Ultrasound-triggered piezoelectric polyetheretherketone with boosted osteogenesis via regulating Akt/GSK3β/β-catenin pathway
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC11375992 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundGood osseointegration is the key to the long-term stability of bone implants. Thermoplastic polyetheretherketone (PEEK) has been widely used in orthopedics; however, its inherent biological inertia causes fibrous tissue to wrap its surface, which leads to poor osseointegration and thus greatly limits its clinical applications.MethodsHerein, we developed a facile yet effective surface modification strategy. A commonly used sulfonation coupled with "cold pressing" treatment in the presence of porogenic agent formed a three-dimensional hierarchical porous structure on PEEK surface. Subsequently, the effects of porous surface on the in vitro adhesion, proliferation and differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) were evaluated. Finally, the osteoinduction and osseointegration of surface-porous PEEK implant were examined in the rat distal femoral defect model.ResultsIn vitro results showed that the surface modification did not significantly affect the mechanical performance and cytocompatibility of PEEK substance, and the porous structure on the modified PEEK substrate provided space for cellular ingrowth and enhanced osteogenic differentiation and mineralization of BMSCs. In vivo tests demonstrated that the surface-porous PEEK implant could effectively promote new bone formation and had higher bone-implant contact rate, thereby achieving good bone integration with the surrounding host bone. In addition, this modification technique was also successfully demonstrated on a medical PEEK interbody fusion cage.ConclusionThe present study indicates that topological morphology plays a pivotal role in determining implant osseointegration and this facile and effective modification strategy developed by us is expected to achieve practical applications quickly.
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Project description:Effect of Low-intensity pulsed ultrasound (LIPUS) assisted BT/MWCNTs/Col (BMC) membrane on gene expression during immune response of macrophages (Raw 264.7).
2023-07-31 | GSE236912 | GEO
Project description:Ethyl linoleate is an unsaturated fatty acid used in many cosmetics for its various attributes, such as antibacterial and anti-inflammatory properties and clinically proven to be an effective anti-acne agent. In this study, we investigated the effect of ethyl linoleate on the melanogenesis and the mechanism underlying its action on melanogenesis in B16F10 murine melanoma cells. Our results revealed that ethyl linoleate significantly inhibited melanin content and intracellular tyrosinase activity in α-MSH-induced B16F10 cells, but it did not directly inhibit activity of mushroom tyrosinase. Ethyl linoleate inhibited the expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase related protein 1 (TRP1) in governing melanin pigment synthesis. We observed that ethyl linoleate inhibited phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β) and reduced the level of β-catenin, suggesting that ethyl linoleate inhibits melanogenesis through Akt/GSK3β/β-catenin signal pathway. Therefore, we propose that ethyl linoleate may be useful as a safe whitening agent in cosmetic and a potential therapeutic agent for reducing skin hyperpigmentation in clinics.
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Project description:YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP's function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with β-catenin and is necessary for maintenance of nuclear β-catenin level and Wnt/β-catenin signaling. Expression of β-catenin in YAP-deficient BMSCs (bone marrow stromal cells) diminishes the osteogenesis deficit. These results thus identify YAP-β-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.
| S-EPMC5984632 | biostudies-literature
Project description:As a chronic metabolic disease, diabetes mellitus (DM) creates a hyperglycemic micromilieu around implants, resulting inthe high complication and failure rate of implantation because of mitochondrial dysfunction in hyperglycemia. To address the daunting issue, the authors innovatively devised and developed mitochondria-targeted orthopedic implants consisted of nutrient element coatings and polyetheretherketone (PEEK). Dual nutrient elements, in the modality of ZnO and Sr(OH)2 , are assembled onto the sulfonated PEEK surface (Zn&Sr-SPEEK). The results indicate the synergistic liberation of Zn2+ and Sr2+ from coating massacres pathogenic bacteria and dramatically facilitates cyto-activity of osteoblasts upon the hyperglycemic niche. Intriguingly, Zn&Sr-SPEEK implants are demonstrated to have a robust ability to recuperate hyperglycemia-induced mitochondrial dynamic disequilibrium and dysfunction by means of Dynamin-related protein 1 (Drp1) gene down-regulation, mitochondrial membrane potential (MMP) resurgence, and reactive oxygen species (ROS) elimination, ultimately enhancing osteogenicity of osteoblasts. In vivo evaluations utilizing diabetic rat femoral/tibia defect model at 4 and 8 weeks further confirm that nutrient element coatings substantially augment bone remodeling and osseointegration. Altogether, this study not only reveals the importance of Zn2+ and Sr2+ modulation on mitochondrial dynamics that contributes to bone formation and osseointegration, but also provides a novel orthopedic implant for diabetic patients with mitochondrial modulation capability.
