EGFR-Activated JAK2/STAT3 Pathway Confers Neuroprotection in Spinal Cord Ischemia-Reperfusion Injury: Evidence from High-Throughput Sequencing and Experimental Models.

This study aimed to investigate the molecular mechanisms underlying spinal cord ischemia-reperfusion (SCI/R) injury. Through RNA-Seq high-throughput sequencing and bioinformatics analysis, we found that EGFR was downregulated in the spinal cord of SCI/R mice and may function via mediating the JAK2/STAT3 signaling pathway. In vitro cell experiments indicated that overexpression of EGFR activated the JAK2/STAT3 signaling pathway and reduced neuronal apoptosis levels. In vivo animal experiments further confirmed this conclusion, suggesting that EGFR inhibits SCI/R-induced neuronal apoptosis by activating the JAK2/STAT3 signaling pathway, thereby improving SCI/R-induced spinal cord injury in mice. This study revealed the molecular mechanisms of SCI/R injury and provided new therapeutic strategies for treating neuronal apoptosis.

Research progress on black phosphorus hybrids hydrogel platforms for biomedical applications.

Hydrogels, also known as three-dimensional, flexible, and polymer networks, are composed of natural and/or synthetic polymers with exceptional properties such as hydrophilicity, biocompatibility, biofunctionality, and elasticity. Researchers in biomedicine, biosensing, pharmaceuticals, energy and environment, agriculture, and cosmetics are interested in hydrogels. Hydrogels have limited adaptability for complicated biological information transfer in biomedical applications due to their lack of electrical conductivity and low mechanical strength, despite significant advances in the development and use of hydrogels. The nano-filler-hydrogel hybrid system based on supramolecular interaction between host and guest has emerged as one of the potential solutions to the aforementioned issues. Black phosphorus, as one of the representatives of novel two-dimensional materials, has gained a great deal of interest in recent years owing to its exceptional physical and chemical properties, among other nanoscale fillers. However, a few numbers of publications have elaborated on the scientific development of black phosphorus hybrid hydrogels extensively. In this review, this review thus summarized the benefits of black phosphorus hybrid hydrogels and highlighted the most recent biological uses of black phosphorus hybrid hydrogels. Finally, the difficulties and future possibilities of the development of black phosphorus hybrid hydrogels are reviewed in an effort to serve as a guide for the application and manufacture of black phosphorus -based hydrogels. Recent applications of black phosphorus hybrid hydrogels in biomedicine.

MicroRNA-145-Mediated KDM6A Downregulation Enhances Neural Repair after Spinal Cord Injury via the NOTCH2/Abcb1a Axis.

Spinal cord injury (SCI) causes a significant physical, emotional, social, and economic burden to millions of people. MicroRNAs are known players in the regulatory circuitry of the neural repair in SCI. However, most microRNAs remain uncharacterized. Here, we demonstrate the neuroprotection of microRNA-145 (miR-145) after SCI in vivo and in vitro. In silico analysis predicted the target gene KDM6A of miR-145. The rat SCI model was developed by weight drop, and lipopolysaccharide- (LPS-) induced PC12 cell inflammatory injury model was also established. We manipulated the expression of miR-145 and/or KDM6A both in vivo and in vitro to explain their roles in rat neurological functional recovery as well as PC12 cell activities and inflammation. Furthermore, we delineated the mechanistic involvement of NOTCH2 and Abcb1a in the neuroprotection of miR-145. According to the results, miR-145 was poorly expressed and KDM6A was highly expressed in the spinal cord tissue of the SCI rat model and LPS-induced PC12 cells. Overexpression of miR-145 protects PC12 cells from LPS-induced cell damage and expedites neurological functional recovery of SCI in rats. miR-145 was validated to target and downregulate the demethylase KDM6A expression, thus abrogating the expression of Abcb1a by promoting the methylation of NOTCH2. Additionally, in vivo findings verified that miR-145 expedites neuroprotection after SCI by regulating the KDM6A/NOTCH2/Abcb1a axis. Taken together, miR-145 confers neuroprotective effects and enhances neural repair after SCI through the KDM6A-mediated NOTCH2/Abcb1a axis.

microRNA-125b and its downstream Smurf1/KLF2/ATF2 axis as important promoters on neurological function recovery in rats with spinal cord injury.

