Search Results (242)

Background: Eosinophilic chronic rhinosinusitis (ECRS) is characterized by refractory nasal polyps and severely impaired mucociliary clearance (MCC). The molecular mechanisms underlying the modulation of mucociliogenesis following IL-4/13 blockade with dupilumab remain poorly understood, notwithstanding its proven clinical efficacy. Methods: Bulk RNA Barcoding and sequencing (BRB-seq) was performed on nasal polyp tissues collected from healthy controls (n = 6), patients with non-ECRS (n = 8), and patients with ECRS both before and four weeks after dupilumab treatment (n = 9) to identify the early molecular drivers underlying ciliary regeneration. Comprehensive gene-set scoring systems were developed to evaluate multiciliogenesis master regulators, master regulators of core/ciliary planar cell polarity (PCP) and PCP components. Interaction scores for epithelial-derived cytokines—thymic stromal lymphopoietin (TSLP), IL-25, and IL-33—were calculated based on ligand and cognate receptor subunit expression. Results: The ciliary master regulatory hierarchy (e.g., FOXJ1, RFX2/3), PCP components (CELSR1 and the ciliogenesis and planar polarity effector (CPLANE) module: FUZ, INTU, WDPCP), and structural ciliogenesis pathways were robustly restored following IL-4/13 blockade. The TSLP interaction score correlated with global mucosal damage, serving as a trigger for compensatory multiciliogenesis. The pre-treatment IL-33 interaction score emerged as a significant predictor of transcriptomic ciliary recovery (p < 0.05). DNASE1L3—the primary endonuclease for degrading eosinophilic extracellular traps (EETs)—remained persistently downregulated post-treatment. Conclusions: IL-4/13 blockade successfully restores the structural and directional “hardware” of the respiratory epithelium but fails to rectify the enzymatic “software” required for mucus degradation. This “residual molecular scar” may explain the persistent mucus hyperviscosity observed in some ECRS patients even after clinical polyp resolution. Full article

Thalassemia is an inherited hemoglobin disorder characterized by chronic hemolytic anemia and substantial long-term healthcare needs. In β-thalassemia major, patients typically require regular red blood cell transfusions with iron chelation to prevent transfusional iron overload. Although supportive care has markedly improved survival, it is associated with a high treatment burden and does not provide a cure. In recent years, curative and disease-modifying therapies have expanded the treatment landscape. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potentially curative option for selected patients, while autologous gene therapy and gene-editing approaches have shown the capacity to achieve transfusion independence in clinical studies. In parallel, pharmacologic advances—including luspatercept, a transforming growth factor-beta (TGF-β) ligand trap—have been shown to enhance erythropoiesis and reduce transfusion requirements, and emerging agents such as fetal hemoglobin inducers (e.g., thalidomide) and the oral pyruvate kinase activator mitapivat have demonstrated clinically meaningful hemoglobin improvements in selected populations. Adjunctive strategies, including antioxidants, are under investigation to mitigate oxidative stress, and applications of artificial intelligence are increasingly used to support screening, diagnosis, and longitudinal monitoring of iron overload. This review synthesizes recent advances in curative therapies, novel pharmacologic agents, supportive strategies, and AI-enabled tools and highlights priorities for future clinical development and implementation. Full article

Osteoclast hyperactivity represents a central mechanism in pathological bone destruction, underscoring the importance of discovering novel anti-resorptive compounds. In this study, we present early-stage evidence that 8-Epixanthatin can inhibit osteoclast differentiation induced by receptor activator of nuclear factor kappa-B ligand (RANKL). 8-Epixanthatin exhibited no significant cytotoxicity at the concentrations used for osteoclast differentiation studies. The compound showed concentration-dependent reductions in TRAP-positive multinucleated osteoclasts, with an IC₅₀ value of 2.3 μM. Our mechanistic investigations revealed that 8-Epixanthatin interferes with RANKL-activated signaling networks, particularly nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) cascades. Collectively, these observations identify 8-Epixanthatin as a promising lead structure for anti-osteoclast drug discovery. Full article

