Search Results (54,652)

Mesenchymal stem cells (MSCs) exert biological effects in part through their secretome which includes extracellular vesicles. In this study, we isolated and characterized the secretome from clinically relevant stem cell lines: human embryonic stem cell–derived mesenchymal stem cell line (ES-MSCs) and Infrapatellar fat pad derived MSC (IPFP-MSC) cultured in xeno-free medium. We assessed the biological activity of concentrated cell secretome or isolated fractions of extracellular vesicles (EVs) on cell proliferation, microvascular formation, and cartilage degradation in a human osteoarthritic (OA) ex vivo model. Serum-free conditioned medium from ES-MSC (N = 1) or IPFP-MSC (N = 2) monolayer cultures were concentrated by ultrafiltration to generate concentrated conditioned medium (CCM). Size exclusion chromatography was used to fractionate extracellular vesicles (EVs). Vesicle size, concentration, morphology, and surface markers were characterized by nanoparticle tracking analysis, transmission electron microscopy, and flow cytometry. Biological activity was evaluated by treating human umbilical vein endothelial cells (HUVECs), IPFP-MSCs, and ES-MSCs with CCM and EVs at defined particle concentrations. Endothelial network formation was tested in fibrin gels with different cell and secretome combinations. For analysis of cartilage degradation, human cartilage explants (N = 4; 3.5 mm in diameter) were harvested from patients undergoing total knee arthroplasty and subjected to IL-1β stimulation to induce an OA phenotype. Explants were treated with varying doses from CCM or EVs. Release of glycosaminoglycan in the medium and RNA analysis of catabolic genes were used as readouts. Secretome preparations yielded on average approximately 50 billion vesicles per mL with a similar particle size distribution between 50–200 nm in ES-MSC and IPFP-MSC cultures. Transmission electron microscopy confirmed vesicle morphology and flow cytometry confirmed expression of exosomal surface markers (CD9, CD63, CD81). Functionally, CCM and EVs enhanced proliferation in a dose-dependent manner. Endothelial networks formed by HUVECs in fibrin were stabilized over 7 days by CCMs, most notably by hypoxic ES-MSC CCM relative to no CCM treatment (control). In the OA cartilage model, IL-1β stimulation increased glycosaminoglycan release, whereas ES-MSC CCM treatment and EV treatment reduced glycosaminoglycan release and ES-MSC CCM reduced gene expression of IL-1β, MMP-1, and MMP-3. We isolated and characterized the concentrated secretome and the isolated vesicle-enriched fractions from xeno-free ES-MSC and IPFP-MSC and demonstrated bioactivity in promoting cell proliferation, modulating endothelial network formation, and mitigating cartilage degradation in osteoarthritic tissue. These findings support the bioactivity and therapeutic potential of stem cell–derived secretomes for OA. Full article

Diabetes mellitus is increasingly recognized as a biologically heterogeneous disorder that extends beyond traditional phenotype-based classifications. Advances in human genetics have revealed that monogenic and polygenic forms of diabetes are not discrete entities, but rather represent points along a continuum of genetic architectures that converge on shared molecular pathways governing pancreatic β-cell identity, function, and survival. Rare monogenic forms, including maturity-onset diabetes of the young and neonatal diabetes, arise from highly penetrant single-gene defects that directly impair transcriptional regulation, glucose sensing, insulin biosynthesis, or stimulus–secretion coupling. Although individually uncommon, these disorders provide high-resolution models of β-cell dysfunction and have demonstrated the clinical value of genotype-guided diagnosis and therapy. At the opposite end of the spectrum, type 1 and type 2 diabetes result from complex interactions between multiple genetic variants and environmental factors, with genome-wide association studies highlighting a central role for genetically determined β-cell vulnerability alongside immune-mediated and metabolic stress pathways. Importantly, intermediate phenotypes such as latent autoimmune diabetes in adults further illustrate the overlap between autoimmune and metabolic mechanisms, challenging rigid diagnostic boundaries. This review synthesizes current evidence on the genetic architecture of diabetes across monogenic and polygenic forms, emphasizing convergent molecular mechanisms and their translational implications. By integrating insights from rare genetic disorders with findings from large-scale population studies, we propose a continuum-based framework that supports a shift from phenotype-driven labels toward a mechanistic, biology-informed approach to diabetes classification, risk stratification, and personalized care. Full article