The purpose of this study is to investigate the role of microRNA-125b (miR-125b) and its mechanism in spinal cord injury (SCI) by targeting Smurf1. After loss- and gain-function approaches were conducted in SCI rat models and neural stem cells (NSCs) isolated from foetal rats, the Basso-Beattie-Bresnahan (BBB) score was calculated, and related protein expression was determined by Western blot analysis and cell apoptosis by TUNEL staining. NSC viability was detected by CCK-8, migration abilities by Transwell assay and apoptosis by flow cytometry. The relationship between miR-125b, Smurf1 and KLF2 was evaluated by dual-luciferase reporter gene experiments, Co-IP and in vivo ubiquitin modification assays. Inhibition of miR-125b and KLF2 and the up-regulation of Smurf1 and ATF2 were observed in SCI rats. BBB scores were elevated, the expression of Nestin, NeuN, GFAP, NF-200 and Bcl-2 protein was enhanced but that of Bax protein was reduced, and cell apoptosis was inhibited in SCI rats after up-regulating miR-125b or silencing ATF2. Smurf1 was a target gene of miR-125b, which promoted KLF2 degradation through its E3 ubiquitin ligase function, and KLF2 repressed the expression of ATF2 in NSCs. The results in vivo were replicated in vitro. miR-125b overexpression promotes neurological function recovery after SCI.

MiR-23b-3p promotes postmenopausal osteoporosis by targeting MRC2 and regulating the Wnt/ß-catenin signaling pathway.

Postmenopausal osteoporosis (PMOP) is one of the most common metabolic bone diseases in postmenopausal women. Increasing evidence has indicated that microRNAs (miRNAs) play vital regulatory roles during osteoporosis progression. This study aimed to investigate the potential function of miR-23b-3p in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). PMOP was induced in mice by bilateral ovariectomy. X-ray absorptiometry was applied to detect BMD and BMC in PMOP mice. Luciferase reporter assay and RIP assay were utilized to investigate the relationship between miR-23b-3p and MRC2. We found the upregulation of miR-23b-3p in bone tissues of PMOP mice. Silencing of miR-23b-3p relieved PMOP in mice. Moreover, miR-23b-3p knockdown facilitated the osteogenic differentiation of hMSCs by increasing the expression of Runx2, OCN, Osterix and promoting ALP activity. Mechanistically, MRC2 is a downstream target gene of miR-23b-3p. MRC2 knockdown significantly rescued the promoting effect of lenti-miR-23b-3p inhibitor on osteogenic differentiation of hMSCs. Furthermore, miR-23b-3p targeted MRC2 to inhibit the Wnt/ß-catenin pathway during the osteogenic differentiation of hMSCs. In summary, inhibition of miR-23b-3p alleviates PMOP by targeting MRC2 to inhibit the Wnt/ß-catenin signaling, which may provide a novel molecular insight for osteoporosis therapy.

Effect of non-invasive brain stimulation on neuropathic pain following spinal cord injury: A systematic review and meta-analysis.

BACKGROUND: In recent years, some studies indicated that repetitive transcranial magnetic stimulation (rTMS) could relieve neuropathic pain (NP) following a spinal cord injury (SCI), whereas some studies showed no pain relief effect. In addition, some studies showed the analgesic effect of transcranial direct current stimulation (tDCS) on NP post SCI, whereas other studies showed no effect. METHODS: We systematically searched on the PubMed, Web of Science, EMBASE, Medline, Google Scholar for studies exploring the analgesic effect of rTMS or tDCS on NP post SCI until November 2019. Meta-analysis was conducted to summarize results of these studies. RESULTS: The present quantitative meta-analysis indicated no significant difference in the effect of treatment on NP following SCI between rTMS and sham rTMS over the motor cortex at about 1 week after the end of the rTMS period (standardized mean difference (SMD) = 2.89, 95% confidence interval (CI) = -0.27 to 6.04). However, the study indicated that rTMS showed significantly better pain relief of treatment compared with sham rTMS between 2 and 6 weeks after the end of the rTMS period (SMD = 3.81, 95%CI: 0.80-7.52). However, no sufficient evidence could be provided to make a meta-analysis for the analgesic effect of tDCS on NP following SCI over the primary motor area (M1). CONCLUSIONS: In conclusion, the present meta-analysis suggested that rTMS did not show early analgesic effect on NP after SCI, but showed better middle-term analgesic effect, compared with sham rTMS. More large scale, blinded randomized controlled trials (RCTs) were needed to explore the analgesic effect of rTMS and tDCS on NP following SCI.

