Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study.

BACKGROUND AIMS: Stem cell transplantation is a potential treatment for intractable spinal cord injury (SCI), and allogeneic human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate because of the advantages of immune privilege, paracrine effect, immunomodulatory function, convenient collection procedure and little ethical concern, and there is an urgent need to develop a safe and effective protocol regarding their clinical application. METHODS: A prospective, single-center, single-arm study in which subjects received four subarachnoid transplantations of hUC-MSCs (1 × 106 cells/kg) monthly and were seen in follow-up four times (1, 3, 6 and 12 months after final administration) was conducted. At each scheduled time point, safety and efficacy indicators were collected and analyzed accordingly. Adverse events (AEs) were used as a safety indicator. American Spinal Injury Association (ASIA) and SCI Functional Rating Scale of the International Association of Neurorestoratology (IANR-SCIFRS) total scores at the fourth follow-up were determined as primary efficacy outcomes, whereas these two indicators at the remaining time points as well as scores of pinprick, light touch, motor and sphincter, muscle spasticity and spasm, autonomic system, bladder and bowel functions, residual urine volume (RUV) and magnetic resonance imaging (MRI) were secondary efficacy outcomes. Subgroup analysis of primary efficacy indicators was also performed. RESULTS: Safety and efficacy assessments were performed on 102 and 41 subjects, respectively. Mild AEs involving fever (14.1%), headache (4.2%), transient increase in muscle tension (1.6%) and dizziness (1.3%) were observed following hUC-MSC transplantation and resolved thoroughly after conservative treatments. There was no serious AE. ASIA and IANR-SCIFRS total scores revealed statistical increases when compared with the baselines at different time points during the study, mainly reflected in the improvement of pinprick, light touch, motor and sphincter scores. Moreover, subjects showed a continuous and remarkable decrease in muscle spasticity. Regarding muscle spasm, autonomic system, bladder and bowel functions, RUV and MRI, data/imaging at final follow-up showed significant improvements compared with those at first collection. Subgroup analysis found that hUC-MSC transplantation improved neurological functions regardless of injury characteristics, including level, severity and chronicity. CONCLUSIONS: The authors' present protocol demonstrates that intrathecal administration of' allogeneic hUC-MSCs at a dose of 106 cells/kg once a month for 4 months is safe and effective and leads to significant improvement in neurological dysfunction and recovery of quality of life.

Casein kinase 1 epsilon facilitates cartilage destruction in osteoarthritis through JNK pathway.

Osteoarthritis (OA) is a high-morbidity skeletal disease worldwide and the exact mechanisms underlying OA pathogenesis are not fully understood. Casein kinase 1 epsilon (CK1ε) is a serine/threonine protein kinase, but its relationship with OA is still unknown. We demonstrated that CK1ε was upregulated in articular cartilage of human patients with OA and mice with experimentally induced OA. Activity of CK1ε, demonstrated by analysis of phosphorylated substrates, was significantly elevated in interleukin (IL)-1ß-induced OA-mimicking chondrocytes. CK1ε inhibitor or CK1ε short hairpin RNA (shRNA) partially blocked matrix metalloproteinase (MMP) expression by primary chondrocytes induced by IL-1ß, and also inhibited cartilage destruction in knee joints of experimental OA model mice. Conversely, overexpression of CK1ε promoted chondrocyte catabolism. Previous studies indicated that CK1ε was involved in canonical Wnt/ß-catenin signaling and noncanonical Wnt/c-Jun N-terminal kinase (JNK) signaling pathway. Interestingly, the activity of JNK but not ß-catenin decreased after CK1ε knockdown in IL-1ß-treated chondrocytes in vitro, and JNK inhibition reduced MMP expression in chondrocytes overexpressing CK1ε, which illustrated that CK1ε-mediated OA was based on JNK pathway. In conclusion, our results demonstrate that CK1ε promotes OA development, and inhibition of CK1ε could be a potential strategy for OA treatment in the future.

Subarachnoid transplantation of human umbilical cord mesenchymal stem cell in rodent model with subacute incomplete spinal cord injury: Preclinical safety and efficacy study.