Surface collisions at Pyrex walls limit the spin coherence in nuclear magnetic resonance gyroscopes (NMRG) vapor cells, while the cavity–stem junction introduces geometry dependent exchange that perturbs the transverse spin relaxation time $T_2$ of ¹²⁹Xe atoms. We combine $T_2$ measurements with Monte Carlo simulations of confined diffusion and surface collisions to decompose the relaxation of Xe atoms and derive a cavity–stem geometry correction for wall relaxation. A structural coupling factor (SCF) is introduced to compress stem length and aperture diameter into a dimensionless metric for diffusion-limited mixing, enabling prediction of the transverse relaxation rate versus geometry. Across eight simulated configurations, the model yields $R^2=0.982$ and agrees with experiments within 7–$9\%$, comparable to the measurement uncertainty ($\pm 0.015{\mathrm{s}}^{-1}$). Using the validated framework, geometry optimization reduces the relaxation rate from $0.225$ to $0.131{\mathrm{s}}^{-1}$ (a $41.8\%$ improvement). This Pyrex surface-collisional analysis provides an in-situ, $T_2$-based route to compare effective surface depolarization across fabrication and surface-treatment protocols while accounting for cavity–stem coupling. Full article

Extrusion-based three-dimensional (3D) bioprinting has enabled the fabrication of complex, cell-laden constructs; however, process parameter selection remains largely empirical and system-specific. As biofabrication workflows scale in complexity and translational ambition, trial-and-error optimization increasingly limits reproducibility, transferability, and informed decision-making. In this work, a formal, optimization-oriented design framework is proposed to structure extrusion-based bioprinting as a constrained, multivariable design problem. Rather than introducing a system-specific predictive model, the framework organizes process parameters, material descriptors, scaffold architecture, and biological feasibility into a unified formulation based on objective functions and admissible constraints. Symbolic coupling relationships are employed to make parameter dependencies, trade-offs, and constraint interactions explicit without imposing restrictive assumptions on material behavior or biological response. A demonstrative computational case study is presented to illustrate how qualitative predictive reasoning emerges through constraint-driven design space analysis and multi-objective considerations. The framework reveals how feasible operating regions are shaped by competing biological, mechanical, and manufacturing limitations, emphasizing robustness-aware parameter selection over isolated optimization. The proposed approach is intended as a transferable methodological foundation that supports structured reasoning, experimental planning, and future integration with numerical models, data-driven tools, and closed-loop biofabrication systems. Full article

Three-dimensional (3D) bioprinting is an advanced additive manufacturing technology that utilizes bioinks composed of living cells and biomaterials to construct tissue-like structures for a wide range of medical applications. This paper reviews key applications, including tissue engineering, organ modeling and printing, drug testing and development, disease modeling, cosmetics and chemical testing, regenerative medicine, and personalized medicine. In parallel, biomimicry of natural plant architectures offers powerful opportunities for innovation in biomedical material design. Among these, the rose stands out for its intricate hierarchical geometry, which provides not only aesthetic appeal but also exceptional mechanical resilience. Incorporating rose-inspired structural elements into 3D-bioprinted medical constructs can significantly enhance mechanical strength, flexibility, and surface adaptability. This review also highlights plant- and rose-inspired approaches in medical applications and outlines the potential of rose-inspired 3D bioprinting to advance the design of functional and biomimetic tissue models. Nature provides a rich source of inspiration for biomimetic design, and translating biological principles into engineering solutions can contribute to sustainable technological development aligned with the Sustainable Development Goals (SDGs). In this regard, roses and other plant systems offer valuable structural and functional inspiration for advancing 3D bioprinting in medical applications. Full article

