Chronic kidney disease–mineral and bone disorder (CKD-MBD) confers a substantial fracture burden that is only partly addressed by therapies targeting phosphate, parathyroid hormone, and vitamin D. Redox dysregulation may represent a complementary mechanism: reactive oxygen species (ROS) are required for receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclastogenesis, whereas excessive ROS impair Wnt/β-catenin signalling in osteoblast precursors and promote osteocyte dysfunction. Uremic toxins, inflammation, and dialysis further increase oxidative stress. Molecular hydrogen (H2) is a highly diffusible redox modulator that has been proposed to limit damaging radical-chain reactions while preserving physiological oxidant signalling. In non-uremic skeletal models, H2 consistently suppresses osteoclast differentiation and bone loss, but evidence for osteoblast rescue is heterogeneous. In CKD and dialysis, H2-based interventions have shown signals of reduced oxidative stress and symptomatic benefit; however, human evidence is predominantly observational, and no study identified in this review assessed a bone-specific endpoint. We therefore integrate uremic bone redox biology with H2 pharmacology and propose a turnover-state-dependent model in which H2 may restrain excessive resorption in high-turnover disease, while its net effect in low-turnover adynamic bone remains uncertain because potential osteoblast rescue competes with anti-osteoclastic activity established only in non-uremic models. H2 should therefore be considered an experimental, mechanistically differentiated strategy requiring direct evaluation in uremic models and turnover-stratified clinical trials with parallel skeletal and vascular safety endpoints.
Colorectal cancer (CRC) exhibits substantial metabolic heterogeneity, but the organization of sphingolipid remodeling remains incompletely understood. In this exploratory single-center study, we integrated patient-matched tissue lipidomics, systemic oxidative stress profiling, and independent transcriptomic analyses. Tumor tissue, adjacent non-neoplastic mucosa, and preoperative serum were collected from 40 patients with CRC, with serum obtained from 23 hospitalized non-cancer controls. Sphingolipids were quantified by UHPLC–MS/MS, while total antioxidant capacity, total oxidant status, and oxidative stress index characterized systemic redox status. Paired lipidomics revealed coordinated remodeling with increased S1P-associated measures, selective ceramide depletion, and elevated S1P-to-ceramide ratios. Multivariate analyses did not identify stable discrete lipidomic subgroups and revealed variation consistent with a continuum-like organization within the measured sphingolipid feature space. In separate principal component analyses, ratio-derived variables showed a more concentrated low-dimensional covariance structure than absolute lipid concentrations. Circulating sphingolipids showed limited correspondence with tumor-local remodeling, whereas oxidative stress markers showed strong apparent discrimination between CRC and hospitalized non-cancer controls, although this finding may be affected by residual confounding. TCGA–GTEx analyses provided complementary pathway-level transcriptomic context, while anatomically resolved analysis of 374 TCGA tumors identified 3376 genes significantly associated with colorectal anatomical position, including six sphingolipid-related genes. Overall, these exploratory findings support a conceptual CRC Metabolic Continuum while requiring validation in larger, independent cohorts.