Alzheimer’s disease (AD) remains an incurable neurodegenerative disorder. The concept of theranostics—combining diagnostic and therapeutic functions within a single nanoplatform—has been explored for over a decade. Despite a growing number of publications, no theranostic system has yet reached clinical application for AD. This critical review analyzes the fundamental conceptual contradictions that hinder the clinical translation of theranostic nanoplatforms for AD and identifies alternative strategies where nanotechnology may still be beneficial. The review presents key aspects essential for understanding theranostics challenges: AD molecular targets, analysis of existing nanoplatforms, identification of three inherent conceptual conflicts, and viable alternative approaches. Our analysis reveals three core conceptual conflicts: the pharmacokinetic conflict, where diagnostics demand rapid accumulation and clearance while therapy requires prolonged retention—exacerbated by minimal brain delivery (1–2% ID/g) and peripheral toxicity risks; the dose conflict, characterized by orders-of-magnitude disparities between diagnostic and therapeutic dosing, rarely quantified for identical particles; and the temporal conflict, pitting one-time diagnostics against chronic therapy needs, as long-persisting particles generate irremovable brain background signals. We further identify a pervasive methodological trap: predominant focus on mature β-amyloid (Aβ) fibrils overlooks soluble oligomers as the primary toxic species. We conclude by proposing viable alternatives: preclinical intervention for time-limited “hit-and-clear” applications; coordinated theranostic monitoring with separate diagnostics/therapy; theranostic pairs using ligand-matched, function-optimized particles; and external stimuli for temporal function separation. A practical roadmap guides the transition from conceptual demonstrations to clinical translation. Addressing these contradictions can transform theranostics from elegant chemical constructs into clinically meaningful AD tools. Full article

PbS quantum dots (QDs) synthesized with oleic acid (OA) ligands suffer from poor charge transport in solid films, necessitating ligand exchange to shorter halide ligands for optoelectronic applications. This study investigates how ligand-exchange temperature governs OA-to-iodide substitution in PbS QDs. At 40 °C, the QD surface shows maximized halide passivation (I/Pb = 0.60) and minimized oxygen-related species (O/Pb = 0.23), suggesting reduced oxygen-associated defect formation and enabling n-type band alignment and reduced trap-mediated losses. PbS QD photodetectors fabricated from the 40 °C-treated QDs have 52% external quantum efficiency (EQE) at 940 nm (vs. 39% at 25 °C), with a responsivity of 0.394 A/W and an estimated detectivity of 2.1 × 10¹³ Jones. Temperature optimization of ligand-exchange provides a straightforward lever to improve device performance and reproducibility. Full article

The ability to assess molecular binding kinetics in real time is critical for advancing our understanding of molecular interactions in biochemical and biotechnological systems. This work presents a novel optical tweezer (OT)-based method to monitor molecular affinity in real time, focusing on the high-affinity streptavidin–biotin system as a model. Transparent poly(methyl methacrylate) (PMMA) microparticles functionalized with streptavidin were trapped before, during, and after binding with biotinylated bovine serum albumin (biotin–BSA), enabling the analysis of forward-scattered signals to detect nanoscale changes in particle size. By applying the Power Spectral Density method, the friction coefficient of individual particles was calculated, allowing for real-time tracking of binding dynamics and the estimation of the association rate constant ($k_{\mathrm{on}}\approx {10}^6{\mathrm{M}}^{-1}{\mathrm{s}}^{-1}$). These results are consistent with literature values and demonstrate the potential of this OT-based approach for non-invasive, label-free detection of molecular interactions. Compared to existing techniques, such as atomic force microscopy and cantilever-based sensors, this method offers significant advantages, including real-time monitoring, adaptability to different bioaffinity systems, and compatibility with miniaturized setups. This work establishes a foundation for using OT-based tools to monitor high-affinity molecular interactions in real time. While demonstrated here using biotinylated BSA as a model ligand, future studies will explore the method’s applicability to smaller ligands and more subtle surface modifications. Full article

