Search Results (188)

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder characterized by hyperphosphatemia and ectopic calcifications. Mutations in GALNT3, which encodes a key enzyme responsible for O-glycosylation of FGF23, represent a major genetic cause of HFTC. This modification is essential for the stability and secretion of FGF23. We investigated a 4-year and 6-month-old Chinese girl with HFTC to characterize the clinical features, identify the causative variants, and explore the underlying pathogenic mechanism. Whole-exome sequencing followed by Sanger validation identified novel compound heterozygous variants in GALNT3 (c.659T>A, p.Ile220Asn and c.1850C>A, p.Ser617*). The patient exhibited hyperphosphatemia with a biochemical profile consistent with FGF23 deficiency, including extremely low intact FGF23 and elevated C-terminal fragments. Functional studies using Western blotting and wheat germ agglutinin affinity chromatography demonstrated that the mutant GALNT3 caused a severe defect in FGF23 O-glycosylation, leading to impaired secretion of intact FGF23. Glycosylated FGF23 was detected only in the medium of cells expressing wild-type GALNT3. These findings indicate that defective O-glycosylation results in failure of FGF23 secretion and functional inactivation. This study expands the mutational spectrum of GALNT3 and provides mechanistic insight into the role of GALNT3 in phosphate homeostasis. Full article

Research in implant dentistry has predominantly focused on bone regeneration, osseous volume maintenance, and successful osseointegration. However, soft tissue healing, which influences implant functional sealing, long-term stability, and esthetic integration, remains underexplored. This study investigated the effects of three xenogenic bone substitutes on gingival healing in vitro. Three experimental groups were established using extracts from bone substitutes diffusing through the OsteoBiol^® Evolution collagen membrane: two collagenated substitutes, OsteoBiol^® Gen-Os^® (Gen-Os) and OsteoBiol^® GTO^® (GTO), and one inorganic substitute, Bio-Oss^® (Bio-Oss). The substitutes were prepared in test tubes, and the extracts diffusing through the collagen membrane were used to evaluate human gingival cell (hGC) proliferation (MTT assay), migration (scratch assay), and growth factor release (ELISA). Angiogenic potential was assessed by endothelial cell proliferation, recruitment (Boyden chambers), and organization (Matrigel^® assays). The indirect interaction between stimulated gingival cells and human bone marrow mesenchymal stem cells (hMSC) was investigated by analyzing hMSC recruitment and osteogenic BMP-2 secretion. Collagenated GTO and Gen-Os significantly enhanced hGC proliferation and migration in the scratch assay, with 1.8-fold and 1.6-fold increases, respectively, compared to control. All three substitutes enhanced neoangiogenesis in vitro. VEGF and FGF-2 secretion was significantly higher with GTO, showing 5-fold and 5.7-fold increases, respectively, resulting in a 3.7-fold increase in tube formation compared to control. Collagenated materials promoted hMSC recruitment, whereas BMP-2 secretion was not affected by any material. The observed effects were higher with the collagenated Gen-Os and GTO, with 2.5-fold and 2.8-fold increases, respectively, than with the non-collagenated Bio-Oss, which showed a 1.5-fold increase. These findings demonstrate that collagenated bone substitutes enhance gingival healing and angiogenic potential through barrier membranes and confirm that stimulated gingival cells indirectly promote hMSC recruitment, indicating that bone substitute effects extend beyond bone regeneration to include soft tissue healing and inter-tissue communication. Full article

Skeletal muscle is increasingly recognized as a dynamic endocrine and paracrine organ that communicates with distal tissues through a diverse secretome of peptides, proteins, metabolites, and extracellular vesicles (EVs), collectively referred to as myokines and exerkines. Beyond cataloging individual factors, emerging evidence suggests that muscle-derived signals can convey information through an integrated, context-dependent “endocrine code”—a pattern defined by secretion kinetics, co-released signal combinations, delivery modalities, and target-tissue receptor landscapes. This review synthesizes current evidence on (i) conceptual and experimental criteria for defining bona fide myokines, (ii) mechanisms governing myokine expression, processing, and release across exercise modes and physiological states, and (iii) major muscle–organ axes that connect physical activity to systemic metabolic homeostasis, immune remodeling, tissue regeneration, and neurocognitive adaptation. We further discuss non-protein mediators such as lactate, succinate, and β-aminoisobutyric acid, and highlight EVs as a multiplexed delivery modality whose interpretation requires stringent isolation, contamination controls, and functional validation. Finally, we evaluate translational opportunities—including biomarker panels, therapeutic targeting of the myostatin/activin, fibroblast growth factor 21 (FGF21), and growth differentiation factor 15 (GDF15) pathways, and precision exercise prescriptions informed by multi-omics and artificial intelligence—while emphasizing analytical standardization, causal validation, and transparent reporting as prerequisites for clinical impact. Full article

