Search Results (9,757)

Dental tissue regeneration, particularly alveolar bone and gingival repair, remains a major challenge in regenerative medicine. 3D bioprinting offers patient-specific and anatomically precise constructs, representing an advanced alternative to conventional grafting. In this study, nanohydroxyapatite (nHA), chitosan (CS), and collagen (CoL) were combined to fabricate and characterize 3D bioprinted dental grafts. SEM revealed a highly porous, interconnected architecture favorable for cell infiltration and nutrient exchange. EDS confirmed Ca/P ratios of 2.06 for nHA/CoL and 1.83 for nHA/CS/CoL, both of which are above the stoichiometric 1.67, indicating the presence of additional mineral phases and ion substitutions. FTIR and XRD verified characteristic functional groups and crystalline phases, including B-type HA with carbonate substitution. Mechanical testing showed that pure nHA exhibited the lowest compressive strength, whereas CoL incorporation improved stiffness. The nHA/CS/CoL composite achieved the highest compressive strength, elastic modulus, and toughness, demonstrating superior mechanical resilience. DSC analysis indicated endothermic peaks at 106.49 °C and 351.91 °C, with enthalpy values (264.91 J/g and 15.09 J/g) surpassing those of nHA alone. TGA revealed ~28.8% weight loss across three degradation stages, confirming enhanced thermal stability. In vitro cytocompatibility testing using L929 fibroblasts validated the biocompatibility of the composites. Collectively, the synergy between bioceramics and biopolymers markedly improved both mechanical and thermal performance. These findings position the nHA/CS/CoL scaffold as a promising candidate for clinical applications in dental tissue regeneration. Unlike conventional grafting materials, this study introduces a synergistically optimized nHA/CS/CoL bio-ink formulation specifically designed for extrusion-based 3D bioprinting of patient-specific dental constructs. The core innovation lies in the precise integration of nHA within a dual-polymer matrix (CS/CoL), which bridges the gap between mechanical resilience and biological signaling, achieving a compressive strength that mimics native alveolar bone while maintaining high cytocompatibility. Full article

Heart failure (HF) is the leading cause of morbidity and mortality worldwide, while myocardial fibrosis acts as a pivotal hallmark, which exacerbates ventricular dysfunction and remodeling in HF. In this study, we found FGF23, a critical endocrine regulator, which regulates phosphate and vitamin D metabolism, was significantly upregulated in fibrotic mouse hearts after transverse aortic constriction (TAC). By using the FGF23 monoclonal antibody, we found that inhibition of FGF23 alleviated TAC-induced cardiac fibrosis, while injection of recombinant FGF23 (rFGF23) protein exacerbated tissue fibrosis in mouse hearts after TAC. RNA sequencing indicated that FGF23 may promote cardiac fibroblast proliferation and activation in stressed mouse hearts. In human primary cardiac fibroblasts, rFGF23 treatment further upregulated the expression of Ki67, Cyclin D1, Cyclin E1, PCNA, α-SMA, and collagen 1A1 after TGF-β stimulation. Further results indicated that FGF23 promoted cardiac fibroblast proliferation and activation through FGFR4 and activated the downstream MAPK/ERK signaling. This study suggests a role of FGF23 in the regulation of myocardial fibrosis, which shows the potential of targeting FGF23 in the treatment of HF and cardiac fibrosis. Full article

Background/Objectives: Peak cough flow (PCF) is an objective measure of cough effectiveness after stroke, but biomarkers reflecting physiological vulnerability related to reduced PCF are not well established. We investigated whether bone turnover markers (BTMs)—C-terminal telopeptide of type I collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)—were associated with PCF in subacute ischemic stroke. Methods: In this retrospective study, 112 patients admitted within 21 days of stroke onset had fasting morning CTX and P1NP measured by electrochemiluminescence immunoassay, and PCF measured within 72 h of admission. Associations were assessed using Spearman correlation and multivariable linear regression with BTMs standardized (per 1 standard deviation increase), adjusting for age, sex, body mass index, onset-to-admission days, National Institutes of Health Stroke Scale score, Korean version of the Modified Barthel Index, estimated glomerular filtration rate, smoking status, and brainstem lesion. Results: CTX showed an inverse correlation with PCF (rho = −0.469; p < 0.001) and remained independently associated with lower PCF after multivariable adjustment (β = −42.32 L/min; 95% confidence interval, −56.12 to −28.52; p < 0.001), whereas P1NP showed weaker associations. In secondary outcome analyses, higher CTX was associated with low PCF (PCF < 160 L/min), aspiration pneumonia, and longer length of stay. Conclusions: Higher CTX levels were independently associated with lower peak cough flow and selected respiratory-related outcomes in this retrospective cohort. These findings are hypothesis-generating, do not imply prognostic validation, and warrant confirmation in prospective multicenter studies assessing incremental predictive value. Full article

