Search Results (3,238)

Background: Imperatorin (IPT) is a natural furanocoumarin featuring robust anti-inflammatory, antifibrotic and antioxidant activities. However, poor aqueous solubility and insufficient oral bioavailability restrict its clinical application. Multiple gastrointestinal barriers, including the mucus barrier, limited epithelial penetration and P-glycoprotein-triggered drug efflux, are major obstacles hindering IPT oral absorption. Methods: N-acetylcysteine (NAC)-functionalized TPGS conjugates were synthesized first. Using Pluronic^® F108 and Lipoid^® S-100 as a matrix, imperatorin@N-acetylcysteine-TPGS/Pluronic^® F108/Lipoid^® S-100 (IPT@NAC-TFS) micelles were fabricated. We characterized their physicochemical features and in vitro release behavior. The Caco-2/HT29-MTX-E12 co-culture cell model was adopted to explore mucus permeation, cellular uptake and transepithelial transport mechanisms. In vivo intestinal distribution and pharmacokinetic tests in rats were carried out to confirm the oral absorption-enhancing effect of micelles. Results: Optimized micelles displayed a uniform shape and favorable encapsulation efficiency. Low CMC maintained structural stability upon gastrointestinal dilution. NAC modification conferred mucus-penetrating capacity on micelles. TPGS simultaneously improved epithelial barrier permeability and inhibited drug efflux, switching IPT transport mode. The micelles effectively cleared intracellular ROS, recovered SOD activity and lowered MDA levels in BLM-impaired MLg fibroblasts. In vivo results revealed enhanced intestinal drug accumulation, with the relative oral bioavailability of IPT increased by 6.07-fold. Conclusions: IPT@NAC-TFS micelles overcome multiple gastrointestinal barriers for oral IPT delivery. Combining mucus penetration, efflux suppression and antioxidative capacity, this system offers a promising strategy to develop oral formulations of poorly soluble antifibrotic natural products. Full article

Prebiotics are predominantly indigestible carbohydrate-based substrates selectively-utilized by beneficial gut-microbes to support host-health. We previously developed protein-containing prebiotics that co-deliver carbohydrate and protein substrates to the colon, where gut-microbes compete for the limited nitrogen availability, thereby enhancing microbial growth, metabolic activity, and host health compared with conventional carbohydrate prebiotics. Resveratrol is a grape-derived polyphenol with antioxidant, anti-inflammatory, and emerging prebiotic activity. Here, we developed a multifunctional protein-containing prebiotic system based on Maillard conjugates of 2′-fucosyllactose–potato protein hydrolysate (2′-FL-PPH) micelles encapsulating resveratrol, followed by genipin crosslinking. This crosslinked 2′-FL-PPH-resveratrol system is designed to limit premature protein and resveratrol absorption, enhancing their colonic co-delivery. We characterized the encapsulation efficacy, physicochemical properties, digestibility and colonic delivery. The conjugates (10 mg/mL 2′-FL-PPH) effectively entrapped resveratrol (600 µM), exhibiting an average particle size of ~28 nm and an encapsulation efficiency of 79.5 ± 4.9%. Binding studies demonstrated predominantly hydrophobic interactions between resveratrol and 2′-FL-PPH. The conjugates prevented resveratrol crystallization in aqueous media, while genipin crosslinking enhanced resistance to simulated gastrointestinal digestion and inhibited premature resveratrol release, increasing the fraction expected to reach the colon. Collectively, this system enables colonic co-delivery of carbohydrate, peptides, and resveratrol, providing a novel strategy for promoting beneficial-microbiota and gut-health. Full article

