Role of CD36 in central nervous system diseases

CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expressed in various cell types in the nervous system,including endothelial cells,pericytes,astrocytes,and microglia.CD36 mediates a number of regulatory processes,such as endothelial dysfunction,oxidative stress,mitochondrial dysfunction,and inflammatory responses,which are involved in many central nervous system diseases,such as stroke,Alzheimer’s disease,Parkinson’s disease,and spinal cord injury.CD36 antagonists can suppress CD36 expression or prevent CD36 binding to its ligand,thereby achieving inhibition of CD36-mediated pathways or functions.Here,we reviewed the mechanisms of action of CD36 antagonists,such as Salvianolic acid B,tanshinone IIA,curcumin,sulfosuccinimidyl oleate,antioxidants,and small-molecule compounds.Moreover,we predicted the structures of binding sites between CD36 and antagonists.These sites can provide targets for more efficient and safer CD36 antagonists for the treatment of central nervous system diseases.

RNA sequencing of exosomes secreted by fibroblast and Schwann cells elucidates mechanisms underlying peripheral nerve regeneration

Exosomes exhibit complex biological functions and mediate a variety of biological processes,such as promoting axonal regeneration and functional recove ry after injury.Long non-coding RNAs(IncRNAs)have been reported to play a crucial role in axonal regeneration.Howeve r,the role of the IncRNA-microRNAmessenger RNA(mRNA)-competitive endogenous RNA(ceRNA)network in exosome-mediated axonal regeneration remains unclear.In this study,we performed RNA transcriptome sequencing analysis to assess mRNA expression patterns in exosomes produced by cultured fibroblasts(FC-EXOs)and Schwann cells(SCEXOs).Diffe rential gene expression analysis,Gene Ontology analysis,Kyoto Encyclopedia of Genes and Genomes analysis,and protein-protein intera ction network analysis were used to explo re the functions and related pathways of RNAs isolated from FC-EXOs and SC-EXOs.We found that the ribosome-related central gene Rps5 was enriched in FC-EXOs and SC-EXOs,which suggests that it may promote axonal regeneration.In addition,using the miRWalk and Starbase prediction databases,we constructed a regulatory network of ceRNAs targeting Rps5,including 27 microRNAs and five IncRNAs.The ceRNA regulatory network,which included Ftx and Miat,revealed that exsosome-derived Rps5 inhibits scar formation and promotes axonal regeneration and functional recovery after nerve injury.Our findings suggest that exosomes derived from fibro blast and Schwann cells could be used to treat injuries of peripheral nervous system.

Chitosan/PLGA-based tissue engineered nerve grafts with SKP-SC-EVs enhance sciatic nerve regeneration in dogs through miR-30b-5p-mediated regulation of axon growth

Extracellular vesicles from skin-derived precursor Schwann cells(SKP-SC-EVs)promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats.This study aimed at expanding the application of SKPSC-EVs in nerve grafting by creating a chitosan/PLGA-based,SKP-SC-EVs-containing tissue engineered nerve graft(TENG)to bridge a 40-mm long sciatic nerve defect in dogs.SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions,supported the outgrowth and myelination of regenerated axons,and alleviated the denervation-induced atrophy of target muscles in dogs.To clarify the underlying molecular mechanism,we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons,and miR-30b-5p was the most important among others.We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK,STAT3 or CREB.Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.

