Search Results (22,307)

Background/Objectives: Poly(lactide-co-glycolide) (PLGA) microspheres support long-acting drug delivery, but their release profiles are difficult to predict because burst release, diffusion, polymer degradation, and formulation-dependent effects interact across multiple time scales. This study aimed to develop a continuous-time model that combines accurate release prediction with physically admissible trajectories and release-component attribution. Methods: MC-NODE encodes ten drug, polymer, and formulation descriptors, decomposes the non-negative release rate into burst, diffusion, degradation-associated late-stage, and neural-residual components, and applies a formulation-dependent plateau through a semi-analytical state map. The model was evaluated on a literature-curated dataset containing 321 in vitro release curves, 4913 observations, 89 drugs, and 113 publications using DOI-grouped five-fold cross-validation, complementary extrapolation and sparse-sampling protocols, synthetic mechanism-recovery experiments, and retrospective orthogonal consistency analysis. Results: MC-NODE achieved an RMSE of $0.094\pm 0.005$ and an $R^2$ of $0.854\pm 0.018$, with all 321 out-of-fold trajectories satisfying monotonicity and range criteria. It recovered synthetic contribution labels more accurately than the ablated variants. The degradation-associated late-stage contribution showed positive associations with experimental degradation, molecular-weight loss, pore-evolution, and mass-loss indicators, while the diffusion contribution was positively associated with an experimental diffusion indicator. Dominant-process agreement was 83.3%, and matched external or out-of-fold trajectories achieved an RMSE of $0.108\pm 0.020$. Under drug-grouped, chemical-cluster, and alternative sparse-sampling evaluations, MC-NODE retained the lowest absolute trajectory-level errors among the compared models. Conclusions: MC-NODE improves formulation-level PLGA release prediction while preserving continuous, monotonic, and bounded trajectories. Its component outputs provide experimentally supported, model-attributed summaries for comparative formulation analysis. Full article

Background/Objectives: Chronic complications of diabetes mellitus are closely associated with increased oxidative stress and the formation of advanced glycation end products (AGEs). This study aimed to investigate the antioxidant and antiglycation potential of hesperetin-7-O-glucoside (HCD) and diosmetin-7-O-glucoside (DCD) formulations complexed with cyclodextrins, using in vitro and in silico experimental models to evaluate their efficacy in mitigating hyperglycemia-induced molecular damage. Methods: Antioxidant activity was assessed using chemical and erythrocyte-based oxidative stress models, whereas antiglycation activity was evaluated in BSA–fructose, BSA–methylglyoxal, and arginine–methylglyoxal models. Results: Both formulations showed measurable antioxidant effects, with concentration-dependent behavior observed in some of the evaluated assays. In the DPPH assay, HCD and DCD achieved maximum inhibition values of 30.71% and 26.61%, respectively. Furthermore, DCD exhibited higher total antioxidant capacity (102.80 µg vitamin C equivalents/mL) and nitric oxide scavenging activity (37.89%) than HCD. In a cellular model, both formulations (200 µg/mL) significantly reduced AAPH-induced hemolysis, with DCD providing superior protection (7.05% vs. 16.63% for HCD). Under oxidative stress induced by high glucose concentration in erythrocytes, HCD and DCD reduced non-protein thiol levels, and HCD significantly increased catalase enzyme activity. Regarding antiglycation activity, DCD demonstrated superior efficacy relative to HCD in the BSA-fructose system, achieving 43.23% inhibition. DCD also displayed concentration-dependent inhibition of fructosamine formation (up to 47.99%) and BSA glycation by methylglyoxal (up to 45.20%). Both formulations significantly reduced carbonylated protein levels and preserved free thiol groups. In the arginine–methylglyoxal model, DCD and HCD reached 44.03% and 48.82% inhibition, respectively. Molecular docking revealed high binding affinity of both flavonoids to the protein active site (−9.00 kcal/mol for hesperetin-7-O-glucoside and −9.04 kcal/mol for diosmetin-7-O-glucoside), suggesting a structural protective role. Conclusions: The HCD and DCD formulations demonstrated antioxidant and antiglycation activities that may contribute to attenuating molecular alterations associated with chronic hyperglycemia through complementary mechanisms, including antioxidant effects, protection against protein carbonylation, and inhibition of glycation. While these findings highlight the potential of the evaluated formulations, additional mechanistic and in vivo studies are required to establish their pharmacological applicability. Full article