Background: Chronic autoimmune thyroiditis (CAT) is characterized by persistent autoimmune activity and increased oxidative stress, which may contribute to thyroid follicular injury and disease progression. Photobiomodulation (PBM) has shown potential beneficial effects on thyroid function and autoimmunity; however, its independent effect on systemic antioxidant status, particularly serum glutathione (GSH), has not been established. This study aimed to evaluate the effect of thyroid-directed PBM on serum GSH concentrations and thyroid-related outcomes in treatment-naïve euthyroid women with CAT. Methods: This prospective, non-randomized, open-label, parallel-group comparative interventional study included 50 treatment-naïve euthyroid women with CAT. Participants were allocated to receive either thyroid-directed transdermal PBM (n = 25) or selenium plus vitamin D supplementation (n = 25). The primary outcome was the change in serum GSH concentration. Secondary outcomes included changes in thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti-thyroid peroxidase antibodies (anti-TPO), anti-thyroglobulin antibodies (anti-Tg), thyroid volume, and anthropometric parameters. Assessments were performed at baseline (T0), after the intervention period (T1), and three months after intervention completion (T2). Results: A significant time × group interaction was observed for serum GSH concentrations (F = 19.101, p < 0.0001). Significant interactions were also observed for anti-TPO (F = 7.513, p = 0.001), anti-Tg (F = 7.389, p = 0.002), and thyroid volume (F = 13.081, p < 0.0001). In the PBM group, GSH increased from baseline to T1 and remained higher at T2, while TSH, anti-TPO, anti-Tg, and thyroid volume decreased, and FT3 and FT4 increased. No significant longitudinal changes in GSH or thyroid autoantibodies were observed in the supplementation group. No participant in the PBM group required levothyroxine (LT4) initiation during follow-up, whereas 24% of participants in the supplementation group initiated LT4 therapy at T1, with some requiring dose escalation by T2. Conclusions: Thyroid-directed PBM was associated with improved systemic GSH status and favorable changes in thyroid autoimmunity, thyroid function parameters, and thyroid volume compared with selenium plus vitamin D supplementation in treatment-naïve euthyroid women with CAT. These findings suggest that modulation of oxidative stress may represent one potential biological pathway underlying the observed effects of PBM. Larger randomized controlled studies with longer follow-up are required to confirm these findings and define the clinical role of PBM in autoimmune thyroid disease.
Polyphenolic antioxidants are incorporated into pharmaceutical, dermopharmaceutical, and cosmetic products because of their capacity to modulate oxidative stress, inflammation, microbial imbalance, skin aging, wound repair, and tumor-related processes. However, formulation is constrained by chemical instability, limited bioavailability, insufficient skin permeation, and degradation during processing or storage. This review integrates the chemical characteristics, natural sources, extraction approaches, antioxidant mechanisms, and evaluation of curcumin and chlorogenic acid, and critically examines their delivery through liposomes, niosomes, ethosomes, and transethosomes. Curcumin is lipophilic and poorly water-soluble, whereas chlorogenic acid is hydrophilic but permeability-limited. Their antioxidant activity is discussed through hydrogen atom transfer, single-electron transfer, interruption of lipid peroxidation, metal chelation, and localization within lipid interfaces, together with chemical, biomimetic, and cellular assessment methods. Vesicular carriers can improve encapsulation, stability, release control, skin interaction, biological performance, and incorporation into semisolid dosage forms. However, these benefits are accompanied by formulation-dependent trade-offs involving manufacturing complexity and cost, long-term stability and reproducibility, excipient-related skin tolerability, scale-up, and an application scope that depends on the intended dermal-delivery endpoint. Therefore, efficacy depends on the interplay among antioxidant properties, vesicle architecture, excipient selection, and processing conditions. Curcumin-loaded vesicles are better documented than chlorogenic-acid-loaded systems, particularly for deformable carriers. Future progress requires quality-by-design strategies, standardized characterization, predictive skin models, long-term stability and safety studies, and scalable manufacturing. Overall, antioxidant-loaded vesicles represent multifunctional platforms for developing stable and effective pharmaceutical and cosmetic products.
The global rise of antibiotic-resistant Pseudomonas aeruginosa (PA) necessitates the development of novel therapeutic approaches. Polyclonal antibodies constitute a promising approach, as they target multiple bacterial epitopes and functions. Moreover, they have recently demonstrated renewed clinical applicability in their humanized format. We developed a glyco-humanized polyclonal antibody (GH-pAb) targeting PA by immunization of pigs with five PA serotypes frequently encountered in clinical settings. This pentavalent GH-pAb, named XAB06, exhibited binding activity against the five serotypes used for the immunization, as well as unrelated PA serotypes. No binding activity was observed against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, or Acinetobacter baumannii, demonstrating the specificity of XAB06 against PA. In addition, XAB06 showed no reactivity against human blood cells. Functional assays revealed that XAB06 significantly inhibited swarming motility, biofilm formation, and pyocyanin production, indicating interference with key virulence determinants of PA. Notably, XAB06 conferred protection in a murine model of sepsis using the reference strains PAO1, PA103, and a ST235 high-risk clone. Collectively, these findings demonstrate the broad PA coverage and the protective activity of XAB06, supporting its potential as a novel therapeutic strategy against PA.
