Search Results (2,632)

Objectives: Pilose antler protein extract (PAE) was investigated for its therapeutic efficacy against ovariectomy (OVX)-induced osteoporosis and its underlying molecular mechanism. Methods: An OVX rat model was established to evaluate the effects of PAE on bone microarchitecture, histopathological changes, and bone metabolism-related parameters. Bone structure was assessed using Micro-CT and histological analysis, and biochemical and bone turnover markers were quantified. In vitro, Mouse calvarial pre-osteoblast subclone 14 (MC3T3-E1) Subclone 14 cells were used to examine the effects of PAE on cell viability, proliferation, osteogenic differentiation, and osteogenesis-related protein expression. Results: High-dose PAE markedly improved trabecular bone microarchitecture in OVX rats, as reflected by increased bone surface area and bone volume fraction and reduced trabecular separation. PAE significantly enhanced bone calcium content and elevated serum Bone Morphogenetic Protein 2 (BMP-2) and Procollagen Type I N-Terminal Propeptide (PINP) levels, while decreasing serum Alkaline Phosphatase (ALP) activity and C-Terminal Telopeptide of Type I Collagen (CTX-I) levels, indicating a shift toward bone formation. Mechanistically, PAE activated the Wnt-3a/β-Catenin signaling pathway in bone tissue and MC3T3-E1 cells, as evidenced by increased expression of Wnt-3a and β-Catenin proteins. In vitro experiments further demonstrated that PAE promoted MC3T3-E1 cell proliferation and upregulated osteogenic markers, i.e., Runt-related transcription factor 2 (RUNX2) and Osteocalcin (OCN). Conclusions: Collectively, these findings suggest that PAE exerts pronounced anti-osteoporotic effects and is associated with activation of the Wnt/β-Catenin signaling pathway. Full article

Background/Objectives: Chronic Mild Stress (CMS) provokes neuroendocrine dysregulation and oxidative injury that compromise neuronal integrity and plasticity. Disruption of the canonical Wnt/β-catenin signaling pathway has been increasingly linked to stress-induced neurobiological dysfunction. Vitamin D3, a neuroactive hormone with antioxidant and immunomodulatory properties, may exert neuroprotection through modulation of this pathway and attenuation of oxidative damage. The study aims to investigate whether vitamin D3 mitigates CMS-induced alterations in Wnt/β-catenin signaling, oxidative stress markers, and oxidative DNA damage in male Wistar rats. Methods: Thirty-two male Wistar rats were randomly allocated into four groups (n = 8/group): control, CMS only, CMS + vitamin D3 (1000 IU/kg), and CMS + vitamin D3 (10,000 IU/kg). Vitamin D3 was administered intramuscularly three times weekly for 28 days. Hippocampal mRNA expression of Wnt pathway components and brain-derived neurotrophic factor (BDNF) was quantified by RT-qPCR using the 2^−ΔΔCt method. Oxidative stress was evaluated by measuring malondialdehyde, glutathione, superoxide dismutase, and catalase, while DNA damage was assessed via 8-OHdG ELISA. Results: CMS significantly downregulated Wnt1, β-catenin, and Axin2 mRNA expression (p < 0.05) while markedly upregulating GSK-3β (p < 0.001). Expression of BDNF was also reduced (p < 0.05). Biochemically, CMS increased MDA and 8-OHdG levels (both p < 0.001) and decreased glutathione (p < 0.001), superoxide dismutase, and catalase activities (p < 0.05). Vitamin D3 supplementation significantly reversed these transcriptional and biochemical alterations, restoring β-catenin signaling, improving antioxidant defenses, and reducing oxidative and genotoxic damage. Conclusions: Vitamin D3 confers significant neuroprotection under chronic stress by modulating Wnt/β-catenin signaling and attenuating oxidative and DNA damage, thereby enhancing neuronal resilience to prolonged stress exposure. Full article

