Search Results (1,511)

Background/Objectives: This 7-day rat tracheocutaneous fistula study considered the not-studied issues of tracheocutaneous fistula course, wound healing, and fistula in the NO-system relations. Therefore, we focused on fistulas’ severe course, tracheocutaneous fistula → air leak → compensatory diaphragmatic/abdominal “heaving”, NO-system failed relations, and therapy resolution. Stable gastric pentadecapeptide BPC 157 was proposed. Methods: Tracheocutaneous fistula rats received daily medication (/kg), alone or combined, BPC 157 therapy (10 µg, 10 ng, in drinking water or intraperitoneally) along with a triple NO-agent approach (L-NAME 5 mg, L-arginine 100 mg, and L-NAME+L-arginine, intraperitoneally). Results: Tracheocutaneous fistulas occurred as specific and NO-system-related as follows: NO system: blockade (L-NAME-aggravation) over-activity (L-arginine-amelioration) or immobilization (L-NAME+L-arginine oppose each other’s effects). Controls presented severe clinical signs of respiratory distress, failed healing, skin and tracheal defects, a not-healed and open, macro/microscopically, and fistulous tract that was well-formed and wide, tracheal shrinking below the fistula, and clinically, open-mouth breathing, “heaving abdomen”, cyanosis (bluish snout, ears, extremities), abundant secretion through the fistula, and weight loss. Fistula tissue NO level decreased, and the malondialdehyde (MDA) level increased. The BPC 157 therapy (both application routes) resulted in rapid recovery. Healing of defects (skin and trachea) and fistula closure, macro/microscopically, corresponded with clinical findings, avoiding observable clinical signs of dyspnea, reducing weight loss, and avoiding any sign of “heaving abdomen”. BPC 157-treated rats displayed regular breathing movements without observable signs of respiratory distress. Finally, when combined, BPC 157 therapy upgrades L-arginine amelioration, abolishes L-NAME-induced worsening, and restores full healing after NO immobilization (L-NAME+L-arginine). BPC 157 counteracted increase in NO level and counteracted increase in MDA level. Conclusions: Thus, first, acting systemically, BPC 157 reverses tracheocutaneous fistula course in rats. It acts through the NO system. Full article

Objective: This umbrella review aimed to synthesize evidence from meta-analyses on the efficacy of rebamipide in major gastrointestinal disorders and dyspeptic symptoms. Methods: This umbrella review followed Joanna Briggs Institute standards and was registered in PROSPERO (CRD420251185686). A comprehensive search of MEDLINE, EMBASE, Cochrane, and Scopus (1 January 1985, to 10 September 2025) was conducted to identify systematic reviews and meta-analyses assessing rebamipide therapy. Methodological quality was appraised using AMSTAR-2, ROBIS, and GRADE tools. Pooled data were analyzed using fixed- or random-effects models according to heterogeneity, as assessed using the I² statistic. Results: Eleven meta-analyses (88 primary studies) were included. Rebamipide significantly improved H. pylori eradication (OR = 1.76; 95% CI: 1.44–2.16), reduced NSAID-induced mucosal injury (OR = 2.72; 95% CI: 1.89–5.14), enhanced ulcer healing after endoscopic submucosal dissection (OR = 2.28; 95% CI: 1.42–3.65), and alleviated dyspeptic symptoms (OR = 2.95; 95% CI: 1.04–8.37). Overall evidence quality was moderate to high, with low to moderate risk of bias. Conclusions: Rebamipide demonstrates consistent therapeutic benefits across diverse gastrointestinal disorders, improving H. pylori eradication rates, mucosal protection, ulcer healing, and symptom relief. These findings support rebamipide as an effective and well-tolerated adjunctive agent for the prevention and management of upper gastrointestinal diseases. Full article