Treatment of symptomatic patients with coccidioidomycosis often involves the use of triazole antifungals. There is concern for reduced susceptibility of Coccidioides to fluconazole, as a high percentage of isolates were previously reported to have elevated fluconazole MICs. We reviewed our recent azole MICs against Coccidioides and examined temporal trends over a 20-year period. Our clinical laboratory database was queried for data against Coccidioides between 2006 and 2025, and trends in GM MICs and the percentage of isolates with elevated MICs to the azoles were assessed. All testing had been performed by broth dilution according to Clinical and Laboratory Standards Institute (CLSI) M38 methods. The results over the 10-year period from 2016 to 2025 were compared to those previously reported by our group from 2001 to 2015. Overall, the results between the two periods showed similar MIC parameters and distributions for fluconazole, itraconazole, posaconazole, and voriconazole, with posaconazole demonstrating the most potent activity, while fluconazole demonstrated reduced susceptibility. Isavuconazole MIC parameters were available during the second period and similar to those of voriconazole. Weak correlations were observed between fluconazole MICs and those of the other azoles. Fluctuations in GM MICs and the percentage of isolates with elevated MICs were observed with fluconazole, itraconazole, and posaconazole, with elevated values observed between 2011 and 2019. Continued surveillance is needed, and outcome data are required to determine if the consistently reduced susceptibility observed with fluconazole or in those infected with strains that have higher MICs results in poorer outcomes in patients with coccidioidomycosis.
Piperacillin-tazobactam is commonly used in critically ill pediatric patients; however, standard dosing regimens may not reliably achieve maximally effective exposures in this population. To characterize the population pharmacokinetics of piperacillin-tazobactam in critically ill pediatric patients and evaluate the adequacy of commonly used dosing regimens, plasma concentrations were obtained around a single dose of piperacillin-tazobactam in critically ill pediatric patients aged 1 month to 12 years. A simultaneous population pharmacokinetic model for piperacillin and tazobactam was developed using nonlinear mixed-effects modeling. Monte Carlo simulations were performed to assess the probability of target attainment (PTA) for short, extended, and continuous infusion regimens across a range of ages and renal function states. Dosing adequacy was defined by simultaneous attainment of target drug exposures for piperacillin (100%fT > MIC) and tazobactam (85%fT > 2 mg/L). Thirty-one patients contributed 102 plasma samples, of which only 22.6% of patients achieved simultaneous piperacillin-tazobactam target exposures, considering a piperacillin MIC of 16 mg/L. Renal function and infusion duration were the primary determinants of attainment of target attainment. Standard short infusions frequently failed to achieve combined target exposures, particularly in patients with preserved renal function or augmented renal clearance (ARC). Extended infusions improved PTA, but remained suboptimal at higher MICs. Continuous infusion consistently achieved the highest target drug exposures across all simulated scenarios. Short intermittent piperacillin-tazobactam infusions and even extended infusions often result in suboptimal exposure in critically ill pediatric patients. Continuous infusion represents a rational dosing strategy to improve combined target attainment, particularly in children with preserved or ARC.