Hepatic osteodystrophy (HOD) is a frequent complication of chronic liver disease, marked by impaired osteogenesis and elevated fracture risk, particularly under sustained alcohol exposure. Bone morphogenetic proteins (BMPs), which play a crucial role in maintaining bone homeostasis, are dysregulated in alcoholic liver disease. Specifically, decreased BMP2 and increased BMP13 have been linked to impaired osteogenesis and cartilage-like shifts in bone progenitors. A human in vitro system that recapitulates this hepatic BMP imbalance is needed to dissect mechanisms and identify targets. To address this, we established a long-term human three-dimensional liver–bone co-culture model that integrates hepatocytes (HepaRG), hepatic stellate cells (LX-2), and human umbilical vein endothelial cells (HUVECs) with bone scaffolds seeded with osteoblast precursors (SCP-1) and osteoclast precursors (THP-1). This study aimed to characterize the effects of chronic 50 mM alcohol exposure on hepatic fibrogenic activation and BMP ligand secretion, and to investigate the associated BMP-responsive signaling involved in bone cell lineage differentiation and functional activity. The results demonstrated alcohol-induced hepatic CYP2E1 activation and fibrogenic remodeling with EMT signatures, as well as a decrease in BMP2 and an increase in BMP13, without affecting BMP9. Liver-derived factors activated both canonical and non-canonical BMP signaling in bone progenitors, reduced osteoblast activity and mineralization, preserved osteoclast TRAP activity, and shifted the lineage toward chondrogenesis (SOX9↑, RUNX2↓). Notably, this BMP profile and skeletal phenotype reflect clinical observations in chronic liver disease, indicating that the model recapitulates key in vivo pathological features. This human liver micro-organoid co-culture reproduces alcohol-induced hepatic BMP dysregulation and downstream bone defects, offering an organoid-centric, microengineered platform for mechanistic studies and BMP-targeted therapeutic screening in HOD. Full article

Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Existing research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous study demonstrated that L-quebrachitol, a methyl derivative of inositol, enhances osteoblastogenesis and bone formation; however, its effect on osteoclastogenesis remains unclear. Consequently, we aimed to investigate the effect of L-quebrachitol on receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis in pre-osteoclastic RAW 264.7 cells, and bone resorption in an ovariectomized rat model. The results revealed that L-quebrachitol suppressed RANK-mediated signaling, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Fos proto-oncogene (cFOS) pathways, at both the gene and protein levels. Moreover, the critical transcription factor for osteoclastogenesis, nuclear factor of activated T cells c1 (NFATc1), was downregulated. Inhibition of osteoclast-associated marker genes encoding proteolytic enzymes, such as tartrate-resistant acid phosphatase (TRAP), matrix metallopeptidase 9 (MMP-9), and cathepsin K, led to reduced formation of TRAP-positive multinucleated cells and resorption pits. In addition, proteasome subunit alpha type-5 (PSMA5), which is involved in the degradation of the NF-κB inhibitor, was also suppressed. In particular, the animal study clearly supported the bone homeostasis property of the agent by increasing the BV/TV (bone volume/total volume) and Tb.Th (trabecular thickness) in ovariectomized rats. These findings demonstrate the dose-dependent inhibitory effect of L-quebrachitol on osteoclastogenesis through the modulation of RANK-mediated signaling pathways and prevention of bone loss in an animal model. However, further exploration of the potential of L-quebrachitol as an effective approach for osteoporosis is required. Full article

