Background/Objectives: Antibiotics are the recommended first-line therapy for acute uncomplicated lower urinary tract infections (cystitis), but antibiotic resistance and tolerability concerns require antibiotic-sparing strategies. This study evaluated D-mannose as a stand-alone alternative. Methods: This multicenter, randomized, controlled, double-blind study compared D-mannose to fosfomycin in women aged 18-70 with cystitis. Clinical cure (CC) was assessed using the Acute Cystitis Symptom Score (ACSS) up to day 8, with non-inferiority tested at the 15% margin. Post hoc analytical approaches accounted for potential bias due to low sample sizes and missing values. Results: The study randomized 118 patients. At baseline, severe symptoms (ACSS ≥ 12) were more frequent in the D-mannose group compared to fosfomycin (32.8% vs. 22.8%). Efficacy analyses were performed on the per-protocol set (D-mannose: N = 57; fosfomycin: N = 54). Median time to CC was 5.0 days (D-mannose) and 3.0 days (fosfomycin) overall, and 4.0 days vs. 3.0 days in the subgroup of moderate disease severity. The point estimate for the CC rate difference on day 8 (-10.1%) favored fosfomycin but was within the non-inferiority margin. Due to wide confidence intervals, non-inferiority was not statistically confirmed. The post hoc analysis yielded smaller confidence intervals with estimated CC rates of 84.2% (D-mannose) vs. 83.5% (fosfomycin) on day 8 and statistically demonstrated the comparability of both treatments. Recurrence rates were similar (13.2% vs. 13.3%), and there was no statistically significant difference for additional antibiotic use (19.3% vs. 11.1%). Investigators and patients favored D-mannose over fosfomycin for tolerability, and gastrointestinal adverse events were less frequent (9.8% vs. 24.6%). Conclusions: Post hoc analysis indicated that D-mannose treatment is comparable to fosfomycin in uncomplicated cystitis in line with the prespecified non-inferiority criteria. These findings warrant confirmation in an adequately powered trial but suggest that D-mannose is a promising alternative to antibiotics given its favorable risk-benefit ratio.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited mechanism-based therapies, and ferroptosis-an iron-dependent lipid peroxidation-driven cell death-has emerged as a critical pathogenic event. Using a machine learning model that combines molecular fingerprints and transfer learning representations to screen for ALOX15 inhibitors, we identified rosmarinic acid (RA) from natural product libraries. RA exhibited high-affinity binding to ALOX15 and maintained stable complex conformation in molecular dynamics simulations. In dextran sulfate sodium-induced colitis mice and lipopolysaccharide-treated intestinal epithelial cells (IEC-6 and mouse colonic epithelial cell), RA alleviated disease activity index, colon shortening, histological damage, and barrier protein loss (ZO-1, Occludin, and Claudin-1). Mechanistically, RA suppressed ferroptosis by restoring GPX4, SLC7A11, and FTH1; reducing ACSL4, COX-2, and lipid reactive oxygen species (ROS); and lowering intracellular Fe2+ and malondialdehyde. Crucially, RA disrupted the ALOX15-VDAC1 protein complex, preserved mitochondrial membrane potential, and reduced mitochondrial ROS, effects that were abrogated by ALOX15 knockdown or VDAC1 knockdown. Serum metabolomics further revealed that RA remodels lipid metabolism pathways (arachidonic acid and linoleic acid metabolism) linked to ferroptosis. Collectively, this artificial intelligence-driven discovery positions RA as a novel ferroptosis inhibitor that targets the ALOX15-VDAC1 axis, offering a promising therapeutic candidate for UC.

Selective bacterial preconcentration remains a key challenge for improving downstream molecular detection. Here, we report carboxymethyl-dextran (CMD) coated magnetic nanoparticle clusters functionalized with lytic T4 bacteriophages (phage@CMD) for selective capture of Escherichia coli. Iron-oxide particles were synthesized by coprecipitation and characterized by dynamic light scattering (DLS), Fourier transform infrared (FT-IR) spectroscopy, and electron microscopy, revealing CMD-stabilized nanoparticle clusters with a hydrodynamic diameter of approximately 181 nm with moderate dispersity (PDI = 0.267). T4 phages were immobilized via EDC/Sulfo-NHS chemistry, yielding a functional loading of ∼5.54 × 1012 PFU-equivalent g-1 (∼0.053 phage per particle). An empirical Langmuir-type analysis was used solely to estimate surface loading capacity. Phage-functionalized particles enabled magnetic capture of E. coli, resulting in experimentally determined separation efficiencies of ∼20-40%, verified by CFU depletion and PCR analysis of particle-associated fractions. Magnetic preconcentration improved the practical PCR input threshold compared to direct amplification of untreated suspensions. While the study represents a proof-of-concept in laboratory media, limitations including random phage orientation, partial loss of activity after immobilization, and lack of complex-matrix validation are discussed. These findings support the use of phage@CMD as a modular magnetic preconcentration platform for bacteria prior to nucleic-acid-based analysis.