Nosocomial Pseudomonas aeruginosa infections are among the most challenging infections to treat, and resistance to last-line agents, including polymyxins and aztreonam-based therapies, risks a future with limited or no clinical treatment options. Bacteriophages (phages) have emerged as a promising therapeutic option, both in cocktails and when given in combination with antibiotics. In this study, we show that the synergy between a lipopolysaccharide (LPS)-specific phage and antibiotics is driven by clinically relevant increases in beta-lactam permeability due to the selection of phage-resistant subpopulations. First, in the Hollow Fiber Infection Model (HFIM), we show that the combination of phage LUZ19 (pili-targeted), phage E215 (LPS-specific), and aztreonam (ATM) eradicated the laboratory host PAO1, whereas monotherapy with neither phage nor ATM could eradicate PAO1. Static time-kill studies (STKS) evaluated the LPS-specific phage PYO2 in combination with either aztreonam/avibactam (ATM/AVI) or polymyxin B (PMB) against an extensively drug-resistant clinical isolate of P. aeruginosa (AR-0231). PYO2 combined with ATM/AVI was determined to be synergistic, with a mean excess-over-bliss (EOB) of 0.350 (P < 0.05), while PYO2 with PMB was also synergistic, with a mean EOB of 0.361 (P < 0.05). Linear regression of STKS using sequential administration showed that, compared to antibiotic-first treatment, phage-first treatment reduced bacterial concentrations at 24 h by -6.19 log10 colony-forming unit (CFU)/mL (P < 0.05), with statistically significant interactions estimated for each antibiotic. These results indicated that bacterial pre-selection by PYO2 improved antibiotic activity. Mass spectrometry studies showed that the PYO2-resistant AR-0231 strain exhibited a >25% increase in the outer membrane permeability surface area coefficient for all major anti-Pseudomonal beta-lactams, including aztreonam. Altogether, our study provides mechanistic insights into phage-induced collateral sensitivity of beta-lactams. These results show how specific beta-lactams can be prioritized and optimized in phage-antibiotic combinations to maximize the antibacterial activity.
Porphyromonas gingivalis (Pg) is a keystone periodontal pathogen associated with biofilm formation and gingipain-mediated virulence. This study evaluated the antioxidant, antibacterial, antibiofilm, and antivirulence activities of a hexane extract of Lycopus lucidus (LLH) and its eight chromatographic fractions (H1–H8). Antioxidant activity was assessed using DPPH and ABTS radical-scavenging assays, whereas antibacterial activity, biofilm formation, and virulence-associated gene expression were evaluated using corresponding in vitro assays. LLH exhibited antioxidant and antibacterial activities, while H4 showed the strongest overall biological activity among the fractions. The DPPH IC50 values of LLH and H4 were 98.33 ± 2.05 and 60.67 ± 3.09 µg/mL, respectively, and the corresponding ABTS IC50 values were 89.24 ± 1.67 and 28.15 ± 1.21 µg/mL, respectively. H4 also showed greater inhibition of biofilm formation than LLH and more pronounced downregulation of several virulence-associated genes. LC–MS/MS analysis tentatively identified α-cyperone as a constituent of H4. Overall, chromatographic fractionation of LLH yielded H4 with enhanced biological activity across several measured endpoints, including radical-scavenging, antibacterial, and antibiofilm effects, together with more pronounced suppression of several virulence-associated genes. However, the contribution of α-cyperone or other individual constituents to these effects remains to be established.
Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as a potential therapeutic strategy. Primary keloid fibroblasts (KFs), normal skin fibroblasts (NFs), adipose-derived stem cells (ADSCs), human keloid tissues, and human keloid xenografts in immunodeficient BALB/c nude mice were analyzed using ultrastructural, molecular, and functional approaches. Freshly isolated NF-derived mitochondria (nMito) and ADSC-derived mitochondria (aMito) were compared at protein-equivalent doses. KFs exhibited mitochondrial abnormalities, impaired oxidative phosphorylation, increased reactive oxygen species, mtDNA leakage, and cGAS/STING pathway activation. Elevated PINK1 expression, reduced Parkin expression and p62 accumulation were consistent with impaired downstream mitophagic clearance. Both nMito and aMito were associated with improved mitochondrial function, changes in mitophagy-related markers, reduced cytosolic mtDNA and cGAS/STING signaling, and attenuated fibroblast activation, with greater aMito-associated changes in selected endpoints. In xenografts, intralesional administration of either mitochondria improved collagen organization and reduced fibrotic and inflammatory signaling. Together, these findings link altered PINK1/Parkin-dependent mitophagy to mtDNA-driven inflammation and fibrosis and support mitochondrial transplantation as a potential organelle-based therapeutic approach.
