Transforming growth factor-β1 (TGF-β1) plays an important role on fibrogenesis in heart disease. MicroRNAs have exhibited as crucial regulators of cardiac homeostasis and remodeling in various heart diseases. MiR-19a-3p/19b-3p expresses with low levels in the plasma of heart failure patients. The purpose of our study is to determine the role of MiR-19a-3p/19b-3p in regulating autophagy-mediated fibrosis of human cardiac fibroblasts. We elucidate our hypothesis in clinical samples and human cardiac fibroblasts (HCF) to provide valuable basic information. TGF-β1 promotes collagen I α2 and fibronectin synthesis in HCF and that is paralleled by autophagic activation in these cells. Pharmacological inhibition of autophagy by 3-methyladenine decreases the fibrotic response, while autophagy induction of rapamycin increases the response. BECN1 knockdown and Atg5 over-expression either inhibits or enhances the fibrotic effect of TGF-β1 in experimental HCF. Furthermore, miR-19a-3p/19b-3p mimics inhibit epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) prodution and invasion of HCF. Functional studies suggest that miR-19a-3p/19b-3p inhibits autophagy of HCF through targeting TGF-β R II mRNA. Moreover, enhancement of autophagy rescues inhibition effect of miR-19a-3p/19b-3p on Smad 2 and Akt phosphorylation through TGF-β R II signaling. Our study uncovers a novel mechanism that miR-19a-3p/19b-3p inhibits autophagy-mediated fibrogenesis by targeting TGF-β R II.

Background The cross-talk between RNA binding proteins (RBPs) and microRNAs (miRNAs) in the regulation of gene expression is a complex process. Here, we describe a new mode of regulation of TRIM25 expression mediated by an antagonistic interplay between IGF2BP3 and miR-3614-3p. Methods The expression level of TRIM25, IGF2BP3, pri-miR-3614 and miR-3614-3p in breast cancer (BC) tissues, non-tumor tissues and BC cell lines were detected by qRT-PCR, Western blot and Immunohistochemistry (IHC). Binding of miR-3614-3p and IGF2BP3 to TRIM25 RNA was verified using luciferase activation assays, RNA immunoprecipitation (RIP) and biotin pull-down assays. In vitro and in vivo loss- and gain-of-function studies were performed to reveal the effects and related mechanism of IGF2BP3-miR-3614-3p-TRIM25 axis in in breast cancer cells proliferation. Findings We found that an intragenic miRNA-3614-3p inhibits the expression of its host gene TRIM25 by binding to its 3′- untranslated region (UTR). Interestingly, IGF2BP3 can competitively occupy this binding site and inhibit miRNA-3614 maturation, thereby protecting TRIM25 mRNA from miR-3614-mediated degradation. The overexpression of miR-3614-3p dramatically inhibited breast cancer cell growth through the downregulation of TRIM25. Furthermore, the silencing of IGF2BP3 reduced TRIM25 expression, suppressed cell proliferation, and exhibited a synergistic effect with miR-3614-3p overexpression. Interpretation Collectively, these results demonstrate that control of TRIM25 RNA by an interplay between IGF2BP3 and miR-3614-3p represents a mechanism for breast cancer cell proliferation. Fund The scientific research and sharing platform construction project of Shaanxi Province, Opening Project of Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, China Postdoctoral Science Foundation and The National Natural Science Foundation of China.

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An injectable hydrogel was developed using mesoporous silica nanoparticles to co-deliver miR222 and aspirin, osteogenesis was enhanced by stimulating innervation.

During bone growth, the lack of a neuralized vascular network in the regenerating area can affect subsequent bone quality. This study aimed to investigate if brain-derived neurotrophic factor (BDNF) could promote neurogenesis and osteogenesis in human bone mesenchymal stem cells (hBMSCs) to improve bone formation during tissue engineering. Initially, a safe and effective BDNF concentration that facilitated hBMSC proliferation in vitro was determined. Subsequently, examination of mineralized nodule formation and evaluation of alkaline phosphatase (ALP) activity and ALP gene expression revealed that the most effective concentration of BDNF to elicit a response in hBMSCs was 100 ng/mL. In addition, we found out that by binding with TrkB receptor, the downstream Erk1/2 was phosphorylated, which promoted the expression of transcription factors, such as Runx2 and Osterix that are associated with osteoblast differentiation. We also found that by day 7 post-treatment, the neurogenic biomarkers, p75 and s100, were highly expressed in 100 ng/mL BDNF-treated hBMSCs. Finally, the effects of BDNF on osteogenesis and neurogenesis in newly formed tissues were assessed using animal models with a β-tricalcium phosphate scaffold. This revealed that treatment with 100 ng/mL BDNF promoted the osteogenesis and neurogenesis of hBMSCs in vivo by increasing expression of the osteogenic marker osteocalcin and various neurogenic biomarkers, including microtubule-associated protein 2, glial fibrillary acidic protein, neural/glial antigen 2, and β-tubulin III. This study has demonstrated that BDNF promotes hBMSC osteogenesis and neurogenesis in vitro and in vivo, and that BDNF may indirectly promote osteogenesis through increased neurogenesis. This further suggests that encouraging neutralization during bone engineering will lead to effective repairing of bone defects. The study may also provide insight into related fields, such as osseoperception and stress feedback regulation after dental implantation.

A major hindrance to successful alveolar bone augmentation and ridge preservation using synthetic scaffolds is insufficient vascularization in the implanted bone grafts. The slow ingrowth of host vasculature from the bone bed of alveolar bone to the top of the implanted bone grafts leads to limited bone formation in the upper layers of the implanted grafts, which hinders the subsequent implantation of titanium dental implants. In this study, macroporous beta‐tricalcium phosphate (β‐TCP) scaffolds with multiple vertical hollow channels are fabricated that play a similar role as blood vessels for nutrient diffusion and cell migration. The results show that the hollow channels accelerate the degradation rate of the β‐TCP scaffolds and the in vitro release of a bone forming peptide‐1, which significantly promote proliferation and osteogenesis of human bone mesenchymal stem cells on the channeled scaffolds, compared to nonchanneled scaffolds in vitro. More volume of newly formed bone tissues with more blood vessels are augmented in the channeled scaffolds when implanted in mandibular bone defects of beagle dogs. Channeled scaffolds significantly promote new bone formation and augment the height of the mandible. These findings indicate channeled scaffolds facilitate vascularization and bone formation and have great potential for vascularized bone augmentation.

Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox-LDL