With limited therapeutic progress despite aggressive multimodal treatment, glioblastoma (GBM) remains one of the deadliest primary brain tumors. Emerging evidence suggests that GSCs are key drivers of tumor initiation, intratumoral heterogeneity, therapeutic resistance, and recurrence. GSCs retain self-renewal capacity, multilineage differentiation potential, and remarkable plasticity, enabling them to adapt to diverse microenvironmental cues. These properties are upheld by dysregulated developmental and oncogenic signaling pathways, including Notch, Wnt/β-catenin, Hedgehog, PI3K/AKT/mTOR, and STAT3, as well as epigenetic and metabolic reprogramming. In addition, dedicated niches such as hypoxic and perivascular microenvironments critically support GSC maintenance and immune evasion. In this review, we summarize the current understanding of the molecular pathways governing GSC biology, examine their interactions with the tumor microenvironment, and discuss emerging therapeutic strategies targeting GSCs, including pathway inhibition, differentiation therapy, immunotherapy, and nanomedicine-based drug delivery. We highlight key challenges and future directions for translating GSC-targeted approaches into effective clinical interventions for GBM. Full article

Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8⁺ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target. Full article

Circular RNAs (circRNAs) exhibit significant sex- and development stage-specific expression patterns in the gonads of various fish species, yet their functions and regulatory mechanisms in male reproductive development remain largely unexplored in crucian carp (Carassius auratus). In this study, we characterized the expression features and biological functions of circSPEF2, a circular RNA derived from the reproduction-related gene spef2. Our results showed that circSPEF2 expression was markedly elevated in mature testes and progressively upregulated during gonadal maturation. Functional studies suggested that circSPEF2 likely does not act through a ceRNA-dependent mechanism. Transcriptome sequencing following circSPEF2 overexpression identified 45 upregulated and 70 downregulated differentially expressed genes, with GO and KEGG enrichment analyses revealing significant alterations in multiple gonadal development-related genes and signaling pathways. Subsequent siRNA-mediated knockdown of circSPEF2, combined with qRT-PCR validation, confirmed that circSPEF2 positively regulates the expression of genes associated with cell maturation and differentiation, including prdm1a, lamc2, and slc25a27, while concurrently suppressing that of proliferation- and apoptosis-related genes such as wnt8b, cpeb3, and bcl2l11. Furthermore, RNA pull-down combined with mass spectrometry identified three candidate circSPEF2-binding proteins, namely, hnRNP A/B, SRSF2, and CFAP263. Collectively, these findings indicate that circSPEF2 plays an important role in male gonadal development in fish and provide new insights into the post-transcriptional regulatory mechanisms underlying vertebrate male reproduction. Full article

Tongue squamous cell carcinoma (TSCC) is an aggressive malignancy with poor prognosis and limited therapeutic options. Herbal medicines with multitarget activities and low toxicity have attracted increasing attention in cancer adjuvant therapy. This study aimed to investigate the anti-tumor effects and underlying mechanisms of the water extract of Andrographis paniculata (APW) in TSCC in vitro and in vivo. Two TSCC cell lines, Cal-27 and SCC25, were used for cell-based functional and mechanistic studies, while a Cal-27 xenograft-bearing mouse model was established for evaluating the in vivo effect of APW treatment. Our results showed that APW could significantly inhibit the proliferation of Cal-27 and SCC25 cells and induce apoptosis in a concentration-dependent manner. APW could promote mitochondrial-mediated apoptosis by upregulating Bax and cleaved caspase proteins but downregulating Bcl-2 in TSCC cells. It also suppressed the Wnt/β-catenin signaling pathway, reducing β-catenin expression and its downstream targets, CCND1, MYC, and JUN. Furthermore, APW disrupted mitochondrial integrity, induced cytochrome c release, and reduced mitochondrial membrane potential. APW also inhibited epithelial–mesenchymal transition, increasing E-cadherin and decreasing N-cadherin and vimentin expressions, thereby suppressing cell migration of TSCC cells. Furthermore, the 5-week APW treatment significantly reduced tumor growth and angiogenesis without evident hepatic or renal toxicity in Cal-27 xenograft-bearing mice. In conclusion, APW exerted potent anti-tumor effects by targeting both the Wnt/β-catenin pathway and mitochondrial apoptotic machinery, suggesting the great potential of APW as an adjuvant therapeutic candidate for TSCC treatment. Full article