Bone marrow mesenchymal stem cell-derived exosomal microRNA-124-3p attenuates neurological damage in spinal cord ischemia-reperfusion injury by downregulating Ern1 and promoting M2 macrophage polarization.

BACKGROUND: Spinal cord ischemia-reperfusion injury (SCIRI) often leads to neurological damage and mortality. In this regard, understanding the pathology of SCIRI and preventing its development are of great clinic value. METHODS: Herein, we analyzed the role of bone marrow mesenchymal stem cell (BMMSC)-derived exosomal microRNA (miR)-124-3p in SCIRI. A SCIRI rat model was established, and the expression of Ern1 and M2 macrophage polarization markers (Arg1, Ym1, and Fizz) was determined using immunohistochemistry, immunofluorescence assay, RT-qPCR, and western blot analysis. Targeting relationship between miR-124-3p and Ern1 was predicted using bioinformatic analysis and verified by dual-luciferase reporter assay. Macrophages were co-cultured with miR-124-3p-containing BMMSC-derived exosomes. M2 macrophages were identified using flow cytometry, and the expression of Arg1, Ym1, and Fizz was determined. In addition, SCIRI rats were injected with miR-124-3p-containing exosomes, spinal cord cell apoptosis was observed using TUNEL assay, and the pathological condition was evaluated with H&E staining. RESULTS: In SCIRI, Ern1 was highly expressed and M2 polarization markers were poorly expressed. Silencing Ern1 led to elevated expression of M2 polarization markers. MiR-124-3p targeted and negatively regulated Ern1. Exosomal miR-124-3p enhanced M2 polarization. Highly expressed exosomal miR-124-3p impeded cell apoptosis and attenuated SCIRI-induced tissue impairment and nerve injury. miR-124-3p from BMMSC-derived exosomes ameliorated SCIRI and its associated nerve injury through inhibiting Ern1 and promoting M2 polarization. CONCLUSION: In summary, exosomal miR-124-3p derived from BMMSCs attenuated nerve injury induced by SCIRI by regulating Ern1 and M2 macrophage polarization.

The transcription factor Foxd3 induces spinal cord ischemia-reperfusion injury by potentiating microRNA-214-dependent inhibition of Kcnk2.

Spinal cord injury after surgical repair of the thoracic or thoracoabdominal aorta is a devastating complication that is associated with pathological changes, including inflammation, edema, and nerve cell damage. Recently, microRNA (miRNA)-modulated control of spinal cord injury has been actively investigated. This study aims to clarify the regulatory effect of miR-214-mediated inhibition of Kcnk2 following spinal cord ischemia-reperfusion injury (SCII) and the possible underlying mechanisms. SCII was induced in rats by occluding the aortic arch followed by reperfusion. Gain-of-function and loss-of-function experiments were conducted to explore the modulatory effects of Foxd3, miR-214 and Kcnk2 on PC12 cells under hypoxia/reoxygenation (H/R) conditions. MiR-214 and Kcnk2 were poorly expressed, while Foxd3 was highly expressed in the rat spinal cord tissues and H/R-treated PC12 cells. Kcnk2 overexpression enhanced the viability and inhibited the apoptosis of the H/R-treated PC12 cells. Notably, Foxd3 activated miR-214, and miR-214 targeted Kcnk2. In addition, upregulation of Kcnk2 or knockdown of Foxd3 promoted the cell viability and reduced the apoptosis of the H/R-treated PC12 cells. Overall, our study identified a novel mechanism of Foxd3/miR-214/Kcnk2 involving SCII, suggesting that either Foxd3 or miR-214 may be a novel target for the treatment of SCII.

