Search Results (523)

Nerve injuries are frequent complications of complex oral and maxillofacial surgical procedures, particularly following extensive tumor resections. Secretome-based, cell-free therapies derived from mesenchymal stromal cells have emerged as promising regenerative approaches; however, robust manufacturing requires the identification of critical quality attributes (CQAs) that ensure product potency and consistency. The influence of replicative senescence during in vitro expansion on the quality of jaw periosteum-derived mesenchymal stromal cell (JPC) secretomes has not yet been established. This study investigated whether the expansion state of JPCs affects the composition and neuro-supportive potency of their secretomes. Secretomes from four independent JPC donors were collected separately at early and late passages, pooled within each passage-specific preparation, and applied to human induced pluripotent stem cell-derived neurons. Neuronal survival, neurite outgrowth, and neuronal marker expression were assessed as functional readouts. Secretome composition was characterized by quantitative proteomics and enzyme-linked immunosorbent assay (ELISA) of selected senescence-associated secretory phenotype (SASP) factors. Secretomes derived from early-passage JPCs significantly enhanced neuronal survival and neurite outgrowth, whereas late-passage secretomes displayed reduced neuro-supportive activity. Proteomic profiling identified a pronounced shift toward inflammatory and stress-associated signaling, whereas performed ELISAs confirmed senescence-associated remodeling of the secretome, including increased abundance of SASP-associated factors in late-passage preparations. These findings demonstrate that prolonged in vitro expansion profoundly influences both the composition and biological potency of JPC-derived secretomes. Collectively, this study identifies the passage-associated senescence-like phenotype of JPCs as a key determinant of secretome quality and supports its consideration as a critical quality attribute for the manufacturing and standardization of JPC-derived secretome products. Monitoring and controlling the expansion state of JPCs may therefore be essential to ensure the consistency, potency, and clinical translation of secretome-based regenerative therapies. Full article

Oral diseases, such as periodontitis, remain a major global concern due to their high incidence and significant morbidity. The principal drivers are bacterial overgrowth and associated inflammation. Bioactive glass of the 45S5 Bioglass^® composition (BG) is known for its remineralising, osteogenic and antibacterial effects via ion release, but its application has been limited in oral environments. In this study, a photocurable GelMA hydrogel was developed as a carrier matrix for BG (1–15% w/v) to obtain synergy between the adhesive properties of the GelMA and the bioactivity of the glass. Incorporation of 10% w/v BG improved ultimate tensile strength (97 kPa) compared to pure GelMA (58 kPa) and reduced swelling by 18%. The composites showed ~60% higher adhesive strength on collagen sheets than GelMA alone. Tensile bonding strengths reached 54 kPa on collagen sheets and 23 kPa on tooth sections. Lap-shear adhesive strengths were 44 kPa on collagen and 18 kPa on implant metal. In vitro studies confirmed the composite’s biocompatibility with dental pulp stem cells and antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus. Overall, the GelMA/BG composite presents a multifunctional platform for dental remineralisation with promising mechanical, adhesive and antibacterial performance. Full article

Tooth loss and bone resorption of the alveolar cavity caused by dental caries and periodontal disease remain major clinical challenges that compromise oral function. Tissue engineering approaches based on biocompatible scaffolds have emerged as promising strategies for bone regeneration; however, the influence of fabrication methods on scaffold performance remains unclear. This study developed hydroxyapatite/poly (lactic-coglycolic acid)/chitosan scaffolds (HAp/PLGA/CS) using freeze-drying and 3D-printing techniques and evaluated their physicochemical, biological, and biomechanical properties. The morphology, porosity, elemental composition, and mechanical properties of the scaffold were characterized, while the biocompatibility and osteogenic potential were evaluated using human dental pulp stem cells (hDPSCs). Finite element analysis (FEA) using COMSOL Multiphysics^® Version 6.2. was performed to evaluate scaffold behavior under simulated dental implant loading conditions. The 3D-printed scaffolds exhibited significantly higher cell viability than the freeze-dried scaffolds, reaching approximately 85% in the 50% filling group compared with 50% in the freeze-dried group. Microstructural analysis revealed interconnected hierarchical porosity, including macro-, micro-, and submicrometer scale pores. Although the 50% infill scaffold showed the highest cell viability, the 70% infill scaffold demonstrated the most favorable osteogenic profile, with enhanced expression of RUNX2 and OSX. Both types exhibited degradation profiles compatible with early bone regeneration. FEA simulations indicated that further mechanical optimization is required to improve load transfer and reduce deformation at the implant–scaffold interface. Overall, HAp/PLGA/CS scaffolds showed potential as experimental bioactive platforms for bone tissue engineering, with 3D-printed scaffolds providing greater architectural control and favorable early osteogenic responses. However, the translational relevance of these findings remains preliminary and requires validation through long-term degradation studies, in vivo bone regeneration and osseointegration models, cyclic mechanical testing, and implant fixation experiments. Full article

