (2-picoline-free) > benzylic C(sp³)–H (2-picoline-coordinated), a preference governed by a wider C_α–Sc–C_α′ angle and shorter Sc···X (X = C_α, C_α′, H) distances that enhance scandium–substrate interaction. Subsequent 1,5-hexadiene insertion proceeds with high 1,2-regioselectivity through a picoline-assisted pathway. The stereoselectivity-determining step reveals a mechanistic dichotomy: while picoline coordination is essential for initial activation, its dissociation is required for intramolecular cyclization. This ligand displacement avoids prohibitive steric repulsion in the transition state, directing the reaction exclusively toward the cis-cyclized product. The cycle concludes with a sterically accessible mono-coordinated protonation. This work establishes a “ligand-enabled then ligand-displaced” mechanism, highlighting dynamic substrate coordination as a critical design principle for achieving high selectivity in rare-earth-catalyzed C–H functionalization. Full article

The increasing demand for rapid identification of bacteria capable of degrading environmentally relevant organic compounds highlights the need for scalable and selective analytical tools. Cupriavidus necator catabolizes several hydroxybenzoic acids, including 2-hydroxybenzoate (salicylate, 2-HBA), 4-hydroxybenzoate (4-HBA), and 3-hydroxybenzoate (3-HBA), funneling them into central aromatic catabolism via monooxygenation to 2,5-dihydroxybenzoate (gentisate, 2,5-dHBA) and 3,4-dihydroxybenzoate (protocatechuate, 3,4-dHBA) followed by the oxidative cleavage reaction, enabling complete conversion to tricarboxylic acid (TCA) cycle intermediates. To quantify how readily C. necator is able to activate catabolic genes in response to hydroxybenzoic acid, an extracellular ligand, we applied an approach centered on a transcription-factor (TF)-based biosensor that combines ligand-bound regulator activity with a fluorescent reporter. This approach allowed to evaluate the ligand sensitivity by determining gene activation threshold AC_min and half-maximal effective concentration EC₅₀. Amongst studied hydroxybenzoic acids, 2-HBA and 4-HBA sensors from C. necator showed very low thresholds 4.8 and 2.4 μM and EC₅₀ values of 19.91 and 13.06 μM, indicating high sensitivity to these compounds and implicating a scavenging characteristic of associated catabolism. This study shows that the TF-based-biosensor approach applied for mapping functional sensing ranges of hydroxybenzoates combined with the research and informatics of catabolism can advance our understanding of how gene expression regulation systems have evolved to respond differentially to the availability and concentration of carbon sources. Furthermore, it can inform metabolic engineering strategies in the prevention of premature pathway activation or in predicting competitive substrate hierarchies in complex mixed environments. Full article

Two series of tri(2-furyl)- and triphenylphosphine-gold(I) complexes, with pyridyl- and pyrimidine-thiolate ligands containing electron-donating (-CH₃) and electron-withdrawing (-CF₃) substituents were synthesized and investigated for cell viability inhibitions. Prior results indicate that several of the gold(I) complexes in these series have high antifungal properties. The observed link between antifungal and anticancer activity provided motivation to investigate their antiproliferative effects, reported here. The synthesized compounds from both series were characterized by ¹H, ¹³C, and ³¹P NMR spectroscopy, mass spectrometry (MS), infrared and UV-Vis spectroscopy, and solution stability studies. In addition, an X-ray crystallographic study was conducted on one of the gold(I) complexes. Analyte solubilities in McCoy’s 5A cell media were evaluated by ICP-MS. Initial screening studies were conducted on the two series to evaluate cell viability using the SK-BR-3 cell line. All ten gold(I) complexes exhibited sub-µM cytotoxicity and the most potent representatives, one from each series, were selected for further evaluation in four additional cell lines. Half-maximal effective concentrations (EC₅₀) were determined for the MCF7 and MDA-MB-231 malignant mammary cell lines as well as the two control cell lines, HEK293T and MCF10A, to probe for specificity. Results indicate significant selectivity towards inhibition of cancer cells compared to non-transformed for tri(2-furyl)- and triphenylphosphine-gold(I) complexes with the 3,5-dimethylpyrimidine thiolate ligand when dissolved in cell media. Additional studies including 1% DMSO as a solubilizing agent revealed its significant impact on cellular responses. Full article

