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Background Medial vascular calcification is commonly identified in chronic kidney disease (CKD) patients and seriously affects the health and life quality of patients. This study aimed to investigate the effects of protein arginine methyltransferase 3 (PRMT3) on vascular calcification induced by CKD. Methods A mice model of CKD was established with a two-step diet containing high levels of calcium and phosphorus. Vascular smooth muscle cells (VSMCs) were subjected to β-glycerophosphate (β-GP) treatment to induce the osteogenic differentiation as an in vitro CKD model. Results PRMT3 was upregulated in VSMCs of medial artery of CKD mice and β-GP-induced VSMCs. The inhibitor of PRMT3 (SGC707) alleviated the vascular calcification and inhibited the glycolysis of CKD mice. Knockdown of PRMT3 alleviated the β-GP-induced osteogenic transfomation of VSMCs by the repression of glycolysis. Next, PRMT3 interacted with hypoxia-induced factor 1α (HIF-1α), and the knockdown of PRMT3 downregulated the protein expression of HIF-1α by weakening its methylation. Gain of HIF-1α reversed the PRMT3 depletion-induced suppression of osteogenic differentiation and glycolysis of VSMCs. Conclusion The inhibitory role of PRMT3 depletion was at least mediated by the regulation of glycolysis upon repressing the methylation of HIF-1α.

MicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional and/or translational level and are deeply involved in the pathogenesis of several types of cancers. Specifically, microRNA-221 (miR-221) is overexpressed in many human cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-221 in human osteosarcoma has not been totally elucidated. In the present study, the effects of miR-221 on osteosarcoma and the possible mechanism by which miR-221 affected the survival, apoptosis, and cisplatin resistance of osteosarcoma were investigated. Real-time quantitative PCR analysis revealed miR-221 was significantly upregulated in osteosarcoma cell lines than in osteoblasts. Both human osteosarcoma cell lines SOSP-9607 and MG63 were transfected with miR-221 mimic or inhibitor to regulate miR-221 expression. The effects of miR-221 were then assessed by cell viability, cell cycle analysis, apoptosis assay, and cisplatin resistance assay. In both cells, upregulation of miR-221 induced cell survival and cisplatin resistance and reduced cell apoptosis. In addition, knockdown of miR-221 inhibited cell growth and cisplatin resistance and induced cell apoptosis. Potential target genes of miR-221 were predicted using bioinformatics. Moreover, luciferase reporter assay and western blot confirmed that PTEN was a direct target of miR-221. Furthermore, introduction of PTEN cDNA lacking 3'-UTR or PI3K inhibitor LY294002 abrogated miR-221-induced cisplatin resistance. Finally, both miR-221 and PTEN expression levels in osteosarcoma samples were examined by using real-time quantitative PCR and immunohistochemistry. High miR-221 expression level and inverse correlation between miR-221 and PTEN levels were revealed in osteosarcoma tissues. These results for the first time demonstrate that upregulation of miR-221 induces the malignant phenotype of human osteosarcoma whereas knockdown of miR-221 reverses this phenotype, suggesting that miR-221 could be a potential target for osteosarcoma treatment.

Mechanical overloading is a major cause of tendinopathy, but the underlying pathogenesis of tendinopathy is unclear. Here we report that high mobility group box1 (HMGB1) is released to the tendon extracellular matrix and initiates an inflammatory cascade in response to mechanical overloading in a mouse model. Moreover, administration of glycyrrhizin (GL), a naturally occurring triterpene and a specific inhibitor of HMGB1, inhibits the tendon's inflammatory reactions. Also, while prolonged mechanical overloading in the form of long-term intensive treadmill running induces Achilles tendinopathy in mice, administration of GL completely blocks the tendinopathy development. Additionally, mechanical overloading of tendon cells in vitro induces HMGB1 release to the extracellular milieu, thereby eliciting inflammatory and catabolic responses as marked by increased production of prostaglandin E2 (PGE2) and matrix metalloproteinase-3 (MMP-3) in tendon cells. Application of GL abolishes the cellular inflammatory/catabolic responses. Collectively, these findings point to HMGB1 as a key molecule that is responsible for the induction of tendinopathy due to mechanical overloading placed on the tendon.

