Search Results (21,342)

Background: Atopic dermatitis (AD) is a chronic inflammatory disease characterized by profound microbial dysbiosis, Staphylococcus aureus (S. aureus) colonization, and a compromised epidermal barrier. Current therapies often face safety and compliance limitations, necessitating proactive, steroid-sparing ecological strategies focused on barrier restoration. Methods: This pharmacological review evaluates a synergistic framework combining Lactobacillus and Saccharomyces postbiotic lysates with Perilla frutescens-derived effector vesicles. The analysis focuses on their molecular impact on skin homeostasis and structural protein synthesis. Results: In vitro evaluations indicate that Lactobacillus enhances innate immunity, while Saccharomyces-derived metabolites support the microbial ecosystem. Preliminary data demonstrate a significant impact on structural integrity, showing an 87.9% increase in elastin secretion and a 61.4% increase in Type I collagen synthesis. Furthermore, Perilla frutescens-derived vesicles modulate the JAK–STAT pathway, demonstrating a potential reduction of Interleukin-6 (IL-6) by 40% and a downregulation of CYP1A1 expression by up to 49% in cell models, thereby suggesting a capacity to mitigate oxidative stress and pruritus. Conclusions: By integrating these components into a “Triple-Action” framework, focusing on immunomodulation, structural restoration, and precision signaling, this review provides a comprehensive roadmap for promising dermo-cosmetic interventions in atopic skin management. Full article

Annona muricata (soursop) is a tropical medicinal plant widely used in traditional medicine across Africa, the Caribbean, and parts of South America. While its ethnomedicinal applications span a range of conditions, including infections, inflammation, and anemia-related symptoms, its potential relevance to hematopoiesis has not been systematically examined. This narrative review synthesizes ethnomedicinal knowledge, phytochemical composition, and experimental evidence to explore the biological plausibility by which A. muricata may indirectly influence hematopoietic processes. Bioactive constituents of A. muricata, including flavonoids, polyphenols, and acetogenins, have demonstrated antioxidant, anti-inflammatory, and immunomodulatory properties in preclinical models. These effects are particularly relevant given the established roles of oxidative stress and chronic inflammation in disrupting hematopoietic stem and progenitor cell function and bone marrow homeostasis. Rather than proposing direct erythropoietic activity, this review emphasizes indirect, marrow-supportive mechanisms through which A. muricata may contribute to the preservation of hematopoietic function under conditions of physiological or inflammatory stress. The limitations of the current evidence base, including the predominance of in vitro and animal studies and the absence of direct hematopoietic endpoints in humans, are critically discussed. Overall, this review provides a cautious, integrative framework linking A. muricata bioactivity to hematopoietic regulation and highlights key gaps that must be addressed before any translational or clinical relevance can be established. Full article

Sturge–Weber Syndrome (SWS) is a rare congenital disorder presenting with a vascular malformation in the upper face and brain, causing impaired blood–brain barrier function and perfusion, increased calcium signaling, inflammation, and seizures. All these neuropathologic processes result in injury to the brain. The somatic GNAQ R183Q variant, which accounts for the majority of SWS cases, increases signaling through MAPK, PI3K, mTOR, and inflammatory pathways, primarily in endothelial cells. The discovery of this variant enabled the creation of transgenic and genetic animal and cell culture models. Generating in vitro models has been challenging due to the mosaic nature of SWS, and attempts to separate unaffected from mutant cells in primary culture have failed, limiting the utility of in vitro work. Ongoing in vitro work seeks to overcome these limitations, shape our understanding of SWS, and lead to translational advances in treatment and prevention by studying the affected molecular pathways and identifying future targets for therapy. Full article