Skin aging is a complex biological process triggered by intrinsic and extrinsic factors, causing structural and functional deterioration, and its mitigation is a priority in cosmetology and functional food science. Skin fibroblasts, which mediate skin repair, wound healing and inflammation, are closely associated with aging. Sea cucumber collagen peptides exhibit prominent anti-aging, immunomodulatory and antioxidant properties, yet their mechanisms in ameliorating skin aging remain elusive, necessitating further exploration. This study verified the anti-skin aging efficacy of sea cucumber collagen peptides in D-galactose-induced aging mice, and explored whether the mechanism involves regulating endoplasmic reticulum (ER) stress in skin fibroblasts. Aging mice were gavaged with sea cucumber collagen peptides; skin moisture, barrier function and hydroxyproline content were measured, and skin morphology was observed. Immunofluorescence and Western Blot were used to detect ER stress-related proteins. Results showed that sea cucumber collagen peptides significantly improved aging mouse skin barrier function, elevated water and collagen fiber contents, and ameliorated the status of fibroblasts and prickle cells. The underlying mechanism may involve inhibiting ER stress in skin fibroblasts and enhancing prickle cell function. These findings confirm the peptides’ high bioavailability and potential as anti-aging functional food ingredients, providing insights for skin aging prevention. Full article

Cutaneous fibrosis is characterized by aberrant wound healing with excessive extracellular matrix deposition, sustained inflammation, and oxidative stress, while currently available therapies show limited efficacy and safety. A Dual Hyaluronic Acid Compound (DHC), consisting of high-molecular-weight, low-molecular-weight, and minimally cross-linked hyaluronic acid, has demonstrated regenerative and antioxidant properties, but its anti-fibrotic effects have not been fully explored. This study investigated the anti-fibrotic potential of DHC using a bleomycin-induced murine dermal fibrosis model and a UVB-irradiated ex vivo human skin model. In C57BL/6 mice, dermal fibrosis was induced by daily bleomycin injections for three weeks, followed by intradermal DHC administration. Histological and biomechanical analyses showed that DHC significantly reduced dermal thickness, collagen deposition, and skin hardness compared with untreated fibrotic controls. DHC decreased α-SMA expression and increased MMP1 levels, indicating attenuation of myofibroblast activation and enhanced matrix remodeling. It also reduced macrophage markers (CD68, CD163) and pro-inflammatory cytokines (IL-1β, TNF-α). Furthermore, DHC restored superoxide dismutase (SOD) and catalase (CAT) activity and upregulated NRF2, HO-1, and NQO1 expression in the in vivo model. Similarly, DHC upregulated SOD and CAT activity and reduced pro-inflammatory cytokines (IL-6, TNF-α) in the ex vivo human skin model. These findings suggest that DHC exerts multimodal anti-fibrotic effects through coordinated regulation of fibroblast activation, inflammation, and oxidative stress, supporting its potential as a therapeutic approach for cutaneous fibrosis. Full article