The limitations of conventional inorganic electrodes call for organic alternatives for advanced energy storage. Metal–covalent organic frameworks (MCOFs) integrate the metal active sites of metal–organic frameworks (MOFs) with the high chemical stability imparted by strong covalent bonds in covalent organic frameworks (COFs) while retaining the high specific surface area and tunable porosity of both material classes. Among these, MCOFs constructed from porphyrin and phthalocyanine building units have emerged as a research hotspot in electrochemical energy storage owing to their inherent 18π-conjugated macrocyclic electronic systems, well-defined M–N₄ coordination sites, and potential bipolar charge storage characteristics. This review systematically summarizes recent advances in this class of materials. First, from the perspective of metal center introduction timing, three core synthetic strategies—pre-metallation, simultaneous metallation, and post-metallation—are categorized and evaluated in terms of coordination precision, synthetic efficiency, and scalability potential. Second, the regulatory effects of two-dimensional layered and three-dimensional interpenetrated structures on charge transport pathways and structural stability are elucidated. Subsequently, the applications of porphyrin/phthalocyanine-based MCOFs in lithium-based batteries, zinc-based batteries, sodium/potassium-ion batteries, and supercapacitors are reviewed in detail, with emphasis on the key roles of metal active sites in catalytic conversion, chemical anchoring/confinement, interface stabilization, and pseudocapacitive contribution. Finally, future directions to address key performance and mechanistic bottlenecks are discussed. This review aims to provide a systematic reference for the rational design and energy storage applications of high-performance porphyrin/phthalocyanine-based MCOFs. Full article

Gonadotropin-Releasing Hormone receptors (GnRHRs) are overexpressed in several hormone-dependent malignancies, making them attractive molecular targets for selective anticancer drug delivery. Peptide–drug conjugates (PDCs) are a promising therapy for cancer and autoimmune diseases with high specificity and reduced toxicity. In this study, the three-dimensional structures of two previously synthesized mitoxantrone–GnRH conjugates, con3 and con7, were elucidated using high-resolution NMR spectroscopy in combination with molecular dynamics (MD) simulations. Complete ¹H and ¹³C resonance assignments were achieved in DMSO-d₆ through two-dimensional NMR experiments. NOESY-derived distance restraints were subsequently used to refine the conformational ensembles obtained from MD simulations performed in water and DMSO. Both conjugates exhibited compact bent conformations with a U-shaped peptide backbone. The mitoxantrone moiety is positioned close to the peptide backbone in water simulations and NMR-refined structures, while it is positioned farther away in DMSO, without affecting the orientation of key residues involved in GnRH receptor binding. Importantly, His², Trp³, and Arg⁸ remain solvent-exposed, whereas the disulfide bond is easily accessible to the solvent, consistent with the proposed drug release mechanism by the thioredoxin system. NMR-restrained molecular modeling confirmed the dominant conformational features predicted by the unconstrained theoretical simulations. Overall, these findings provide better structural understanding of the molecular organization of mitoxantrone–GnRH conjugates, highlighting key receptor-recognition residues and supporting both the proposed thioredoxin-mediated drug release mechanism and their previously reported biological properties. These insights may facilitate the rational design and optimization of improved GnRH peptide–drug conjugates for targeted therapy. Full article

Preclinical models play a critical role in the development of PSMA-targeted radiopharmaceuticals for prostate cancer. However, many existing models have practical limitations, including slow tumor growth, low engraftment rates, and restricted availability, and all human PSMA-positive lines are confined to immunodeficient hosts. We developed and characterized a novel PSMA-expressing transgenic cell line, CT26-PSMA, as a practical tool for preclinical screening of PSMA-targeting agents. The CT26-PSMA cell line was established by stable transfection of the murine colon carcinoma CT26 cell line with human PSMA using the Sleeping Beauty transposon system. PSMA expression was confirmed by RT-qPCR (reverse transcription quantitative polymerase chain reaction), flow cytometry, and radioligand saturation binding on intact cells. Two [⁶⁸Ga]Ga-labeled radioconjugates—the well-established PSMA-617 and a newly synthesized conjugate (Conjugate-1)—were used to validate the functionality of the model through in vitro binding, uptake and internalization studies, and through ex vivo biodistribution in CT26-PSMA tumor-bearing athymic male nu/nu mice. The CT26-PSMA cell line demonstrated high and stable PSMA expression, with approximately 95% of cells expressing the biomarker and no measurable loss over 16 passages in antibiotic-free medium. Saturation binding gave a receptor density of ∼3.5 × 10⁶ sites per cell, approximately four-fold higher than that of LNCaP cells (∼0.8 × 10⁶), with dissociation constants that were indistinguishable between the two radioconjugates and between the two cell lines (K_d 9.0–11.6 nM). Subcutaneous tumors reached ~300 mm³ within 8–10 days of inoculation, with a take rate of 10/10 versus 1/10 for LNCaP (Fisher’s exact test, p = 1.2 × 10⁻⁴). Both radiotracers showed saturable, 2-PMPA-blockable binding and uptake in CT26-PSMA cells, confirming the functional activity of the recombinant receptor. Biodistribution studies revealed accumulation of both conjugates in CT26-PSMA tumors, with generally comparable tumor-to-background profiles. The CT26-PSMA cell line represents a robust, rapid, and reproducible platform for preclinical evaluation of PSMA-targeting radiopharmaceuticals, and its murine BALB/c origin permits engraftment in immunocompetent or minimally immunosuppressed hosts, whereas existing human PSMA-positive lines do not. It is intended as a screening platform rather than as a model of prostate cancer biology. The validation data obtained with [⁶⁸Ga]Ga-labelled conjugates confirm the suitability of this cell line for future studies of PSMA-directed compounds. Full article