| S-EPMC8529468 | biostudies-literature
Project description:Tribbles homolog 2 (TRIB2) is implicated in tumorigenesis and drug resistance in various types of cancers. However, the role of TRIB2 in the regulation of tumorigenesis and drug resistance of cancer stem cells (CSCs) is still elusive. In the present study, we showed increased expression of TRIB2 in spheroid-forming and aldehyde dehydrogenase-positive CSC populations of A2780 epithelial ovarian cancer cells. Short hairpin RNA-mediated silencing of TRIB2 expression attenuates the spheroid-forming, migratory, tumorigenic, and drug-resistant properties of A2780 cells, whereas overexpression of TRIB2 increases the CSC-like characteristics. TRIB2 overexpression induced GSK3β inactivation by augmenting AKT-dependent phosphorylation of GSK3β at Ser9, followed by increasing β-catenin level via reducing the GSK3β-mediated phosphorylation of β-catenin. Treatment of TRIB2-ovexpressed A2780 cells with the phosphoinositide-3-kinase inhibitor LY294002 abrogated TRIB2-stimulated proliferation, migration, drug resistance of A2780 cells. These results suggest a critical role for TRIB2 in the regulation of CSC-like properties by increasing the stability of β-catenin protein via the AKT-GSK3β-dependent pathways.
| S-EPMC8334352 | biostudies-literature
Project description:Upregulation of regenerating gene 4 (Reg4) is observed in many human gastrointestinal malignancies including colorectal cancer (CRC). We previously reported a Reg4-mediated induction of epidermal growth factor receptor-Akt-AP1 signaling regulating CRC cell apoptosis. However, the role of Reg4 in the regulation of CRC cell division is poorly understood. This study tests the hypothesis that Reg4 induces Akt-GSK3β-β-Catenin-TCF-4 signaling to regulate CRC cell division. In vitro models of human CRC were used to determine the role of Reg4 in regulation of CRC cell division. Cell cycle studies demonstrated that Reg4 treatment significantly decreased CRC cell number in G1 phase and increased in G2 phase. Subsequently Reg4 significantly increased the mitotic index of CRC cells. As assessed by real-time RT-PCR and Western blot analyses, Reg4 significantly increased the expression of cell cycle regulatory genes Cyclin D1 and D3, and associated Cyclin-dependent kinases (CDK4 and CDK6). Reg4-mediated increase in these genes involved a pathway that included an induced Akt activity by increasing phosphorylation of Thr308 and Ser473, a reduced glycogen synthase kinase 3β (GSK-3β) activity by increasing phosphorylation of Ser9, an induced nuclear translocation of β-Catenin by decreasing phosphorylation of Ser33/37/Thr41, and an increased TCF-4 transcriptional activity. Furthermore, antagonism of Reg4-signaling using Reg4-specific mAbs (2H6 and 3E5) and Akt inhibitor significantly decreased, whereas agonism using GSK-3β antagonist (SB216763) significantly increased mitotic index and proliferation of CRC cells. These results identify Reg4 as a key regulator of the CRC cell division and proliferation, hence a potential target of human CRC treatment.