Limosilactobacillus fermentum MC1 is an exopolysaccharide (EPS)-producing strain with previously determined probiotic potential in vitro. This study aimed to investigate the in vivo capacity of the MC1 strain or its EPSs to modulate intestinal microbiota and assess its anti-inflammatory effects in both healthy and dysbiotic conditions. Therefore, Lb. fermentum MC1 and its EPSs were administered to a mouse model of dextran sulfate sodium (DSS)-induced colitis (DIC) and to a healthy group, and the effects were observed. Microbiome analysis was used to detect taxonomic differences between treatments. According to the results, administration of the MC1 strain and MC1-EPSs significantly altered gut microbiome composition at different taxonomic levels. The most notable effect was an increased relative abundance of Firmicutes and decreased levels of Candidatus saccharibacteria. Llb. fermentum MC1, and its EPS administration positively affected several disease parameters: reduced disease activity index (DAI), reduced mouse colitis histology index (MCHI), reduced expression of inflammation-related genes and levels of bleeding, and induced polarization of M1 macrophages to the M2-like macrophage phenotype in the DIC mice. These results, along with those related to the induction of antioxidant enzymes and changes in NF-κB-related gene expression, suggest that strain MC1 and MC1-EPSs could be further investigated for their capacity to alleviate DSS-induced histopathological changes and modulate pro-inflammatory cytokine gene expression in colon tissue, which positively correlates with the secretion of inflammatory cytokines, the delay of intestinal inflammation and the maintenance of intestinal barrier function. The obtained data provide a basis for further research into the potential application of intact or microencapsulated Llb. fermentum MC1 cells and its EPSs in colitis therapy. Full article

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is challenging to treat due to poor understanding of its pathogenesis and etiology. Clearly understanding and dissecting the therapeutic effects of potential treatment in animal models are important. It has been shown that human alpha-1 antitrypsin (hAAT) holds therapeutic potential for the treatment of autoimmune diseases including lupus. However, the mechanism underlying its protective effect requires further investigation. In the present study, we used a chronic graft-versus-host disease-induced lupus mouse model to test the effect of hAAT on lupus development. We performed adoptive transfer of MHC I-aβ mismatched bm12 splenocytes into hAAT transgenic mice and showed that hAAT significantly blocked the production of anti-dsDNA IgG autoantibodies. Mechanistically, hAAT inhibited T cell activation and proliferation, including that of effector memory T (Tem) and T follicular helper (Tfh) cells. In addition, hAAT suppressed germinal center formation and functions. These results advanced the current understanding of hAAT functions and provide a new insight for the treatment of SLE. Full article

Background: The regulation of glucose metabolism is contingent on a multifaceted interaction between intestinal absorption, pancreatic endocrine function, and the hepatic response to insulin. Axis disruption contributes to insulin resistance and type 2 diabetes. Methods: This study tested mulberry, bilberry, and black currant extracts individually and in combination in an integrated in vitro gut, pancreas, and liver model. The extracts were phytochemically characterised and tested at optimal concentrations selected through dose–response studies. Results: The combined treatment preserved and enhanced the intestinal barrier, as evidenced by increased tight-junction levels and reduced oxidative stress. In the pancreas, the combination significantly improved cell viability, enhanced insulin and C-peptide secretion, and increased glucokinase expression, indicating improved glucose-sensing function. In the liver, the combined treatment synergistically activated insulin signalling, increasing the expression of IRS1, GLUT2, AMPK, AKT, and PGC-1α. This resulted in increased glucose absorption, glycogen synthesis, and a marked reduction in extracellular glucose levels under hyperglycaemic conditions. The results show that combining mulberry, bilberry, and blackcurrant produces additive benefits for intestinal barrier integrity and synergistically modulates key elements of hepatic insulin signalling. Conclusions: These findings support a mechanistic rationale for exploring multi-targeted nutraceutical formulations as complementary approaches to modulating processes involved in glycaemic regulation. Full article