Curcuma longa is a medicinal plant valued for its diverse phytochemicals and antioxidant properties. However, the effects of thermal processing on its phytochemical composition and antioxidant function remain insufficiently understood. This study investigated heat-induced changes in curcuminoids, sesquiterpenoids, and their degradation products in C. longa extracts heated at 180 °C for 0–90 min under dry, aqueous, olive oil, and corn oil conditions using UHPLC–MS/MS and GC–MS. Curcuminoids progressively decreased during heating, whereas sesquiterpenoids exhibited greater thermal stability, particularly in oil matrices. Antioxidant properties were also better preserved in oil-treated extracts than in those heated under dry or aqueous conditions. However, in an oil-in-water emulsion system exposed to continuous LED illumination (14,600 lux), extracts obtained after dry heating accelerated lipid oxidation, as evidenced by enhanced oxygen depletion, hydroperoxide formation, and conjugated diene accumulation. This pro-oxidative effect was markedly suppressed by EDTA, suggesting the involvement of metal-mediated oxidation pathways. These findings demonstrate that thermal processing differentially alters the phytochemical profile and antioxidant properties of C. longa depending on the heating matrix, while highlighting that preserved antioxidant capacity does not necessarily translate into improved oxidative stability in illuminated emulsion systems. Full article

Gastrointestinal (GI) cancers represent a diverse group of malignancies that remain a major cause of cancer-related morbidity and mortality worldwide. Their management is increasingly complex, reflecting differences in tumor biology, anatomical location, stage, and molecular profile. In recent years, advances in molecular diagnostics, immunotherapy, and targeted treatment have moved clinical decision-making beyond a purely organ- and stage-based approach toward more individualized, biomarker-guided care. This narrative review summarizes established and emerging biological and targeted therapies used in esophageal, gastric and gastroesophageal junction, colorectal, pancreatic, hepatocellular, and biliary tract cancers. It focuses on immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4; HER2-directed monoclonal antibodies and antibody–drug conjugates; antiangiogenic and anti-EGFR therapies; and newer strategies involving CLDN18.2, FGFR2b, and tumor-agnostic alterations such as NTRK fusions. The review also considers the predictive biomarkers used to guide treatment selection and the growing integration of systemic therapy with surgery in neoadjuvant, perioperative, adjuvant, and conversion settings. However, clinical efficacy alone does not determine whether new treatments become part of routine practice. Regulatory approval, reimbursement, access to molecular testing, and the availability of specialized multidisciplinary care are equally important. The rapidly evolving treatment landscape for GI cancers therefore requires clinical decisions that account for tumor biology, anatomical resectability, molecular eligibility, expected benefit, treatment-related toxicity, and local access to therapy. Expanding access to comprehensive biomarker testing and effective molecularly guided treatments will be essential to translate progress in precision oncology into more personalized and equitable care for patients with GI cancers. Full article