Background: As a common clinical anticancer drug, doxorubicin (DOX) easily triggers obvious doxorubicin-induced cardiotoxicity (DIC) during clinical application. Accumulating evidence has proven that ferroptosis dominates the pathological process of DIC yet efficient targeted treatment strategies remain scarce. The present work mainly focused on clarifying the protective role of quercetin (QUE) against DIC. Methods: In vivo rat models and in vitro cardiomyocyte injury models were constructed to mimic DIC. Echocardiographic detection and histological staining were adopted to observe overall cardiac function and myocardial fibrotic changes. Ultrastructural alterations of intracellular mitochondria were observed under a transmission electron microscope. Relevant ferroptosis and oxidative stress levels were further determined. Moreover, a Western blot assay and NRF2 gene transfection technique were applied to confirm the involvement of the NRF2 signaling pathway. Results: In vivo and in vitro experimental outcomes showed that QUE treatment effectively relieved abnormal cardiac function and myocardial fibrotic lesions and improved damaged mitochondrial morphology. It also markedly restrained excessive iron accumulation and abnormal lipid peroxidation and restored disturbed redox balance in cardiomyocytes. Further mechanism exploration revealed that QUE could facilitate NRF2 entry into the cell nucleus and activate downstream SLC7A11/GPX4 signaling to maintain cellular glutathione homeostasis. Silencing NRF2 expression could fully reverse the above beneficial influences of QUE. Conclusions: Collectively, our experimental data demonstrated that QUE confers cardioprotective effects against DIC within subacute rat models and cultured cardiomyocyte injury models. Further mechanistic observations revealed that this protective phenotype is closely linked to the activation of NRF2/SLC7A11/GPX4 signaling alongside obvious reductions in multiple characteristic ferroptosis markers. Full article

Smartphone-based augmented reality (AR) may help dentists visualize an implant axis during treatment or training. Before a virtual overlay can be displayed, however, the application must first recognize the real target reliably. This in vitro study tested how five lighting conditions affected recognition of a two-colored, 3D-printed polylactic acid (PLA) dental model by a Unity/Vuforia smartphone application. The application ran on a Samsung Galaxy S22. A GoPro HERO10 recorded the smartphone display at 240 frames per second, and the videos were evaluated frame by frame. Red, green, blue, daylight-like light-emitting diode (LED) and halogen illumination were tested at a central and an eccentric model position, with ten repetitions per condition and position. The model was not recognized under red or blue illumination within the predefined observation interval. Recognition was successful in all repetitions under green, daylight-like and halogen illumination. Recognition speed differed among these successful conditions, and the eccentric position delayed recognition under daylight-like and halogen illumination. A supplementary region-of-interest analysis also showed lighting-dependent differences in image brightness and contrast. These findings indicate that lighting should be standardized and documented when smartphone-based dental AR systems are developed and tested. Full article

Background/Objectives: Metabolically dysregulated-associated steatotic liver disease (MASLD) is a complex, multifactorial disorder characterised by hepatic lipid accumulation, insulin resistance, oxidative stress, and dysfunction of the gut–liver axis. Given its intricate pathophysiology, multi-target nutritional strategies represent a promising complementary approach. This study aimed to evaluate the biological effects of a multi-component nutraceutical formulation using an integrated in vitro platform replicating intestinal, hepatic, and pancreatic–liver interactions. Methods: The formulation was tested on Caco-2 intestinal cells to assess cell viability, transepithelial electrical resistance (TEER), probiotic functional properties, and glucose absorption. Intestinally processed metabolites were then applied to HepaRG liver cells under hyperglycemic (glucose) or lipotoxic conditions (oleic acid/palmitic acid) to analyse lipid accumulation, cholesterol biomarkers (HMGR, LDL), bile acid production, and cellular damage (ALT, AST). Finally, a pancreas–liver co-culture model (EndoC-βH5 and HepaRG) was employed to investigate insulin secretion and downstream hepatic metabolic signalling (IRS1, GLUT2, glycogen). Results: The formulation preserved intestinal barrier integrity and enhanced probiotic functionality, including aggregation and hydrophobicity. In hepatic models, the treatment significantly reduced intracellular lipid accumulation and triglycerides, while increasing bile acid production and improving cholesterol profiles. Under steatotic stress, it lowered transaminase levels and downregulated lipogenic signalling. In the pancreas–liver axis model, the formulation restored glucose-stimulated insulin secretion and improved hepatic metabolic signalling by increasing IRS1 levels and glycogen synthesis, indicating enhanced insulin sensitivity. Conclusions: These findings support the biological plausibility of a multi-target nutraceutical approach for MASLD. The formulation demonstrates coordinated beneficial effects on intestinal barrier function, hepatic lipid management, and glucose metabolism, providing a strong rationale for further clinical investigation. Full article