Long noncoding RNA LINC00958 accelerates the proliferation and matrix degradation of the nucleus pulposus by regulating miR-203/SMAD3.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) play important roles in the development of intervertebral disc degeneration (IDD). LncRNA LINC00958 has recently been shown to play crucial roles in the development of tumors. However, the role of LINC00958 in IDD remains unclear. We showed that the expression of lncRNA LINC00958 was upregulated in degenerative NP samples, and LINC00958 expression increased gradually along with the grade of exacerbation of disc degeneration. Ectopic expression of LINC00958 promoted nucleus pulposus (NP) cell proliferation, inhibited aggrecan and Col II expression and promoted MMP-2 and MMP-13 expression. In addition, we showed that miR-203 expression was downregulated in degenerative NP samples, and miR-203 expression reduced gradually along with the grade of exacerbation of disc degeneration. Moreover, we demonstrated that the expression of miR-203 was inversely related with LINC00958 expression in NP samples. Ectopic expression of miR-203 inhibited NP cell growth and inhibited ECM degradation. Furthermore, we showed that ectopic expression of miR-203 suppressed the luciferase activity of the wild-type LINC00958 3'-UTR but not the mutant LINC00958 3'-UTR. Elevated expression of LINC00958 inhibited the expression of miR-203 and promoted the expression of SMAD3. In addition, we demonstrated that lncRNA LINC00958 exerted its function by targeting miR-203 in the NP cells. These data suggested that dysregulated lncRNA LINC00958 expression might play an important role in the development of IDD.

Bone marrow mesenchymal stem cells could reduce the toxic effects of hexavalent chromium on the liver by decreasing endoplasmic reticulum stress-mediated apoptosis via SIRT1/HIF-1α signaling pathway in rats.

This study focused on the effect of bone marrow mesenchymal stem cells (BMSCs) on the repair of rat liver injury induced by Cr (VI). Twenty-four Wistar rats were randomly divided into the control, model and cell therapy group, with 8 rats in each group. Potassium dichromate solution containing 0, 0.4 and 0.4 mg/kg·bw Cr (VI) was administered 5 times a week for 30 days. At the end of treatment, rats in the cell therapy group were administered 1 × 107 BMSCs. Two weeks later, serum alanine and aspartate aminotransferase levels in the cell therapy group were significantly improved compared with those in the model group, CM-Dil-labeled BMSCs were localized in rat livers. Compared with the model group, in the cell therapy group the number of apoptotic hepatocytes by TUNEL assay, MDA content, the expression of HIF-1α, endoplasmic reticulum (ER) stress-mediated apoptosis-related proteins including Grp78, CHOP, Cleaved-Caspase-12, ATF6, and Bax was significantly lower, and SOD activity, the expression of SIRT1 and Bcl-2 was significantly higher. It is suggested that BMSCs are localized in livers and reduce the toxic effects of Cr (VI) on the liver, and the possible mechanism may be related to the mechanisms of BMSCs decreasing ER stress-mediated hepatocyte apoptosis via the SIRT1/HIF-1α signaling pathway.

Surgical treatment for acute ischial tuberosity avulsion fracture: A case report.

RATIONALE: Ischial tuberosity avulsion fracture (ITAF) is a very rare sports injury, and there is currently no consensus on its diagnosis and treatment. Although conservative treatment is adequate for most patients, those with large displacement of the fracture need surgical management. PATIENT CONCERNS: A 13-year-old male athlete experienced tearing pain in the right hip during a sprint. Radiographic examination showed an avulsion fracture of the right ischial tuberosity. DIAGNOSIS: Right ITAF. INTERVENTIONS: On the 3rd day of injury, the patient was treated with open reduction and internal fixation of ITAF under general anesthesia. OUTCOMES: The patient received a systematic postoperative exercise in 2 weeks, and the fracture healed 4 weeks later. After 8 months, the patient returned to the field to participate in the competition. LESSONS: Early surgical treatment can bring about good results in the treatment of ITAF with large displacement. The longitudinal incision and subgluteal approach is an ideal choice for the operative procedure.