(1) Background: In Saudi Arabia, a high-income country with a publicly funded healthcare system, sickle cell disease (SCD) remains a major pediatric health challenge. This study aimed to identify factors associated with healthcare utilization, specifically inpatient (IP), outpatient (OP), and emergency department (ED) visits, among children with SCD in Saudi Arabia. (2) Methods: A retrospective observational study was conducted using data from the KAIMRC registry (2015-2023), including 450 children under 12 years old diagnosed with SCD. Negative binomial regression models were employed to analyze the annual average visits, accounting for clinical, demographic, and regional healthcare resource variables. (3) Results: Key predictors of IP visits included complication count, crisis episodes, and region (eastern, western, and southern regions had higher utilization than central). ED visits were positively associated with complications, crisis episodes, and hydroxyurea use, but negatively associated with bone marrow transplant receipt. OP visits increased with higher Charlson Comorbidity Index scores, age, and bone marrow transplant, but were lower in the eastern region. (4) Conclusions: These findings highlight the influence of clinical and regional factors even within an equitable, high-resource healthcare system. Full article

Cancer metabolism is a cornerstone of tumor biology, characterized by profound alterations in cellular energy production and biosynthetic pathways that drive malignancy. The seminal discovery of the “Warburg effect”, the preference of cancer cells for aerobic glycolysis even under oxygen-rich conditions, provided the first major insight into this field. Historically, this observation was attributed to defective mitochondria, but modern research has revealed a far more complex picture of metabolic reprogramming that is actively driven by oncogenes, tumor suppressor genes, and the tumor microenvironment (TME). This review advances a unifying framework for understanding cancer metabolism as a dynamic ecosystem defined by three interconnected adaptations: metabolic plasticity, oncometabolite-driven epigenetic remodeling, and immune-metabolic crosstalk. These adaptations extend beyond glycolysis to encompass glutamine metabolism, lipid synthesis, amino acid utilization, and mitochondrial dynamics, all coordinated to fuel rapid proliferation, promote survival, and enable metastasis. By examining the drivers, consequences, and therapeutic barriers within this framework, we highlight emerging strategies for precision intervention. Although understanding the mechanistic basis of these pathways has unveiled new therapeutic avenues, clinical translation has been limited by metabolic redundancy, microenvironmental buffering, and patient heterogeneity. Strategies such as metabolic inhibitors, dietary interventions, and immuno-metabolic combinations offer promising prospects for disrupting tumor growth when guided by biomarker-driven patient selection and emerging technologies, including spatial metabolomics and AI-driven network modeling. Full article

Background/Objectives: There is high demand for Anshenbunao syrup (ABS) in Chinese medicine owing to its steady therapeutic efficacy for insomnia and neurasthenia. However, it contains a substantial proportion of Polygoni Multiflori Radix Praeparata (PMRP), which is associated with reported cases of drug-induced liver injury (DILI). Here, we aim to establish an integrated approach combining PK screening with a dual-model toxicity verification system to systematically identify liver injury components (from high to low concentrations and from direct to idiosyncratic hepatotoxicity) to accurately uncover diverse potential hepatotoxicity markers. Methods: A sensitive UPLC-MS/MS method was used to accurately quantify the components in plasma at the ng/mL level and conduct a pharmacokinetic analysis. Rat models were used to evaluate exposure levels of the eight active constituents and three major metabolites after a single oral gavage dose of 10 mL/kg ABS and identify the quality markers. The early-stage and high-throughput assessment of direct and idiosyncratic hepatotoxicity was conducted in vitro utilizing HepG2 cells. After the administration of the quality markers (0.01–80 μM), CCK-8 was used to detect cell viability on both normal and susceptible cells, and the latter was induced by lipopolysaccharide. Results: As a result, seven quality markers were screened based on their contents and exposure levels in rat plasma by UPLC–MS/MS, including emodin (EM), liquiritin (LI), 2,3,5,4′–Tetrahydroxystilbene–2–O–β–D–glucoside (TSG), icariin, emodin–8–O–β–D–glucoside, baohuoside I (BA), and 18β–glycyrrhetinic acid (GTA). Moreover, the half maximal inhibitory concentration values of both normal cells and the lipopolysaccharide-induced immune stress liver injury cells were fitted within the concentration range of 0.01–80 μM, based on which, EM, BA, and GTA were identified as the principal hepatotoxic constituents in ABS at elevated concentrations. This study is the first to demonstrate that TSG, EM, LI, and GTA exhibit synergistic cytotoxicity in LPS-sensitized hepatocytes at clinically relevant concentrations, whereas EM was also a direct hepatotoxic component. Given that TSG is one of the major ingredients in ABS, the underappreciated idiosyncratic hepatotoxicity could elevate the risk of adverse clinical outcomes. Conclusions: In conclusion, this study effectively identifies hepatotoxic constituents in ABS and evaluates their hazards under immune stress and toxicity profiles in clinical concentrations, which also provides a robust foundation for the awareness of PMRP-induced DILI due to ABS. Full article