Chronic constipation is a prevalent functional gastrointestinal disorder with limited long-term treatment options. This study examined whether a fucoidan preparation derived from Sargassum fusiforme (SF) ameliorates loperamide (LOP)-induced constipation in male ICR mice. SF was administered by oral gavage at 50, 100 or 200 mg/kg/day for 35 days, and constipation was induced with LOP (5 mg/kg) during the final 7 days; the design is therefore preventive rather than therapeutic. Defecation endpoints were recorded at the cage level (n = 3 cages per group) and fecal moisture in individual mice (n = 7 per group), whereas colonic cytokine and myeloperoxidase (MPO) measurements (n = 3–4 per group) and Western blot analyses (n = 3 per group) were performed in a small subset of animals, and histological analyses in n = 6–8 per group. SF increased fecal output and fecal moisture content with increasing dose; at 200 mg/kg the relative fecal number returned to the level of the Vehicle control group, although the absolute daily pellet count remained lower than that of the Vehicle control and of the Positive control group. SF administration was associated with lower colonic TNF-α, IL-6, IL-1β and MPO concentrations, with reduced phosphorylation of p38, JNK and ERK, with higher C-kit and stem cell factor (SCF) levels, with normalization of the LOP-induced increase in aquaporin-3 (AQP3), and with recovery of colonic mucosal thickness and mucin content. 16S rRNA gene sequencing showed a shift in fecal microbiota community structure (PERMANOVA p = 0.0002) and a dose-related increase in the combined relative abundance of Lactobacillus and Bifidobacterium, without a reduction in alpha diversity. These findings indicate that SF ameliorates LOP-induced constipation in male mice and that this effect is accompanied by changes in colonic inflammatory signaling, motility-related protein expression, mucosal architecture and gut microbiota composition. Full article

Fructooligosaccharides (FOSs) are a class of functional prebiotics that effectively modulate the composition of the intestinal microbiota and regulate metabolic processes in animals. This study aimed to determine how early FOS supplementation affects jejunal development, which is vital for the rapid growth of suckling piglets. Sixty newborn piglets (Duroc × Landrace × Large White) from six litters were randomly assigned to either a control (CON) or an FOS group (n = 5 per litter per group). From days 2 to 21, piglets in the FOS group received 5 mL of an FOS solution orally (3 g/day/piglet), while those in the CON group received an equal volume of saline. Piglets were weighed on days 1, 7, 14, and 21, and samples were collected on days 7, 14, and 21. Early FOS intervention can enhance the growth performance of suckling piglets (p < 0.01), which is related to the development of the jejunum. Specifically, it improved intestinal morphology, stem cell function, and nutrient transport by increasing mRNA and protein expression of key genes in the Wnt/β-catenin signaling pathway. This may be related to increased abundance of jejunal Lactobacillus and the concentrations of metabolites such as lactate and short-chain fatty acids (SCFAs). Early FOS intervention drove jejunal development through Wnt/β-catenin activation, a process mediated by microbiota-metabolite shifts that augmented intestinal stem cell renewal. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited therapeutic options for patients at high risk of disease recurrence and metastasis. The cyclic nucleotide-degrading enzyme, phosphodiesterase 10A (PDE10), that hydrolyzes both cAMP and cGMP has been previously reported to be expressed in multiple cancers and regulates key cellular signaling pathways involved in cancer cell proliferation, survival, and maintenance of stem cell-like properties. We found that PDE10 overexpression was associated with poor relapse-free survival of TNBC patients and identified its potential as a therapeutic target for TNBC using a novel inhibitor, ADT-030. Our results showed that ADT-030 inhibited the growth of TNBC cells, reduced colony-forming efficiency and enhanced the therapeutic efficacy of paclitaxel. A TNBC mouse model demonstrated that oral administration of ADT-030 significantly suppressed syngeneic tumor growth and enhanced the antitumor efficacy of paclitaxel. ADT-030 treatment altered differentially expressed genes (DEGs), signaling pathways, and cellular processes. Overall, our findings suggest that ADT-030, as a monotherapy or in combination with standard-of-care chemotherapy, may be an effective therapeutic approach for TNBC. Further studies are warranted to better understand the oncogenic role of PDE10 in TNBC and the mechanisms by which ADT-030 modulates the tumor microenvironment (TME) and enhances chemotherapy response. Full article