Background: Emerging evidence has established ferroptosis as a vital factor in the pathogenesis of cardiovascular diseases, especially in septic cardiomyopathy (SCM). Meanwhile, ondansetron (OND), a well-established 5-HT3 receptor antagonist, has gained increasing attention for its pleiotropic effects. However, its potential to modulate ferroptosis in the cardiovascular field remains unexplored. This study aims to fill this gap by exploring the potential of OND as an innovative therapeutic intervention for SCM. Methods: This study utilized both in vitro and in vivo models of septic cardiomyopathy (SCM), which was induced by lipopolysaccharide (LPS) stimulation in neonatal rat cardiomyocytes (NRCMs) and C57BL/6 mice. Through RNA sequencing, as well as molecular and functional assessments—including echocardiography and ferroptosis-related measurements—we revealed the anti-ferroptotic effect of ondansetron (OND). Mechanistically, ATF3 was identified as a pivotal regulator, with its overexpression via AAV9 in vivo and ADV in vitro confirming its role in OND-induced cardioprotection. Results: Ondansetron (OND) showed potent anti-ferroptotic effects in both cellular and murine models of septic cardiomyopathy (SCM). Treatment with OND not only improved cardiac performance but also reduced ferroptotic markers, mitigated lipid peroxidation and iron overload, and bolstered antioxidant defense. Notably, OND administration attenuated oxidative and endoplasmic reticulum (ER) stress while restoring mitochondrial integrity. Mechanistically, the anti-ferroptotic activity of OND was mediated through the HTR3A/ATF3 axis: ATF3 overexpression negated OND’s protective effects, while HTR3A antagonism with VUF10166 recapitulated its benefits. Conversely, HTR3A agonism with PBG attenuated ferroptosis resistance, further implicating this pathway as central to OND’s mechanism. Conclusions: This study demonstrated a novel pharmacological role for ondansetron (OND) in attenuating ferroptosis in septic cardiomyopathy (SCM) via the HTR3A/ATF3 signaling pathway. This finding delineates a novel therapeutic avenue and supports the repurposing of OND beyond its traditional antiemetic use to cardiovascular applications. Full article

Mesenchymal stromal cells are increasingly used for their immunomodulatory and regenerative properties, yet their interaction with the hemostatic system remains incompletely understood. This review examines the mechanisms through which these cells influence coagulation within the broader framework of immunothrombosis. Evidence from in vitro studies, animal models, and early clinical observations indicates that mesenchymal stromal cells can promote thrombin generation through tissue factor expression and phosphatidylserine exposure, while also engaging complement pathways, platelets, and innate immune responses. Counter-regulatory mechanisms, including adenosine-mediated platelet inhibition and immune reprogramming after cellular clearance, contribute to a context-dependent biological effect. Functional assays, rather than tissue factor expression alone, appear necessary to estimate the effective procoagulant potential of these products. Clinical data suggest that major thrombotic events remain uncommon, although subclinical activation of coagulation pathways may occur. The hemostatic impact of mesenchymal stromal cells depends on multiple variables, including cell source, dose, route of administration, and host inflammatory status. The available evidence supports a working model in which early coagulation and complement activation may be followed by immune modulation, supporting integrated strategies to optimise both safety and therapeutic efficacy. A central conclusion is that tissue factor, although mechanistically necessary for MSC-associated procoagulant activity, is not by itself an independent predictor of clinical thrombotic risk; the effective coagulation response also depends on phosphatidylserine exposure, membrane context, and host inflammatory conditions. Full article

Melanoma is an aggressive skin cancer with rapid progression and high metastatic potential, and resistance to current therapies remains a major clinical challenge. In this study, Listeria monocytogenes-derived membrane vesicles (LM MVs) were isolated, characterized, and evaluated for their immunomodulatory and antitumor activities. LM MVs showed an average diameter of approximately 160 nm and contained multiple bacterial proteins, including listeriolysin O. In vitro, LM MVs promoted pro-inflammatory activation of RAW264.7 macrophages, as indicated by increased CD80/CD86 expression and enhanced transcription of inflammatory mediators. LM MV treatment was accompanied by IκB-α degradation and NF-κB p65 nuclear translocation, whereas pharmacological inhibition of NF-κB attenuated macrophage activation. In a macrophage–melanoma co-culture system, LM MVs-activated macrophages reduced the viability, migration, and invasion of B16 melanoma cells and increased tumor cell apoptosis. Additional inhibition and immunofluorescence analyses suggested that iNOS and TNF-α-associated mechanisms contributed to these tumor-suppressive effects. In a murine melanoma model, LM MVs significantly inhibited tumor growth without overt systemic toxicity, whereas macrophage depletion markedly weakened this effect. These findings indicate that LM MVs exert antitumor activity against melanoma, at least in part through macrophage activation involving NF-κB signaling. Full article