Mitochondria are crucial carriers of maternal effects, and their function is closely related to energy metabolism and disease occurrence. Previous studies have shown that chickens with different mitochondrial haplogroups exhibit differences in production performance, but the underlying mechanism remains unclear. This study investigates the differences in mitochondrial structure and function-related indices between the A and E mitochondrial haplogroups (referred to as A-group and E-group) in recessive white-feathered chickens. It was achieved using in vivo fasting/refeeding models and an in vitro model of treating hepatocytes with nutritional factors (glucose and fatty acids). In vivo study indicated that compared to A-group chicken hepatocytes, E-group hepatocytes had shorter perimeters of mitochondria and shorter lengths of mitochondria associated with the endoplasmic reticulum membrane during refeeding (p < 0.05); mitochondria were more abundant (p = 0.05) but displayed compromised structural integrity during fasting; mitochondrial swelling was more severe during both refeeding and fasting (p < 0.01, p < 0.05); the protein level of mitofusin 2 (MFN2) was lower during fasting (p < 0.05); and there were more vacuoles and lipid accumulation in liver sections during refeeding (p < 0.05). In cultured hepatocytes, compared to A-group cells, E-group cells had higher reactive oxygen species (ROS) level after oleic acid treatments (p < 0.001); the protein level of microtubule-associated protein 1A/1B-light chain 3 beta (LC3) was lower after glucose treatment (p < 0.01), and the protein levels of MFN2 and LC3 were lower after oleic acid treatment (p < 0.01, p < 0.05). These findings suggest that mitochondrial haplogroups are associated with mitochondrial structure and function, oxidative stress, autophagy, and lipid metabolism of chicken hepatocytes in response to energy stimulation. The findings may explain how mitochondrial haplogroups affect chicken production performance. Full article

This study examines the histological, ultrastructural, and immunohistochemical features of the lip skin of the goldfish (Carassius auratus, Linnaeus, 1758), a sensory-rich region that plays an essential role in feeding and environmental perception. Our findings highlight the coexistence and close association of immune, epithelial, and sensory cells within the epidermis and dermis. For the first time in goldfish, intraepidermal macrophages, eosinophilic granular cells, rodlet cells, Merkel cells, and several specialized sensory structures—neuromasts, taste buds, and tuberous-like sensory units—were simultaneously identified within the same integumentary field. Quantitative morphometry demonstrated a high density of eosinophilic granular cells, rodlet cells, and neuromasts per unit epithelial area, reinforcing the functional specialization of the goldfish lip as a sensory–immune interface. Immunohistochemical markers (CK20, S100, CD68, CD64, CD117, and E-cadherin) were applied as complementary tools to describe phenotypic labeling patterns. These findings are interpreted cautiously as supportive evidence consistent with epithelial, neural-associated, stromal, and immune cell distributions observed morphologically. Transmission electron microscopy further uncovered fine structural details such as synapse-like contacts in taste buds and Merkel cells, dense-core granules in eosinophilic granular cells, and telocyte–nerve fiber associations in the dermis. By integrating cellular, structural, and immunohistochemical perspectives, this study provides a novel descriptive reference for the goldfish lip skin as a region characterized by the close spatial association of sensory and immune-related elements, underscoring its value as a model for vertebrate cutaneous biology and neuroimmunology. Full article