Cancer stem cell (CSC) persistence drives recurrence and therapy resistance in oral squamous cell carcinoma (OSCC), but what keeps cells locked in this stem-like state is poorly understood. In this narrative review, we propose that CSC state is sustained not by any single pathway but by joint dysregulation of three interacting cell-biological systems: membrane potential (V_mem), communication between neighbouring cells through gap junctional intercellular communication (GJIC), and the Hippo–YAP pathway. We argue that these systems act together on one common point—the YAP protein, retained in the nucleus—which switches on a SOX2-centred stemness gene programme and stabilises a self-reinforcing CSC state. Drawing on evidence from cancer genomics, developmental bioelectricity, connexin biology, and OSCC-specific studies, we reconstruct how membrane depolarisation, loss of gap junction coupling, FAT1 mutation, and Hippo pathway inactivation could converge on persistent nuclear YAP, and how betel quid—the principal risk factor across South and Southeast Asia—may engage all three systems at once. Because the model holds that each input reinforces the others, it predicts that targeting several together should displace CSC state more durably than targeting any one alone. We set out the testable predictions this framework generates. Full article

Feline chronic gingivostomatitis (FCGS) is a chronic inflammatory disease of the oral mucosa. Mesenchymal stem cell (MSC) treatments have been investigated as a potential treatment for this condition; however, the biodistribution profile of MSCs remains poorly understood. The goal of this study was to assess the relative pharmacokinetics of MSCs by comparing their biodistribution in healthy cats to that in cats suffering from FCGS. Two studies were performed to evaluate the biodistribution of radiolabelled equine peripheral blood-derived mesenchymal stem cells (ePB-MSCs) following intravenous and subcutaneous administration in healthy cats (n = 3) and in cats with FCGS (n = 4). Total body scintigraphic scans were obtained using a gamma camera. Free ^99mTechnetium accumulation was primarily observed in the heart, lungs, stomach, bladder, thyroid, and salivary glands. Following intravenous administration of radiolabelled ePB-MSCs, increased radiopharmaceutical uptake (IRU) was mainly detected in the lungs, liver, kidneys, and bladder. After subcutaneous administration, IRU was predominantly observed at the injection site. In cats affected by FCGS, a higher radiotracer signal was observed in the rostral oral region following intravenous administration, with a mean 3.4-fold increase compared with healthy cats. The biodistribution pattern of radiolabelled ePB-MSCs differed from that of free ^99mTechnetium. These findings provide preliminary information regarding the biodistribution of radiolabelled ePB-MSCs in cats. Full article

Periodontal diseases are highly prevalent conditions characterized by chronic inflammation, which leads to progressive destruction of tooth-supporting tissues. Conventional therapies, including scaling and root planing, grafting, and surgical procedures, are effective in controlling infection but show limited regenerative capacity. In this context, hydrogels—three-dimensional, highly hydrated polymeric biomaterials that mimic the extracellular matrix—have emerged as promising tools in periodontal regeneration. These materials can be engineered to modulate mechanical properties, porosity, and the delivery of bioactive molecules. Hydrogels can function as barrier membranes for guided tissue regeneration, scaffolds for stem cell support, and carriers for antimicrobial, anti-inflammatory, and osteogenic agents, enabling sustained and localized drug release. Recent studies have demonstrated their potential to inhibit bacterial biofilms, enhance osteogenic differentiation, and reduce inflammation in preclinical models. However, challenges remain regarding mechanical stability in the oral environment, controlled and sequential release of therapeutic agents, biocompatibility, and cost-effectiveness. Overall, hydrogels represent a promising adjunct in regenerative periodontal therapy, although further research is required to support their translation into routine clinical practice. Full article