Chronic low-grade inflammation, a key driver of diabetes and fatty liver disease, is present in obesity, which affects 2.1 billion adults as of 2021. Plant-derived bioactive peptides have emerged as promising alternatives to treat inflammation in these pathological processes. This study evaluated the effect of pre- and post-ultrasound-assisted enzymatic hydrolysis on bioactive peptide production and antioxidant activity from common bean (Phaseolus vulgaris L.) and pumpkin (Cucurbita argyoesperma) seed proteins. Pre-treated hydrolysates were fractionated by molecular weight (<3 kDa and 3–10 kDa) and evaluated for their anti-inflammatory properties by measuring nitric oxide and reactive oxygen species in three treatment schemes (pre-, co-, and post-treatment) in an obesity/inflammatory macrophage model. Ultrasound pre-treatment achieved a higher degree of hydrolysis (peptide production) compared to post-treatment, with corresponding increases in antioxidant activity as measured by the ABTS and ORAC assays. All hydrolysate fractions demonstrated dose-dependent inhibition of pro-inflammatory markers. Fractions administered as a co-treatment showed the strongest anti-inflammatory effect, reducing Nos-2 and Cox-2 mRNA expression, as well as secreted levels of pro-inflammatory cytokines (TNF-α, IL-6, MCP-1). These findings indicate that ultrasound treatment, mainly as pre-treatment, represents an effective strategy for producing bioactive peptide hydrolysates with anti-inflammatory properties in vitro that warrant deeper investigation. Full article

Iron overload significantly contributes to chronic kidney disease progression by triggering oxidative stress and mitochondrial impairment via the Fenton reaction. This study investigates the protective role of aldehyde dehydrogenase 1a3 (ALDH1a3), an enzyme that detoxifies reactive aldehydes, in renal iron overload. C57BL/6N mice were fed a 2.25% ferric citrate diet for 24 weeks to establish a chronic model, followed by treatment with the chelator Dimercaprol (DP). In vitro, TCMK−1 cells were subjected to iron intervention with ALDH1a3 overexpression or inhibition. Chronic iron overload induced significant renal iron deposition, lipid peroxidation (elevated MDA, depleted GSH), and mitochondrial structural damage. ALDH1a3 was endogenously upregulated in renal tubular epithelial cells under iron stress. Overexpressing ALDH1a3 significantly enhanced cell viability, suppressed reactive oxygen species and MDA levels, and preserved mitochondrial membrane potential, whereas its inhibition exacerbated cellular damage. Furthermore, DP treatment reduced iron deposition and was associated with increased ALDH1a3 expression. In conclusion, ALDH1a3 acts as a critical endogenous protective factor against iron−induced nephrotoxicity by mitigating oxidative damage and maintaining mitochondrial stability. These findings indicate that ALDH1a3 is a promising potential therapeutic target for the treatment of iron overload−related kidney diseases. Full article

Background: Ursolic acid (UA) is a natural pentacyclic triterpenoid with notable antitumor activity, yet its poor water solubility and insufficient targeting restrict clinical translation. Methods: Forty novel ursolic acid-phosphine derivatives bearing seven distinct lipophilic cationic moieties were synthesized via C28 modification and structurally characterized by ¹H NMR and ¹³C NMR. Their antitumor activities in PC3-M cells were evaluated via in vitro assays. Mechanistic investigations were performed using transcriptomic analysis and Western blot. Molecular docking was performed to predict the binding profile of Compound 25 with FGFR1. In vivo antitumor efficacy and biosafety were assessed in RM-1 xenograft models in C57BL/6 mice. Results: Compound 25 (bearing a tris(3,5-dimethylphenyl)phosphine group at the C28 position with an alkyl chain length of five methylene units) exhibited the most potent activity against PC3-M cells, dose-dependently inhibiting proliferation, migration, and invasion and inducing apoptosis. It triggered mitochondrial apoptosis via ROS accumulation and disrupted cytoskeletal homeostasis by suppressing the FGFR1/KRAS/RAC1/PIP4K2 axis. Molecular docking results suggested its strong binding affinity and specificity. In vivo studies confirmed its significant antitumor effect and favorable safety. Conclusions: These results highlight the potential of Compound 25 as a promising lead compound and provide valuable insights for further medicinal chemistry optimization and the development of novel anticancer drugs derived from ursolic acid. Full article