Persistent corpus luteum (PCL) and ovarian quiescence (OQ) are key manifestations of ovarian dysfunction (OD) that lead to reduced reproductive capacity in beef cattle, posing a serious challenge to the industry. Anthocyanins (ACNs) are known for their antioxidant properties. This study aimed to investigate the regulatory effects of ACNs on PCL and OQ and to explore the underlying mechanisms. Forty-eight beef cows diagnosed with both OQ and PCL were selected and continuously fed ACNs for 60 days. The results showed that the regulatory effects of ACNs were dose-dependent. A high dose of ACNs (ACNH) significantly increased the number of large follicles and reduced the occurrence of PCL. ACNH treatment significantly decreased serum progesterone (P4) levels and increased estradiol (E2) levels. Furthermore, ACNH reduced microbial diversity in OD cows but significantly increased the abundance of Patescibacteria, Actinobacteriota, Proteobacteria, and Chloroflexi, while decreasing the abundance of Desulfobactera, indicating that ACNs may affect ovarian function by regulating the gut microbial environment. In an ovarian granulosa cell model of oxidative damage, ACN intervention could reduce oxidative stress levels and mitigate oxidative damage. ACNs downregulated various pro-apoptotic genes, such as P53, Fas, and Bax, while upregulating anti-apoptotic genes Bcl-2 and Bcl-xL, suggesting that ACNs significantly inhibit cell apoptosis. To conclude, these results demonstrate that ACNs improve the ovarian function of beef cows by regulating gut microbiota and reducing oxidative stress-induced apoptosis in ovarian granulosa cells, thereby enhancing the reproductive capacity of beef cattle that show reproductive disorders. These findings provide a theoretical basis for the application of ACNs in the cattle industry and showcase their potential value as natural antioxidants. Full article

Background/Objectives: Chlamydia trachomatis (CT) infection is one of the most prevalent sexually transmitted infections (STIs) worldwide and has been consistently associated with adverse reproductive outcomes, including female infertility. However, the molecular mechanisms underlying this association remain incompletely understood. This study aimed to investigate whether genes previously associated with female infertility display altered expression patterns in response to CT infection by reanalyzing publicly available transcriptomic data derived from a human in vitro infection model. Methods: An integrative in silico approach was employed. A curated list of 106 genes associated with female infertility was compiled from publicly available databases and integrated with transcriptomic data from the Gene Expression Omnibus (GEO) dataset GSE109428, which profiles primary human fallopian tube mesenchymal cells infected in vitro with CT serovar L2. Gene expression changes were evaluated at two time points (24 and 48 h post-infection) by comparing infected cells with uninfected control samples, followed by functional and phenotype enrichment analyses. Results: One female infertility-associated gene (AKAP12) was consistently dysregulated at both 24 and 48 h post-infection. In addition, fourteen genes (ANAPC4, BMP1, BNC2, BTG4, EFHD1, FBXO43, INHBB, PATL2, SCARB1, SND1, SYNE1, TRIP13, TTC28, and TUBA1C) became significantly dysregulated exclusively at 48 h post-infection, indicating a time-dependent host transcriptional response to CT infection. Functional and phenotype enrichment analyses revealed associations with biological processes related to embryonic development and meiosis, as well as phenotypes linked to female infertility. These enriched terms were supported by a small subset of genes and were therefore interpreted cautiously. Conclusions: Overall, these findings suggest that CT infection modulates the expression of several infertility-associated genes and may influence biological pathways critical for female reproductive function. While exploratory, this study provides a molecular context that aligns with previously reported associations between CT infection and female infertility. Full article