High-grade osteosarcoma presents a significant clinical challenge due to unpredictable therapeutic responses and aggressive progression. This study aimed to identify the critical molecular pathways driving chemotherapy resistance and aggressive phenotypes in osteosarcoma patients. Through transcriptomic and bioinformatic analyses, we identified cholesterol biosynthesis as a key upregulated metabolic pathway in poor chemotherapy responders, where squalene epoxidase (SQLE) emerged as an exploratory candidate hub gene whose elevated expression significantly correlates with shortened survival in the TCGA cohort. We validated these findings by administering terbinafine, a known SQLE inhibitor. In highly chemoresistant SaOS-2 cells exhibiting the highest baseline SQLE expression, terbinafine synergistically sensitized cells to doxorubicin by driving cell death partly through apoptosis, as confirmed by caspase inhibition. The combination also promoted ferroptosis, indicated by elevated ROS and MDA along with decreased FSP1 and GPX4 expression. Furthermore, the co-treatment effectively suppressed clonogenic potential, induced G2/M phase cell cycle arrest, and inhibited metastatic progression. These effects were mediated by the modulation of cell proliferation, metastasis, and survival genes through the coordinated regulation of the PI3K/AKT/mTOR, ERK, and JNK signaling cascades. Together, these results highlight the therapeutic potential of targeting the SQLE pathway to overcome doxorubicin resistance and suppress aggressive progression in high-grade osteosarcoma.
Amniotic oxidative stress in women with vaginal infection but no documented intra-amniotic infection has received little attention. In this prospective cohort study of 90 women undergoing elective cesarean delivery, 45 had symptomatic, culture- or Nugent-confirmed vaginal infection and 45 were asymptomatic controls. Amniotic fluid advanced oxidation protein products (AOPP) and malondialdehyde (MDA) were measured by commercial ELISA. Both were higher in the infection group (median 7.96 versus 5.77 ng/mL and 12.49 versus 7.73 nmol/mL, both p < 0.001), with lower cord blood pH (p = 0.003) and more frequent neonatal intensive care unit (NICU) admission (26.7% versus 4.4%, p = 0.007). AOPP was associated with NICU admission (area under the curve 0.917, 95% CI 0.777 to 0.999), although this rests on 14 events with thresholds derived and evaluated in the same sample. Elevations were largest in the bacterial vaginosis and aerobic bacterial subgroups, but the etiologies did not differ. Both kits were designed for serum and are not validated for amniotic fluid, and 16.7% of MDA measurements fell outside the calibration range, so the MDA results are semi-quantitative. Vaginal infection at cesarean delivery is associated with higher amniotic oxidative stress markers; these findings are exploratory and require external validation.
HIV infection remains a critical global public health concern. A potential long-acting therapeutic agent, 4'-ethynyl-2-fluoroadenosine analog 1c (CL-197), was investigated in a first-in-human phase 1 clinical trial. This single-center, randomized, double-blind, dose-escalation, placebo-controlled study assessed the safety and pharmacokinetics (PKs) of five doses of CL-197 (1, 10, 30, 60, and 100 mg) in healthy adults aged 18-45 years. The 1 mg group was open-label (n = 4), while the other groups were randomized 4:1 to CL-197 or placebo. The primary endpoints were safety and tolerability. The PK evaluation involved the characterization of systemic exposure parameters (based on plasma drug concentrations and peripheral blood mononuclear cell [PBMC] drug concentrations) and urinary excretion parameters. CL-197 was well tolerated at all dose levels. The most frequently reported adverse reactions were sinus arrhythmia, followed by decreased apolipoprotein B, decreased blood iron, increased triglycerides, and elevated low-density lipoprotein. Plasma PKs showed dose-proportional exposure, with a mean time to maximum plasma concentration (Tmax) of 0.50-1.00 h. As the dose increased, the elimination time was prolonged. The plasma drug concentrations were approximately dose-proportional, whereas AUC 0-t and AUC 0-∞ exhibited non-linear characteristics within the range of 1-100mg, with the mean elimination half-life (t1/2) increasing from 1.39 to 10.20 h across doses. The mean t1/2 in PBMCs was 61.29 h and 43.80 h in the 30 mg and 60 mg dose groups, respectively, and the median Tmax was 12 h. In conclusion, a single administration of CL-197 demonstrated an acceptable safety profile in younger adults. The intracellular CL-197-TP in PBMCs had a long half-life, providing preliminary support for the potential use of extended dosing intervals in further development.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05944848.