Sea cucumber cooking liquid contains water-soluble macromolecules, but its bioactive polysaccharide fractions remain insufficiently characterized. In this study, a polysaccharide-rich fraction, P0.7, was isolated from sea cucumber cooking liquid and evaluated for its antitumor activity against HCT-15 colorectal cancer. P0.7 was characterized as a relatively homogeneous sulfated acidic heteropolysaccharide-rich fraction containing 83.61 ± 3.65% total sugar, 13.67 ± 2.48% sulfate, 9.98 ± 1.22% uronic acid, and 5.11 ± 0.34% protein. It was mainly composed of galactose, mannose, and glucose, accounting for 34.12%, 26.93%, and 17.99%, respectively. Among the tested tumor cell lines, HCT-15 cells showed the highest sensitivity to P0.7, with inhibition rates of approximately 45% and 63% at 100 and 200 μg/mL, respectively. P0.7 promoted apoptosis, induced G2/M-phase accumulation, increased ROS production, disrupted mitochondrial membrane potential, regulated Bax, Bcl-2, and cleaved caspase-3 expression, and enhanced γ-H2AX-related DNA damage-response signaling in HCT-15 cells. In an HCT-15 xenograft mouse model, P0.7 reduced terminal tumor volume and tumor weight without causing obvious body weight loss. Histological and immunohistochemical analyses further showed reduced Ki67 staining, increased TUNEL-positive signals, and enhanced γ-H2AX staining in tumor tissues. These findings indicate that P0.7 suppresses HCT-15 colorectal cancer growth in vitro and in vivo, possibly through mechanisms associated with ROS accumulation, mitochondrial apoptosis, and γ-H2AX-related DNA damage response. These findings provide additional experimental evidence supporting the investigation of sea cucumber-derived polysaccharides for potential pharmaceutical applications. Full article

The survival of Candidozyma (Candida) auris under gastric conditions remains poorly understood, particularly in veterinary species. This pilot in vitro study evaluated the resistance of two cat-derived C. auris strains and Candida parapsilosis ATCC 22019 in simulated gastric fluid (SGF). Yeast suspensions were exposed to SGF adjusted to pH 1–5 and 7 for up to 4 h at 37 °C, and colony-forming units (CFUs) were enumerated at 1, 2, and 4 h. Results were expressed as mean log10 CFU/mL ± standard deviation. A clear pH-dependent effect was observed: At pH 7, all strains showed increased CFU counts over time, whereas acidic conditions induced a marked reduction in culturability. At pH 1, reductions of approximately 3–4 log10 units occurred within 1 h, while at pH 2–5 a more moderate decrease of about 1 log10 unit was observed, with most reduction occurring early and stabilizing over time. Two-way ANOVA confirmed significant effects of pH and exposure time, with a significant interaction for all strains (p < 0.0001). Overall, gastric-like acidity strongly reduced, but did not completely abolish, the culturability of the two feline C. auris isolates under the specific in vitro conditions tested. Further studies using larger isolate collections and more physiologically relevant gastrointestinal models are needed to determine whether these findings translate into in vivo survival, intestinal transit, or colonization. Full article