Background/Objectives: Bacterial biofilms formed by Escherichia coli pose a significant challenge in veterinary medicine due to their intrinsic resistance to antibiotics. Antimicrobial peptides (AMPs) represent a promising alternative. AMPs exert their bactericidal activity by binding to negatively charged phospholipids in bacterial membranes via electrostatic interactions, leading to membrane disruption and rapid cell lysis. Methods: In vitro assays including MIC determination, biofilm eradication testing (crystal violet, colony counts, and CLSM), swimming motility, and EPS quantification were performed. CRISPR/Cas9 was used to construct and complement a kduD mutant. A transposon mutagenesis library was screened for biofilm-defective mutants. In an in vivo murine excisional wound infection model treated with the mouse cathelicidin-related antimicrobial peptide (CRAMP-34), wound closure and bacterial burden were monitored. Gene expression changes were analyzed via RT-qPCR. Results: CRAMP-34 effectively eradicated pre-formed biofilms of a clinically relevant, porcine-origin E. coli strain and promoted wound healing in the murine infection model. We conducted a genome-wide transposon mutagenesis screen, which identified kduD as a critical gene for robust biofilm formation. Functional characterization revealed that kduD deletion drastically impairs flagellar motility and alters exopolysaccharide production, leading to defective biofilm architecture without affecting growth. Notably, the anti-biofilm activity of CRAMP-34 phenocopied aspects of the kduD deletion, including motility inhibition and transcriptional repression of a common set of biofilm-related genes. Conclusions: This research highlights CRAMP-34 as a potent anti-biofilm agent and unveils kduD as a previously unrecognized regulator of E. coli biofilm development, which is also targeted by CRAMP-34. Full article

Background: Due to chronic venous insufficiency, venous leg ulcers (VLUs) develop as chronic wounds characterized by impaired healing, persistent inflammation, and endothelial dysfunction. Nitrosative stress, mitochondrial damage, and tissue apoptosis caused by excess nitric oxide (NO) produced by iNOS in macrophages and fibroblasts are contributing factors in the chronic wound environment; therefore, pharmacological modulation of iNOS presents an attractive mechanistic target in chronic wound pathophysiology. Methods: Herein, we present the use of a structure-based computational strategy to assess the inhibition of tavaborole, a boron-based antifungal agent, against iNOS using human iNOS crystal structure (PDB ID: iNOS) by molecular docking using AutoDock 4.2, 500 ns simulation of molecular dynamics (MD), with equilibration within ~50 ns and analyses over full trajectory and binding free energy calculations through the MM-PBSA approach. Results: Docking studies showed favorable binding of tavaborole (–6.1 kcal/mol) in the catalytic domain, which stabilizes contacts with several key residues (CYS200, PRO350, PHE369, GLY371, TRP372, TYR373, and GLU377). MD trajectories for 1 ns showed stable structural configurations with negligible deviations (RMSD ≈ 0.44 ± 0.10 nm) and hydrogen bonding, and MM-PBSA analysis confirmed energetically favorable complex formation (ΔG_binding ≈ 18.38 ± 63.24 kJ/mol) similar to the control systems (L-arginine and 1400W). Conclusions: Taken together, these computational findings indicate that tavaborole can stably occupy the iNOS active site and interact with key catalytic residues, providing a mechanistic basis for further in vitro and ex vivo validation of its potential as an iNOS inhibitor to reduce nitrosative stress and restore endothelial homeostasis in venous leg ulcers, rather than direct therapeutic proof. Full article

Cosmeceutical peptides (CPs), which modulate various biological activities, including skin regeneration and wound healing, have emerged as promising agents in skincare. In this study, we investigated the regenerative and wound healing potential of a short peptide, CP-02 (sequence CDARSDAR), using human dermal fibroblast cells (HDFs) in vitro and a zebrafish model in vivo. In HDFs, CP-02 treatment at concentrations of 50, 100, and 200 µg/mL significantly accelerated wound closure in a dose-dependent manner (p < 0.05) and upregulated the mRNA expression of CCND1, MYC, FGF2, EFG, and IL-8 at 12 h post-treatment. In amputated zebrafish larvae, exposure to CP-02 (5 µg/mL) for 72 h significantly increased fin regeneration, with a fin area of 3.5 mm² and fin-fold length of 0.2 mm, compared with those in controls (2 mm² and 0.07 mm, respectively). Intramuscular administration of CP-02 significantly improved the healing rates in wounded adult zebrafish to 58% and 76% on 12 and 16 days post wounding (dpw), respectively, compared with the vehicle (35% and 44%, respectively). Histological analysis (H&E staining) revealed reduced inflammatory cell infiltration, complete granulation, and re-epithelialization in the CP-02-treated tissues at 12 dpw. Furthermore, mRNA expression levels of tnf-α, il-1β, tgfb1, mmp9, mmp13, and timp2b were elevated in the CP-02 group at 4 dpw, whereas those of pro-fibrotic mediators, including acta2, ctgfb, cdh1, and col9a3 reduced in muscle tissue on 12 dpw. Collectively these findings demonstrate that CP-02 promotes effective, scar-reducing regeneration and wound healing, highlighting its strong potential as a therapeutic peptide for future skincare and cosmeceutical applications. Full article