Our previous work demonstrated that bovine milk-derived extracellular vesicles (mEVs) could alleviate the inflammatory response of mice colitis, along with hundreds of differentially expressed (DE) mRNAs. This study further analyzed the profiles of non-coding RNAs (ncRNAs) and explored the correlation with DE mRNAs by constructing ceRNA networks. Six-week-old male C57BL/6 mice were fed either a control diet or a diet added with mEVs for 30 days. Then the mice were given dextran sulphate sodium in drinking water for 7 days to induce colitis. A total of 40 miRNAs, 541 lncRNAs and 643 circRNAs exhibited changes in mEVs pretreatment group. Among these DE miRNAs, mEVs pretreatment significantly increased the expressions of miR-122, miR-147, miR-210, miR-1224, miR-148a, and miR-212, which might participate in the inflammatory response of the colitis models. The expression of Tug1 increased after mEVs pretreatment, while Snhg5 and H19 decreased, which might be involved in intestinal barrier restoration. Functional analysis of the DE ncRNAs suggested mEVs might exert protective effects not only through modulation of inflammatory responses but also by enhancing intestinal stem cell function and epithelial regeneration, which were mainly regulated by Wnt and Hippo signaling pathways according to the ceRNA networks. Full article

Osteocytes, once viewed mainly as passive bone-embedded cells, are now recognized as active regulators of the metastatic bone niche. Emerging evidence indicates that these cells integrate mechanical, inflammatory, and tumor-derived cues to influence metastatic seeding, dormancy, reactivation, and lesion progression in bone. This review synthesizes current understanding of osteocyte contributions to skeletal metastasis. We discuss core signaling axes, including osteocyte-derived RANKL/OPG balance, Wnt antagonists (sclerostin/DKK1), mechanotransduction pathways (Piezo1 signaling and connexin-43 hemichannels), and osteocyte paracrine mediators (extracellular vesicles and senescence-associated factors), and examine how each axis modulates tumor cell dormancy, osteolysis, or osteoblastic progression. We then review translational strategies targeting osteocytes, recent preclinical and clinical insights. Emerging biomarkers (e.g., serum sclerostin, DKK1, bone turnover markers) and immune–skeletal imaging approaches are also considered. Controversies, including the paradoxical effects of sclerostin blockade and the identity of in vivo RANKL sources, are discussed. Finally, we outline key knowledge gaps and propose endpoints for future trials. In summary, an osteocyte-centric perspective reveals novel targets and strategies for managing bone metastases, guiding future translational research. Full article

Keloid is a benign skin disease with excessive growth of fibroblasts, characterized by too much abnormal extracellular matrix deposited in the dermis. It is generally believed that transforming growth factor-β (TGF-β) is the core cytokine that causes keloid. Previously, it was thought that its pathogenic effect was mainly attributed to the classical Smad-dependent pathway. It directly shuttles signals to the nucleus to trigger pro-fibrotic gene transcription. However, accumulating evidence now points to the equally vital role of Smad-independent signaling. Unlike the direct nuclear translocation of Smads, these alternative pathways transmit signals through rapid intracellular kinase cascades. They jointly direct the proliferation, migration, anti-apoptosis, fibrogenesis, and chronic inflammation of fibroblasts in keloids. This review attempts to comprehensively clarify the molecular processes regulated by TGF-β through non-Smad pathways (such as MAPK, PI3K/Akt, Rho GTPase, Wnt/β-catenin, JAK/STAT). Translating these non-Smad insights helps to overcome the high recurrence rates of traditional therapies. Targeting these specific molecular hubs through combination and precision therapies serves to reprogram the fibrotic microenvironment. Full article

The link between neurodevelopment in infants exposed to maternal gestational diabetes mellitus (GDM) and fetal DNA methylation remains unexplored. We conducted this hypothesis-generating study to investigate the association between fetal DNA methylation and neurodevelopmental outcomes in children of mothers with GDM. We carried out a prospective, observational pilot cohort study comparing infants exposed to maternal GDM with an unexposed control group. Umbilical cord blood DNA methylation was assessed using targeted methylome sequencing covering 3.34 million CpG sites. Infant neurodevelopment was evaluated at age two years using the Bayley-III Scales. Bioinformatics processing identified differentially methylated regions (DMRs), followed by multiple enrichment analyses of DMR-associated genes and partial correlation analyses. Multi-dimensional enrichment analysis of the 1053 identified DMR-associated genes revealed a significant convergence of pathways related to neurogenesis, synaptic components, and axonal guidance. Infants born to mothers with GDM exhibited lower scores in cognitive, language, and motor domains, which were associated with identifiable DNA methylation signatures at birth. Significant correlations were observed in genes essential for brain scaffolding and synaptic circuitry, most notably WNT4, the PCDHG alpha/beta clusters, and PALM. Additionally, methylation patterns in FOXF2 and CHFR suggest a potential impact on blood–brain barrier integrity, while associations with FSTL3 and H6PD highlight a systemic metabolic ‘cross-talk’ influencing neurodevelopment. Although these pilot findings are hypothesis-generating and require further functional validation, this study provides pioneering evidence that neurodevelopmental alterations in the offspring of mothers with GDM are potentially associated with intrauterine epigenetic modifications detectable at birth. Full article