Oral squamous cell carcinoma (OSCC) accounts for most head-and-neck cancers, and effective biological adjuvants remain limited. Gingival mesenchymal stem cells (GMSCs) exhibit anti-tumour paracrine activity, but the underlying molecular mechanisms and their relevance in patient cohorts remain incompletely understood. Consensus apoptosis–reactive oxygen species (ROS) effectors were identified through integrated transcriptomic analyses of TCGA-HNSC and three GEO cohorts. Candidate genes were evaluated in primary OSCC cells exposed to GMSC-conditioned medium or indirect Transwell co-culture. Findings were further examined using patient-cohort validation, single-cell ligand–receptor analysis, pathway and transcription-factor activity inference, and drug-repurposing approaches. Computational analyses identified an apoptosis–ROS network centred on BAX, BCL2, CASP3, CASP9, NOX1, and GPX1. Indirect GMSC co-culture reduced intracellular ROS, increased early apoptosis, and induced G2/M accumulation, whereas conditioned medium produced inconsistent effects, suggesting a requirement for live bidirectional paracrine signalling. BAX was the only consistently up-regulated effector. The axis demonstrated concordant differential expression across independent HPV-negative OSCC cohorts but was not independently prognostic under leakage-free cross-validation or external validation. Pathway analyses supported ROS suppression, apoptosis activation, and altered stromal–tumour communication. Drug-repurposing analyses identified HSP90 inhibitors and the FDA-approved TOP2 inhibitor mitoxantrone as candidate therapeutic agents. GMSC paracrine activity targets a biologically interpretable apoptosis–ROS axis in OSCC that is reproducibly expressed across patient cohorts but does not constitute an independent prognostic biomarker. The identified therapeutic candidates warrant further experimental investigation. Full article

The Warburg effect is better understood as regulated metabolic plasticity rather than mitochondrial failure. Many malignant cells retain functional mitochondria while increasing aerobic glycolysis, lactate production, and redox remodeling to support growth, immune escape, and adaptation to microenvironmental stress. Within the context of the cancer microenvironment, this review examines xylitol as a hypothetical metabolic modifier within a broader host-microbe-mitochondria framework. Xylitol, a five-carbon sugar alcohol, is derived endogenously through the pentose phosphate pathway (PPP) and the glucuronate–xylulose pathway, and is metabolized efficiently in humans, rats, and pigs through xylitol dehydrogenase (XDH) in hepatic mitochondria and the cytosol; whereas, it is less tolerated by obligate carnivores who lack this enzyme. Preclinical studies show that partial substitution of glucose with xylitol can reduce proliferation and glycolytic markers in oral squamous carcinoma models, and preliminary studies link xylitol to glutathione depletion, endoplasmic reticulum (ER) stress, autophagy-associated death, and altered tumor metabolomics. On the other hand, oral pathogens such as Fusobacterium nucleatum and Porphyromonas gingivalis promote tumor stemness, extracellular vesicle signaling, metastasis, and immune evasion. In addition, Streptococcus mutans, the primary cariogenic pathogen, contributes to systemic bacteremia and epithelial–mesenchymal transition. Oral and gut microbiomes modulate macrophage polarization, T cell activity, and the senescence-associated secretory phenotype (SASP), possibly promoting cancer immune evasion. The anti-adhesive properties of xylitol may limit pathogen attachment to immune cell receptors, reducing the generation of pro-tumorigenic senescent immune cells. Xylitol also offers metabolic benefits, a low glycemic index, partial insulin-independent metabolism, and potential diabetes-prevention activity that are relevant, considering the established link between metabolic disease and cancer risk. A recent study reported that higher levels of endogenous xylitol were associated with adverse cardiovascular events, but confirmation of this requires large scale prospective studies. The evolutionary dietary context of MIS 6, during which hominin populations in sub-Saharan Africa depended on polyol-rich underground storage organs, provides a biological basis for human tolerance of xylitol. As a result, we hypothesize that xylitol may be a context-dependent metabolic modifier within an integrated host–microbe–mitochondria–cancer stem cell network. Full article

Cancer stem cells (CSCs) drive therapeutic resistance and tumor relapse by exploiting redundant regulatory networks that integrate Wnt/β-catenin, Notch, and Hedgehog signaling with metabolic reprogramming, epigenetic plasticity, and tumor microenvironment crosstalk, a network architecture that renders single-pathway inhibition strategies insufficient. This review systematically examines evidence that natural compounds (curcumin, sulforaphane, resveratrol, EGCG, berberine, and quercetin) act as multitarget modulators of CSC plasticity, analyzing their molecular mechanisms of action in specific cancer models. Each compound engages distinct regulatory nodes: curcumin suppresses β-catenin nuclear translocation and STAT3 phosphorylation in lung cancer CSC models; sulforaphane represses ΔNp63α-driven stemness transcription in colorectal cancer and reduces CSC self-renewal in prostate and head and neck models; resveratrol dissociates the β-catenin–GLI-1 interaction in oral and lung CSC populations and induces Wnt/β-catenin-dependent autophagy in breast CSCs; EGCG inhibits DNMT and HDAC activity in glioblastoma and colorectal models; berberine activates AMPK-mediated suppression of mTORC1 in colorectal cancer; and quercetin suppresses PI3K/AKT/mTOR signaling while downregulating EMT transcription factors in breast and colorectal systems. We critically assess persistent methodological limitations, including bulk cell-line models, supraphysiological concentrations, and the absence of functional tumor-initiating validation, that currently prevent stronger translational conclusions. Natural compounds from Latin American biodiversity are identified as an underexplored source of CSC-active molecules. We conclude by defining the experimental standards required to reposition natural compounds as clinically relevant network-level modulators of CSC plasticity. Full article