Background/Objectives: Persistent inflammation and impaired tissue regeneration delay mucosal and cutaneous wound healing. Potato (Solanum tuberosum L.) preparations contain bioactive metabolites with anti-inflammatory and regenerative potential, yet their wound-healing mechanisms have not been systematically mapped. This scoping review aimed to map potato-derived bioactive metabolites and their roles in modulating inflammation and promoting tissue regeneration during wound healing. Methods: A scoping review was conducted in accordance with the PRISMA-ScR guidelines. Articles published between 2015 and 2025 were retrieved from the Scopus, PubMed, EBSCO, and ScienceDirect databases combined with hand searching. Eligible studies included in vivo animal models; mechanistically relevant in vitro studies; and limited clinical or human skin safety studies investigating potato-derived extracts, fractions, or defined preparation effects in wound, ulcer, and burn healing. Results: Among the 583 records identified, only 15 met the inclusion criteria. These studies reported five major bioactive metabolite classes—flavonoids/anthocyanins, polyphenols, alkaloids, polysaccharides, and peptides—together with potato-derived exosomal vesicles as an extracellular vesicle/delivery system (not a metabolite class). Potato-derived preparations have been associated with accelerated wound closure, enhanced fibroblast proliferation, collagen deposition, and the attenuation of inflammatory mediators. Molecular evidence, which was included in only six studies, supported the modulation of NF-κB, STAT1/3, COX-2, iNOS, cytokines, and MMP-9. In addition, five priority gaps were identified: lack of standardization, fragmented biomarker profiling, limited compound-specific validation, scarce clinical translation, and absence of omics-based and complex wound models. Conclusions: Potato-derived bioactive metabolites show multi-target preclinical associations with wound healing and warrant further development as potential adjunctive therapies for mucosal and cutaneous wounds after standardization and clinical validation. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular mechanisms to develop targeted therapies. Long non-coding RNAs (lncRNAs) play a critical role in cancer progression. However, the majority of lncRNAs involved in ESCC progression remain to be elucidated. Methods: We integrated bioinformatic analyses of the TCGA and GEO datasets to identify differentially expressed lncRNAs in ESCC, and the biological functions of the candidate lncRNA LINC01446 were investigated using loss-of-function assays in ESCC cell lines, including colony formation, wound healing, Transwell invasion, C11-BODIPY staining, malondialdehyde (MDA) quantification, and glutathione (GSH) evaluation. A nude mouse xenograft model was established for in vivo validation, and the underlying molecular mechanism was explored through RNA sequencing, fluorescence in situ hybridization (FISH), dual-luciferase reporter assays, AGO2-RIP, and rescue experiments. Results: LINC01446 was significantly upregulated in ESCC tissues and cell lines. Based on univariate analysis, high expression of LINC01446 was associated with poorer overall survival (OS). Functional studies showed that LINC01446 knockdown suppressed ESCC cell proliferation, migration, and invasion, promoted ferroptosis-related changes in vitro and was associated with increased lipid peroxidation and possible ferroptosis-related changes in vivo. Mechanistic analyses supported a regulatory relationship in which LINC01446 may function as a competing endogenous RNA (ceRNA) for miR-338-3p, thereby contributing to the upregulation of its downstream target, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1), in ESCC cells. Moreover, APEX1 was found to be overexpressed in ESCC and associated with poor OS. Conclusions: This study suggests that the LINC01446/miR-338-3p/APEX1 regulatory axis may contribute to ESCC progression and ferroptosis-related regulation. Additionally, LINC01446 and APEX1 represent promising prognostic biomarkers and therapeutic targets for ESCC. Full article

Thermoforming remains the predominant fabrication route for clear thermoplastic orthodontic appliances, yet it reduces and redistributes sheet thickness, which governs force delivered to teeth. Simultaneous thermoforming of two models may reduce fabrication time and material waste; however, its effect on final appliance thickness has not been evaluated. This in vitro study compared appliance thickness after thermoforming over a single model or two models simultaneously, using ten commercial aligner brands with different polymer composition and initial thickness. Thickness was measured with a digital caliper at anterior, canine and posterior sites, and analyzed using three-way ANOVA with Tukey post hoc tests. A significant three-way interaction (measurement point × number of models × brand; p < 0.001) was found. Significant single- versus dual-model differences emerged in some brand–region combinations; in most, dual-model appliances were thicker than single-model appliances. Four brands showed no significant difference at any site. Within the limits of this study, simultaneous fabrication of two appliances in a single thermoforming cycle produced appliances with thicknesses comparable to, and often slightly greater than, those fabricated over a single model. Simultaneous thermoforming maintained comparable appliance thickness and may improve manufacturing efficiency. Full article