Objectives: The objective of this study was to evaluate the effect of 21-day dietary omega-3 fatty acid supplementation on the levels of postexercise inflammation response, oxidative stress, and selected exerkine secretion among physically active young men. Methods: In a randomized double-blind study, 24 physically active men were assigned to two groups: a supplementation group (n = 12), receiving 3250 mg of n-3 polyunsaturated fatty acids (PUFAs) daily, and a placebo group (n = 12). Blood samples were collected before and after twenty-one days of dietary supplementation to measure total fatty acids and inflammatory markers, including IL-1β, IL-6, IL-10, BDNF, and FGF23. Results: After 21 days of n-3 fatty acid supplementation, there were no significant changes in anaerobic performance parameters. However, significant interactions were found in the systemic immune-inflammation index (SII), FGF-23, IL-1β, IL-1Ra, IL-6, and IL-10 in response to exercise and supplementation. Conclusions: 21 days of n-3 fatty acid supplementation modified PUFA content and influenced inflammation status, but did not affect maximal anaerobic performance. Full article

Runx2 plays essential roles in osteoblast differentiation and chondrocyte maturation. Runx2 in the perichondrium has been reported to inhibit chondrocyte maturation through Fgf18 induction. To further investigate the functions of Runx2 in the perichondrium, we generated Runx2^fl/−Cre mice by crossing Runx2^fl/+, Runx2^+/−, and 2.3-kb Col1a1 Cre mice and compared them with Runx2^fl/− mice at E15.5, when the endochondral bones were cartilaginous. Skeletal preparation of the upper limbs in Runx2^fl/−Cre mice showed reduced mineralization of the humerus and scapula, and histological analysis of the femurs showed delays in the terminal differentiation of chondrocytes, as indicated by the absence of mineralization and Spp1 expression in the cartilage and osteoblast differentiation in the perichondrium, compared to those in Runx2^fl/− mice. mRNA sequence analysis showed that the expression of Nell1, which encodes a secreted protein that enhances chondrocyte maturation, in Runx2^fl/−Cre femurs was more than two-fold lower than that in Runx2^fl/− femurs. Nell1 expression was reduced in the perichondrium of Runx2^fl/−Cre femurs compared to that in Runx2^fl/− femurs. Nell1 expression was upregulated by Runx2 overexpression and downregulated by Runx2 siRNA. These findings indicate that Runx2 in perichondrial osteoblasts enhances the terminal differentiation of chondrocytes by inducing Nell1 expression. Full article

Alopecia profoundly impacts psychological well-being and quality of life, yet current therapeutic options such as minoxidil and finasteride exhibit limited efficacy. Fibroblast growth factor 7 (FGF-7), also known as keratinocyte growth factor (KGF), is a paracrine growth factor secreted by dermal papilla cells that specifically activates the epithelial receptor FGFR2b. Receptor engagement triggers multiple downstream signaling cascades, including the MAPK/ERK, PI3K/Akt, and Wnt/β-catenin pathways, promoting keratinocyte proliferation, stem cell activation, and the transition of hair follicles into the anagen phase. Both in vitro and in vivo animal studies consistently demonstrate that FGF-7 accelerates telogen-to-anagen transition and enhances follicular regeneration. FGF-7 acts synergistically with insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) to sustain nutrient delivery and cell proliferation. Human scalp studies further reveal a strong association between the FGF-7/FGFR2b signaling and follicular activity; however, clinical trials remain scarce. Topical application of FGF-7 has demonstrated an excellent safety profile, whereas systemic administration necessitates careful monitoring. Future directions include the development of engineering to extend the systemic half-life, advanced delivery systems, and gene or mRNA-based therapeutic approaches. Thus, the FGF-7/FGFR2b axis is a highly compelling molecular target for next-generation hair regeneration therapies. Full article