Background/Objectives: Wound healing represents a pervasive and urgent clinical challenge. Hard-to-heal chronic wounds are frequently complicated by infections, inflammatory responses, and oxidative stress. Currently, wound dressings are broadly categorized into dry and moist types, with moist wound dressings for chronic wounds accounting for approximately 70% of market revenue. Recently, adipose-derived stem cells (ADSCs), which possess self-renewal and multi-lineage differentiation capabilities, have emerged as a promising strategy for promoting tissue regeneration and wound repair. Methods: In this study, we developed a novel luteolin nanoparticle–ADSCs composite hydrogel (GelCA@LUT@ADSCs). This system was constructed by first encapsulating ADSCs within a chitosan/alginate hydrogel (GelCA), followed by coating the hydrogel with luteolin-loaded nanoparticles (LUT@NPs). Results: The sustained release of LUT@NPs from the hydrogel modulates the wound microenvironment, enhancing the pro-healing functions of ADSCs at the wound site. The GelCA hydrogel exhibited excellent biocompatibility. Both in vitro and in vivo results demonstrated that GelCA@LUT@ADSCs treatment effectively reduced inflammation, promoted angiogenesis and collagen deposition, stimulated cell proliferation and migration, and polarized macrophages toward an anti-inflammatory, pro-healing M₂ phenotype, thereby accelerating wound healing. Conclusions: Overall, this innovative therapeutic approach provides a novel strategy for wound management through a synergistic division of labor between pharmaceutical agents and stem cells. Full article

The growing global threat of antimicrobial resistance (AMR), particularly in cutaneous wound infections, represents a significant clinical and economic challenge. Biofilm formation by multidrug-resistant pathogens, such as Acinetobacter baumannii, often complicates healing and leads to therapeutic failure. Antimicrobial peptides (AMPs) are a promising alternative to conventional antibiotics due to their potent membrane-disrupting mechanism of action and lower propensity to induce resistance. Background/Objectives: This study aimed to evaluate the antibacterial, antibiofilm, and in vivo efficacy of four snake venom-derived cathelicidin-like peptides—Btn (15-34) and BotrAMP14 from Bothrops atrox, and Ctn (15-34) and CrotAMP14 from Crotalus durissus—against multidrug-resistant A. baumannii, Escherichia coli, and Pseudomonas aeruginosa clinical isolates from skin infections, with emphasis on A. baumannii, a WHO priority pathogen. Methods: Minimal Inhibitory Concentration (MIC), Minimal Bactericidal Concentration (MBC), and Minimal Biofilm Inhibitory Concentration (MBIC) were determined against A. baumannii, Escherichia coli, and Pseudomonas aeruginosa. Time-kill kinetics, hemolytic activity, and cytotoxicity assays were performed. A murine skin wound infection model was established to evaluate in vivo antibacterial efficacy and safety. Results: MIC/MBC values ranged from 0.78 to 25 µM against planktonic cells. In comparison, MBIC ranged from 1.56 to 12.5 µM against biofilms. BotrAMP14 eradicated A. baumannii within 4 min, while CrotAMP14 achieved bactericidal action in 20 min at 1.56 µM. Both peptides exhibited no hemolytic activity up to 128 µM and low cytotoxicity (IC₅₀ > 128 µM). In vivo, BotrAMP14 and CrotAMP14 demonstrated significant antibacterial activity at 24 h and 48 h post-infection, respectively, surpassing that of meropenem. Conclusions: These findings suggest that BotrAMP14 and CrotAMP14 are promising topical antimicrobial agents for managing multidrug-resistant skin infections and may help address the urgent need for alternative therapies against antibiotic-resistant pathogens. Full article