The prevalence of non-susceptibility to ceftolozane-tazobactam (C/T) among Pseudomonas aeruginosa remains low, but novel mechanisms of C/T resistance are of concern. Herein, we describe a novel P. aeruginosa genotype associated with high-level C/T resistance (>256/4 µg/mL) in a single patient. Whole-genome sequencing of the isolate was compared to that of a susceptible isolate cultured from the same patient 2 months earlier. Analysis of the sequences revealed two different P. aeruginosa high-risk clones: sequence type (ST)111 followed by ST235. The C/T-resistant ST235 isolate contained five copies of a genetic element composed of an L2 β-lactamase gene (blaL2) and a truncated ampRL2 transcriptional regulator gene, which are commonly found together in Stenotrophomonas maltophilia strains and have not been reported to mediate resistance to C/T. Comparative genomic analysis with other P. aeruginosa isolates failed to identify alternative explanations for the observed C/T resistance. We found that exogenous expression of blaL2 increased C/T minimum inhibitory concentrations (MICs) in genetically distinct P. aeruginosa strains. A screen of our archived isolates identified two P. aeruginosa clinical isolates, PS2045 and PS2046, with one and two copies, respectively, of the genetic element containing blaL2 and truncated ampRL2. Interestingly, disruption of the gene blaL2 but not the truncated ampRL2 in PS2045 led to a decrease in C/T MIC. Thus, we report a novel mechanism of C/T resistance in P. aeruginosa partially mediated by an L2 β-lactamase independently of its canonical regulator, AmpRL2.
Skin aging is a complex process influenced by oxidative stress, protein glycation, chronic inflammation, and increased extracellular matrix remodeling. Intensive research is underway on new anti-aging substances with multi-target mechanisms of action while maintaining safety and efficacy. Ergothioneine, selenoneine, and ovothiol A are natural histidine derivatives of marine origin, in which the oxygen atom of the hydroxyl group has been replaced with sulphur or selenium. In recent years, a broad spectrum of their biological activity has been demonstrated. Despite the well-documented antioxidant potential of these compounds, their anti-aging effects, particularly in terms of antiglycation and anti-inflammatory activity, remain insufficiently understood. This study presents the current state of knowledge regarding the biological activity of ergothioneine, selenoneine, and ovothiol A, and discusses available cosmetic preparations and dietary supplements containing these compounds. Meanwhile, significant research gaps have been identified regarding their potential use in the prevention and treatment of skin aging.