Mesenchymal stem cell-derived exosomes represent a promising therapeutic avenue for tissue regeneration, yet their clinical translation is hindered by rapid clearance following systemic administration and the lack of optimized, sustained-release delivery strategies. To address these challenges, we crafted a biomimetic hydrogel to carry and gently release MSC-derived exosomes. We engineered a biocompatible, dextran-based composite hydrogel (carboxymethyl chitosan-oxidized dextran/tannic acid-iron complex, CMC-OD/TA-Fe(III)) for the encapsulation and sustained release of human umbilical cord MSC-derived exosomes. We systematically compared the organ biodistribution of exosomes delivered via this hydrogel platform using three distinct local routes: intraperitoneal injection, oral (intragastric) administration, and rectal administration, employing in vivo imaging and tissue immunofluorescence analyses in C57BL/6J mice. Following a single intraperitoneal dose, released exosomes accumulated primarily in the liver and spleen, with minimal brain enrichment. Notably, both oral and rectal administration-non-invasive alternatives to injection-facilitated considerable exosome dissemination to multiple organs. The significant distribution observed via the oral route specifically challenges the prevailing assumption regarding the inefficacy of gastrointestinal delivery for exosome-based therapeutics. This study provides critical insights into administration-route-dependent biodistribution patterns and proposes novel, non-invasive delivery strategies to enhance the therapeutic efficacy and application scenarios of exosomes.

Iron deficiency remains the most prevalent nutritional disorder worldwide. Conventional ferrous supplements are prone to oxidation into poorly bioavailable ferric iron and may induce free radical damage. To address this, this study developed a novel iron delivery system (WPHF-DEX-Fe) based on the covalent grafting of enzymatically hydrolyzed whey protein fibrils (WPHF) with oxidized dextran. Controlled grafting was achieved via a mild wet-heating Maillard reaction. Ultraviolet-visible spectroscopy (increased A₂₉₄ without a rise in A₄₂₀) confirmed the formation of Schiff bases without significant browning. Grafting induced conformational adjustments in the protein, significantly (p < 0.05) enhancing the antioxidant capacity of the complex; the superoxide anion scavenging efficiency of WPHF-DEX was 2.1 times that of the unmodified protein fibrils (WPF). This system effectively stabilized ferrous iron, with X-ray photoelectron spectroscopy analysis revealing an Fe2+ proportion of 77%. After 15 days of storage at 50 °C and 75% relative humidity, its ferrous retention remained at 45.6%, which is 18.6 times higher than that of WPF-Fe. In vitro digestion studies indicated that after rapid iron release in the gastric phase, iron bioaccessibility stabilized under neutral intestinal conditions while maintaining a high proportion of Fe2+, suggesting possible re-integration into a stable complex. This behavior is conducive to iron bioaccessibility and may reduce intestinal irritation. Cell experiments confirmed the good biocompatibility of the material, with iron uptake by Caco-2 cells being 1.3 times that of the ferrous sulfate group. These results demonstrate that WPHF-DEX-Fe is a potential nutraceutical carrier capable of synchronously improving iron stability and bioavailability, offering a new strategy for developing efficient iron supplements.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options and high relapse rates. Live bacterial therapeutics (LBTs) offer a promising alternative by restoring mucosal integrity, modulating immunity, and rebalancing gut microbiota; however, their clinical translation is constrained by poor storage stability, low gastrointestinal survivability, and limited therapeutic functionality. Here, we report a multilevel, modular encapsulation strategy that integrates a metal-polyphenol network (MPN) and silica-based shell with iron-based metal-organic framework (MIL-101(Fe)) nanocomponents to construct a biohybrid probiotic system (Bif@FCSM(A), where "A" denotes 5-aminosalicylic acid). This hierarchical assembly forms an oxygen-shielding, mechanically reinforced shell, resulting in a 41-fold improvement in aerobic storage stability and an 871-fold enhancement in gastric survivability of the anaerobe Bifidobacterium longum. Incorporation of MIL-101(Fe) enables high-capacity drug loading and inflammation-responsive disassembly via transferrin (Tf)-mediated Fe[3] [+] chelation in inflamed colonic tissue, thereby achieving spatiotemporally controlled bacterial activation and drug release. Guided by UC transcriptomic signatures, this combinatorial design concurrently targets immune dysregulation and microbial imbalance. In a dextran sulfate sodium-induced murine UC model, Bif@FCSM(A) markedly alleviated disease severity, suppressed pro-inflammatory cytokines, restored mucosal immune homeostasis, and enriched short-chain fatty acid-producing taxa. This work establishes a programmable, pathology-responsive probiotic platform with translational potential for complex inflammatory diseases.