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management. Full article

There is a wealth of information available about endogenous fatty acid ligands for peroxisome proliferator-activated receptor α/δ/γ (PPARα/δ/γ); however, there are few comparative studies of PPARα/δ/γ activation using standardized experimental systems. This study investigated which of 14 major free long-chain fatty acids (LCFAs: C12:0–C22:6) and 15-deoxy-Δ^12,14-prostaglandin J2 (15d-PGJ2) activate PPARα/δ/γ using a coactivator recruitment assay. We recently discovered that eight different synthetic PPAR agonists recruit four different coactivator peptides (PGC1α, CBP, SRC1, TRAP220) with varying potency and efficacy, so we examined the ligand-concentration-dependent recruitment of these four coactivators. All 15 fatty acids (FAs) activated PPARα/δ at high concentrations, but only palmitic acid, stearic acid, oleic acid, and linoleic acid significantly activated PPARα/δ at physiologically relevant concentrations. Lauric acid, myristic acid, palmitic acid, and 15d-PGJ2 activated PPARγ at high concentrations, but only palmitic acid slightly activated PPARγ at physiologically relevant concentrations. FA ligands exhibited different coactivator preference compared to synthetic PPAR agonists, including approved drugs such as pemafibrate, seladelpar, and pioglitazone, suggesting that these agonists may regulate target gene transcription in a different manner than natural FA ligands. Such differences may be relevant to the pathogenesis of side effects of synthetic PPAR agonists occasionally observed in (pre)clinical studies. Full article

Perylenediimide derivatives are materials that exhibit singlet fission (SF), capable of absorbing a single photon to generate multiple triplet excitons. This exciton multiplication process holds the potential to surpass the Shockley-Queisser limit. To effectively harness the energy of triplet excitons, they must possess sufficient diffusion capability. However, the diffusion of triplet excitons in perylenediimide derivatives has rarely been studied. In this work, we synthesized perylenediimide derivative crystals (C5) and fabricated composites (C5-Pe-QDs) by incorporating surface-ligand-functionalized quantum dots (Pe-QDs) at varying concentrations. The Pe-QDs act as traps within the C5 crystals, capturing triplet excitons when they diffuse into their capture range. The experimental and computational results indicate that the diffusion coefficient of triplet excitons in C5 crystals is approximately 3.58 × 10⁻⁵ cm² s⁻¹, with a diffusion length of about 50.9 nm. Using Monte Carlo simulations, we estimated the triplet exciton capture probability by Pe-QDs under ideal distribution conditions to be around 79.5%. The above findings indicate that, in the C5-Pe-QDs composites, triplet excitons can efficiently diffuse to the quantum dots, providing a novel and viable pathway for the effective utilization of triplet exciton energy in silicon-based photovoltaic systems. Full article

The synthesis of a small library of fused Cyclic Aryl Amino Carbon (f-CArAC) carbene precursors in the form of 1,1,2,4-tetraaryl-1H-isoindol-2-ium triflate (6), (7-R) (R = ^tBu, CF₃) or 3,3-dimethyl-2,8-bis-arene-substituted-3,4-dihydro-isoquinolin-2-ium hydrogen-dichloride (8) and 2,4,8-tri(substituted)-isoquinolin-2-ium tosylate salts (12) has been achieved. All of them feature an arene incorporated on the annulated benzene ring of the corresponding heterocycle, introduced at the early stages of their synthesis via the Suzuki cross-coupling reaction between 2,6-dibromo-benzaldehyde and the desired aryl boronic acid. The terphenyl-2′carbaldehyde by-products of this Suzuki reaction are useful starting points for the preparation of two new iminium iodide salts (10-R) (R = H, CF₃) as potential precursors to access ACyclic Amino Carbon (ACAC) carbenes. Compounds (6) and (7-^tBu) react readily with hydroxide either in THF or in a biphasic Et₂O/aqueous OH⁻ solution to produce the substituted isoindolinols (13) and (14), respectively. The thermal dehydration of the former generates the corresponding f-CArAC carbene in situ, which is trapped by Cu(I)Cl furnishing, a rare example of a two-coordinate Cu(I) complex (15) supported by this new ligand scaffold. Full article