The research on cytokine or growth factor (GF) release by leukaemic blasts is a largely unexplored area. This study aimed to evaluate the differential secretory potential of paediatric B-cell precursor and T-cell acute lymphoblastic leukaemia (BCP-ALL and T-ALL, respectively) and acute myeloid leukaemia cells (AMLs) for selected GFs, both basally and upon stimulation with phytohemagglutinin (PHA), lipopolysaccharide (LPS), or phorbol 12-myristate 13-acetate with ionophore A23187 (PMA + I). The concentrations of five GFs: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) in the supernatants were measured using the Bio-Plex multiplex immunoassay. AML blasts showed the highest basal concentrations of G-CSF, GM-CSF, and VEGF. PHA and LPS stimulation non-selectively enhanced the secretion of G-CSF, GM-CSF, VEGF, and PDGF in BCP-ALL and AML blasts. PMA + I was the strongest GF release inducer, particularly for BCP-ALL and T-ALL blasts, with the latter also showing higher responsiveness to PHA and LPS. Our findings reveal differential, leukaemia-type dependent GF secretion patterns. Lineage-specific responses may be exploitable for targeted therapeutic approaches for distinct AL types. This study is the first to comprehensively assess the extracellular secretion of multiple GFs by paediatric AL cells in cultures using a Bio-Plex multiplex immunoassay. Full article

Physical exercise is a potent non-pharmacological strategy for the prevention and management of chronic non-communicable diseases (NCDs), including type 2 diabetes, cardiovascular diseases, obesity, and certain cancers. Growing evidence demonstrates that the benefits of exercise extend beyond its physiological effects and are largely mediated by coordinated molecular and cellular adaptations. This review synthesizes current knowledge on the key mechanisms through which exercise modulates metabolic health, emphasizing intracellular signaling pathways, epigenetic regulation, and myokine-driven inter-organ communication. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, mTOR, MAPKs, and NF-κB, leading to enhanced mitochondrial biogenesis, improved oxidative capacity, refined energy sensing, and reduced inflammation. Additionally, repeated muscle contraction stimulates the release of myokines—including IL-6, irisin, BDNF, FGF21, apelin, and others—that act through endocrine and paracrine routes to regulate glucose and lipid metabolism, insulin secretion, adipose tissue remodeling, neuroplasticity, and systemic inflammatory tone. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term metabolic reprogramming. Collectively, these molecular adaptations establish exercise as a systemic biological stimulus capable of restoring metabolic homeostasis and counteracting the pathophysiological processes underlying NCDs. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in preventive and therapeutic medicine. Full article

Background: In regenerative medicine, there is interest in using acellular therapy based on the secretome of mesenchymal stem cells (MSC) to promote wound healing. Wharton’s jelly cells (WJ-MSCs) are a readily available source. Their secretion has been optimized when stimulated with FGF and EGF to induce proliferation and prevent senescence. Therefore, evaluating the effect on proliferation and wound closure of human fibroblasts in vitro with different concentrations of the secretome of WJ-MSCs stimulated with growth factors is necessary to identify the most efficient work concentration. Methods: The secretome of human WJ-MSC was collected from passage 1 to passage 2 stimulated with FGF and EGF (W FGF/EGF) and the unstimulated secretome (WO FGF/EGF). The immunophenotype of WJ-MSCs after stimulation was evaluated by flow cytometry for the markers: CD105+, CD73+, CD90+, HLA-ABC+, CD44+, HLA-DR−, CD34−, CD11b−, CD19−, and CD45−. The presence of 14 growth factors in the secretome was evaluated using LEGENDplex through flow cytometry. Fibroblasts were cultured, and their culture medium was supplemented with two different concentrations: one of 1.25 mg/mL and another of 6.25 mg/mL of both stimulated and unstimulated secretome. Proliferation, cellular metabolism, and wound closure were evaluated in vitro. Results: The immunophenotype of WJ-MSCs after stimulation remained unchanged, and the production of growth-assessed factors was increased in stimulated WJ-MSCs. The optimal concentration that induced proliferation and wound closure in vitro was 1.25 mg/mL of stimulated WJ-MSC secretome. Conclusions: This study demonstrates that stimulation of WJ-MSCs with FGF and EGF enhances the secretion of growth factors, and that a concentration of 1.25 mg/mL of their secretome promotes optimal fibroblast proliferation and wound closure in vitro. These findings support the potential of optimized WJ-MSC secretome as a promising acellular strategy for regenerative medicine. Full article