Functional multipotency renders human umbilical cord mesenchymal stem cell (hUC-MSC) a promising candidate for the treatment of spinal cord injury (SCI). However, its safety and efficacy have not been fully understood for clinical translation. In this study, we performed cellular, kinematic, physiological, and anatomical analyses, either in vitro or in vivo, to comprehensively evaluate the safety and efficacy associated with subarachnoid transplantation of hUC-MSCs in rats with subacute incomplete SCI. Concerning safety, hUC-MSCs were shown to have normal morphology, excellent viability, steady proliferation, typical biomarkers, stable karyotype in vitro, and no tumorigenicity both in vitro and in vivo. Following subarachnoid transplantation of hUC-MSCs in the subject rodents, the biodistribution of hUC-MSCs was restricted to the spinal cord, and no toxicity to immune system or organ function was observed. Body weight, organ weight, and the ratio of the latter upon the former between stem cell-transplanted rats and placebo-injected rats revealed no statistical differences. Regarding efficacy, hUC-MSCs could differentiate into osteoblasts, chondrocytes, adipocytes and neural progenitor cells in vitro. While in vivo studies revealed that subarachnoid transplantation of stem cells resulted in significant improvement in locomotion, earlier automatic micturition recovery and reduced lesion size, which correlated with increased regeneration of tracking fiber and reduced parenchymal inflammation. In vivo luminescence imaging showed that a few of the transplanted luciferase-labeled hUC-MSCs tended to migrate towards the lesion epicenter. Shortened latency and enhanced amplitude were also observed in both motor and sensory evoked potentials, indicating improved signal conduction in the damaged site. Immunofluorescent staining confirmed that a few of the administrated hUC-MSCs integrated into the spinal cord parenchyma and differentiated into astrocytes and oligodendrocytes, but not neurons. Moreover, decreased astrogliosis, increased remyelination, and neuron regeneration could be observed. To the best of our knowledge, this preclinical study provides detailed safety and efficacy evidence regarding intrathecal transplantation of hUC-MSCs in treating SCI for the first time and thus, supports its initiation in the following clinical trial.

Free vitamin D correlate better with bone mineral density and thoracolumbar junction osteoporotic vertebral fractures than serum vitamin D.

BACKGROUND: Vitamin D deficiency has long been studied as a risk factor for osteoporosis. However, the association between serum vitamin D status, bone mineral density (BMD) and the incidence of vertebral fractures (OVFs) remain controversial. It is believed that free portion of the circulating vitamin D carries the metabolic activities of vitamin D. Therefore, the aim of the present study is to analyse if free vitamin D correlates with BMD and osteoporotic fragile vertebral fractures in the elderly population. METHODS: A total of 90 consecutive patients, including 81 female and 9 male patients, aged > 48 years, were included in this cross sectional study between March and July of 2018. Total vitamin D (total 25(OH)D), free vitamin D (free 25(OH)D), calcium and phosphorus were measured. BMD was measured using dual energy X-ray absorptiometry (DEXA) and osteoporotic vertebral fracture was assessed using plain radiograph. Multiple linear regression was performed to find out the association between total vitamin D, free vitamin D and BMD at various sites. To evaluate the association with osteoporotic vertebral multivariate logistic regression model was used. RESULTS: The mean total vitamin D and free vitamin D were 25.1 ± 10.2 and 6.1 ± 1.7 respectively. Free vitamin D had a linear correlation with total vitamin D (R2 = 0.69). While free vitamin D had a positive correlation with lumbar BMD roles (p < 0.05), total vitamin D didn't have any association with BMD at any site. Of the total patients, 62 patients (68.9%) had thoracolumbar junction OVFs. Free vitamin D level correlated with the prevalence of OVFs as well as lumbar osteoporosis (p < 0.05). However, there was no statistical correlation between serum vitamin D status and the OVFs. CONCLUSIONS: Free vitamin D was significantly related to the occurrence of thoracolumbar junction OVFs and lumbar BMD, which assumed to be a positive predictor for fracture and osteoporosis prevention. However, total serum vitamin D levels did not have any association with BMD at different sites as well as fragile vertebral fracture. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov NCT03605173.