CBL-B is an intracellular E3 ubiquitin ligase that acts as a T cell checkpoint by raising activation thresholds and limiting effector function. Here, genetic targeting of CBL-B enhances the performance of adoptively transferred T cells and CAR T cells under tumor microenvironment-like stress. In fully immunocompetent mouse models, Cblb deficiency or transient Cblb silencing improves control of MC-38 colon carcinoma and autochthonous mammary tumors, demonstrating that CBL-B restrains anti-tumor immunity. Cblb-deficient T cells show enhanced expansion and effector/effector-memory differentiation during an in vivo mixed lymphocyte reaction, confirming a cell-intrinsic brake function of CBL-B during sustained antigenic challenge. In a syngeneic Panc02-EpCAM model, Cblb-deficient anti-EpCAM CAR T cells show superior tumor control, enhanced infiltration, prolonged survival, and preserved effector function despite chronic antigen exposure and TGF-β. Mechanistically, Cblb targeting maintains granzyme B and IFN-γ production and is associated in vitro with increased GSDME-linked pyroptotic tumor cell death, consistent with features of immunogenic cell death. These findings extend previous CBL-B CAR T work from lymphocyte-deficient to immunocompetent settings and support CBL-B inhibition as a strategy to engineer CAR T cells that resist suppressive tumor microenvironments while promoting a more inflammatory mode of tumor killing. Full article

Pityriasis versicolor (PV) is a condition of the skin caused by the yeast Malassezia that manifests itself through scaly, well-demarcated patches with a dark, depigmented or erythematous coloration. Recurrence is common, and few treatment alternatives are available in the market. In this study, we aim to develop a body lotion for the improvement of PV skin with natural ingredients, such as essential oils and natural mineral waters. The antimicrobial activity of the selected ingredients was evaluated by the broth microdilution test, the volatile assay and the checkerboard assay. In addition, the cytotoxicity to HaCaT was assessed by the MTT assay. Finally, the most promising ingredients were combined in a formulation for topical application, and its efficacy and safety profile was assessed in vitro. Origanum vulgare essential oil was found to be the most active against M. furfur (MIC 0.625% v/v) and synergic with São Pedro do Sul natural mineral water (SPS NMW), while also being biocompatible with keratinocytes (EC50 < 0.06% v/v). The body lotion that was formulated with the most natural ingredients possible (>95%) and showed great activity against M. furfur, being able to reduce its growth by 100%; in addition, it was found to be a non-irritant in 3D reconstructed skin models. Full article

Background: Biofilm-associated microbial burden is a major barrier to wound healing and is increasingly difficult to control in the era of antimicrobial resistance. This translational study evaluated the antimicrobial performance and tissue compatibility of a commercially available large-area cold atmospheric plasma (CAP) system (CPTpatch^®/CPTcube^®; Coldplasmatech GmbH, Greifswald, Germany) across in vitro, porcine, and clinical patient settings. Methods: CAP was tested against seven wound-relevant bacterial species, including multidrug-resistant strains, and the fungus Candida albicans in vitro, in two porcine MRSA-infected deep dermal wound models, and in a clinical service-evaluation cohort of 20 chronic lower-limb wounds in 14 patients; 17 wounds had evaluable longitudinal MolecuLight^® (Toronto, ON, Canada) fluorescence series. Results: In vitro, CAP induced rapid multi-log killing across the bacterial panel and showed a marked antifungal effect against C. albicans. In porcine MRSA wounds, CAP reduced bacterial burden versus sham by 1.65, 1.89, and 2.04 log10 CFU/g on Days 4, 8, and 11, equivalent to 97.8%, 98.7%, and 99.1% reductions. In a 72-h post-inoculation MRSA biofilm model, the strongest 5×/week regimen achieved 2.51 log10 (99.69%) and 3.18 log10 (99.93%) reductions versus baseline after 2- and 4-min CAP exposures, respectively. Clinically, twice-weekly CAP was associated with a significant decline in MolecuLight^® fluorescence grades over 5 weeks (p < 0.001); effective surface disinfection at 5 weeks was observed in 16/17 evaluable wounds. Conclusions: From bench to bedside, the investigated CAP system delivered rapid broad-spectrum antimicrobial activity, reduced MRSA burden in biofilm-infected porcine wounds, and was associated with clinically measurable suppression of wound surface bioburden while remaining tissue-sparing. These findings support further controlled studies to define clinical benefit in wound care. Full article