Sheng Mai San (SMS), a traditional Chinese medicine formula for treating qi and yin deficiency, is widely used in the management of conditions such as cardiovascular diseases and heatstroke. However, its role in mitigating heat stress (HS)-induced liver injury remains underexplored. In this study, a rat model of HS was established under high-temperature and high-humidity conditions, and SMS was administered as an intervention. The pharmacodynamic effects of SMS were comprehensively evaluated through histopathological examination, detection of heat shock protein 70 (HSP70) and heat shock protein 90(HSP90) expression, and analysis of liver function biomarkers (AST, ALT). Meanwhile, oxidative stress indicators were measured using biochemical assay kits (GSH, SOD, CAT, MDA, T-AOC), and transmission electron microscopy was employed to observe mitochondrial ultrastructure, thereby assessing the protective effects of SMS on hepatic oxidative stress and mitochondrial damage induced by HS. In vitro, BRL-3A cells were cultured, subjected to HS, and treated with SMS. Cell viability was assessed using the CCK-8 assay, and changes in mitochondrial reactive oxygen species (ROS) levels, mitochondrial permeability transition pore (MPTP) opening, and mitochondrial membrane potential (MMP) were evaluated using fluorescent probes. The results showed that SMS effectively restored HS-induced histopathological damage in rat liver tissues, reduced serum AST and ALT levels, and downregulated the mRNA expression of HSP70 and HSP90 in liver tissues. Meanwhile, SMS strengthened the hepatic antioxidant system by increasing the levels of GSH, SOD, T-AOC, and CAT, while decreasing MDA content. In vitro experiments confirmed that SMS increased the viability of BRL-3A cells, reduced ROS production, improved MPTP opening/closing regulation, and stabilized MMP. This study provides a clinical reference for its application in treating HS-related conditions in humans and animals. Full article

Multiple mycotoxins in feed threaten animal health and food safety, demanding sustainable mitigation strategies. This study evaluated acid-modified mangosteen peel (AMP), an agricultural by-product, as a potential multi-mycotoxin adsorbent. Physicochemical characterization using scanning electron microscopy (SEM), Brunauer–Emmett–Teller (BET) surface area analysis, and Fourier transform infrared spectroscopy (FTIR) analyses demonstrated that acid modification increased surface area (1.9 to 9.03 m²/g), pore volume (0.005 to 0.027 cm³/g), and surface negativity, indicating enhanced adsorption properties. In vitro binding experiments assessed adsorption of aflatoxin B₁ (AFB₁), zearalenone (ZEA), ochratoxin A (OTA), T-2 toxin, deoxynivalenol (DON) and fumonisin B₁ (FB₁) under different pH conditions. AMP exhibited high adsorption efficiencies for AFB₁, ZEA, OTA, and T-2 toxin, particularly at pH 3, whereas DON and FB₁ showed limited binding. Adsorption behavior was dose-dependent and best described by Langmuir and Freundlich isotherm models. Simulated gastrointestinal digestion indicated stable binding of AFB₁ and ZEA under gastric conditions, with partial release of some toxins at neutral pH. Cytotoxicity assessment in porcine intestinal epithelial cells (IPEC J2) showed no apparent cytotoxic effects at 0.25–1 mg/mL. Therefore, AMP demonstrated improved multi-mycotoxin adsorption compared to the untreated material and showed no apparent cytotoxic effects in vitro within the tested concentration range, indicating its potential as a promising feed additive candidate. Full article

Background/Objectives: Pediatric cancers are disorders of dysregulated development driven largely by genomic and epigenetic alterations. Precisely modeling these developmental differences is essential for understanding the unique biology of childhood cancers. Patient-derived organoids (PDOs) offer a powerful in vitro platform that recapitulates tumor heterogeneity, plasticity, microenvironment (including immune cells) and disease-relevant features. Methods: Here, we describe a step-by-step protocol for the establishment of PDOs from cells derived from pediatric brain tumors and extracranial solid tumor biopsies and bone marrow aspirates, including tumor processing, organoid culture/subculture, and cryopreservation. Results: Furthermore, we present the use of PDOs for further experimental analysis such as fluorescence imaging, Western blotting, flow cytometry, and immunohistochemistry (IHC) to investigate the underlying pathophysiology of tumorigenesis. Conclusions: Expanding the application of organoids to childhood malignancies holds exceptional promise for elucidating pediatric tumor biology and advancing therapeutic strategies, representing the long-overdue convergence of technology and clinical need. Full article