Ropivacaine microsphere-loaded electroconductive nerve dressings for long-acting analgesia and functional recovery following diabetic peripheral nerve injury.

In recent years, electroconductive hydrogels (ECHs) have shown great potential in promoting nerve regeneration and motor function recovery following diabetic peripheral nerve injury (PNI), attributed to their similar electrical and mechanical characteristics to innate nervous tissue. It is well-established that PNI causes motor deficits and pain, especially in diabetics. Current evidence suggests that ropivacaine (ROP) encapsulated in poly lactic-co-glycolic acid (PLGA) microspheres (MSs) yield a sustained analgesic effect. In this study, an ECH electroconductive network loaded with MS/ROP (ECH-MS/ROP) was designed as a promising therapeutic approach for diabetic PNI to exert lasting analgesia and functional recovery. This dual delivery system allowed ROP's slow and sequential release, achieving sustained analgesia as demonstrated by our in vivo experiments. Meanwhile, this system was designed like a lamellar dressing, with desirable adhesive and self-curling properties, convenient for treating injured nerve tissues via automatically wrapping tube-like structures, facilitating the process of implantation. Our in vitro assays verified that ECH-MS/ROP was able to enhance the adhesion and motility of Schwann cells. Besides, both in vitro and in vivo studies substantiated that ECH-MS/ROP stimulated myelinated axon regeneration through the MEK/ERK signaling pathway, thereby improving muscular denervation atrophy and facilitating functional recovery. Therefore, this study suggests that the ECH-MS/ROP dressing provides a promising strategy for treating diabetic PNI to facilitate nerve regeneration, functional recovery and pain relief.

Dynamic Changes in Microbial Communities and Physicochemical Characteristics During Fermentation of Non-post Fermented Shuidouchi.

Non-post fermented Shuidouchi is a Chinese spontaneously fermented soybean food with multifunctionality in human health. The functionality and safety of this plant-based food will be affected by the microorganisms during fermentation. In this study, microbial diversity was investigated using culture-dependent and culture-independent methods. The functional metabolites such as polyamines and alkylpyrazines were also determined at different time points during fermentation. We found that Bacillus was the most dominant microbe throughout the fermentation process, while the temperature was the most important influencing factor. During fermentation, the microbial diversity increased at a moderate temperature and decreased at a high temperature (52°C). High temperature caused the prosperity of the spore-producing bacteria such as Bacillus (more than 90% relative abundance in bacteria) and Aneurinibacillus (2% or so relative abundance in bacteria), and the inhibition of fungi. Furthermore, it was found by correlation analysis that the relative abundances of Bacillus and Aneurinibacillus were positively correlated with the relative content of amino acid metabolism pathway and the content of most alkylpyrazines and biogenic amines. Meanwhile, the relative abundances of many non-dominant bacteria were negatively correlated with the content of biogenic amines and positively correlated with the relative content of carbohydrate metabolism pathway. These effects were helpful to control the biogenic amine contents under the safety limits, increasing the alkylpyrazine type and product functionality. A two-stage temperature control strategy-a moderate temperature (35-42°C) first, then a high temperature (52°C)-was concluded from the spontaneous fermentation of non-post fermented Shuidouchi. This strategy could improve the safety of product by inhibiting or sterilizing the thermolabile microbes. The non-post fermented Shuidouchi product is rich in functional compounds such as polyamines and alkylpyrazines.