Hair follicle stem cells (HFSCs) are resident stem cells within hair follicles (HFs) that possess self-renewal and differentiation capacities, serving as a critical model for regenerative medicine research. Their dynamic interaction with dermal papilla cells (DPCs) plays a decisive role in HF development and cycling. FGF22 is a paracrine fibroblast growth factor that can regulate the proliferation, differentiation and migration of epithelial cells. This study established a DPC-HFSC co-culture system, revealing that FGF22 overexpression in DPCs significantly upregulated FGFR1/FGFR2 mRNA expression levels in HFSCs (p < 0.05), with a 1.67-fold increase in EdU-positive cell proportion (p < 0.01). CCK-8 assays demonstrated markedly enhanced HFSC viability (p < 0.01), with a 17% reduction in HFSC apoptosis (p < 0.05). Conversely, FGF22 knockout downregulated FGFR1/FGFR2 expression (p < 0.05), reduced HFSC proliferation capacity by 25% (p < 0.01), and increased HFSC apoptosis levels by 1.81-fold (p < 0.05). In addition, FGF22 overexpression promotes the proliferation and differentiation of HFSCs by activating Wnt/β-Catenin, Sonic Hedgehog (Shh) and Notch signaling pathways, or inhibiting BMP signaling pathways. Knockout of FGF22 weakens these processes and inhibits the activation and differentiation of HFSCs. This study, through the DPCs-HFSCs co-culture system, revealed the regulatory mechanism of FGF22 secreted by DPCs on the proliferation and differentiation of HFSCs, thereby providing theoretical references for fields such as fine-wool sheep breeding, human regenerative medicine, and hair loss treatment. Full article

Background/Objectives: Understanding the relationship between metabolism and eating behavior may improve how we treat and prevent obesity. Fibroblast growth factor 21 (FGF21) is a hormone secreted by the liver with a putative role in energy expenditure, energy intake, and weight regulation. In this secondary analysis, we studied how fasting FGF21 is correlated with eating behavior and decision making, as measured by the Three-Factor Eating Questionnaire (TFEQ) and the Iowa Gambling Task (IGT), respectively. Methods: Participants (n = 98; women = 19; white = 31) were medically healthy, between 18 and 55 years of age, weight-stable 6 months before admission, and had normal glucose regulation. Women were premenopausal and not pregnant. Pearson partial correlations were determined, accounting for age, sex, and body fat percentage. A mediation analysis examining whether the association between hunger and IGT score was mediated by FGF21 values was performed using general linear models. Results: In partial correlations adjusted for age, sex, and body fat percentage, we found that fasting FGF21 concentrations were positively correlated with hunger susceptibility (sum of internal and external cues) (partial r = 0.26, p = 0.02) and internal hunger (partial r = 0.22, p = 0.04), disinhibition (partial r = 0.27, p = 0.01), and better decision making (higher IGT scores) (partial r = 0.40, p = 0.0001). We also found a correlation between hunger susceptibility and better decision making, including the same covariates (partial r = 0.25, p = 0.03). However, this correlation was mediated (36%) by fasting FGF21. Conclusions: In this study, participants with greater susceptibility to hunger cues had higher IGT scores (better decision making) in the setting of higher fasting FGF21 concentrations. This provides further evidence of the role of FGF21 in the interplay between eating behavior and decision making. Further studying this topic may improve our understanding of the complex relationship between assessing energy requirements and cognitive processes related to eating behavior. Full article

Peripheral nerve injuries remain a major clinical problem, and cell-free therapies using stem cell-derived bioproducts have emerged as promising alternatives. This study evaluated the influence of neurogenic differentiation and passage number on the secretomic and exosomal profile of human dental pulp stem cells (hDPCSs). Conditioned media from undifferentiated and neurodifferentiated hDPSCs, and exosomes derived from undifferentiated hDPSCs at passages 4 and 7, were analyzed using multiplex immunoassays, RT-PCR, and scanning electron microscopy (SEM). Neurodifferentiated hDPSCs at early passages secreted higher levels of neurotrophic, angiogenic and immunomodulatory factors, including FGF-2, IL-6, IL-8, and PDGF-AA. Exosomes from early-passage undifferentiated cells showed a more abundant and relevant neuroregenerative mRNA cargo in comparison to the later passages. Both cell types and exosomes adhered to the Reaxon^® nerve guidance conduit, confirming the permissive nature of the materials regarding cells and cellular products, allowing adhesion and survival. Neurite outgrowth assays performed on neurodifferentiated hDPSCs confirmed functional neural behavior. In later passages, a decline in secretory and exosomal activity was noted. These results highlight the relevance of early-passage hDPSCs as a source of bioactive factors and support their application in cell-free approaches for peripheral nerve regeneration. Full article

