Genomic divergence and demographic history of Quercus aliena populations.

BACKGROUND: Quercus aliena is a major montane tree species of subtropical and temperate forests in China, with important ecological and economic value. In order to reveal the species' population dynamics, genetic diversity, genetic structure, and association with mountain habitats during the evolutionary process, we re-sequenced the genomes of 72 Q. aliena individuals. RESULTS: The whole chloroplast and nuclear genomes were used for this study. Phylogenetic analysis using the chloroplast genome dataset supported four clades of Q. aliena, while the nuclear dataset supported three major clades. Sex-biased dispersal had a critical role in causing discordance between the chloroplast and nuclear genomes. Population structure analysis showed two groups in Q. aliena. The effective population size sharply declined 1 Mya, coinciding with the Poyang Glaciation in Eastern China. Using genotype-climate association analyses, we found a positive correlation between allele frequency variation in SNPs and temperature, suggesting the species has the capacity to adapt to changing temperatures. CONCLUSION: Overall, this study illustrates the genetic divergence, genomic variation, and evolutionary processes behind the demographic history of Q. aliena.

Extracellular matrix hydrogels with fibroblast growth factor 2 containing exosomes for reconstructing skin microstructures.

Decellularized extracellular matrix hydrogel (ECM hydrogel), a natural material derived from normal tissue with unique biocompatibility properties, is widely used for tissue repair. However, there are still problems such as poor biological activity and insufficient antimicrobial property. To overcome these drawbacks, fibroblast growth factor 2 (FGF 2) containing exosome (exoFGF 2) was prepared to increase the biological activity. Furthermore, the antimicrobial capacity of ECM hydrogel was optimised by using copper ions as a ligand-bonded cross-linking agent. The decellularized extracellular matrix hydrogel, intricately cross-linked with copper ions through ligand bonds and loaded with FGF 2 containing exosome (exoFGF 2@ECM/Cu2+ hydrogel), has demonstrated exceptional biocompatibility and antimicrobial properties. In vitro, exoFGF 2@ECM/Cu2+ hydrogel effectively promoted cell proliferation, migration, antioxidant and inhibited bacterial growth. In vivo, the wound area of rat treated with exoFGF 2@ECM/Cu2+ hydrogels were significantly smaller than that of other groups at Day 5 (45.24% ± 3.15%), Day 10 (92.20% ± 2.31%) and Day 15 (95.22% ± 1.28%). Histological examination showed that exoFGF 2@ECM/Cu2+ hydrogels promoted angiogenesis and collagen deposition. Overall, this hydrogel has the potential to inhibit bacterial growth and effectively promote wound healing in a variety of clinical applications.

The dual role of CCND1 in heterotopic ossification: A Non-canonical Pathway for Celecoxib treatment.

Objective: To explore the effective targets of Celecoxib in the treatment of heterotopic ossification using network pharmacology methods. Methods: Potential molecules related to heterotopic ossification were obtained by retrieving the GEO and CTD databases and intersecting them. Potential binding targets of Celecoxib were acquired from the STITCH database. A protein-protein interaction network was constructed between potential binding targets of Celecoxib and potential related molecules of heterotopic ossification using the STRING database. Molecules in the protein-protein interaction network were further analyzed using GO and KEGG enrichment analysis in R software, followed by enrichment analysis of active molecules in the Celecoxib-heterotopic ossification target dataset. Hub genes were selected based on the "degree" value and enrichment within the protein-protein interaction network. The binding affinity of hub genes to Celecoxib was observed using molecular docking techniques. Finally, in vitro experiments were conducted to validate the effectiveness of hub genes and explore their regulatory role in the progression of heterotopic ossification. Additionally, the therapeutic effect of Celecoxib, which modulates the expression of the hub genes, was investigated in the treatment of heterotopic ossification. Results: 568 potential molecules related to heterotopic ossification and 76 potential binding targets of Celecoxib were identified. After intersection, 13 potential functional molecules in Celecoxib's treatment of heterotopic ossification were obtained. KEGG analysis suggested pathways such as Rheumatoid arthritis, NF-kappa B signaling pathway, Pathways in cancer, Antifolate resistance, MicroRNAs in cancer play a role in the treatment of heterotopic ossification by Celecoxib. Further enrichment analysis of the 13 potential functional molecules identified 5 hub genes: IL6, CCND1, PTGS2, IGFBP3, CDH1. Molecular docking results indicated that Celecoxib displayed excellent binding affinity with CCND1 among the 5 hub genes. Experimental validation found that CCND1 is highly expressed in the progression of heterotopic ossification, promoting heterotopic ossification in the early stages and inhibiting it in the later stages, with Celecoxib's treatment of heterotopic ossification depending on CCND1. Conclusion: In the process of treating heterotopic ossification with Celecoxib, immune and inflammatory signaling pathways play a significant role. The therapeutic effect of Celecoxib on heterotopic ossification depends on the hub gene CCND1, which plays different roles at different stages of the progression of heterotopic ossification, ultimately inhibiting the occurrence of heterotopic ossification.

Cartilage decellularized matrix hydrogel loaded with protocatechualdehyde for targeted epiphycan treatment of osteoarthritis.