Machine Learning-based Prediction of Prolonged Intensive Care Unit Stay for Critical Patients with Spinal Cord Injury.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The objective of the study was to develop machine-learning (ML) classifiers for predicting prolonged intensive care unit (ICU)-stay and prolonged hospital-stay for critical patients with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: Critical patients with SCI in ICU need more attention. SCI patients with prolonged stay in ICU usually occupy vast medical resources and hinder the rehabilitation deployment. METHODS: A total of 1599 critical patients with SCI were included in the study and labeled with prolonged stay or normal stay. All data were extracted from the eICU Collaborative Research Database and the Medical Information Mart for Intensive Care III-IV Database. The extracted data were randomly divided into training, validation and testing (6:2:2) subdatasets. A total of 91 initial ML classifiers were developed, and the top three initial classifiers with the best performance were further stacked into an ensemble classifier with logistic regressor. The area under the curve (AUC) was the main indicator to assess the prediction performance of all classifiers. The primary predicting outcome was prolonged ICU-stay, while the secondary predicting outcome was prolonged hospital-stay. RESULTS: In predicting prolonged ICU-stay, the AUC of the ensemble classifier was 0.864 ±â€Š0.021 in the three-time five-fold cross-validation and 0.802 in the independent testing. In predicting prolonged hospital-stay, the AUC of the ensemble classifier was 0.815 ±â€Š0.037 in the three-time five-fold cross-validation and 0.799 in the independent testing. Decision curve analysis showed the merits of the ensemble classifiers, as the curves of the top three initial classifiers varied a lot in either predicting prolonged ICU-stay or discriminating prolonged hospital-stay. CONCLUSION: The ensemble classifiers successfully predict the prolonged ICU-stay and the prolonged hospital-stay, which showed a high potential of assisting physicians in managing SCI patients in ICU and make full use of medical resources.Level of Evidence: 3.

Exosomes derived from miR-26a-modified MSCs promote axonal regeneration via the PTEN/AKT/mTOR pathway following spinal cord injury.

BACKGROUND: Exosomes derived from the bone marrow mesenchymal stem cell (MSC) have shown great potential in spinal cord injury (SCI) treatment. This research was designed to investigate the therapeutic effects of miR-26a-modified MSC-derived exosomes (Exos-26a) following SCI. METHODS: Bioinformatics and data mining were performed to explore the role of miR-26a in SCI. Exosomes were isolated from miR-26a-modified MSC culture medium by ultracentrifugation. A series of experiments, including assessment of Basso, Beattie and Bresnahan scale, histological evaluation, motor-evoked potential recording, diffusion tensor imaging, and western blotting, were performed to determine the therapeutic influence and the underlying molecular mechanisms of Exos-26a in SCI rats. RESULTS: Exos-26a was shown to promote axonal regeneration. Furthermore, we found that exosomes derived from miR-26a-modified MSC could improve neurogenesis and attenuate glial scarring through PTEN/AKT/mTOR signaling cascades. CONCLUSIONS: Exosomes derived from miR-26a-modified MSC could activate the PTEN-AKT-mTOR pathway to promote axonal regeneration and neurogenesis and attenuate glia scarring in SCI and thus present great potential for SCI treatment.

Hot Deformation Behavior and Microstructural Evolution of PM Ti43Al9V0.3Y with Fine Equiaxed γ and B2 Grain Microstructure.

The hot deformation behavior and microstructure evolution of powder metallurgy (PM) Ti43Al9V0.3Y alloy with fine equiaxed γ and B2 grains were investigated using uniaxial hot compression. Its stress exponent and activation energy were 2.78 and 295.86 kJ/mol, respectively. The efficiency of power dissipation and instability parameters were evaluated, and processing maps at 50% and 80% strains were developed. It is demonstrated that the microstructure evolution was dependent on the temperature, strain, and strain rate. Both temperature and strain increases led to a decrease in the γ phase. Moreover, dynamic recrystallization (DRX) and grain boundary slip both played important roles in deformation. Reasonable parameters for secondary hot working included temperatures above 1100 °C but below 1200 °C with a strain rate of less than 1 s-1 at 80% strain. Suitable hot working parameters at 50% strain were 1150-1200 °C/≤1 s-1 and 1000-1200 °C/≤0.05 s-1.

Enhanced recovery after surgery (ERAS) pathway for microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion.