The increasing prevalence of peri-implantitis has led to a growing clinical use of implantoplasty, a procedure involving intraoral machining of the dental implant surface to remove biofilm. The absence of standardized clinical protocols may contribute to premature fatigue failure of dental implants. The present study aimed to evaluate the influence of machining depth on the cyclic mechanical behavior of dental implants. A total of 250 commercially pure grade 4 titanium dental implants were distributed into four groups according to machining depth: untreated (original), 0.2 mm, 0.4 mm, and 0.6 mm wall reduction. The implant system featured an internal connection with a thread height of 0.4 mm. Finite element analysis was performed for each machining depth to evaluate von Mises stress distribution and simulate fatigue behavior. The numerical models were validated through experimental fatigue testing using a servo-hydraulic MTS Bionix testing machine under ISO 14801:2016 conditions, showing a high correlation between simulated and experimental results (correlation coefficients > 0.9). The results indicated that maximum von Mises stresses were concentrated at the junction between the implant thread and the implant body. The fatigue limit of the untreated implants was approximately 351 N. Implants subjected to 0.4 mm machining exhibited a fatigue limit of 301 N, whereas lower fatigue limits were observed for 0.2 mm (255 N) and 0.6 mm (185 N) reductions. These findings suggest a significant mechanical effect of thread removal: 0.4 mm implantoplasty may provide improved fatigue performance compared to 0.2 mm, potentially due to reduced stress concentration at the thread–body junction. At high applied loads, fracture occurred in the coronal region of the implant, whereas at lower loads failure shifted to the implant–abutment connection. Although a good agreement between numerical and experimental results was observed, these findings should be interpreted with caution due to the in vitro testing conditions and the assumptions inherent to the finite element simulations. Therefore, while the results suggest that implantoplasty depth should not exceed the original thread height, further validation under clinically relevant conditions is required to confirm its impact on long-term mechanical reliability. Full article

Biodegradable magnesium implants offer significant clinical promise, but their safe use requires reliable real-time in vivo monitoring of coating integrity. Existing methods lack sufficient sensitivity and temporal resolution to detect degradation at early stages, and there are no computational tools able to predict the success of a given sensor design before animal experiments. In the present paper, we present BioElectroSynth—a digital simulator of an implantable zero-resistance ammetry (ZRA) corrosion sensor in a mouse model. The simulator combines electrochemical noise, cardiac and muscular bioelectric interference, and instrumental limitations into a unified model, enabling virtual experiments, which mimic the complexity of the in vivo system. Using Monte Carlo analysis, we establish that a 2% breach in a chitosan coating on an AZ91 magnesium alloy electrode is statistically detectable from approximately 30 recordings of 30 s each, and quantify how electrode area, its location, sampling rate, and coating quality jointly determine detection sensitivity. The framework provides the first quantitative tool for predicting in vivo experiment feasibility from standard in vitro electrochemical data alone. By identifying instrument and design configurations that are statistically underpowered before any animal use, the approach directly supports the 3R principles of humane research. Full article

Staphylococcus aureus biofilms formed on titanium surfaces are highly relevant to orthopedic implant-associated infection and remain difficult to control after maturation. This study aimed to evaluate whether ultraviolet A (UVA, 365 nm) combined with cinnamaldehyde (CA) could improve antibiofilm activity against titanium-associated S. aureus biofilms in a stage-resolved in vitro model and to examine whether the observed responses were associated with reactive oxygen species (ROS). Early stage (8 h) and 24 h biofilm models were established on total hip arthroplasty (THA)-derived titanium discs. After condition screening, 0.5 mM CA combined with 5 min UVA exposure was selected for subsequent experiments. Biofilm biomass was assessed by crystal violet staining, bacterial viability by live/dead staining and colony-forming unit (CFU) enumeration, ROS-associated fluorescence by dihydroethidium (DHE) imaging, and biofilm-associated gene expression by quantitative real-time PCR (qRT-PCR). Chondrocyte viability was also evaluated under the selected antibiofilm-effective conditions. The combined treatment showed stage-dependent antibiofilm effects, with greater biomass reduction in the 8 h biofilm model and marked impairment of bacterial viability and culturability in both models. ROS-associated fluorescence increased under combined exposure and was partially attenuated by N-acetyl-L-cysteine (NAC) in the 24 h biofilm model. In parallel, CA + UVA was associated with lower expression levels of clfA, icaA, and icaD in the 8 h biofilm model and of icaA, icaB, and icaD in the 24 h biofilm model, with partial NAC attenuation in the latter. Chondrocyte viability was lower in all treatment groups than in the untreated control, although the combined treatment did not show an obvious additional decrease compared with the single-treatment groups. These findings indicate that UVA combined with CA exerts stage-dependent antibiofilm effects in an in vitro titanium-associated S. aureus biofilm model. The observed ROS-associated responses were consistent with, but do not establish, mechanistic involvement. The current treatment setting also requires further optimization before translational applicability can be more confidently considered. Full article