Cellular adaptation to a hypoxic microenvironment is essential for tumor progression and is largely mediated by HIF-1α through coordinated regulation of hypoxia-responsive genes. The chemokine SDF-1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers. In this study, we investigated the response of osteosarcoma cells to hypoxia and the expression of CXCR4 and HIF-1α in human osteosarcoma specimens and explored the roles of CXCR4 and HIF-1α in the cell migration process. We performed immunohistochemistry, immunocytochemistry, quantitative real-time PCR, Western blots and fluorescent reporter assays to evaluate the correlation between CXCR4 and HIF-1α expression in human osteosarcoma specimens or SOSP-9607 cells under normoxic and hypoxic conditions. Transwell assays were used to assess cell migration under different conditions. Exposure of SOSP-9607 cells to hypoxic conditions resulted in significantly increased migration. When SOSP-9607 cells were subjected to hypoxic conditions, the mRNA and protein levels of CXCR4 were significantly increased in a time-dependent manner. Moreover, siHIF-1α significantly decreased the mRNA and protein levels of CXCR4 under hypoxia, whereas pcDNA-HIF-1α significantly increased the mRNA and protein levels of CXCR4 under normoxia. A luciferase reporter gene study showed that siHIF-1α reduced pGL3-CXCR4 luciferase activity. Furthermore, coexpression of HIF-1α and CXCR4 was significantly higher in patients with distant metastasis compared with those without metastasis. The hypoxia-HIF-1α-CXCR4 pathway plays a crucial role during the migration of human osteosarcoma cells, and targeting this pathway might represent a novel therapeutic strategy for patients suffering from osteosarcoma.

Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-β-caryophyllene (TBC) and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future.

Trigeminal postherpetic neuralgia (TPHN) often presents with moderate to severe pain, hyperalgesia, and allodynia. Conventional analgesic treatments are poorly effective, which seriously affects the quality of life. This retrospective study aimed to evaluate the efficacy of pulsed radiofrequency (PRF) for the treatment of TPHN. A total of 90 TPHN patients were selected between January 2014 and December 2016 in the Department of Pain Management, Shengjing Hospital, China Medical University. Patients were randomly divided into two groups according to the order of enrollment ( = 45 per group): group A, peripheral nerve (supraorbital nerve, infraorbital nerve and mental nerve) PRF; group B, gasserian ganglion PRF. Follow-up assessments of visual analogue scale (VAS) pain assessment, SF-36 health status questionnaire, total efficiency rate, and drug dosage of anticonvulsants and opioid analgesics were performed at time points of 1 week, 1 month, 3 months, 6 months, and 1 year after surgery. At each postsurgery time point, the VAS decreased, SF-36 (physical and mental components) increased, and drug dosage of anticonvulsants and opioids analgesics decreased in both treatment groups; values at each time point were significantly different from presurgery values ( < 0.05). Compared with group A, VAS decreased, SF-36 increased, and dosage of anticonvulsants and opioids analgesics decreased significantly in group B ( < 0.05). The total efficiency rates one year after surgery in group A and group B were 68.9 and 86.7%, respectively. The total efficiency rate of group B was statistically higher than that of group A ( < 0.05). PRF relieved TPHN, and gasserian ganglion PRF was more effective than peripheral nerve PRF. The method was effective and improved the quality of life of the patients. PRF is recommended as a treatment for TPHN.