The in vivo effect of platelet-rich plasma (PRP) on supraspinatus tendon morphology and subacromial bursa cell gene expression in degenerative rotator cuff tears remains unclear. This randomized controlled trial evaluated the effect of preoperative leukocyte-poor PRP (LP-PRP) subacromial injection on supraspinatus tendon histology and subacromial bursa gene expression. Sixteen patients with full-thickness supraspinatus tears were randomized to receive an ultrasound-guided LP-PRP injection (n = 8) or no injection (n = 8) six weeks before arthroscopic repair. Tendon biopsies were assessed using the modified Movin score. Gene expression of collagen type I, II and III, metalloproteinase 3 and 13, and interleukin 1β and 6 genes from subacromial bursa cells was quantified using quantitative real-time PCR. The results of the two groups were compared to determine any statistically significant difference regarding all the examined parameters. The PRP group demonstrated a significantly lower total modified Movin score than controls (6.5 vs. 12.1, p = 0.002), with lower scores for fiber structure, fiber arrangement, nuclear rounding, inflammation and cell density (all p < 0.003), while angiogenesis did not differ (p = 0.149), indicating an architecture closer to that of normal tendon. No statistically significant differences in gene expression were observed (all p > 0.05), although collagen II and metalloproteinase 3 and 13 showed biologically relevant downregulation [fold change 0.23 (95%CI 0.05–1.09), 0.24 (95%CI 0.002–26.10), and 0.26 (95%CI 0.02–2.76), respectively]. The LP-PRP injection was associated with improved supraspinatus tendon histological characteristics and biologically relevant reductions in selected bursal genes, in the setting of supraspinatus tendon tear. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by irreversible fibrosis. Aberrant cell differentiation plays a crucial role in the development of IPF. Although recent studies have suggested that mitochondrial dysfunction may play a role in IPF, its direct impact on fibrosis remains unclear. This study aimed to clarify the role of mitochondria in lung cell differentiation and pulmonary fibrosis development by employing mito-mice ND6^M, in which the activity of respiratory chain complex I is decreased due to a mitochondrial DNA mutation (G13997A). Pulmonary fibrosis was induced by administering bleomycin (BLM) to both wild-type and mito-mice ND6^M. Bone marrow-derived macrophages and primary lung fibroblasts, generated from both types of mice, were analyzed to evaluate M1/M2 polarization and myofibroblast differentiation, respectively. Compared to wild-type mice, mito-mice ND6^M exhibited more severe fibrosis and lower survival rates following BLM inoculation. Lactate production in the lungs after BLM administration was significantly higher in mito-mice ND6^M than in wild-type mice. TGF-β1-treated fibroblasts from mito-mice ND6^M exhibited increased α-smooth muscle actin expression. While type I collagen expression was not different between these mice, TGF-β1-induced expression of phosphoserine phosphatase and serine hydroxymethyltransferase2, two of the enzymes involved in the serine–glycine pathway, was significantly higher in mito-mice ND6^M than in wild-type mice. On the other hand, mitochondrial dysfunction had a small effect on pulmonary inflammation and on M1/M2 macrophage polarization. In conclusion, mitochondrial dysfunction promotes TGF-β1-induced myofibroblast differentiation and BLM-induced pulmonary fibrosis. Mitochondria-dependent metabolic reprogramming may therefore represent a promising therapeutic target in IPF. Full article

In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) and the fibrotic stroma generate form a dense stromal barrier that restricts the intratumoural exposure and spatial distribution of oxaliplatin. To enable local stromal remodelling of this pathological stromal compartment, we selected fibroblast activation protein (FAP) as a stromal target and co-assembled two amphiphilic conjugates, oncoFAP and retinoic acid (RA), into an FAP-directed RA nanoformulation termed LRA^FAP. LRA^FAP exhibited a uniform size distribution (107.1 ± 5.8 nm), remained stable for at least 7 d at 37 °C in PBS or serum-containing PBS, and showed accelerated esterase-responsive release. In a TGF-β-induced CAF-like model, LRA^FAP markedly suppressed the expression of CAF activation-associated markers, reducing Fap and Acta2 mRNA levels by approximately 70% and 60%, respectively. In vivo, LRA^FAP showed enhanced accumulation in CAF-enriched tumours and an increase in intratumoural oxaliplatin levels of approximately 2.5-fold relative to oxaliplatin alone. LRA^FAP also reduced collagen deposition and CAF activation markers, and enhanced the antitumour efficacy of oxaliplatin while maintaining good tolerability. Collectively, these findings indicate that LRA^FAP promotes local stromal remodelling and improves intratumoural oxaliplatin exposure, thereby enhancing the efficacy of oxaliplatin-based chemotherapy in CRC. Full article