Osteoarthritis (OA) is a prevalent chronic disease, characterized by chronic inflammation and cartilage degradation. This study aims to deepen the understanding of OA's pathophysiology and to develop novel therapeutic strategies. Our study underscores the pivotal role of Epiphycan (EPYC) and the IL-17 signaling pathway in OA. EPYC, an essential extracellular matrix constituent, has been found to exhibit a positive correlation with the severity of OA. We have discovered that EPYC modulates the activation of the IL-17 signaling pathway within chondrocytes by regulating the interaction between IL-17A and its receptor, IL-17RA. This regulatory mechanism underscores the intricate interplay between the extracellular matrix and immune signaling in the pathogenesis of OA Another finding of our study is the therapeutic effectiveness of protocatechualdehyde (PAH) in OA. PAH significantly reduces chondrocyte hypertrophy and supports cartilage tissue recovery.by targets EPYC. To reduce the side effects of orally administered PAH and maintain its effective drug concentration, we have developed a decellularized matrix hydrogel loaded with PAH for intra-articular injection. This novel drug delivery system is advantageous in minimizing drug-related side effects and ensuring sustained release PAH within the joint cavity.

Small Extracellular Vesicles Released from Bioglass/Hydrogel Scaffold Promote Vascularized Bone Regeneration by Transferring miR-23a-3p.

Background: The treatment of critical-size bone defect is a great difficulty in orthopedics. Osteogenesis and angiogenesis are critical issue during the process of bone repair and remodeling. Mesenchymal stem cells (MSCs)-derived exosomes have the same therapeutic effect to MSCs-based therapies. The effect of human umbilical cord MSCs-derived sEVs (hUC-MSCs-sEVs) on vascularized bone regeneration and the potential mechanism remains to be investigated. Herein, we aimed to explore the therapeutic effect and the mechanism of hUC-MSCs-sEVs on critical-size bone defect. Methods: To investigate the potential osteogenesis and angiogenesis effects of sEVs in vitro, we extracted sEVs from hUC-MSCs, and then sEVs were co-incubated with BMSCs and HUVECs. We next investigated the effect and potential mechanism of sEVs on the effects of osteogenesis and angiogenesis. We fabricated 3D-printed bioglass scaffold with Gelma/nanoclay hydrogel coatings to load sEVs (BG-gel-sEVs) to ensure in vivo sustained efficacy of sEVs. Finally, the skull defect model was used to evaluate the capacity of vascularized bone regeneration of the composited scaffolds. Results: hUC-MSCs-sEVs facilitated calcium deposition and the endothelial network formation, inducing osteogenic differentiation and angiogenesis by delivering miR-23a-3p to activate PTEN/AKT signaling pathway. Additionally, the BG-gel-sEVs composited scaffold achieved vascularized bone regeneration in vivo. Conclusion: This finding illuminated that hUC-MSCs-sEVs promoted osteogenesis and angiogenesis by delivering miR-23a-3p to activate PTEN/AKT signaling pathway, achieving vascularized bone regeneration.

Facile extrusion 3D printing of gelatine methacrylate/Laponite nanocomposite hydrogel with high concentration nanoclay for bone tissue regeneration.

The extrusion 3D printing of hydrogels has evolved as a promising approach that can be applied for specific tissue repair. However, the printing process of hydrogel scaffolds with high shape fidelity is inseparable from the complex crosslinking strategy, which significantly increases the difficulty and complexity of printing. The aim of this study was to develop a printable hydrogel that can extrude at room temperature and print scaffolds with high shape fidelity without any auxiliary crosslinking during the printing process. To this end, a novel formulation consisting of a Laponite suspension with a high solid concentration and a gelatine methacrylate (GelMA) nanocomposite hydrogel was developed. A homogeneously dispersed high-concentration (up to 20% w/v) Laponite suspension was obtained by stirring at 0 °C. The addition of Laponite with high concentration improved the rheological properties, the degradation stability, and the mechanical strength of the hydrogel. The formulation of 15% (w/v) GelMA and 8% (w/v) Laponite nanocomposite hydrogel exhibited desirable printability and biocompatibility. The GelMA/Laponite hydrogels significantly promoted bone marrow mesenchymal stem cell (BMSC) proliferation and osteogenic differentiation. Both desirable printability under mild conditions and cyto-compatibility enable composite hydrogel a potential candidate as biomaterial inks to be applied for bone tissue regeneration.

miR-23a-3p-abundant small extracellular vesicles released from Gelma/nanoclay hydrogel for cartilage regeneration.

Articular cartilage has limited self-regenerative capacity and the therapeutic methods for cartilage defects are still dissatisfactory in clinic. Recent studies showed that exosomes derived from mesenchymal stem cells promoted chondrogenesis by delivering bioactive substances to the recipient cells, indicating exosomes might be a novel method for repairing cartilage defect. Herein, we investigated the role and mechanism of human umbilical cord mesenchymal stem cells derived small extracellular vesicles (hUC-MSCs-sEVs) on cartilage regeneration. In vitro results showed that hUC-MSCs-sEVs promoted the migration, proliferation and differentiation of chondrocytes and human bone marrow mesenchymal stem cells (hBMSCs). MiRNA microarray showed that miR-23a-3p was the most highly expressed among the various miRNAs contained in hUC-MSCs-sEVs. Our data revealed that hUC-MSCs-sEVs promoted cartilage regeneration by transferring miR-23a-3p to suppress the level of PTEN and elevate expression of AKT. Moreover, we fabricated Gelatin methacrylate (Gelma)/nanoclay hydrogel (Gel-nano) for sustained release of sEVs, which was biocompatible and exhibited excellent mechanical property. In vivo results showed that hUC-MSCs-sEVs containing Gelma/nanoclay hydrogel (Gel-nano-sEVs) effectively promoted cartilage regeneration. These results indicated that Gel-nano-sEVs have a promising capacity to stimulate chondrogenesis and heal cartilage defects, and also provided valuable data for understanding the role and mechanism of hUC-MSCs-sEVs in cartilage regeneration.