Near-infrared photoimmunotherapy (NIR-PIT) has recently attracted attention as a highly selective cancer treatment, with good treatment outcomes observed from the only antibody-based drug currently available for clinical use. However, since only a single agent is currently used clinically and the development of new antibodies is costly, exploring other therapeutic modalities is important. In this study, we investigated a novel peptide-based PIT drug targeting programmed death-ligand 1 (PD-L1), which is overexpressed in many types of cancer. The WL12 peptide, which is known to bind to PD-L1, was conjugated with the photoabsorber IRDye700DX (IR700), and its usefulness was evaluated in vitro and in vivo. In therapeutic experiments on PD-L1-positive cells, NIR-PIT with WL12-IR700 induced PIT-like morphological changes in cells and reduced cancer cell viability in an NIR light dose- and drug concentration-dependent manner. In vivo experiments showed significant suppression of tumor growth and an extended overall survival rate. These results indicate that the developed peptide-based drug can be used for PD-L1-targeted NIR-PIT. Full article

Analysis of pulmonary vascular dysfunction in various lung pathologies remains challenging due to the lack of functional ex vivo models. Paracrine signaling in the lung plays a critical role in regulating endothelial maturation and vascular homeostasis. Previously, we employed single-cell RNA-sequencing (scRNAseq) to systematically map ligand–receptor (L/R) interactions within the lung vascular niche. However, the functional impact of these ligands on endothelial biology remained unknown. Here, we systematically evaluated selected ligands in vitro to assess their effects on endothelial barrier integrity, anti-inflammatory responses, and phenotypic maturation. Among the top soluble ligands, we found that adrenomedulin (ADM) exhibited superior barrier enhancing effect on human pulmonary endothelial cell monolayers, as evidenced by electrical cell impedance sensing (ECIS) and XperT assays. ADM also exhibited anti-inflammatory properties, decreasing ICAM1 and increasing IkBa expression in a dose-dependent manner. Perfusion is commonly used in bioengineered vascular model systems. Shear stress (15 dynes/cm²) alone increased endothelial characteristics, including homeostatic markers such as CDH5, NOS3, TEK, and S1PR1. ADM treatment maintained the enhanced level of these markers under shear stress and further improved anti-coagulation by increasing THBD and decreasing F3 expression and synergistically enhanced the expression of the native lung aerocyte capillary endothelial marker EDNRB. This effect was completely attenuated by a blockade of ADM receptor, RAMP2. Together, these findings identify ADM/RAMP2 signaling as a key paracrine pathway that enhances vascular barrier integrity, anti-inflammatory phenotype, and endothelial homeostasis, providing a framework for improving the physiological relevance of engineered vascular models. Full article

Background/Objectives: This review integrates evolutionary, metabolic, genetic, and nutritional perspectives to explain how sterol-derived vitamin D pathways shape human physiology and inter-individual variability in vitamin D status. Methods: The literature on sterol and vitamin D metabolism across animals, plants, fungi, and algae was synthesized with data from metabolomics databases, genome-wide association studies, RNA-seq resources (including GTEx), structural biology, and functional genomics. Results: Vitamin D₂ and vitamin D₃ likely emerged early in evolution as non-enzymatic photochemical sterol derivatives and were later co-opted into a tightly regulated endocrine system in vertebrates. In humans, cytochrome P450 enzymes coordinate vitamin D activation and degradation and intersect with oxysterol production, thereby linking vitamin D signaling to cholesterol and bile acid metabolism. Tissue-specific gene expression and regulatory genetic variants, particularly in the genes DHCR7, CYP2R1, CYP27B1, and CYP27A1, contribute to population-level differences in vitamin D status and metabolic outcomes. Structural analyses reveal selective, high-affinity binding of 1,25-dihydroxyvitamin D₃ to VDR, contrasted with broader, lower-affinity ligand recognition by LXRs. Dietary patterns modulate nuclear receptor signaling through distinct yet convergent ligand sources, including cholesterol-derived oxysterols, oxidized phytosterols, and vitamin D₂ versus vitamin D₃. Conclusions: Sterol and vitamin D metabolism constitute an evolutionarily conserved, adaptable network shaped by UV exposure, enzymatic control, genetic variation, and diet. This framework explains inter-individual variability in vitamin D biology and illustrates how evolutionary and dietary modulation of sterol-derived ligands confers functional flexibility to nuclear receptor signaling in human health. Full article