Successful embryo implantation requires intimate crosstalk between the blastocyst and the uterine epithelium within a defined window of receptivity. However, the metabolic signals that mediate this process in mammals remain poorly understood. In this study, pregnant mice, primary uterine cell culture and uterine epithelial organoids were used to examine the regulation and function of heme oxygenase-1 (HO-1) during mouse embryo implantation and decidualization. We demonstrate that embryo-derived lactic acid drives heme catabolism and regulates epithelial receptivity in mice through a hypoxia-inducible factor 1α (HIF1α) -heme oxygenase-1 (HO-1) signaling axis. Specifically, lactic acid stabilizes HIF1α to induce HO-1 expression in uterine epithelial cells by promoting von Hippel-Lindau (VHL) nucleolar sequestration and downregulating PHD2/3. Additionally, lactic acid suppresses the transcriptional repressor BACH1, further facilitating HO-1 induction. At physiological heme levels, HO-1-derived bilirubin promotes epithelial receptivity by increasing phosphorylated STAT3 (p-STAT3) and downregulating MUC1. A low dose of hemin promotes epithelial receptivity and decidualization, whereas a high dose of hemin suppresses these processes. Pharmacological inhibition of HO-1 in mice markedly reduces implantation sites, establishing the functional necessity of this pathway. However, when heme levels exceed the regulatory capacity of HO-1, epithelial dysfunction ensues, characterized by reduced p-STAT3 and elevated MUC1, which ultimately disrupts implantation. Consistent with this, chronic heme exposure by oral gavage in mice increases uterine heme levels and upregulates BACH1, thereby suppressing HO-1 and trapping the uterus in a non-receptive state, causing implantation failure. Our findings define a lactic acid-HIF1α-HO-1-heme metabolic checkpoint that couples glycolytic signaling to heme regulation and endometrial receptivity. Dysregulation of this checkpoint may contribute to implantation disorders associated with heme stress, providing mechanistic insights into heme stress-related uterine receptivity failure.
Mung bean seed coat (MBSC) is a byproduct of commercial vermicelli production that possesses essential activities capable of delaying diabetic wound progression. This study aimed to evaluate the potential of MBSC extracts to promote diabetic wound healing, an effect that has not yet been reported. The hypoglycemic effect was assessed by glucose uptake stimulation in L6 myotubes and by an α-glucosidase inhibition assay. Antiglycation was determined by BSA-glucose and BSA-methylglyoxal assays. Intracellular reactive oxygen species (ROS) reduction and wound healing were assessed in human keratinocytes (HaCaT) exposed to high glucose (HG), and gene expression in HG-wounded cells was analyzed by qPCR. The results demonstrated that the ethanolic extract (EE) from MBSC exhibited glucose-lowering effects and suppressed glycation reactions at the early and intermediate stages, with IC50 values of 75 and 140 µg/mL, respectively. EE reduced ROS by 70%, stimulated cell proliferation by 57% in the high-glucose (HG)-exposed HaCaT cells, and accelerated cell migration to close the HG-exposed wound. EE increased the gene expression of Nrf2, NQO-1, SOD2, and CAT. It also downregulated TNF-α, upregulated TGF-β1, and downregulated MMP-9. In conclusion, EE has the potential to delay the progression of diabetic wounds by lowering blood glucose levels, inhibiting AGE and ROS formation, and enhancing cell proliferation and migration in HG-exposed HaCaT cells. The gene regulatory effects of EE were demonstrated as an Nrf2 activator that reduced oxidative stress, exerted anti-inflammatory effects, and regulated ECM balance. The preparation of oral and topical products could be further developed.
Background: Postpartum hypogalactia is a prevalent obstetric complication worldwide, closely associated with excessive oxidative stress and impaired antioxidant defense in mammary tissue. Current hormone-based therapies carry endocrine disruption risks, while natural antioxidant bioactive agents such as extracellular vesicles (EVs) are largely limited by rapid in vivo clearance and poor tissue retention. Methods: We constructed an injectable gelatin methacryloyl (GelMA) hydrogel system to encapsulate chemically induced mammary epithelial cell-derived EVs (CiMECs-EVs) and systematically evaluated their antioxidant and lactogenic activities via multi-omics analysis, cellular functional assays and a bromocriptine-induced murine hypogalactia model. Results: CiMECs-EVs induced a functional mammary epithelial-like phenotype in fibroblasts in a dose-dependent manner with functional cargo enriched in glutathione metabolism and redox-regulatory miRNAs. The GelMA matrix protected EV integrity and enabled sustained release, and the composite system significantly ameliorated mammary duct structure and lactation function in vivo with specific mammary tropism and no systemic toxicity, outperforming free EV treatment. Conclusions: This study presents a safe protein biomacromolecule-based antioxidant delivery platform that effectively restores mammary redox balance and antioxidant defenses, providing a promising non-hormonal therapeutic strategy for postpartum hypogalactia.
