Spinal cord injury (SCI) is one of the most devastating injuries. Treatment strategies for SCI are required to overcome comprehensive issues. Implantation of biomaterial scaffolds and stem cells has been demonstrated to be a promising strategy. However, a comprehensive recovery effect is difficult to achieve. In the comprehensive treatment process, the specific roles of the implanted scaffolds and of stem cells in combined strategy are usually neglected. In this study, a peptide-modified scaffold is developed based on hyaluronic acid and an adhesive peptide PPFLMLLKGSTR. Synchrotron radiation micro computed tomography measurement provides insights to the three-dimensional inner topographical property and perspective porous structure of the scaffold. The modified scaffold significantly improves cellular survival and adhesive growth of mesenchymal stem cells during 3D culture in vitro. After implantation in transected spinal cord, the modified scaffold and mesenchymal stems are found to function in synergy to restore injured spinal cord tissue, with respective strengths. Hindlimb motor function scores exhibit the most significant impact of the composite implant at 2 weeks post injury, which is the time secondary injury factors begin to take hold. Investigation on the secondary injury factors including inflammatory response and astrocyte overactivity at 10 days post injury reveals the possible underlying reason. Implants of the scaffold, cells, and especially the combination of both elicit inhibitory effects on these adverse factors. The study develops a promising implant for spinal cord tissue engineering and reveals the roles of the scaffold and stem cells. More importantly, the results provide the first understanding of the bioactive peptide PPFLMLLKGSTR concerning its functions on mesenchymal stem cells and spinal cord tissue restoration.

Metallothionein (MT) is a low-molecular-weight protein with a number of roles to play in cellular homeostasis. MT is synthesized as a consequence of a variety of cellular stressors, and has been found in both intracellular compartments and in extracellular spaces. The intracellular pool of this cysteine-rich protein can act as a reservoir of essential heavy metals, as a scavenger of reactive oxygen and nitrogen species, as an antagonist of toxic metals and organic molecules, and as a regulator of transcription factor activity. The presence of MT outside of cells due to the influence of stressors suggests that this protein may make important contributions as a "danger signal" that influences the management of responses to cellular damage. While conventional wisdom has held that extracellular MT is the result of cell death or leakage from stressed cells, there are numerous examples of selective release of proteins by nontraditional mechanisms, including stress response proteins. This suggests that MT may similarly be selectively released, and that the pool of extracellular MT represents an important regulator of various cellular functions. For example, extracellular MT has effects both on the severity of autoimmune disease, and on the development of adaptive immune functions. Extracellular MT may operate as a chemotactic factor that governs the trafficking of inflammatory cells that move to resolve damaged tissues, as a counter to extracellular oxidant-mediated damage, and as a signal that influences the functional behavior of wounded cells. A thorough understanding of the mechanisms of MT release from cells, the conditions under which MT is released to the extracellular environment, and the ways in which MT interacts with sensitive cells may both illuminate our understanding of an important control mechanism that operates in stressful conditions, and should indicate new opportunities for therapeutic management via the manipulation of this pool of extracellular MT.

Accumulating evidence indicates the critical importance of cerebrovascular dysfunction in the pathogenesis of Alzheimer's disease (AD). However, systematic comparative studies on the precise brain vasculature of wild-type and AD model mice are still rare. Using an image-optimization method for analysing Micro-Optical Sectioning Tomography (MOST) data, we generated cross-scale whole-brain 3D atlases that cover the entire vascular system from large vessels down to smallest capillaries at submicron resolution, for both wild-type mice and a transgenic (APP/PS1) mouse model of AD. In addition to distinct vascular patterns in different brain regions, we found that the main vessels of the molecular layer of the hippocampal dentate gyrus (DG-ml) undergo abrupt changes in both diameter and branch angle, spreading a unique comb-like pattern of capillaries. By using a quantitative analysis workflow, we identified in the hippocampus of AD mice an overall reduction of the mean vascular diameter, volume fraction and branch angle, with most significant impairment in the DG-ml. In addition, virtual endoscopy revealed irregular morphological features in the vessel lumen of the AD mice, potentially contributing to the impairment of blood flow. Our results demonstrate the capability of high-resolution cross-scale evaluation of brain vasculature and underscore the importance of studying hippocampal microcirculation for understanding AD pathogenesis.