Background and Objectives: Chemotherapeutic agents are known to disrupt wound healing; however, the influence of administration timing on skin graft repair remains insufficiently characterized. This study aimed to investigate the time-dependent effects of vinblastine exposure on full-thickness skin graft healing in a rat model. Materials and Methods: Twenty-four female Wistar albino rats were allocated into four groups (n = 6). The control group underwent grafting without pharmacologic intervention, whereas the experimental groups received a single intraperitoneal dose of vinblastine (2 mg/kg), followed by grafting in the first week, second week and third week after administration. Graft specimens were harvested on postoperative day 7 for histopathological evaluation performed by a blinded pathologist. Hematoxylin-eosin-stained sections were scored for inflammation, granulation tissue formation, fibroblast maturation, collagen deposition, re-epithelialization, and neovascularization. Intergroup comparisons were conducted using the Kruskal–Wallis test with Dunn–Bonferroni post hoc analysis. Results: Vinblastine exposure produced significant time-dependent differences in several healing parameters. Fibroblast maturation was markedly reduced in the second-week graft group compared with controls (p < 0.001). Re-epithelialization was significantly delayed in the second- and third-week groups (p = 0.033). Granulation tissue formation differed between groups (p = 0.014), with higher early scores observed in the first-week group. Notably, neovascularization was significantly greater in the third-week group than in the control and second-week groups (p = 0.010), suggesting partial recovery of angiogenic activity over time. No significant differences were detected in inflammation or collagen deposition. Conclusions: Vinblastine exposure appears to exert time-dependent effects on skin graft healing, with the second week representing a period of less favorable histopathological repair. Partial recovery observed with later grafting suggests that the interval between chemotherapeutic exposure and reconstructive procedures may influence graft outcomes and support improved surgical planning. Full article

Modeling immune cell recruitment within a wound-relevant microenvironment remains challenging. Here, we developed a novel skin-derived extracellular matrix (ECM) hydrogel model to study monocyte (THP-1) entry and phenotypic changes within a dermal fibroblast-populated (NHDF) matrix. The main novelty of this study is that it compares the effects of fibroblast-derived soluble signals and active monocyte infiltration in a 3D biomimetic model. Signaling by fibroblast-secreted soluble factors enhanced a pro-angiogenic secretome (e.g., >3-fold upregulation of VEGFA at day 1) and promoted endothelial tube formation (increasing network junctions to 1.16 ± 0.16 vs. 0.93 ± 0.23 in monoculture). In contrast, this paracrine signaling did not induce the matrix-driven pro-fibrotic response in hydrogels. Crucially, physical immune infiltration restricted monocyte penetration (mean depth of 8.92 ± 2.27 μm vs. 121.1 ± 15.9 μm in monoculture at day 5), reduced hydrogel-induced myofibroblast activation (decreasing α-SMA+ cells from 79.1% to 54.3% upon initial contact), and was associated with slower collagen loss during the early phase. (retaining a high-density collagen ratio of 3.46 ± 0.33 vs. 2.02 ± 0.29 in monoculture at day 1). These observations were accompanied by a shift toward a matrix-stabilizing profile, including increased TIMP expression and reduced pro-fibrotic markers. (ACTA2 and COL1A1). By including active immune infiltration (which was absent in previous tSVF models), we capture the transition from inflammation to the proliferation stage. Although the later stages of extensive ECM remodeling appear suppressed here, they may occur as repair progresses. Overall, our findings highlight that the immune cell is a key regulatory component for coordinating matrix preservation and vascular support. Importantly, this model replicates the early phases of wound healing, a stage where the monocyte–fibroblast secretome supports endothelial network formation. We established this innovative 3D ECM hydrogel system as a practical and physiologically relevant platform to investigate immune–matrix–stromal crosstalk. Full article