OBJECTIVES: Enhanced recovery after surgery (ERAS) principle and minimally invasive surgery allow patients to recover faster and better postoperatively. Due to a paucity of their integration, this retrospective study aims to assess clinical outcomes of ERAS pathway in microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). PATIENTS AND METHODS: A total of 72 consecutive cases were enrolled. According to their inclusion order, the former 21 cases received microendoscopy-assisted MIS-TLIF without any ERAS approach (control group), while the latter 51 participants underwent the same surgery with ERAS protocol (observation group). Perioperative parameters, including operative duration, intraoperative estimated blood loss (EBL), length of stay, postoperative analgesic usage and ambulatory time, were recorded. Visual analogue scale (VAS, back and leg), Barthel index were obtained before and at three days, one month, six months postoperatively. Modified MacNab criteria and Bridwell grading were used to assess surgical outcome and interbody fusion at one week and two years after surgery, respectively. RESULTS: Observation group had statistically improved perioperative parameters (operative duration, intraoperative EBL, length of stay, postoperative analgesic usage and ambulatory time) in comparison with control group. Remarkable decreases in VAS (back and leg) were observed continuously at three days, one month and six months post-surgery in both groups when compared with scores prior to the surgery. More significant improvement of VAS (back and leg) was found in observation group at both three days and one month postoperatively. Regarding Barthel index, despite its transient decrease at three days after surgery in control group, it showed statistical increase at postoperative one month when compared with preoperative values in both groups; moreover, its inter-groups comparison revealed much more improvement in patients receiving ERAS recommendations; while at final follow-up, it continued further increase in either group. Marginally higher proportion of patients in observation group showed perfect or good clinical outcome, as well as solid interbody fusion. CONCLUSIONS: ERAS pathway in microendoscopy-assisted MIS-TLIF has advantages of decreased operative time, reduced intraoperative haemorrhage, increased initial back pain relief, decreased length of stay, lowered analgesic usage and earlier daily activity recovery and thus, benefit postoperative rehabilitation further.

Microstructure Evolution and Mechanical Properties of PM-Ti43Al9V0.3Y Alloy.

A novel strategy of microstructure design is introduced to improve the mechanical properties of TiAl alloys, fabricated by powder metallurgy. The gas atomization powder and as-HIPed (Hot isostatic pressing) TiAl are investigated by scanning electron microscopy, energy dispersive spectrometry, transmission electron microscopy, and electron backscattered diffraction. The dispersed submicron precipitate in the microstructure is determined to be Y2O3. A microstructure with uniform fine grain is obtained. The room temperature strength and strain reach 793 MPa and 1.5%, respectively. The strength and strain at 700 °C are still as high as 664 MPa and 9.2%, respectively. The fine grain and precipitate lead to a high room-temperature plasticity.

Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) support revascularization, inhibition of inflammation, regulation of apoptosis, and promotion of the release of beneficial factors. Thus, they are regarded as a promising candidate for the treatment of intractable spinal cord injury (SCI). Clinical studies on patients with early chronic SCI (from 2 months to 1 year post-injury), which is clinically common, are rare; therefore, we will conduct a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial at the Third Affiliated Hospital of Sun Yat-sen University, West China Hospital of Sichuan University, and Shanghai East Hospital, Tongji University School of Medicine, China. The trial plans to recruit 66 early chronic SCI patients. Eligible patients will undergo randomization at a 2:1 ratio to two arms: the observation group and the control group. Subjects in the observation group will receive four intrathecal transplantations of stem cells, with a dosage of 1 × 106/kg, at one calendar month intervals. Subjects in the control group will receive intrathecal administrations of 10 mL sterile normal saline in place of the stem cell transplantations. Clinical safety will be assessed by the analysis of adverse events and laboratory tests. The American Spinal Injury Association (ASIA) total score will be the primary efficacy endpoint, and the secondary efficacy outcomes will be the following: ASIA impairment scale, International Association of Neural Restoration-Spinal Cord Injury Functional Rating Scale, muscle tension, electromyogram, cortical motor and cortical sensory evoked potentials, residual urine volume, magnetic resonance imaging-diffusion tensor imaging, T cell subtypes in serum, neurotrophic factors and inflammatory factors in both serum and cerebrospinal fluid. All evaluations will be performed at 1, 3, 6, and 12 months following the final intrathecal administration. During the entire study procedure, all adverse events will be reported as soon as they are noted. This trial is designed to evaluate the clinical safety and efficacy of subarachnoid transplantation of hUC-MSCs to treat early chronic SCI. Moreover, it will establish whether cytotherapy can ameliorate local hostile microenvironments, promote tracking fiber regeneration, and strengthen spinal conduction ability, thus improving overall motor, sensory, and micturition/defecation function in patients with early chronic SCI. This study was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2018]-02) on March 30, 2018, and was registered with ClinicalTrials.gov (registration No. NCT03521323) on April 12, 2018. The revised trial protocol (protocol version 4.0) was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2019]-10) on February 25, 2019, and released on ClinicalTrials.gov on April 29, 2019.