A keloid is a benign fibroproliferative cutaneous disorder characterized by excessive extracellular matrix deposition, which is driven by persistent fibroblast proliferation and aberrant wound healing. Its complex pathogenesis involves genetic susceptibility, chronic inflammation, mechanical tension and dysregulated cellular signaling, resulting in poor clinical efficacy and high recurrence rates. Cellular senescence has recently become a central focus in exploring keloid pathophysiology, offering a novel perspective for elucidating its initiation, progression and recurrence. This review systematically summarizes the biological roles of cellular senescence in keloid pathology: it elaborates on the basic concepts and core molecular features of cellular senescence, details the spatial heterogeneity of senescent cell accumulation, the activation and pathological effects of senescence-associated secretory phenotype (SASP), and clarifies the molecular link between senescence-resumed proliferation (SRP) and keloid recurrence and treatment resistance. It also summarizes advances in senescence-related markers, the regulatory roles of the p53/p21 and Wnt/β-catenin pathways, and potential senescence-targeted therapies (senolytic, senomorphic, signaling intervention, cell reprogramming). Finally, we discuss the challenges and future perspectives for translating senescence research into clinical keloid treatments, aiming to provide a novel theoretical framework and therapeutic targets for keloid management. Full article

Adipose tissue functions not only as a primary energy reservoir but also as a metabolically active endocrine organ. However, the morphological and molecular differences among adipose depots from different anatomical sites in Yili horses remain unclear. This study aimed to compare the morphological characteristics and proteomic profiles of subcutaneous adipose tissue (SAT) and pericardial adipose tissue (PCAT). To this end, adipose tissue samples from 18 Yili horses were analyzed using hematoxylin and eosin (H&E) staining, while a subset of samples from 6 horses was subjected to proteomic analysis. The results demonstrated that adipocytes in PCAT showed significantly larger areas and diameters but a lower number per field than those in SAT (p < 0.01). Proteomic profiling identified 451 differentially expressed proteins (DEPs) between SAT and PCAT. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that these DEPs were primarily involved in fatty acid catabolism, glycolysis, ECM–receptor interaction, thermogenesis, Wnt signaling, and other related pathways. Notably, enrichment analyses further revealed that SAT exhibited more active substrate utilization, energy metabolism, and lipid turnover, whereas PCAT was more associated with structural regulation and cardiovascular-related signaling pathways. Furthermore, correlation analysis between adipocyte morphological metrics and proteomic data identified ACAA2, ENO1, TPI1, PLIN1, COL6A3, and ITGB1 as candidate proteins regulating the site-specific differences in morphology and metabolic function between SAT and PCAT. These findings reveal distinct morphological and proteomic features of different adipose depots in Yili horses, providing a foundation for understanding depot-specific adipose function and its underlying regulatory mechanisms. Full article

Skin aging and wound healing are the result of intricate and interconnected processes involving chronic inflammation, oxidative stress, cellular senescence and extracellular matrix degradation. Mesenchymal stem cell (MSC)-derived exosomes are rich in bioactive components, particularly microRNAs (miRNAs), which play a crucial role in regulating gene expression and key signaling pathways critical for maintaining skin homeostasis. This article reviews the current evidence regarding the roles of MSC-derived exosomal miRNAs (MSC-Exo-miRNAs) in cutaneous repair and rejuvenation. Specific exosomal miRNAs are analyzed for their ability to modulate inflammatory responses, promote fibroblast proliferation and collagen synthesis, enhance angiogenesis, and facilitate keratinocyte migration and re-epithelialization. Their roles in regulating key signaling pathways are discussed in the context of skin regeneration and aging, including nuclear factor-κB (NF-κB), PI3K/Akt, TGF-β/Smad, Wnt/β-catenin, and nuclear factor erythroid 2-related factor 2 (Nrf2). Additionally, emerging engineering strategies aimed at optimizing miRNA cargo loading, improving delivery efficiency, and advancing clinical translation are highlighted. Overall, MSC-Exo-miRNAs represent a promising cell-free therapeutic strategy for skin repair and rejuvenation; however, further mechanistic investigations and rigorous clinical studies are necessary to fully realize their translational potential. Full article