Mesenchymal stem cells (MSCs) spontaneously assemble into three-dimensional (3D) spheroids under matrix-deficient conditions such as the synovial cavity, although their functional significance has yet to be fully elucidated. In this study, we used concave microwell cultures to promote the spontaneous aggregation of adipose-derived MSCs (ASCs) from OA patients, thereby mimicking the intra-articular microenvironment. We analyzed the paracrine factors of ASC aggregates and compared it with that of conventional 2D monolayer cultures. Notably, 3D aggregation significantly increased the secretion of HGF and VEGF, whereas FGF2 levels remained relatively unchanged. These results indicate that the structural characteristics of ASC aggregates enhance the secretion of key paracrine factors involved in angiogenesis and tissue repair. To functionally evaluate the biological relevance of the secreted factors, conditioned media (CM) from ASC aggregates were applied to human articular chondrocytes. The CM significantly promoted chondrocyte proliferation, an effect that was abolished by the addition of HGF-neutralizing antibodies, thereby highlighting HGF as a central mediator of the regenerative response. Additionally, we further explored whether extracellular factors could modulate growth factor expression such as HGF. In this context, we investigated the impact of low-concentration hyaluronic acid (HA), a key synovial component widely used in OA treatment. Co-treatment with HA not only amplified the expression and secretion of HGF, VEGF, and FGF2, but also promoted ASC proliferation. ASCs forming functional aggregates may exert regenerative effects as active paracrine modulators, and the addition of low-dose hyaluronic acid is expected to further enhance this function, offering a promising strategy for MSC-based osteoarthritis therapy. Full article

(1) Background: The pursuit of ingredients that possess both anti-melanogenesis and post-inflammatory hyperpigmentation (PIH) prevention effects has become a new research frontier in cosmetics, though there is little work on plant extract-derived ingredients in this direction. (2) Methods: The study involved evaluating the impact of dark tea extract on melanin content and tyrosinase activity in B16 cells. Meanwhile, Ultraviolet B (UVB)-irradiated assays were conducted on HaCaT cells to assess the secretion of inflammatory factors (IL-1α and IL-1β) and paracrine melanogenic factors (α-MSH, bFGF, and ET-1). Additionally, we performed quantitative real-time polymerase chain reaction (RT-PCR) tests to determine whether the signaling pathways of anti-melanogenesis and PIH punctuation are incorrect. (3) Results: The results showed that dark tea extract significantly inhibited melanin content and tyrosinase activity in B16 cells. In HaCaT cells, the extract reduced the secretion of the aforementioned inflammatory and paracrine melanogenic factors, thereby inhibiting PIH. Moreover, the RT-PCR and the Western Blot results indicated that the dark tea extract could inhibit the melanogenesis signaling pathway of α-MSH/MC1R/MITF and their downstream multiple targets of TYRP-1, TYRP-2, and TYR in B16 cells, while it exerted a PIH inhibition effect by downregulating the p38 MAPK/Nrf2/HO-1 signaling pathway. (4) Conclusions: This study suggests that dark tea extract can not only suppress melanogenesis through multiple targets but also can inhibit UVB-induced PIH, hinting at its skin-brightening efficacy as an agent for the restoration of pigmentation disorders. Full article

IGF-1 (insulin-like growth factor 1) is a growth factor primarily secreted by dermal papilla cells on hair-bearing skin that stimulates hair follicle proliferation and vascularization, and promotes the transition to the anagen growth phase of the hair follicle by activating key pathways such as PI3K/Akt and MAPK/ERK. IGF-1 also inhibits apoptosis, prolongs the follicular growth phase, and boosts VEGF expression, which supports microcirculation and nutrient delivery to hair follicles. The combined effects of IGF-1 and other growth factors, including VEGF, KGF (FGF-7), and PDGF, further amplify its effects on follicular cell proliferation and tissue repair. IGF-1’s ability to regulate the hair growth cycle and its interactions with other signaling pathways make it a compelling therapeutic target for hair loss disorders. Both preclinical models and clinical evidence highlight IGF-1 as a promising therapeutic option for conditions like androgenetic alopecia (AGA), where IGF-1 levels are typically diminished. While topical IGF-1 treatments have shown efficacy and safety with minimal systemic absorption, additional research is needed to improve delivery methods, such as liposomal gels and exosome-based carriers, and to evaluate long-term effects. Full article