FGF1 reduces cartilage injury in osteoarthritis via regulating AMPK/Nrf2 pathway.

Osteoarthritis (OA) is a systemic joint degenerative disease involving a variety of cytokines and growth factors. In this study, we investigated the protective effect of fibroblast growth factor 1 (FGF1) knockdown on OA and its underlying mechanisms in vitro. In addition, we evaluated the effect of FGF1 knockout on the destabilization of the medial meniscus (DMM) and examined the anterior and posterior cruciate ligament model in vivo. FGF1 affects OA cartilage destruction by increasing the protein expression of Nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), which is associated with the phosphorylation of AMPK and its substrates. Our study showed that FGF1 knockdown could reverse the oxidative damage associated with osteoarthritis. Nrf2 knockdown eliminated the antioxidant effect of FGF1 knockdown on chondrocytes. Furthermore, AMPK knockdown could stop the impact of FGF1 knockdown on osteoarthritis. These findings suggested that FGF1 knockdown could effectively prevent and reverse osteoarthritis by activating AMPK and Nrf2 in articular chondrocytes.

LINC02381, a sponge of miR-21, weakens osteogenic differentiation of hUC-MSCs through KLF12-mediated Wnt4 transcriptional repression.

INTRODUCTION: Human umbilical cord blood-derived MSCs (hUC-MSCs) have the potential to differentiate into osteoblasts. This study investigated the function and potential mechanisms of a novel lncRNA LINC02381 in hUC-MSC osteogenic differentiation. MATERIALS AND METHODS: hUC-MSCs were maintained in osteogenic differentiation medium. RT-qPCR assay was performed to assess LINC02381 expression. Alizarin Red S (ARS) and alkaline phosphatase (ALP) staining were performed to evaluate osteogenic differentiation. The interaction between miR-21 and LINC0238/KLF12 was determined by luciferase reporter and RNA immunoprecipitation (RIP) assays. Chromatin immunoprecipitation (ChIP) assay was used to confirm the transcriptional regulation of KLF12 on Wnt4 promoter. The nuclear translocation of ß-catenin was evaluated using immunofluorescence. hUC-MSCs seeded on Bio-Oss Collagen scaffolds were transplanted into nude mice to assess in vivo osteogenesis. Bone formation was observed by H&E and Masson's trichrome staining. OSX and OPN levels were assessed by immunohistochemistry. RESULTS: LINC02381 was up-regulated in the clinical samples of osteoporotic patients. However, LINC02381 expression was reduced during osteogenic differentiation of hUC-MSCs. Enforced expression of LINC02381 suppressed the osteogenic differentiation of hUC-MSCs. Mechanistically, LINC02381 sponged miR-21 to enhance KLF12 expression, which led to the inactivation of Wnt/ß-catenin signaling pathway. Furthermore, miR-21 mimics or KLF12 silencing counteracted LINC02381-induced inhibition of osteogenic differentiation, whereas IWP-4 (an inhibitor of Wnt pathway) abolished this effect. CONCLUSION: In summary, LINC02381 repressed osteogenic differentiation of hUS-MSCs through sponging miR-21 to enhance KLF12-mediated inactivation of Wnt/ß-catenin pathway, indicating that LINC02381 might be a therapeutic target for osteoporosis.

The efficacy and safety of gemcitabine-based induction chemotherapy for locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiation: A meta-analysis.

OBJECTIVES: To assess the efficacy and toxicity of gemcitabine-based induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Both observational studies (OBS) and randomized controlled trials (RCT) were included in the meta-analysis. Systematic online searches were conducted in Web of Sciences, PubMed, Embase, meeting proceedings and ClinicalTrials.gov from the inception to May 25, 2020. The primary endpoint of interest was overall survival. RESULTS: five OBSs and 2 RCTs including 1680 patients were incorporated in the analysis. The evidence from the RCTs showed that adding gemcitabine-based induction chemotherapy to CCRT significantly improved progression free survival (hazard ratio (HR): 0.60, 95% confidence interval (CI): 0.40-0.88; P = .010; chi square P = .25; I2 = 24%) and overall survival (HR: 0.47; 95% CI: 0.28-0.80; P = 0.005; chi square P = .49, I2 = 0%) and was related to a higher risk of hematological toxicities. Furthermore, based on the data of OBSs, overall survival (HR: 0.52; 95% CI: 0.31-0.88; P = .02; chi square P = .37, I2 = 6%) was significantly improved in patients treated with gemcitabine-based induction chemotherapy compared to those treated with taxane-based induction chemotherapy. However, the progression free survival (HR: 0.67; 95% CI: 0.45-1.01; P = .06; chi square P = .74; I2 = 0%) showed no significant difference. CONCLUSIONS: For LA-NPC patients, adding gemcitabine-based induction chemotherapy to CCRT significantly improved overall survival and progression free survival with a higher risk of hematological toxicities when compared to CCRT alone. Also, gemcitabine-based regimen could be used as an alternative induction chemotherapy regimen to taxane-based regimen in the treatment of LA-NPC.

Feedback loop in miR-449b-3p/ADAM17/NF-κB promotes metastasis in nasopharyngeal carcinoma.

An emerging body of evidence has promoted the understanding of the role of microRNAs (miRNAs) in tumorigenesis and progression, but the mediating function of miRNAs in nasopharyngeal carcinoma (NPC) development remains poorly elucidated. In this study, miR-449b-3p was downregulated in NPC specimens (P < .001) and cells (P < .05). Cytological and animal experiments provided evidence that miR-449b-3p inhibited NPC metastasis in vitro and in vivo. Disintegrin and metalloproteinase 17 (ADAM17) was revealed as a direct target of miR-449b-3p. Rescue experiments suggested that the downregulation of ADAM17 in the miR-449b-3p knockdown cells partially reversed the inhibition of cell invasion and migration. Luciferase reporter assay, chromatin immunoprecipitation assay, and Western blot analysis showed that ADAM17 could suppress the promoter activity and expression of miR-449b-3p by inducing NF-κB transcriptional activity. In conclusion, our study provided new insights into the underlying mechanism of the invasion and metastasis of NPC. The novel miR-449b-3p/ADAM17/NF-κB feedback loop could be a target for the clinical treatment of NPC.

Analysis of olfactory ensheathing glia transplantation-induced repair of spinal cord injury by electrophysiological, behavioral, and histochemical methods in rats.

This study examined the efficacy of transplanting olfactory ensheathing glia (OEG) in repairing spinal cord injury (SCI) using behavioral tests, retrograde labeling, as well as somatosensory and motor evoked potentials in rats. One week after surgery, motor function in OEG-treated rats was significantly superior to untreated controls (P < 0.05). Also, we found that up to 8 weeks following surgery to induce SCI, somatosensory and motor evoked potentials were found in the OEG-treated groups, but not in the transplantation and damage control groups. Retrograde labeling from the area distal to the SCI produced a higher number of labeled neurons in the ventrolateral division of red nucleus and motor cortex of OEG-treated rats compared to controls, which showed no retrograde labeling (P < 0.05). We believe that this study has important implications for characterizing the mechanisms of OEG transplantation as a treatment for SCI.