Antibody–drug conjugates (ADCs) have matured from a technically challenging concept into an established therapeutic platform across hematologic and solid malignancies. By linking a monoclonal antibody to a potent cytotoxic payload, ADCs seek to increase tumor-directed drug delivery while limiting systemic exposure; however, clinical performance depends on much more than target expression. Target accessibility, antigen density and heterogeneity, internalization, intracellular trafficking, linker stability, payload properties, drug-to-antibody ratio, bystander effect, tumor penetration, and host-tissue handling jointly shape efficacy and toxicity. This review provides a clinician-oriented assessment of the contemporary ADC landscape and the principal biologic and pharmacologic determinants of benefit. We discuss signature toxicities, including interstitial lung disease and ocular injury, and summarize evolving mechanisms of resistance and biomarker development. Particular emphasis is placed on three translational problems that are becoming increasingly important as ADCs move into earlier lines and overlapping disease settings: dose optimization beyond the maximum tolerated dose, sequencing across targets and payload classes, and biologically rational combination strategies. We also present a conceptual Sequential Tumor Attack Model as a hypothesis-generating framework for tumor-access priming, ADC-mediated cytotoxic injury, and immune amplification, while explicitly recognizing that the complete model has not been clinically validated. The future impact of ADCs will depend not only on next-generation constructs, but also on rigorous evidence for how these agents should be dosed, ordered, and combined in practice. Full article

Pine wilt disease is a devastating forest disease caused by Bursaphelenchus xylophilus infection. The associated bacterium Pseudomonas fluorescens and its flagellin protein have been implicated in this process, but the role of the flagellin-encoding gene fliC in pathogenesis remains unclear. Current gene knockout strategies in P. fluorescens are limited by low transformation efficiency and cumbersome procedures, which constrain functional studies of this gene. To address this methodological gap, we established a fliC knockout method based on the pT18sacB-sacB counterselection system. Short homologous arms were constructed by splice overlap extension PCR, and the knockout mutant ΔfliC was obtained through S17-1 λpir-mediated conjugation and sucrose counterselection. The mutant was verified by junction PCR, internal PCR, and sequencing. Using Pinus massoniana callus as the experimental material, we preliminarily compared the wild-type strain and the ΔfliC mutant in individual pathogenicity and in promoting complex infection by B. xylophilus. The ΔfliC mutant showed delayed symptom onset and lower disease severity than the wild type, and its ability to promote complex infection also appeared reduced. These results provide preliminary evidence that fliC contributes to symptom development in this callus assay. The established fliC knockout technique provides a methodological basis for further investigating the role of associated bacteria in pine wilt disease. Full article

γ-Hydroxybutyric acid (GHB), a colorless and odorless central nervous system depressant associated with drug-facilitated sexual assault, demands rapid on-site detection. Polydiacetylene (PDA) colorimetric sensors derived from 10,12-pentacosadiynoic acid (PCDA) conjugates are a promising platform, but the molecular origin of GHB recognition in PCDA–gabazine systems has remained unresolved. Here, we compare a series of structurally related PCDA conjugates to examine how the chemical state of the EDA-derived unit affects the GHB-induced colorimetric response. A side-by-side substituent screen of three PCDA derivatives showed that PCDA–EDA produced the largest colorimetric response (ΔR = 53) within 30 s, the hydrazide analogue gave a moderate response (ΔR = 34), and a simple amide was negligible (ΔR = 12). By contrast, a PCDA–gabazine mat prepared by the same protocol showed only a subtle, barely discernible color shift after several hours and remained predominantly blue even after approximately 24 h, without a visually appreciable blue-to-red transition. This difference suggests that the accessible free primary amine of PCDA–EDA is an important factor contributing to its faster and stronger response. Building on this mechanistic finding, we replaced the previously used PVDF–HFP/PEO matrix with a cellulose/PVDF–HFP formulation processed from DMF and adopted multi-nozzle electrospinning, reducing the fabrication time from approximately 120 to 30 min per sheet, corresponding to a 75% reduction in processing time. The sensor mat showed a clearly distinguishable, dose-dependent visual response across 0.5–3% w/v GHB within 30 s, covering the forensically relevant concentration window. These findings reposition linker architecture as a central design parameter for PDA-based forensic colorimetric sensors. Full article