RETRACTED: Inhibition of miR-140-3p or miR-155-5p by antagomir treatment sensitize chordoma cells to chemotherapy drug treatment by increasing PTEN expression.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors and the Editor-in-Chief as the validity of the data cannot be guaranteed. The journal was initially contacted by the corresponding author to report that, when the authors verified post publication PTEN as their former target of miR-140-3p, they found that treatment with miR-140-3p or miR-155-5p antagomir increased PTEN protein levels in patient-derived chordoma cells without having a significant effect on the malignancy of the tumor cells. The journal further requested the author to provide more information about their post publication findings with regard to this article. However, the author was not able to fulfil this request.

The efficacy of oral versus intravenous tranexamic acid in reducing blood loss after primary total knee and hip arthroplasty: A meta-analysis.

BACKGROUND: Blood management after arthroplasties has become a serious problem. The objective is to perform a meta-analysis to compare the efficacy and safety between oral tranexamic acid (TXA) and intravenous TXA for blood management in total knee and hip arthroplasty. METHODS: We systematically searched randomized controlled trials (RCTs) from Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and Google scholar. Eligibility criteria: Patients: adult patients with end-stage joint osteoarthritis, rheumatoid arthritis, and osteonecrosis of the femoral head, who prepared for TJA; Interventions: The experiential group received the intravenous form of TXA; Comparisons: Oral form of TXA; Outcomes: Total blood loss, hemoglobin reduction, transfusion requirements, duration of hospitalization, and thrombotic complications including deep vein thrombosis (DVT) and pulmonary embolism (PE); Study design: Randomized control trials (RCTs) and non-RCT. Meta-analysis results were collected and analyzed by the software STATA 11.0. After testing for heterogeneity between studies, data were aggregated for random-effects models when necessary. RESULTS: Four RCTs and 2 non-RCTs were included in the meta-analysis. The present meta-analysis revealed that there were no significant differences regarding total blood loss (WMD = -25.013, 95% CI: -51.002 to 0.977, P = .059), postoperative hemoglobin decline (WMD = -0.090, 95% CI: -0.205 to 0.024, P = .122), or transfusion rate (RD = -0.039, 95% CI: -0.080 to 0.002, P = .062) between the 2 groups. CONCLUSION: Oral TXA shows comparable efficacy to that of the intravenous forms after total knee and hip arthroplasty. Due to the limited quality of evidence currently available, higher quality RCTs is necessary.

Recombinant human BMP-7 grafted poly(lactide-co-glycolide)/hydroxyapatite scaffolds via polydopamine for enhanced calvarial repair.

Poly(lactic-co-glycolic acid) (PLGA) and hydroxyapatite (HA) are considered potential osteoinductive materials because of their biodegradability and mineralization features. However, the hydrophobicity of scaffold surfaces is less supportive of cell attachment and proliferation because of poor wettability. The mode of binding of growth factors to the scaffold also affects cell differentiation into osteoblasts. The half-life of a growth factor in vivo can be increased by binding the factor to the scaffold surface. In this work, we prepared a porous PLGA/HA scaffold grafted with recombinant human bone morphogenic protein-7 (rhBMP-7) attached via polydopamine (pDA) for bone repair. The pDA coated PLGA/HA (pDA-PLGA/HA) scaffolds were characterized by energy dispersive X-ray analysis and Fourier-transform infrared spectroscopy. The microstructure and porosity of PLGA/HA scaffolds were analyzed by scanning electron microscopy and micro-computed tomography. The release profile of rhBMP-7 grafted onto the pDA-PLGA/HA (pDA-PLGA/HA/BMP-7) scaffolds was examined for 21 days. The attachment efficiency, cell proliferation rate, alkaline phosphatase activity, calcium deposition, and osteoblast-related gene expression of bone marrow-derived stem cells to PLGA/HA, pDA-PLGA/HA, and pDA-PLGA/HA/BMP-7 scaffolds were evaluated. To assess the ability of bone repair in vivo, scaffolds were implanted into critical-sized calvarial defects created in mice, and the in vivo tissue-engineered bone was monitored by micro-computed tomography and histology. In vivo experiments revealed rapid healing of the defects treated with the pDA-PLGA/HA/BMP-7 scaffolds compared with pDA-PLGA/HA and PLGA/HA scaffolds at week 8 post-surgery. These results collectively demonstrate that the rhBMP-7-immobilized PLGA/HA scaffold via pDA is a promising candidate for calvarial repair.