Background: Metabolic disorder-associated fatty liver disease (MASLD) is closely related to obesity and type 2 diabetes. Its pathogenesis involves many factors, including mitochondrial dysfunction, endoplasmic reticulum stress and intestinal flora disorders. Notoginsenoside R1 (NGR1) is a key bioactive component of Panax notoginseng. The purpose of this study was to investigate the therapeutic effect of notoginsenoside R1 (NGR1) on metabolic disorder-associated steatohepatitis (MASH) and its potential mechanism. Methods: Mice were fed a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) for 6 weeks and received NGR1 (50/100 mg/kg/day) in the last 3 weeks. The role of NGR1 was evaluated by developing metabolomics, proteomics and functional analysis. In addition, the effects of NGR1 on lipid droplet content, mitochondrial function and fatty acid oxidation in hepatocytes were also verified. Results: NGR1 improved MASH progression in CDAHFD-fed mice, significantly reduced liver triglyceride content from 31.2 ± 5.1 mmol/g to 20.5 ± 4.8 mg/g (p < 0.001), free fatty acid from 0.12 ± 0.03 mmol/g prot to 0.06 ± 0.028 mg/g (p < 0.001), TNF-α (p < 0.01), IL-1β (p < 0.001), α-SMA (p < 0.05) and Collagen1A1 levels (p < 0.01), as well as serum ALT and AST concentrations (p < 0.001), and alleviated hepatomegaly and lipid droplet accumulation. Metabolomics and proteomics analysis showed that NGR1 normalized liver metabolism in MASH mice and upregulated mitochondrial OXPHOS components, including NADH: ubiquinone oxidoreductase core subunit S2 (NDUFS2), and effectively reversed CDAHFD-induced mitochondrial dysfunction. Mitochondrial membrane potential and ATP production were restored. Conclusions: This study confirmed that NGR1 has significant therapeutic potential for MASH and improves mitochondrial function by upregulating NDUFS2. This study provides new insights for the future clinical treatment of MASH. Full article

Background/Objectives: Wound healing is a complex biological process involving inflammatory, proliferative, and remodeling phases. Plant-derived essential oils are increasingly investigated as topical therapeutic agents, although their biological effects are strongly influenced by composition and formulation. The present study evaluated the effects of topical Mentha spicata essential oil on cutaneous wound healing in a rat excisional wound model and explored potential molecular mechanisms using a network-based bioinformatic approach. Methods: Twenty-one male Wistar rats were randomly assigned to three groups and treated twice daily for 14 days with a formulation containing 5% Mentha spicata essential oil diluted in olive oil, olive oil alone, or no treatment. Wound healing was assessed through macroscopic monitoring and histological scoring. The chemical composition of the essential oil was characterized using gas chromatography–mass spectrometry analysis. Predicted molecular targets of the major monoterpenes were analyzed through protein interaction networks and pathway enrichment analysis. Results: Macroscopic wound closure progressed in all groups by day 14. Histological analysis revealed that the olive oil group showed more advanced collagen deposition, re-epithelialization, and granulation tissue maturation, whereas the Mentha spicata group displayed a more pronounced inflammatory and proliferative histological pattern. Network-based analysis highlighted signaling pathways related to receptor-mediated cellular responses as potential molecular mechanisms associated with early inflammatory and proliferative processes. Conclusions: These findings suggest that the biological effects of Mentha spicata essential oil in wound repair may be phase-dependent and influenced by concentration and formulation. The results support further studies aimed at optimizing dose and delivery strategies for essential oil–based wound therapies. Full article