Glioblastoma (GB) is the most aggressive primary central nervous system tumor in adults and the most common malignant primary brain tumor, representing approximately 50.9% of all malignant CNS tumors, with a median overall survival of approximately 14.6 months despite standard multimodal treatment, consisting of surgical resection, concurrent radiotherapy, and temozolomide (TMZ), followed by adjuvant TMZ (Stupp protocol). Tumor recurrence is inevitable and attributed to diffuse infiltration of neoplastic cells into the brain parenchyma, marked intratumoral heterogeneity, the presence of glioma stem cells, and the protection conferred by the BBB. Flavonoids are plant-derived polyphenolic compounds with more than 8000 identified. They have attracted growing interest as potential therapeutic agents because of their capacity to modulate multiple oncogenic signaling pathways and their favorable toxicity profile. Here we synthesize the preclinical evidence on the main flavonoids with documented activity in GB models, with emphasis on quercetin, apigenin, luteolin, and EGCG, while distinguishing glioblastoma-specific evidence from indirect findings derived from other experimental systems. We analyze their underlying molecular mechanisms, including induction of apoptosis through the intrinsic and extrinsic pathways, inhibition of cell proliferation and angiogenesis, suppression of migration and invasion, epigenetic modulation, and, particularly, the capacity to target the glioma stem cell population. We also examine the limited oral bioavailability and restricted penetration across the BBB, as these factors remain major barriers to translational development. We conclude with an analysis of emerging nanotechnological strategies, targeted delivery systems, and synergistic combinations with conventional chemotherapeutic agents, together with a cautious assessment of the current clinical evidence, which remains insufficient to support the use of flavonoids outside controlled clinical trials. Full article

The management of acute myeloid leukemia (AML) remains characterized by high relapse rates despite advances in induction and consolidation therapy. Relapse prevention represents a major unmet need, particularly in patients ineligible for allogeneic hematopoietic stem cell transplantation (allo-HSCT) or at high risk of post-transplant recurrence. This review examines current evidence supporting maintenance strategies following intensive chemotherapy or allo-HSCT, with emphasis on measurable residual disease (MRD)-guided approaches and targeted therapies. We summarize data from randomized and phase II/III trials evaluating hypomethylating agents, FLT3 inhibitors, IDH inhibitors, and immunotherapeutic strategies in post-remission settings. Oral azacitidine (CC-486) demonstrated overall survival benefit in older patients in first complete remission who were not transplant candidates, establishing a standard of care in this population. In FLT3-mutated AML, post-transplant maintenance with sorafenib and gilteritinib reduces relapse risk, with emerging evidence supporting MRD as a predictive biomarker for benefit. Other targeted agents and immunotherapies have shown promising early-phase results, although confirmatory data are limited. Ongoing phase III studies will clarify optimal patient selection, treatment duration, and integration with transplantation, aiming to transform post-remission management from passive surveillance to precision-based relapse prevention. Full article

Background: Toxic epidermal necrolysis (TEN) is a rare but life-threatening complication that may occur in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in the context of extensive drug exposure. In this population, TEN can closely resemble severe acute graft-versus-host disease (GVHD), making diagnosis and management challenging. Case presentation: We report the clinical course of an allo-HSCT recipient who developed a rapidly progressive skin rash early after transplantation, and we analyzed the clinical features, histopathology, treatment and outcome. Results: The patient developed rapidly progressive epidermal detachment with severe oral, ocular, and genital mucosal involvement shortly after exposure to trimethoprim/sulfamethoxazole (TMP-SMX). Disease severity was reflected by a SCORTEN score of 5, corresponding to a very high predicted mortality risk. The clinical picture raised concern for both TEN and severe acute GVHD, while histopathological findings favored TEN but were not definitive. Management included systemic corticosteroids, intravenous immunoglobulin, ruxolitinib, and intensive supportive care. The patient gradually re-epithelialized and recovered without long-term sequelae. Conclusions: This case underscores the diagnostic difficulty of distinguishing TEN from severe acute GVHD in the early post-transplant period. Careful assessment of drug exposure, clinical evolution, and multidisciplinary evaluation are essential to guide timely and appropriate management. Full article