Microbial polysaccharides are promising components for wound-care products. This study reports the development of wound-healing antimicrobial hydrogels, based on pullulan from Aureobasidium pullulans, combined with mesenchymal cell-derived conditioned medium. Structural characterization of pullulan was confirmed by FTIR and NMR. Twenty-three formulations containing pullulan, chitosan, gelatin, citric acid, and antimicrobial agents were prepared. Physicochemical screening identified optimal hydrogels: No. 22 (1.2% pullulan, 1.2% chitosan, 0.2% citric acid, 2.4% gelatin, 0.1% conditioned medium, 0.4% glutaraldehyde) and No. 23 (2.4% pullulan, no chitosan, the remaining components identical to those in No. 22). Both exhibited pH values of 5.34 and 5.49, moisture content of 92%, swelling capacities of 175% and 213%, and dynamic viscosity between 58–120 mPa·s. Cytotoxicity testing with human mesenchymal stem cells showed no significant toxicity, with both hydrogels supporting cell adhesion and proliferation. Antimicrobial assays demonstrated inhibitory activity against Staphylococcus aureus and Escherichia coli for both formulations; only hydrogel No. 23 inhibited Pseudomonas aeruginosa. In vitro scratch assays revealed that hydrogel No. 23 significantly promoted fibroblast migration, achieving 30.25% scratch closure after 24 h. The developed formulations combine favorable physicochemical properties with antimicrobial efficacy and regenerative potential, supporting further evaluation as advanced wound-healing and anti-burn dressings. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication of antiresorptive and antiangiogenic drugs with no consensus on optimal treatment. This study aimed to evaluate the clinical outcomes of MRONJ patients managed at a tertiary referral center over a 15-year period. Methods: We conducted a retrospective cohort study of 130 patients diagnosed with MRONJ (per AAOMS criteria) at a single tertiary hospital between 2006 and 2021. Data on demographics, underlying disease, drug history, MRONJ stage, triggering events, and treatment (conservative vs. surgical) were collected from medical records. Treatment outcomes were categorized as complete resolution, stable disease, or progression. Univariate and multivariate logistic regression analyses were performed to identify predictors of resolution. Results: Most patients (84.6%) had an underlying malignancy. The primary causative agents were zoledronic acid (47.7%) and denosumab (30.0%), the most frequent site was the mandible (66.2%), and the main trigger was dental extraction (59.2%). Crude resolution rates were 20.3% for conservative management versus 83.6% for surgical management. Treatment was stage-driven, with surgery common in advanced stages. At 12 months, 43.1% of all patients achieved complete resolution, and 52.3% remained stable. Multivariate analysis confirmed surgical treatment as the only independent predictor of complete resolution (OR = 20.1, 95% CI: 8.1–50). Conclusions: In this cohort, conservative care was generally sufficient for Stage I disease, while surgical intervention was the strongest predictor of healing and provided reliable outcomes for advanced MRONJ. These findings support an individualized, stage-appropriate treatment strategy. Full article

Topical antibiotics have long been used for the prevention and treatment of superficial skin and soft tissue infections; however, increasing evidence indicates that their clinical value is undermined by rising antimicrobial resistance, high rates of allergic sensitization, inadequate activity against biofilms, and a lack of wound-healing properties. Agents such as bacitracin, neomycin, polymyxin B, mupirocin, and fusidic acid act through narrow, target-specific mechanisms that facilitate resistance selection and provide limited benefit in chronic or polymicrobial wound environments. Contemporary antimicrobial stewardship frameworks therefore discourage routine use of topical antibiotics and increasingly favor non-antibiotic antiseptics with broad-spectrum activity and low resistance risk, including silver, iodine, polyhexamethylene biguanide, octenidine, and medical-grade honey. These modalities, however, primarily serve to reduce microbial burden and do not directly address the underlying biological impairments that prevent healing. Nitric oxide-releasing gels (NORGs) represent a novel class of topical antimicrobials that combine multi-target bactericidal activity with physiologic pro-healing effects. Nitric oxide exerts potent antimicrobial and antibiofilm effects via oxidative and nitrosative stress, disruption of metabolic pathways, inhibition of DNA replication, and interference with quorum sensing. Simultaneously, nitric oxide enhances angiogenesis, modulates inflammation, improves microvascular perfusion, and promotes fibroblast and keratinocyte function. Preclinical models and early-phase clinical studies demonstrate broad-spectrum efficacy—including activity against multidrug-resistant organisms—with favorable tolerability and minimal risk of resistance development. Although the current evidence base remains preliminary, NORGs offer a promising antimicrobial platform with the potential to reduce reliance on topical antibiotics while simultaneously addressing key barriers to wound healing. Larger randomized controlled trials, direct comparisons with established advanced dressings, and robust pharmacoeconomic evaluations are needed to define their optimal role within stewardship-aligned wound-care practice. Full article