microRNAs are a novel set of small, non-protein-coding nucleotide RNAs that negatively regulate the expression of target mRNAs. miRNA-21 is a microRNA that is highly enriched in endothelial cells. miRNA-21 has been shown to be a potential pro-angiogenic factor in some biological systems. Our previous study showed that the expression of miRNA-21 was up-regulated after spinal cord injury. However, the effect of miRNA-21 on angiogenesis in the spinal cord was unclear. In this study, to understand the role of miRNA-21 on injured endothelial cells exclusively, an oxygen and glucose deprivation model of endothelial cells was constructed, and the up-regulation of miRNA-21 was discovered in this model. An increased level of miRNA-21 by mimics promoted the survival, migration and tube formation of endothelial cells, which simultaneously inhibited tissue inhibitor of metalloproteinase-3 (TIMP3) expression and promoted matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) expression and secretion. A decreased level of miRNA-21 by antagomir exerted an opposite effect. As is well known, survival, migration and tube formation of endothelial cells are necessary prerequisites for angiogenesis after injury. TIMP3 was validated as a direct target of miRNA-21 by dual-luciferase reporter assay. Silencing with small interfering RNA against TIMP3 promoted tube formation and increased MMP2 and MMP9 expression at the protein level. In vivo, we found that decreased levels of miRNA-21 inhibited angiogenesis after spinal cord injury in rats using synchrotron radiation micro-computed tomography. In summary, these findings suggest that miRNA-21 has a protective effect on angiogenesis by reducing cell death and promoting cell survival, migration and tube formation via partially targeting the TIMP3 by potentially regulating MMP2 and MMP9. TIMP3 is a functional target gene. Identifying the role of miRNA-21 in the protection of angiogenesis might offer a novel therapeutic target for secondary spinal cord injury, in which angiogenesis is indispensable.

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The angioarchitecture is a fundamental aspect of brain development and physiology. However, available imaging tools are unsuited for non-destructive cerebral mapping of the functionally important three-dimensional (3D) vascular microstructures. To address this issue, we developed an ultra-high resolution 3D digitalized angioarchitectural map for rat brain, based on synchrotron radiation phase contrast imaging (SR-PCI) with pixel size of 5.92 μm. This approach provides a systematic and detailed view of the cerebrovascular anatomy at the micrometer level without any need for contrast agents. From qualitative and quantitative perspectives, the present 3D data provide a considerable insight into the spatial vascular network for whole rodent brain, particularly for functionally important regions of interest, such as the hippocampus, pre-frontal cerebral cortex and the corpus striatum. We extended these results to synchrotron-based virtual micro-endoscopy, thus revealing the trajectory of targeted vessels in 3D. The SR-PCI method for systematic visualization of cerebral microvasculature holds considerable promise for wider application in life sciences, including 3D micro-imaging in experimental models of neurodevelopmental and vascular disorders.

Background:The association between serum lipids and diabetic retinopathy (DR) was controversial. Therefore, we performed a meta-analysis to evaluate the relationship between triglycerides (TG), serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and DR.Methods:A systematic review and meta-analysis of observational studies was carried out to explore the association between serum lipids and DR. Studies related were initially indentified by searching PubMed, Cochrane Library, and Elsevier databases through June, 2017. Then a manual retrieval was also performed. RevMan 5.3 software was used to calculate the pooled mean differences (MDs) and related 95% confidence intervals (CIs). To test the stability of the final results, a sensitivity analysis was also performed.Results:A total of 7 studies were included in this meta-analysis. When compared with the controls, the DR cases did not show significantly higher TG levels (MD 9.18 mg/dL, 95%CI –4.14 to 22.49, P = .18), higher TC levels (MD 3.77 mg/dL, 95%CI: –2.45 to 9.98, P = .24), as well as lower HDL-C levels (MD –1.14 mg/dL, 95%CI: –2.43 to 0.15, P = .08). But slightly higher LDL-C levels were observed (MD 3.74 mg/dL, 95%CI: 0.13–7.35, P = .04). In addition, whether serum lipids involved in the progression of DR were relatively unexplored, but fenofibrate was confirmed to benefit the DR cases.Conclusions:Based on recent published data, we did not find obvious differences in TG, TC, and HDL-C levels between patients with DR and without DR. However, slightly higher LDL-C levels were observed in the DR cases.

Background: Metallothionein (MT) is a cysteine-rich, metal-binding protein that can be induced by a variety of agents. Modulation of MT levels has also been shown to alter specific immune functions. We have noticed that the MT genes map close to the chemokines Ccl17 and Cx3cl1. Cysteine motifs that characterize these chemokines are also found in the MT sequence suggesting that MT might also act as a chemotactic factor.