Magnetic Stimulation of Gigantocellular Reticular Nucleus with Iron Oxide Nanoparticles Combined Treadmill Training Enhanced Locomotor Recovery by Reorganizing Cortico-Reticulo-Spinal Circuit.

Background: Gigantocellular reticular nucleus (GRNs) executes a vital role in locomotor recovery after spinal cord injury. However, due to its unique anatomical location deep within the brainstem, intervening in GRNs for spinal cord injury research is challenging. To address this problem, this study adopted an extracorporeal magnetic stimulation system to observe the effects of selective magnetic stimulation of GRNs with iron oxide nanoparticles combined treadmill training on locomotor recovery after spinal cord injury, and explored the possible mechanisms. Methods: Superparamagnetic iron oxide (SPIO) nanoparticles were stereotactically injected into bilateral GRNs of mice with moderate T10 spinal cord contusion. Eight-week selective magnetic stimulation produced by extracorporeal magnetic stimulation system (MSS) combined with treadmill training was adopted for the animals from one week after surgery. Locomotor function of mice was evaluated by the Basso Mouse Scale, Grid-walking test and Treadscan analysis. Brain MRI, anterograde virus tracer and immunofluorescence staining were applied to observe the tissue compatibility of SPIO in GRNs, trace GRNs' projections and evaluate neurotransmitters' expression in spinal cord respectively. Motor-evoked potentials and H reflex were collected for assessing the integrity of cortical spinal tract and the excitation of motor neurons in anterior horn. Results: (1) SPIO persisted in GRNs for a minimum of 24 weeks without inducing apoptosis of GRN cells, and degraded slowly over time. (2) MSS-enabled treadmill training dramatically improved locomotor performances of injured mice, and promoted cortico-reticulo-spinal circuit reorganization. (3) MSS-enabled treadmill training took superimposed roles through both activating GRNs to drive more projections of GRNs across lesion site and rebalancing neurotransmitters' expression in anterior horn of lumbar spinal cord. Conclusion: These results indicate that selective MSS intervention of GRNs potentially serves as an innovative strategy to promote more spared fibers of GRNs across lesion site and rebalance neurotransmitters' expression after spinal cord injury, paving the way for the structural remodeling of neural systems collaborating with exercise training, thus ultimately contributing to the reconstruction of cortico-reticulo-spinal circuit.

Ginkgolide B Protects Against Ischemic Stroke via Targeting AMPK/PINK1.

Introduction: Ginkgolide B (GB), which is an active constituent derived from Ginkgo biloba leaves, has been reported to ameliorate Alzheimer's disease (AD), ischemic stroke, as well as other neurodegenerative diseases due to its viable immunosuppressive and anti-inflammatory functions. However, it has yet to be proven whether GB inhibits neuronal apoptosis in ischemic stroke. Methods: In the present research, the inhibition function of GB on neuronal apoptosis and its underpinning process(s) after cerebral ischemia were studied through transient middle cerebral artery occlusion (t-MCAO) in an in vivo rat model as well as in cultured SH-SY5Y cells subjected to oxygen and glucose deprivation (OGD)/reoxygenation in vitro. The neurological score was calculated and Nissl and TUNEL staining were performed to evaluate the stroke outcome, neuronal loss, and neuronal apoptosis. Subsequently, the western blot was utilized to detect Bcl2 and p-AMPK/AMPK expression. Results: Compared to t-MCAO rats, rats receiving GB treatment showed a significant reduction of neuronal loss and apoptosis and improved neurological behavior at 72 h after MCAO. GB treatment also upregulated the expression of Bcl2 and p-AMPK. In vitro, GB suppressed the apoptosis in OGD/reoxygenation-challenged neuronal SH-SY5Y cells through AMPK activation. Conclusions: Our observations suggest that GB enhanced AMPK activation in neural cells, reducing neuronal apoptosis, thus eventually preventing ischemic stroke.

Quercetin inhibits fibroblasts proliferation and reduces surgery-induced epidural fibrosis via the autophagy-mediated PI3K/Akt/mTOR pathway.

Epidural fibrosis (EF) is a serious complication when the patients suffer from operations of lumbar laminectomy. It is reported that quercetin plays a positive role in the prevention of various fibrotic diseases. However, the role of quercetin in the prevention of epidural fibrosis (EF) and its possible mechanism are unclear. Fibroblast proliferation is considered to be the main cause of epidural fibrosis.Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development, and homeostasis.Although autophagy has been associated with fibrosis of different tissues, the effect of autophagy on epidural fibrosis is still unknown.The aim of this study was to investigate the function and mechanism of autophagy induced by quercetin, a polyphenol derived from plants. In vivo, the effect of quercetin on reducing epidural fibrosis was confirmed via histological staining and immunohistochemical analysis. The results showed that quercetin had significant suppressive effects on epidural fibrosis following laminectomy in rats.In vitro,, cell counting kit-8 (CCK-8), Western blot analysis, immunofluorescence and Edu staining, TUNEL staining and transmission electron microscopy were used to detect the effects of quercetin on the proliferation and apoptosis of fibroblasts and explore the possible signal transduction pathway. Results indicated that quercetin could induce autophagy and inhibit proliferation in fibroblasts. In conclusion, Quercetin could regulate fibroblast proliferation, apoptosis, migration and other biological behaviors through autophagy, thereby preventing epidural fibrosis. The specific corresponding pathway may be the PI3K/Akt/mTOR signaling pathway.

MEX3C promotes osteosarcoma malignant progression through negatively regulating FGF14.

PURPOSE: Previous studies have shown that MEX3C is an oncogene; however, its role in osteosarcoma (OS) development has not been reported. We aimed at investigating whether MEX3C could be engaged in the malignant progression of OS through regulating FGF14. METHODS: MEX3C levels in tumor tissues and adjacent ones of 52 OS patients were studied by quantitative real-time polymerase chain reaction (qRT-PCR), and the relationship between MEX3C expression and clinicopathological characteristics of OS patients was analyzed. At the same time, qRT-PCR further verified the MEX3C level in OS cell lines, and HOS and MG63 OS cell lines were selected to construct MEX3C overexpression and knockdown cell model, respectively. The impact of MEX3C on OS cell functions were determined by cell wound healing and transwell assay. In addition, the interaction between MEX3C and FGF14 was further determined by luciferase assay, western blot and recovery experiments. RESULTS: MEX3C had increased expression both in OS tissue samples and in OS cell lines. High expression of MEX3C was predictive of high incidence of nodal involvement or distant metastasis. Silencing MEX3C remarkably attenuated the migration ability of OS cells, while, conversely, overexpression enhanced that. Bioinformatics analysis and luciferase assay confirmed that MEX3C bind to FGF14 directly, and the expression of FGF14 was significantly reduced in OS tumor tissue specimens, and was negatively correlated with MEX3C. Overexpression of FGF14 was able to reverse the promoting effect of MEX3C on the crawling ability and invasiveness of OS cells. CONCLUSIONS: MEX3C was remarkably increased in OS tissues and was remarkably correlated with the incidence of metastasis of OS patients. In addition, MEX3C accelerated the malignant progression of OS through negatively modulating FGF14.