| S-EPMC4565142 | biostudies-literature
Project description:The eradication of cancer stem cells (CSCs) is significant for cancer therapy and prevention. In this study, we evaluated WM130, a novel derivative of matrine, for its effect on CSCs using human hepatocellular carcinoma (HCC) cell lines, their sphere cells, and sorted EpCAM+ cells. We revealed that WM130 could not only inhibit proliferation and colony formation of HCC cells, but also suppress the expression of some stemness-related genes and up-regulate some mature hepatocyte marker genes, indicating a promotion of differentiation from CSCs to hepatocytes. WM130 also suppressed the proliferation of doxorubicin-resistant hepatoma cells, and markedly reduced the cells with CSC biomarker EpCAM. Moreover, WM130 suppressed HCC spheres, not only primary spheres but also subsequent spheres, indicating an inhibitory effect on self-renewal capability of CSCs. Interestingly, WM130 exhibited a remarkable inhibitory preference on HCC spheres and EpCAM+ cells rather than their parental HCC cells and EpCAM- cells respectively. In vivo, WM130 inhibited HCC xenograft growth, decreased the number of sphere-forming cells, and remarkably decreased the levels of EpCAM mRNA and protein in tumor xenografts. Better inhibitory effect was achieved by WM130 in combination with doxorubicin. Further mechanism study revealed that WM130 inhibited AKT/GSK3β/β-catenin signaling pathway. Collectively, our results suggest that WM130 remarkably inhibits hepatic CSCs, and this effect may via the down-regulation of the AKT/GSK3β/β-catenin pathway. These findings provide a strong rationale for the use of WM130 as a novel drug candidate in HCC therapy.
| S-EPMC5346734 | biostudies-literature
Project description:BackgroundDiabetic retinopathy (DR) is the most common microvascular complication of diabetes and the main cause of non-traumatic blindness in adults. Pericyte loss is known to be an early pathological change of DR. Our group's previous research indicated that prostaglandin F2α (PGF2α) acts as an eicosanoidal protector against non-proliferative DR that can regulate the mobility of pericytes in a RhoA-mediated manner. However, the effect of PGF2α on pericyte apoptosis has yet to be described.MethodsTwo animal models were constructed: a high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetes mouse model and a spontaneous type 2 diabetes db/db mouse model. We analyzed pathological changes, and performed TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining and western blot to detect apoptosis in the retinas of diabetic mice. For our in vitro experiments, we selected human retinal pericytes and subjected them to high-glucose (HG), PGF2α, and AL8810 (an antagonist of the PGF2α receptor) treatment. Subsequently, apoptosis and the levels of PI3K/Akt/GSK3β/β-catenin pathway-related proteins were detected by TUNEL staining and western blot, respectively.ResultsThe levels of apoptosis were increased in the retinas of diabetic mice in both T2DM models. In vitro, HG treatment increased apoptosis and inhibited PI3K/Akt/GSK3β/β-catenin signaling in pericytes. In contrast, PGF2α treatment inhibited pericyte apoptosis while increasing the levels of the PI3K, p-Akt/t-Akt, p-GSK3β/t-GSK3β, and β-catenin proteins; however, these PGF2α-induced effects were eliminated by ALL80.ConclusionsPGF2α may make a key contribution to reducing pericyte apoptosis and protecting against DR via its inhibition of the PI3K/Akt/GSK3β/β-catenin signaling pathway.
| S-EPMC8267281 | biostudies-literature
Project description:Perfluorooctanoic acid (PFOA), a typical environmental contaminant, has been observed in tissue samples of various diseases, including liver cancer. PFOA can lead to hepatotoxicity, but the underlying molecular mechanism remains unclear. Our results showed that PFOA significantly inhibited HL-7702 (L02) and MIHA cell viability in a time- and dose-dependent manner. Furthermore, PFOA could cause oxidative stress, mitochondrial injury, and ferroptosis. In addition, PFOA upregulated the levels of malondialdehyde and glutathione/oxidized glutathione and downregulated the expressions of SLC7A11 and GPX4, which refer to typical phenotypes of ferroptosis. PFOA suppressed phosphorylation of signaling cascades AKT/GSK3β/β-catenin, indicating the signal pathway might be related to ferroptosis. In order to prove the above hypothesis, the Wnt signaling pathway activator chir99021 was used and the result revealed that PFOA-induced inhibition of p-AKT and its downstream effectors p-GSK3β, SLC7A11, and GPX4 was counteracted. On the other hand, the inhibitor of p-AKT, Ly294002, strengthened PFOA's regulatory actions on these factors. Overall, our results suggest that PFOA can lead to liver cell injury by inducing oxidative stress and ferroptosis. The effects are conferred through the regulation of the AKT/GSK3β/β-catenin signaling cascades.
| S-EPMC11780420 | biostudies-literature