The genus Plantago (Plantaginaceae) is widely distributed worldwide. The Plantago species are used in traditional medicine as wound healers, anti-inflammatory agents, antipyretics, and analgesics. This study aimed to investigate the phytochemical composition from the aerial parts of Plantago indica L. and to evaluate its biological activities. Isolation studies and in vitro investigations were conducted on an aqueous phase of 80% EtOH extract of Plantago indica. In addition, in vivo studies were carried out using the MeOH, 80% EtOH, and water extracts. Plantarenaloside (1), 3-oxo-α-ionol β-glucoside (2), martynoside (3), acteoside (4), feruloyl gardoside (5), and ursolic acid (6) were isolated from the extract. The structures of the compounds were elucidated using 1D- and 2D-NMR and ESI-MS analyses. The extract, fractions, and pure compounds were tested in vitro for cytotoxicity (MTT), anti-inflammatory activity (NO, IL-6, and TNF-α production), wound healing (scratch test), and antioxidant capacity (DPPH, ABTS, SO). Feruloyl gardoside (20.11–58.27%) significantly reduced NO levels at concentrations of 25–100 µM. It significantly reduced IL-6 levels (40.17%) at 100 µM. Additionally, the in vivo anti-inflammatory (acetic acid-induced vascular permeability) and wound healing (incision and excision models) effects of the extracts were investigated. The findings suggest that P. indica may be considered to be a potential therapeutic option for managing inflammation and for promoting wound healing. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a devastating complication arising primarily after invasive dentoalveolar procedures in patients treated with antiresorptive, antiangiogenic, or targeted therapies. Although recognized risk factors are established, the distinctive vulnerability of jawbones compared to long bones is not fully understood. This review comprehensively synthesizes recent advances regarding the embryological, anatomical, and physiological disparities that contribute to region-specific susceptibility to MRONJ. Recent evidence suggests that jawbones diverge significantly from long bones in embryonic origin, ossification pathways, vascular architecture, innervation patterns, and regenerative capacities. These differences affect bone metabolism, healing dynamics, response to pharmacologic agents, and local cellular activities, such as enhanced bisphosphonate uptake and specialized microcirculation. Experimental and clinical evidence reveals that mandibular periosteal cells exhibit superior osteogenic and angiogenic potentials, and the jaws respond differently to metabolic challenges, trauma, and medication-induced insults. Furthermore, site-specific pharmacologic and inflammatory interactions, including altered periosteal microcirculation and leukocyte–endothelial interactions, may explain the development of MRONJ, although rare cases of medication-related osteonecrosis have also been reported in long bones. Emerging research demonstrates that immune dysregulation, particularly M1 macrophage polarization with overexpression of matrix metalloproteinase-13 (MMP-13), plays a crucial role in early MRONJ development. Understanding these mechanisms highlights the critical need for region-specific preventive measures and therapeutic strategies targeting the unique biology of jawbones. This comparative perspective offers new translational insights for designing targeted interventions, developing tissue engineering solutions, and improving patient outcomes. Future research should focus on gene expression profiling and cellular responses across skeletal regions to further delineate MRONJ pathogenesis and advance personalized therapies for affected patients. Full article