Integrated analysis of competing endogenous RNA (ceRNA) networks in subacute stage of spinal cord injury.

This study aims to investigate the genetic and epigenetic mechanisms involved in the pathogenesis of subacute stage of spinal cord injury (SCI). Gene-expression datasets associated with SCI were downloaded from the Gene Expression Omnibus (GEO) database, and differential expression analyses were performed in order to identify differentially expressed genes (DEGs). Multiple network types were constructed and analyzed, including protein-protein-interaction (PPI) network, miRNA-target network, lncRNA-associated competing endogenous RNA (ceRNA) network, and miRNA-transcription factor (TF)-target network. Cluster analyses were performed to identify significant modules. To verify the prediction accuracy of the in-silico identified molecules, qRT-PCR experiments were conducted. The results depicted the Ywhae gene as the hub gene with the highest degree in the PPI network. The ceRNA network identified specific genes (Flna, ID3, and HK2), miRNAs (miR-16-5p, miR-1958, and miR-185-5p), and lncRNAs (Neat1, Xist, and Malat1) as playing critical regulating roles in the pathological mechanisms of SCI. The miRNA-TF-gene interaction network identified four important TFs (Sp1, Trp53, Jun, and Rela). The miRNA-gene-TF interaction loops from the significant modules indicated that miR-325-3p can interact with the Asah1 gene and TF-Sp1 by forming a closed loop. The qRT-PCR experiments verified four selected genes (Flna, ID3, HK2, and Ywhae) and two selected TFs (Jun, and Sp1) as significantly up-regulated following SCI. The results indicated that four genes (Flna, ID3, HK2, and Ywhae), four transcription factors (Sp1, Trp53, Jun, and RelA), two miRNAs (miR-16-5p and miR-325-3p), and three lncRNAs (Neat1, Xist, and Malat1) are likely to be involved in the molecular mechanisms underlying the subacute stage of SCI. These findings uncover putative pathogenic mechanisms involved in SCI and might bear translation significance for future research towards therapeutic development.

MicroRNA-135a-5p Promotes the Functional Recovery of Spinal Cord Injury by Targeting SP1 and ROCK.

Emerging evidence indicates that microRNAs play a pivotal role in neural remodeling after spinal cord injury (SCI). This study aimed to investigate the mechanisms of miR-135a-5p in regulating the functional recovery of SCI by impacting its target genes and downstream signaling. The gene transfection assay and luciferase reporter assay confirmed the target relationship between miR-135a-5p and its target genes (specificity protein 1 [SP1] and Rho-associated kinase [ROCK]1/2). By establishing the H2O2-induced injury model, miR-135a-5p transfection was found to inhibit the apoptosis of PC12 cells by downregulating the SP1 gene, which subsequently induced downregulation of pro-apoptotic proteins (Bax, cleaved caspase-3) and upregulation of anti-apoptotic protein Bcl-2. By measuring the neurite lengths of PC12 cells, miR-135a-5p transfection was found to promote axon outgrowth by downregulating the ROCK1/2 gene, which subsequently caused upregulation of phosphate protein kinase B (AKT) and phosphate glycogen synthase kinase 3ß (GSK3ß). Use of the rat SCI models showed that miR-135a-5p could increase the Basso, Beattie, and Bresnahan (BBB) scores, indicating neurological function recovery. In conclusion, the miR-135a-5p-SP1-Bax/Bcl-2/caspase-3 and miR-135a-5p-ROCK-AKT/GSK3ß axes are involved in functional recovery of SCI by regulating neural apoptosis and axon regeneration, respectively, and thus can be promising effective therapeutic strategies in SCI.

Exosomes derived from miRNA-210 overexpressing bone marrow mesenchymal stem cells protect lipopolysaccharide induced chondrocytes injury via the NF-κB pathway.

Bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (Exos) have anti-inflammatory and anti-apoptotic functions. miRNA-210 has also been confirmed to play a role in inhibiting proinflammatory cytokines. Herein, we aimed to explore the effects of Exos derived from miRNA-210-overexpressing BMSCs (BMSCs-210-Exos) and the mechanisms by which they provide protection to chondrocytes from lipopolysaccharide (LPS)-induced injury. BMSCs were transfected with or without miRNA-210. Exos substantially improved the proliferation of chondrocytes and inhibited LPS-induced cell apoptosis. Furthermore, BMSCs-210-Exos promoted the proliferation of chondrocytes and prevented LPS-induced cell apoptosis better than BMSCs-Exos not overexpressing miRNA-210. In addition, tumor necrosis factor receptor superfamily member 21 (Tnfrsf21) expression was inhibited and the NF-κB pathway was attenuated by both BMSCs-Exos and BMSCs-210-Exos during LPS-induced chondrocyte injury. Collectively, these results suggest that BMSCs-210-Exos enhance the protection of chondrocytes from LPS-induced injury via the NF-κB pathway.

Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis.

BACKGROUND: This study aimed to investigate the effect of bone marrow mesenchymal stem cell (BMSC)-derived exosome injection on cartilage damage and pain relief in both in vitro and in vivo models of osteoarthritis (OA). METHODS: The BMSCs were extracted from rat bone marrow of the femur and tibia. Chondrocytes were treated with IL-1ß to establish the in vitro model of OA. Chondrocyte proliferation and migration were assessed by CCK-8 and transwell assay, respectively. A rat model of OA was established by injection of sodium iodoacetate. At 6 weeks after the model was established, the knee joint specimens and dorsal root ganglion (DRG) of rats were collected for histologic analyses. For pain assessment, paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were evaluated before model establishment and at 1, 2, 4, and 6 weeks after model establishment. RESULTS: Exosomes can be endocytosed with the chondrocytes in vitro. Exosome treatment significantly attenuated the inhibitory effect of IL-1ß on the proliferation and migration of chondrocytes. Exosome pre-treatment significantly attenuated IL-1ß-induced downregulation of COL2A1 and ACAN and upregulation of MMP13 and ADAMTS5. In the animal study, exosome treatment significantly upregulated COL2A1 protein and downregulated MMP13 protein in the cartilage tissue of the OA rat. At weeks 2, 4, and 6, the PWL value was significantly improved in the exosome-treated OA rats as compared with the untreated OA animals. Moreover, exosome treatment significantly alleviated the upregulation of CGRP and iNOS in the DRG tissue of OA rats. CONCLUSION: BMSC-derived exosomes can effectively promote cartilage repair and extracellular matrix synthesis, as well as alleviate knee pain in the OA rats.

Melatonin Promotes Neuroprotection of H2O2-induced Neural Stem Cells via lncRNA MEG3/miRNA-27a-3p/MAP2K4 axis.

Melatonin is crucial for protecting neural stem cells (NSCs) from reactive oxygen species (ROS). However, the mechanism underlying these processes is unclear. In this study, we first investigated the significantly upregulated lncRNA MEG3 biomarker in the H2O2-induced NSCs and control groups. Melatonin inhibited the expression of MEG3 by methylation. MEG3 overexpression reversed the positive effects of melatonin on NSCs against H2O2. Furthermore, MEG3 reduced the expression levels of its targeted miRNA-27a-3p, which could be considered a neuroprotective effect. In addition, the elevated miRNA-27a-3p decreased JNK phosphorylation by targeting MAP2K4. Overexpression of MAP2K4 suppressed the neuroprotective effects of miRNA-27a-3p. Therefore, melatonin appeared to protect NSCs from H2O2-induced ROS by modification of the MEG3/miRNA-27a-3p/MAP2K4 axis.

The improved properties and microstructure of ß-solidify TiAl alloys by boron addition and multi steps forging process.