Iron deficiency is the primary nutritional deficiency globally and iron dextran nanoparticles (IDN) are used for supplementation. Here we have applied theoretical, computational and experimental studies to understand the behavior of IDN and its interaction with a micrometric crosslinked gelatin scaffold (MCGS) to potentially develop a drug delivery system. Modeling single IDN reveals a complex network of interactions ranging from strong coordination bonds to weak van der Waals forces. Computational analyses reveal that multiple IDN (4 units) exhibit self-aggregation from 100 ns. In the presence of collagen (used to simulate MCGS), disaggregation occurs. The IDN-MCGS interactions are preferentially established (16-18 %) with the smaller/flexible amino acids alanine, proline and glycine. We hypothesize that the disaggregation of IDN in the presence of collagen is responsible for the low encapsulation efficiency (6.2-8.3 %) and low loading charge (1.9-3.7 %) during experimental encapsulation in MCGS (14-21 μm). X-ray diffraction reveal the absence of new crystalline arrangements resulting from the IDN-MCGS formulation. This is the first time that theoretical, computational and experimental studies were applied to IDN, multiple IDN and interactions with MCGS. These tools could be used for other protein scaffolds to predict drug encapsulation and delivery.

Iron deficiency anemia (IDA) is one of the most common nutritional disorders worldwide. However, traditional iron supplement often induces adverse gastrointestinal effects (e.g. nausea, vomiting, abdominal pain) due to their gastrointestinal irritation and poor bioavailability. To overcome this defect, we designed an antioxidative whey protein hydrolysate fibril-dextran (WPHF-DEX) complex system, which can delivery low-irritant and highly biocompatible iron oxide by in-situ co-precipitation and enhancing iron bioavailability. After mixing with WPH and grafting with dextran, the antioxidant of WPHF-DEX was significantly improved. Moreover, the more iron oxide binding sites of fibril was exposed. FTIR spectroscopy showed that the WPHF-DEX can bind to iron oxide via a coordination bond, and the WPHF-DEX‑iron oxide (WPHF-DEX-Fe) complex had good stability. In vitro digestion indicated that the WPHF-DEX could maintain the oxidation state of iron in the intestine, reducing the irritation to the gastric mucosal. Furthermore, this stabilized iron form and WPHF-DEX encapsulation significantly enhanced subsequent absorption by the intestine. The iron bioavailability of WPHF-DEX-Fe was 1.4-folds than that of FeSO4in vitro without observable cytotoxicity. Therefore, the WPHF-DEX composite system can become a novel iron oxide delivery system with high loading capacity and bioavailability.

The present study focuses on developing novel gradient thin films for surface-based magnetic resonance imaging of fluids such as water. Four types of magnetic-polymer colloids were investigated as T2 contrast agents, including Janus magnetic-polystyrene and core-shell magnetic-poly(styrene/divinylbenzene/methacrylic acid) particles. These colloids were coated with amino dextran to enhance their performance. Key factors such as emulsion composition, particle size, and surface properties were systematically examined. Gradient thin films were fabricated on glass slides using a layer-by-layer self-assembled multilayer (LbL-SAMu) technique. The films consisted of positively charged poly(dimethyl diallyl ammonium chloride) and negatively charged magnetic-polymer colloids. The developed colloids and thin films were characterized by their surface wettability, surface morphology, and zeta potential. These films exhibited relatively improved hydrophilicity and T2 contrast. The utilization of such gradient thin films as molecular probes could enhance clinical MRI for in vitro diagnosis. This study indicated that thin-film gradients can offer a facile technique for unique cellular imaging via a lab-on-chip device to enable effective point-of-care molecular diagnostics.