This manuscript describes the development of a nano-sized synthetic smectic clay hydrogel (LAP) that enables controlled oxygen delivery, making it a promising candidate for treating skin wound infections and promoting healing. LAP is an ingredient in various dermatological products, including powders, creams and emulsions. We investigated the antibacterial effect of the LAP hydrogel by incorporating calcium peroxide (CPO), an oxygen-releasing agent, and measuring the size of the inhibitory halo. We found that CPO hydrogels in LAP showed a significant increase in oxygen release during the first five hours, especially at low CPO concentrations. For example, the hydrogel with 5% CPO showed a controlled release profile with a final percentage oxygen release of 2.47 ± 0.01% after 5 h. In contrast, the hydrogels with 10% and 20% CPO achieved lower final oxygen release values, 0.67 ± 0.01% and 0.75 ± 0.01%, respectively, suggesting that the encapsulation efficiency of LAP is higher at higher concentrations. LAP also proved to be an effective oxygen barrier and showed inherent antimicrobial activity. The research confirmed the antibacterial properties of the hydrogel, with inhibition sites observed against both E. coli and S. aureus. These results emphasize the potential of this hydrogel to serve as an effective tool for wound treatment by providing sustained oxygenation and fighting microbial infections. Full article

Antimicrobial peptides (AMPs) have been shown to have pro-angiogenic activity, capable of enhancing neovascularization and facilitating the healing of chronic wounds. However, information as such remains rather limited. Here we clearly showed that the fish phosvitin-derived AMP Pt5-1c was able to enhance angiogenesis in both murine full-thickness wound models and zebrafish with vascular defects models. We also showed that Pt5-1c was able to promote endothelial cell motility, adhesion, survival, filopodia protrusion, and induce endothelial tube formation. In addition, we found that Pt5-1c could upregulate production of proangiogenic factors including VEGF, PDGF, FGF and EGF. It was revealed that Pt5-1c promoted endothelial cell motility, growth and survival via activation both PI3K/AKT/mTOR and p38 MAPK pathways as well as HIF-1-VEGF axis. It is apparent that Pt5-1c is a novel candidate of pro-angiogenic agents for vascular regenerative therapy. Full article

Background/Objectives: Cervical cancer remains a major global health challenge, and treatment resistance limits the long-term success of chemotherapy. Drug repurposing strategies offer new opportunities for improving therapeutic outcomes by combining existing agents with established chemotherapeutics. Sitagliptin, a DPP-4 inhibitor commonly used in type 2 diabetes, has recently gained attention for its potential anticancer effects. This study aimed to investigate the cytotoxic, apoptotic, and anti-metastatic effects of sitagliptin and doxorubicin, individually and in combination, on human cervical cancer cells (HeLa), and to determine whether their combined use exerts a synergistic anticancer effect. Methods: HeLa cells were treated for 48 h with increasing concentrations of sitagliptin, doxorubicin, or their combination. Cell viability was assessed using the MTT assay. Apoptosis was evaluated by Annexin V-FITC/PI staining and caspase-8/9 activity assays. Synergy was quantified using the Chou–Talalay method, and Combination Index (CI) values were used to determine synergistic interactions. Intracellular ROS levels were measured using the DCFDA assay. Migration and invasion capacities were analyzed using wound healing and Transwell assays. MMP-1, MMP-2, TIMP-1, and TIMP-2 levels were quantified via ELISA with normalization to viable cell counts. Gene expression levels of PI3K/Akt and MAPK/ERK pathway components were measured by qRT-PCR. Bioinformatic analyses (STRING, GeneMANIA, GO, KEGG) were performed to identify common molecular targets and enriched pathways affected by both agents. Results: The combination of sitagliptin and doxorubicin significantly reduced cell viability and demonstrated a synergistic interaction (CI < 1). Combined treatment induced a marked increase in ROS production and significantly elevated apoptosis rates compared to monotherapies. Caspase-8 and caspase-9 activities were also higher in the combination group. Migration and invasion assays revealed substantial suppression of cell motility and invasive capacity. After normalization to viable cell numbers, MMP and TIMP reductions remained significant, confirming true biological inhibition rather than cell-death–related artifacts. qRT-PCR analyses showed downregulation of Akt and ERK expression, indicating suppression of key survival and proliferation pathways. Bioinformatic analyses supported these findings by highlighting enrichment in apoptotic, oxidative stress, and metastasis-related pathways. Conclusions: Sitagliptin enhances the anticancer efficacy of doxorubicin by amplifying ROS-mediated apoptosis, inhibiting migration and invasion, and modulating PI3K/Akt and MAPK/ERK signaling in cervical cancer cells. The combination exhibits a clear synergistic effect and demonstrates strong potential as a supportive therapeutic strategy. These findings warrant further in vivo and clinical-level investigations to evaluate the translational applicability of sitagliptin in cervical cancer therapy. Full article