A novel forging process has been designed for better mechanical properties of Ti-43Al-6Nb-1Mo-1Cr-(0,0.6)B alloys in this paper. Multi step forging process could provide much finer microstructure, higher room-temperature strength, increased high-temperature strength and elongation with these alloys. The forged alloys without boron exhibit strength and elongation as 676.05 ± 11.37 MPa and 41.32 ± 1.38% at 800 °C, while the average grain size represents as 12.63 ± 3.77 µm. The forged alloys with 0.6 at.% B represent better mechanical properties than the forged alloys without boron, due to the refined microstructure with dispersive borides. Meanwhile, the detailed mechanism of increased strength and elongation caused by finer microstructure were concluded and discussed.

Therapeutic Effects and Safety of Percutaneous Disc Decompression with Coblation Nucleoplasty in Cervical Vertigo: A Retrospective Outcome Study with 74 Consecutive Patients and Minimum 1-Year Follow-Up.

BACKGROUND: Surgical treatment of cervical vertigo has been rarely reported. This is the first retrospective study to evaluate the clinical outcomes of percutaneous disc decompression with coblation nucleoplasty (PDCN) for treatment of cervical vertigo. OBJECTIVES: To assess the clinical outcomes of patients with cervical vertigo who failed to improve with conservative care and who were subsequently treated with PDCN. STUDY DESIGN: This study used a retrospective design. SETTING: The research was conducted within an interventional vertigo management and spine practice. METHODS: Seventy-four consecutive patients with cervical vertigo underwent PDCN and were followed for at least one year. Outcome measures included the dizziness intensity Visual Analog Scale (VAS), dizziness frequency, the Dizziness Handicap Inventory (DHI), and neck pain intensity. Clinical efficacy was assessed by rating scale and the modified MacNab evaluation criteria. Surgical complications during the operation and follow-up were also recorded. RESULTS: The vertigo VAS score, frequency of dizziness, DHI, and neck pain intensity were all decreased significantly from evaluation before surgery to one week after surgery and to the last follow-up, giving a mean effective rate of 94.6% one week after surgery and 90.6% at the last follow-up. Good to excellent results were attained in 85.1% of these patients one week after PDCN and in 75.7% of the sufferers at the last follow-up (P < 0.001). There were 5 patients with transient adverse effects (6.25%) reported within the first month after surgery; they all recovered after conservative treatment. No neurological complications were found and no patient went on to spinal fusion surgery thereafter. LIMITATIONS: The rate of follow-up was 70% and a placebo effect cannot be excluded. There is no gold standard for the diagnosis and treatment of cervical vertigo so far. CONCLUSION: The clinical outcomes of PDCN for cervical vertigo were satisfactory in both the early and late postoperative period. PDCN is an effective, low-complication, minimally invasive procedure used to treat cervical vertigo. Further prospective randomized controlled trials are essential to verify this conclusion. KEY WORDS: Cervical vertigo, percutaneous disc decompression, coblation nucleoplasty, long-term outcome, dizziness intensity, dizziness frequency, dizziness handicap inventory, clinical efficacy, surgical complication, retrospective study.

The Influences of Process Annealing Temperature on Microstructure and Mechanical Properties of near ß High Strength Titanium Alloy Sheet.

The influences of process annealing temperature during cold rolling on microstructure and mechanical properties of Ti-3.5Al-5Mo-6V-3Cr-2Sn-0.5Fe near ß high strength titanium alloy sheets have been investigated. Results showed that the alloy mainly included the deformation induced dislocation structures after cold rolling but no obvious band structure, twin crystal or martensite were observed in this work. The texture components, which were affected by process annealing, are mainly γ-fiber, α-fiber and weak Goss texture. The γ-fiber of alloy when process annealed at 780 °C (α/ß phase field) is stronger than at 830 °C (ß phase field), where the Goss texture of alloy with process annealing temperature of 830 °C is more obvious. Results of annealing heat treatments showed that the recrystallization of the cold rolled was basically completed in a relatively short time of 2 min at 750 °C for 2 min. The refinement of grain size led to a significant increase of plasticity compared to rolled alloy. Results of tensile testing of aged alloy display the excellent combination of strength and plasticity, and the cold rolled alloy with process annealed at α/ß phase field exhibits the better mechanical properties than at ß phase field.