Background/Objectives: Epithelial ovarian cancer (EOC) remains a gynecologic malignancy with a poor prognosis, with a 5-year survival of approximately 29% in advanced-stage disease. Despite cytoreductive surgery and platinum- and taxane-based chemotherapy, most patients relapse within 2 years. Major therapeutic barriers include chemoresistance, molecular heterogeneity, and an immunosuppressive peritoneal microenvironment. This review summarizes emerging therapeutic strategies for EOC, their mechanisms of action, and their potential to overcome treatment resistance. Methods: PubMed/MEDLINE was searched for preclinical studies, phase I–III clinical trials, systematic reviews, and meta-analyses addressing novel ovarian cancer therapies and resistance mechanisms. Results: The review covers molecularly targeted therapies, immunotherapies, metabolic and epigenetic approaches, cellular and gene therapies, targeted drug-delivery systems, and locoregional and physical modalities. Strategies include PARP inhibitors, antiangiogenic agents, antibody–drug conjugates, pathway inhibitors, immune checkpoint inhibitors, cancer vaccines, adoptive cell therapies, metabolic and epigenetic modulators, CAR-T, CAR-NK, CRISPR/Cas9, HIPEC, PIPAC, ablation, photodynamic therapy, and sonodynamic therapy. Conclusions: The clinical maturity of these approaches varies substantially. PARP inhibitors, antiangiogenic agents, selected antibody–drug conjugates, MAPK-directed therapy in LGSOC, and HIPEC in selected settings have the strongest clinical support. Most immune combinations, metabolic and epigenetic therapies, adoptive cell therapies, gene-editing approaches, and novel delivery or physical modalities remain early clinical or predominantly preclinical. Progress will depend on biomarker-guided patient selection, reassessment of evolving resistance mechanisms, and rational treatment sequencing and combinations. Full article

(1) Background: Impaired diabetic wound healing stems from systemic dysregulation of the wound-healing cascade under hyperglycemic conditions, producing a disordered microenvironment marked by sustained inflammation, defective angiogenesis, and aberrant extracellular matrix remodeling, multifactorial, multistage pathological interactions demanding multi-target intervention. (2) Methods: We constructed a multifunctional nanocomposite hydrogel dressing (PGAs@CDV) based on a “drug-carrier integration” strategy, targeting the dysregulated hemostasis, inflammation, and proliferation phases of diabetic wound healing. An amphiphilic micelle carrier (PNO-GA) was synthesized by covalently conjugating Panax notoginseng oligosaccharide with gallic acid, loaded with Anemoside B4 to yield drug-loaded nanomicelles (PGAs), embedded into a carboxymethyl chitosan-dopamine-vanillin hydrogel (CDV) matrix to form PGAs@CDV. We then examined how PGAs@CDV affected diabetic wound healing. (3) Results: In vitro, PGAs@CDV enhanced cell migration and angiogenic capacity, exhibited potent antioxidant activity, and promoted M1-to-M2 macrophage polarization. We tested PGAs@CDV in a streptozotocin-induced diabetic mouse wound model. Wounds treated with PGAs@CDV closed faster than those treated with the control, CDV, PNO@CDV, and AB4@CDV. Four readouts tracked this difference: hemostasis was quicker, inflammation was lower, more blood vessels formed, and collagen deposition was higher. At the pathway level, PGAs@CDV suppressed NF-κB signaling and activated PI3K/AKT/HIF-1α. These two arms map onto the anti-inflammatory and pro-angiogenic effects observed above. (4) Conclusions: This nanocomposite hydrogel integrates a bioactive carrier with a therapeutic payload to enable coordinated intervention across multiple phases of diabetic wound repair. By combining structural support with sustained pharmacological activity, it offers a promising strategy for the treatment of chronic diabetic wounds. Full article