Knockdown of ANRIL aggravates H2O2-induced injury in PC-12 cells by targeting microRNA-125a.

Spinal cord injury (SCI) is a devastating and common neurological disorder which causes local oxidative damage. The study aimed to investigate the underlying role of ANRIL in H2O2-induced cell injury of rat PC-12 cells. Cell injury was evaluated on the basis of cell viability, migration, invasion and apoptosis. The effect of ANRIL on H2O2-induced cell injury was estimated after cell transfection. Then, the interaction between ANRIL and miR-125a was explored by qRT-PCR and estimation of cell injury. Predicted by TargetScan, the possible target gene of miR-125a was verified. After that, the effects of aberrantly expressed target gene on cell viability, migration, invasion and apoptosis as well as phosphorylation of key kinases involved in JAK/STAT and ERK/MAPK pathways were evaluated. Results revealed that H2O2-induced PC-12 cell injury could be aggravated by ANRIL suppression. ANRIL appeared to act as a sponge of miR-125a, and ANRIL suppression promoted H2O2-induced cell injury by up-regulation of miR-125a. MCL-1 was a target of miR-125a, and MCL-1 was negatively correlated with miR-125a. Subsequent experiments showed the effect of MCL-1 silence on H2O2-induced PC-12 cell injury was the same as ANIRL suppression. MCL-1 attenuated H2O2-induced PC-12 cell injury by activating JAK/STAT and ERK/MAPK pathways. These findings suggested that knockdown of ANRIL aggravates H2O2-induced injury in PC-12 cells by targeting miR-125a. This might provide novel insights in the role of ANRIL in pathogenesis of oxidative damage during SCI.

MicroRNA-187 exerts tumor-suppressing functions in osteosarcoma by targeting ZEB2.

MicroRNA-187 (miR-187) has been reported to be involved in the occurrence and development of several types of cancers; however, a role for miR-187 in osteosarcoma (OS) has not yet been reported. Here, miR-187 was found to be significantly downregulated in OS cell lines and tissue samples, and decreased miR-187 expression was shown to be correlated closely with the TNM stage and lymph node metastasis. miR-187 overexpression suppressed OS cell proliferation, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT). Mechanically, zinc finger E-box binding homeobox 2 (ZEB2) was shown to serve as a direct target of miR-187 in OS cells and the overexpression of ZEB2 rescued the miR-187-induced suppression of proliferation, colony formation, migration, and invasion in OS cells. In clinical OS specimens, ZEB2 expression levels were elevated and were inversely correlated with miR-187 expression. These results suggest that miR-187 functions as a tumor suppressor in OS, partially by targeting ZEB2, and that miR-187 can serve as a promising candidate for OS.

Enhanced antitumor immunity is elicited by adenovirus-mediated gene transfer of CCL21 and IL-15 in murine colon carcinomas.

The chemokine CCL21 is a potent chemoattractant for T cells and dendritic cells. IL-15 elicits powerful antitumor immune responses through the stimulation of natural killer cells. We constructed a CCL21/IL-15-expressing adenovirus (Ad-CCL21-IL-15) and evaluated its antitumor effects in vitro and in vivo. We found that the intratumoral injection of Ad-CCL21-IL-15 into murine colon carcinomas significantly inhibited tumor growth. Splenocytes from mice treated with Ad-CCL21-IL-15 developed tumor-specific cytotoxic T cells and were protected from subsequent challenges with tumor cells. This study indicates that providing cancer therapy by combining CCL21 and IL-15 can induce antitumor immune responses and is an effective strategy for cancer immunotherapy.