In idiopathic azoospermia caused by non-obstructive infertility with AZFc deletion, the testicle usually contains an increased number of mast cells (MCs)—which are responsible for collagen synthesis in the testes—as well as Leydig cell hyperplasia. However, the relationship between MCs and telocytes in this pathology remains unexplored. The aim of this study was to examine ultrastructural changes in the interstitial tissue microenvironment of the convoluted seminiferous tubules in the testis, using clinical specimens from men with genetically determined non-obstructive infertility with AZFc deletion. Histological, immunohistochemical, and electron microscopic (EM) studies were performed on surgical materials from 14 patients with AZFc deletion. The IHC study was performed using a panel of antibodies: tryptase, chymase, carboxypeptidase A3, and αSMA. The EM study was performed on ultrathin sections with a thickness of 100–120 nm. MCs were found to be in a functionally active state and characterized by a variety of secretory activities. For the first time, telocytes and their colocalization with MCs and Leydig cells were visualized. It is possibly the telocytes—interacting with MCs—that synchronize the functional activity of the entire MC population of the testis. The interaction of MCs with telocytes, as well as individual secretory granules associated with loci of tropocollagen and collagen microfibril accumulation, leads to the accumulation of collagen fibrils in the interstitium, as observed in idiopathic infertility with AZFc deletion. Even with a small number of MCs in the interstitium of the convoluted seminiferous tubules in the testis, the telocytes are able to synchronize MCs’ activation and secretory activity, supporting the development of a profibrotic phenotype of the tissue microenvironment. The obtained results advance our understanding of idiopathic infertility with AZFc deletion by delineating the ultrastructural landscape of the testicular interstitium and establishing telocytes as key regulators of cellular crosstalk. Telocytes use complex mechanisms for the spatial integration of MCs and fibroblasts in the profibrotic phenotype formation of the convoluted seminiferous tubule tissue microenvironment. Potentially, telocytes can directly be involved in synchronizing such processes by activating the biogenesis and secretion of collagen monomers by fibroblasts; the MC secretome directly affects the polymerization of collagen monomers and dimers into microfibrils in the extracellular matrix, stimulating excessive collagen fiber formation and the development of fibrotic changes. Full article

Five previously undescribed steroids, chrysogenones A–E (1–5), were isolated from the deep-sea-derived Penicillium sp. MCCC 3A00121. Their chemical structures were unambiguously established through comprehensive spectroscopic analyses, density functional theory (DFT)-based electronic circular dichroism (ECD) calculations, and X-ray crystallography. Chrysogenones represent a class of oxidatively modified ergosterone-type derivatives, with 1, 2, and 5 featuring an uncommon malonyl substitution at C-12 of the ergosterone skeleton. Biologically, 1–5 exhibited varying degrees of inhibitory activity against renal fibrosis, as evidenced by the downregulation of the key fibrotic markers α-smooth muscle actin (α-SMA) and collagen I (COL1A1). Among them, chrysogenone B (2) emerged as the most promising candidate, demonstrating superior potency and pronounced inhibition of activated NRK-49F cell proliferation. Integrated network pharmacology analysis and molecular docking studies further suggested that the anti-renal fibrotic effects of compound 2 may be mediated through its interaction with putative molecular targets, including AKT1, HSP90AA1, and MDM2. Full article

Background: Tendons adapt to mechanical loading by increasing cross-sectional area (CSA), stiffness, and matrix organization, with structural remodeling critical for both rehabilitation and performance. Collagen supplementation has been proposed to enhance this process by supplying key amino acids for collagen synthesis; however, inconsistent results across trials have limited its clinical and athletic application. Methods: A systematic review of randomized controlled trials evaluating collagen supplementation in humans was conducted. PubMed, EMBASE, CINAHL, and Web of Science were searched from database inception through May 2025. Risk of bias was assessed using the PEDro scale (≥6/10 classified as good-to-excellent quality). Due to substantial heterogeneity in supplementation protocols, training modalities, and outcome measures, results were synthesized narratively without meta-analysis. Data extraction included collagen type, dose, training modality, intervention duration, and outcome measures. Results: Of 887 unique citations, eight RCTs (n = 257; ages 18–52; 246 M:11 F) met the inclusion criteria. All studies incorporated resistance or plyometric training (3–15 weeks). Three of four studies reported significantly greater increases in tendon CSA in collagen groups versus placebo. Four studies investigated tendon stiffness and Young’s modulus; the two using higher doses (15–30 g/day) demonstrated significant between-group improvements favoring collagen, while lower-dose studies (~5 g) showed only within-group effects. Muscle strength improved with training in all trials, but no additive effects of collagen were observed. One study reported improvements in eccentric rate of force development and deceleration impulse with collagen, though gross explosive metrics (e.g., jump height) were unaffected. Conclusions: Collagen supplementation (15–30 g) with vitamin C (≥50 mg) may enhance tendon remodeling when combined with high-intensity resistance training (≥70% 1 RM). The current literature suggests strong evidence (GRADE A) for increases in tendon CSA and stiffness, strong evidence (GRADE A) against an effect on muscle strength, and conflicting evidence (GRADE C) for muscle cross-sectional area and physical performance. Limitations include small sample sizes, heterogeneous protocols, and short intervention durations. Full article