Background: Tumor-promoting inflammation and immune evasion are hallmarks of cancer, contributing to the survival and proliferation of tumor cells. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation and immune evasion. Neutrophils are leukocytes that contribute to inflammation and have immunomodulatory functions. They are shown to have pro- or anti-tumorigenic roles contingent on cancer type. Methods: In this study, we examined the role of neutrophil recruitment in pancreatic cancer (PC) progression using patient samples and murine models. Results: We observed enhanced neutrophil infiltration and neutrophil extracellular trap (NET) formation, which were dependent on disease stage and tumor site. Our murine model studies showed that the infiltration of neutrophils and NETs was dependent on disease progression. Moreover, chemokine receptor CXCR2 and its ligands played a crucial role in neutrophil recruitment. The expression of CXCR2 and its ligands was associated with a worse prognosis for patients. Conclusions: Our data demonstrates that gemcitabine therapy enhances neutrophil recruitment and NET formation in PC. In addition, we observed altered neutrophil phenotypes in PC dependent on disease progression, suggesting a context-dependent immunomodulatory role. Together, our data demonstrate that CXCR2-driven neutrophil recruitment increases with PC progression, is enhanced by gemcitabine chemotherapy, promotes an immunosuppressive microenvironment, and is associated with poor patient survival. Full article

Cesium halide perovskite nanocrystals (PNCs) have emerged as promising materials for application in high-color-purity displays due to their exceptional optoelectronic properties, which include narrow emission linewidths, tunable bandgaps, and high photoluminescence quantum yields (PLQYs). However, preserving these characteristics during purification remains a major challenge as surface ligand detachment during the washing process can lead to increased defect states, reduced quantum efficiency, and spectral broadening. The choice of anti-solvent plays a crucial role in maintaining the structural and optical integrity of PNCs, as it directly influences ligand retention and material stability. In this study, we propose an optimized purification strategy for mixed-halide perovskite nanocrystals that incorporates post-synthetic ligand supplementation, in which controlled amounts of oleic acid (OA) and oleylamine (OAm) are sequentially introduced into the crude solution prior to anti-solvent treatment. This approach reinforces surface passivation, suppresses trap state formation, and minimizes halide loss. Consequently, a near-unity PLQY with narrow full-width-at-half-maximum emissions is achieved for both green- and red-emissive nanocrystals, markedly enhancing color purity and providing a promising route toward next-generation wide-color-gamut display technologies. Full article

Background/Objectives: Osteoporosis is caused by excessive osteoclast activation via the receptor activator nuclear factor kappa B ligand (RANKL), which is released from osteoblasts or osteocytes. RANKL regulates osteoclast activity by binding to the receptor activator of nuclear factor kappa B (RANK) in the canonical pathway or leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) in the non-canonical pathway. In this study, we attempted to develop an intact small-fragment protein based on RANKL by removing the RANK-binding site and transforming the amino acid residues at crucial sites to inhibit osteoclast activity and treat osteoporosis. Methods: We expressed a small-fragment variant of RANKL as a soluble glutathione S-transferase (GST) or 6x histidine (His)-tagged fusion protein using a GST- or His-binding domain tag expression vector system. To generate an intact form of small-fragment RANKL, ribosome-inactivating protein–His-fusion RANKL was purified using HisTrap affinity chromatography and treated with tobacco etch virus nuclear inclusion endopeptidase to remove the His-tag fusion protein. Tartrate-resistant acid phosphatase (TRAP) and bone resorption pit formation assays were performed to analyze the inhibitory effects on osteoclast differentiation and activation. Results: The intact forms of 225RANKL295P and 225RANKL295A showed the strongest inhibitory effects on TRAP activity and bone resorption pit formation. Conclusions: Using an optimal construct design, a large and diverse range of small RANKL fragments could be generated. This suggests that the generation of small-fragment RANKL provides a promising avenue for the advancement of novel therapeutic approaches to osteoporosis. Full article