Painful diabetic peripheral neuropathy (PDPN) is one of the most common complications of diabetes. PDPN seriously affects the quality of life and is difficult to treat; therefore, there is an urgent need for new cost-effective treatment methods for PDPN. To investigate the efficacy and safety of radiofrequency thermocoagulation (RF) combined with anhydrous ethanol (AE) chemical blockade of lumbar sympathetic ganglia (LSG) in patients with PDPN using computed tomography (CT). Retrospective comparative study. Shengjing Hospital of China Medical University. Ninety patients diagnosed with PDPN were enrolled in this study. The patients were randomly divided into AE group (A, n=30), RF group (B, n=30), and RF+ AE group (C, n=30). The follow-up included preoperative basic conditions, visual analog scale (VAS), the total remission rate (TRR), skin temperature (ST) and the improvement of numbness and hyperalgesia in the lower extremities, complications, and degree of satisfaction (DOS) before and after surgery. Postoperative VASs were significantly decreased compared to preoperative VASs in all groups ( <0.05). The VAS in group A began to increase 3 months (3M) after surgery; VAS scores at 3M, 6 months (6M) and 1 year (1Y) were significantly different compared to group B and C ( <0.05); VAS in group B began to increase after 6M; VAS scores at 6M and 1Y were significantly different compared to group C ( <0.05); Moreover, group C maintained relatively long duration of pain relief. TRR in group A, group B and group C at 1Y after operation was 66.7%, 73.3% and 93.3%, respectively; TRR in group C was statistically different compared to groups A and B ( <0.05). Higher ST in the lower extremities was observed after surgery in all groups compared to peroration ( <0.05); nonetheless, the difference was not statistically significant. The numbness and hyperalgesia improved in all three groups after surgery compared to preoperational time, the numbness in group C was significantly higher compared to groups A and B. In addition, no severe complications were observed. At 6M and 1Y after surgery, the degree of satisfaction in patients from group C was significantly higher compared to groups A and B. Radiofrequency thermocoagulation combined with AE chemical blockade of the LSG was safe and effective. Nevertheless, the details underlying analgesic mechanisms still need to be investigated.

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, which play regulatory roles at the post-transcriptional level by suppressing the translation of protein-coding genes or inducing mRNA cleavage. Dysregulated expression of miRNAs is involved in multiple types of cancers and plays important roles in regulating various biological processes including metastasis. miR-101 is downregulated in various types of cancer and functions as a suppressor of cell migration and invasion. Meanwhile, enhancer of zeste homolog 2 (EZH2) is associated with the metastatic potential of several aggressive tumors. In the present study, we reported that ectopic overexpression of miR-101 downregulated the expression level of EZH2 and significantly inhibited migration and invasion of osteosarcoma cells. In addition, knockdown of EZH2 by siRNA showed the same effect of miR-101 on migration and invasion. To conclude, these results indicate that miR-101 may act as a tumor suppressor in osteosarcoma, as it has a suppressive role in cell migration and invasion by targeting EZH2.

4E-BP1 is a tumor suppressor regulating cap-dependent translation that is in turn controlled by mechanistic target of rapamycin (mTOR) or cyclin-dependent kinase 1 (CDK1) phosphorylation. 4E-BP1 serine 82 (S82) is phosphorylated by CDK1, but not mTOR, and the consequences of this mitosis-specific phosphorylation are unknown. Knock-in mice were generated with a single 4E-BP1 S82 alanine (S82A) substitution leaving other phosphorylation sites intact. S82A mice were fertile and exhibited no gross developmental or behavioral abnormalities, but the homozygotes developed diffuse and severe polycystic liver and kidney disease with aging, and lymphoid malignancies after irradiation. Sublethal irradiation caused immature T-cell lymphoma only in S82A mice while S82A homozygous mice have normal T-cell hematopoiesis before irradiation. Whole genome sequencing identified PTEN mutations in S82A lymphoma and impaired PTEN expression was verified in S82A lymphomas derived cell lines. Our study suggests that the absence of 4E-BP1 S82 phosphorylation, a subtle change in 4E-BP1 phosphorylation, might predispose to polycystic proliferative disease and lymphoma under certain stressful circumstances, such as aging and irradiation.

Background There is very little published literature and none that discussed care in a neonate regarding anesthetic risk and management of neonate with congenital bronchobiliary fistula during thoracoscopy and thoracotomy. This article analyzes related risk factors and literature review from perioperative ventilation, circulation and other aspects of management. Case presentation A neonate diagnosed as congenital bronchobiliary fistula combined with severe chemical pneumonia, consolidation of the lungs, and infection was facing the risk of anaesthesia under thoracoscopy exploration surgery, who experiened more than 20 days diagnostic period before operation. Many risk factors have led to conversion from minimally invasive surgery to thoracotomy, including persistent hypoxemia, hypercapnia, difficult surgical exposure and extremly difficulty of intraoperative ventilation management. Anesthesia maintenance after conversion to open access remained problematic. Fortunately the patient showed no sign of any adverse CNS effects after 4 months of follow-up. Conclusions The most prominent anesthesia challenges are hypoxemia, increased airway resistance, impaired ventilation, and the risk of metabolic acidosis. Close cooperation among the entire neonatal medical team is the key factors in successful management of this rare case.