This study aimed to investigate the regulatory effect of lipocalin-2 (LCN2) knockdown on DHODH-mediated mitochondrial ferroptosis in sepsis-induced myocardial injury (SIMI) and clarify the underlying STAT3-related molecular mechanism in a cecal ligation and puncture (CLP) mouse model and lipopolysaccharide (LPS)-stimulated HL-1 cardiomyocyte injury model. We established a classic cecal ligation and puncture (CLP)-induced SIMI mouse model. Pharmacological suppression of ferroptosis was performed to confirm the pathogenic role of ferroptosis in SIMI progression. Subsequently, LCN2-knockdown mice were utilized to explore the biological function of LCN2 in modulating myocardial ferroptosis and septic cardiac injury, and the direct protein interaction between LCN2 and DHODH was verified via molecular docking and co-immunoprecipitation assays. In vitro, we constructed stable DHODH-overexpressing HL-1 cardiomyocytes via lentiviral transfection and established a lipopolysaccharide (LPS)-induced cardiomyocyte injury model. The results showed that LCN2 expression was markedly upregulated in SIMI. Both GPX4- and DHODH-dependent mitochondrial ferroptosis were significantly activated during SIMI. Lentivirus-mediated DHODH overexpression exerted prominent protective effects against LPS-induced cardiomyocyte injury. Importantly, pharmacological blockade of DHODH by Brequinar reversed the reduction of p-STAT3 induced by LCN2 silencing. However, Fin56-mediated specific inhibition of mitochondrial GPX4 exhibited no significant effect on STAT3 phosphorylation level, revealing distinct regulatory mechanisms for these two pathways. In summary, LCN2 knockdown inhibits DHODH-mediated mitochondrial ferroptosis to alleviate SIMI. Pharmacological inhibition of DHODH abrogates the cardioprotective effect of LCN2 knockdown by restoring STAT3 phosphorylation. These findings provide novel insights into the prevention and treatment of sepsis-induced myocardial injury. Full article

Articular cartilage possesses a limited intrinsic repair capacity, and current treatment strategies frequently result in fibrocartilaginous repair tissue with inferior structural and mechanical properties compared with native hyaline cartilage. Increasing evidence indicates that successful restoration of joint function requires regeneration of the entire osteochondral unit and adequate integration between cartilage and subchondral bone. Cartilage tissue engineering has emerged as an effective approach for repairing damaged cartilage. The present study evaluated the long-term performance of electrospun PLA/PCL (70/30) scaffolds coated with iodine-doped polypyrrole (PPy-I), with and without aggrecan incorporation, in a rabbit osteochondral defect model after 12 months of implantation. Two scaffold formulations were evaluated: M1 (PLA-PCL-PPy-I) and M2 (PLA-PCL-PPy-I-AG), each implanted either without cells or after in vitro pre-culture with autologous chondrocytes prior to implantation. Histological analyses were performed to assess tissue organization and osteochondral integration, while indentation testing was used to characterize the mechanical behavior of the regenerated tissues. Experimental force–displacement data were further analyzed using a generalized nonlinear Maxwell viscoelastic model. Histological evaluation revealed that scaffold composition and cellularization influenced the characteristics of the regenerated tissue. The M2 scaffold pre-cultured with autologous chondrocytes exhibited the structural organization most closely resembling native hyaline cartilage, including a tri-zonal architecture and a continuous tidemark indicative of improved osteochondral integration. Mechanical testing demonstrated nonlinear viscoelastic behavior and hysteresis in both regenerated and native tissues. The proposed generalized nonlinear Maxwell viscoelastic model provides a practical framework for the mechanical characterization of regenerated osteochondral tissues using only two effective parameters representing the elastic and viscous response, and may support future studies aimed at estimating their intrinsic mechanical properties. Full article