Battery thermal management systems (BTMSs) are essential for maintaining the performance, efficiency, durability, and safety of electric-vehicle battery packs. Although fin-enhanced air-cooled BTMSs offer a simple and leakage-free cooling solution, their practical implementation is often limited by increased weight, insufficient temperature uniformity, and restricted heat-dissipation capability under high thermal loads. This study numerically investigates a compact air-cooled BTMS for two types of cylindrical lithium-ion batteries using aluminum and polypropylene (PP-$\beta$) circumferential fins in inline and staggered cell arrangements. Unlike previous fin-based air-cooling investigations, the present study combines a compact 2 × 4 battery pack with transverse and longitudinal center-to-center cell pitches of 1.2D, a direct comparison between metallic and lightweight polymer fins, and an assessment of two 18650 battery types with different capacities, thermophysical properties, and heat-generation characteristics. A three-dimensional steady-state conjugate heat-transfer model was developed in ANSYS Fluent to evaluate the effects of fin number, fin material, cell arrangement, ambient temperature, and inlet airflow velocity under discharge rates ranging from 1 C to 4 C. The results reveal that increasing the number of fins consistently reduced the maximum cell temperature but increased the pressure drop. The inline configuration generally achieved a lower maximum temperature and higher Nusselt number (Nu), whereas the staggered arrangement maintained a substantially lower pressure drop. Relative to the corresponding finless configurations, the Nu increased by 64.4–71.2% for the inline arrangement and 86.4–98.1% for the staggered arrangement. Polypropylene fins provided thermal performance close to that of aluminum fins in terms of maximum temperature while reducing the total fin mass by approximately 44.8%; however, aluminum fins maintained better temperature uniformity. These findings quantify the trade-offs among thermal performance, pressure drop, compact cell spacing, and system weight, providing design guidance for compact fin-enhanced air-cooled BTMSs. Full article

Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), remains a major global health challenge. The prolonged duration of treatment and the emergence of multidrug-resistant strains have highlighted the need for alternative therapeutic strategies. This study investigated the therapeutic potential of Ag85A aptamer-conjugated PEGylated niosomes encapsulating ethanolic extract of propolis (Ag85A-PEGNio/EEP) using Mtb-infected macrophage model. Ag85A-PEGNio/EEP exhibited efficient cellular uptake, with more than 99.8% internalization by macrophages, and trafficked host phagolysosome, facilitating targeted delivery of EEP to intracellular Mtb. Ag85A-PEGNio/EEP treatment showed an anti-mycobacterium efficacy by reducing intracellular Mtb viability by approximately 51.2% compared with untreated controls. Moreover, Ag85A-PEGNio/EEP modulated macrophage immune responses by significantly increasing the expression of the pro-inflammatory cytokines IL-12 (8.4-fold) and IL-6 (3.8-fold), while markedly decreasing the expression of the anti-inflammatory cytokine IL-10 (6.4-fold). Protein–protein interaction (PPI) network analysis further revealed the association of proteins with immune regulation and antioxidant responses in treated cells. These findings suggest that Ag85A-PEGNio/EEP functions as a dual-action therapeutic platform by enhancing intracellular anti-mycobacterial activity while balancing host immune responses. This targeted nano-delivery system represents a promising candidate for host-directed TB therapy and further investigations are needed to validate these outcomes and explore their potential applications against TB treatment challenges. Full article

Background/Objectives: Antibody selection is critical for advancing pretargeted PET imaging toward clinical translation. This study directly compared two clinically approved anti-HER2 antibodies—trastuzumab and pertuzumab—within an identical pretargeting system, utilizing the specific chemical ligation between tetrazine and trans-cyclooctene (TCO) via the inverse electron-demand Diels–Alder (IEDDA) cycloaddition. Methods: In HER2-positive SKOV3 tumor-bearing mice, TCO-conjugated antibodies were administered 1–13 days prior to injection of a fluorine-18-labeled tetrazine probe ([¹⁸F]PEG₁₂-Tz). Results: Both strategies enabled high-contrast imaging, overcoming the kinetic mismatch between slow-clearing antibodies and the short-lived ¹⁸F isotope. Distinct profiles were observed: pertuzumab-TCO yielded higher tumor uptake and a broader imaging window (3–13 days), whereas trastuzumab-TCO resulted in lower uptake and a narrower window (1–5 days). These differences are not affinity-driven, as both conjugates showed similar Kd values (~11–14 nM). Instead, pertuzumab-TCO’s superiority stems from a dual mechanism: (1) slower cellular internalization (65.1% vs. 94.0% at 60 min) preserves surface TCO for click reaction; and (2) markedly slower blood clearance (t_1/2β = 285.9 h vs. 106.0 h) ensures sustained bioavailability and tumor extravasation. Conclusions: This head-to-head evaluation demonstrates that epitope-dictated internalization and clearance are decisive parameters for antibody selection, providing a mechanism-based framework for optimizing pretargeted imaging. Full article