双频双脉冲(ND:YAG)激光机和钬(Ho:YAG)激光机在结石上移和碎石效率方面的体外比较

目的为了比较FREDDY激光机、钬激光机和气压弹道碎石机在结石上移和碎石方面的临床效果。方法上移的水下试验装置包括一个水平方向放置的硅树脂导管(直径为1.3cm),和一个固定支架,使激光机的石英光纤和气压弹道碎石机的撞针可以直接接触石头。将预先称过重的圆柱状Bego石头(BegoUSA公司提供)放于该装置中,分别由FREDDY激光机、钬激光机和气压弹道碎石机进行碎石。FREDDY激光机和钬激光机都采用相近的脉冲能量和频率。为了具有可比性,气压弹道碎石机采用了半硬性撞针和单脉冲,在100、200、300kPa各档压力设置下分别对石头进行30次撞击。“平均后退距离”定义为直接测得的石头最终静止点到原点的距离(每档设置都记录测试结果)。另外,两台激光机分别对称过重的石头(熟石膏成分)进行碎石,以比较碎石效果。石头固定于一个水下装置(由一个倒置的硅注射器和一个固定装置组成)中。激光光纤(钬激光和FREDDY激光的光纤内径分别是365μm和280μm)穿过注射器的针头出来抵住石头。总共24颗石头被分成4组,每组6颗,其中两组用FREDDY激光分别以300J和400J的总能量碎石,另两组用钬激光分别以300J和480J的总能量碎石。“碎石率”定义为石头重量缺失的百分比。结果FREDDY激光机在能量设置为160mJ时,分别以5、10和15Hz的频率碎石,石头的平均后退距离为7.6、8.1和6.8cm;钬激光机在能量设置为0.8J时,分别以5和10Hz的频率碎石,石头的平均后退距离为3.3和4.9cm;气压弹道碎石机在压力设置分别为100、200、300kPa时,石头的平均后退距离为8.5、9.9和13.8cm。一般来说,FREDDY激光机造成的石头后退距离都要少于气压弹道碎石机,尽管这只有在后者处于最高压力设置时才有统计意义(p<0.05)。而FREDDY激光机造成的石头后退距离要多于钬激光机,在临床上常见的设置中有统计意义(p<0.05)。FREDDY激光机以300J和400J的总能量碎石时,石头重量的缺失率分别为44.9%和86.8%,都有统计意义(p<0.05);钬激光机以300J和480J的总能量碎石时,石头重量的缺失率分别为3.3%和7.1%,都有统计意义(p<0.05)。结论FREDDY激光机造成的石头后退距离要明显大于钬激光机(在低频设置时),但又明显少于气压弹道碎石机(在所有设置时)。因此我们建议,在进行腔内输尿管镜碎石术,或在输尿管肾盂连接处进行腔内激光碎石术时,于接近结石处使用阻断装置,如StoneCone-石椎(BostonScientific公司提供)。FREDDY激光机在体外碎石的效率要明显好于钬激光机,对于结石病人来说,前者是个更优、更经济的选择。

基于自适应多特征融合的路沿检测与跟踪方法研究

为减少路沿检测过程中存在的误检和漏检,以三维激光雷达为传感器,提出了一种新的路沿检测与跟踪方法。首先,对点云进行预处理,采用基于距离的滤波器对原始点云中存在的影响特征提取的干扰点进行滤除,以提高路沿点的提取精度,对滤波后的点云,采用地面平面分段拟合的地面分割方法提取地面点云;然后,利用高度差、平滑度与角度阈值等路沿空间特征,设计了一种自适应多特征融合的路沿点提取算法;其次,针对由障碍物遮挡所造成的部分路沿缺失问题,利用饶-布莱克维尔化粒子滤波跟踪器对路沿点进行跟踪预测;最后,将该方法应用于无人环卫车进行了多工况实验,结果表明该方法能准确地检测出道路的边界信息,有效地减少了路沿点的误检和漏检。

Effect of hepatocyte growth factor signaling pathway activation on Plasmodium berghei infection

Objective:To explore the effect of hepatocyte growth factor signaling pathway activation on Plasmodium berghei infection.Methods:In this study,hepatocyte growth factor was detected by ELISA and Western blotting assay.Hepatocyte injury was detected by FITC-dextran absorption assay,and hepatocyte growth factor expression was shown to be expressed in the same injury cells by immunofluorescence against hepatocyte growth factor.In addition,Activation of hepatocyte growth factor and its receptor signaling pathway was detected with immunoprecipitation and detection of phosphorylation status.Results:It was found that injury of hepatocytes by sporozoite migration induced the secretion of hepatocyte growth factor and it was hepatocyte growth factor that rendered hepatocytes susceptible to Plasmodium sporozoite infection.In addition,hepatocyte infections depended on activation of the hepatocyte growth factor and its receptor signaling pathway.Conclusions:Our results indicate that hepatocyte growth factor and its receptor may possibly be potential targets for new approaches to malaria treatment.

KIAA1199 induces advanced biological behavior and development of ovarian cancer through activation of the IL-6/STAT3 pathway

Recently,abnormal expression of KIAA1199 has been detected in Epithelial Ovarian Cancer(EOC).However,the underlined anti-ovarian cancer mechanism of KIAA1199 remains to be enlightened.In our study,we performed to elucidate the effects of KIAA1199 on the advanced biological behavior of EOC cells through activation of the IL-6/STAT3 pathway.Confirmed by immunohistochemistry,KIAA1199 was highly expressed in ovarian borderline and malignant epithelial tumors.A retrospective analysis found that EOC patients with low expression of KIAA1199 had a significantly higher 5-year survival rate than those with high expression.Mechanistically,IL-6 was used to stimulate EOC cells,and the expression of KIAA1199,STAT3 and p-STAT3 increased after IL-6 stimulation.These results could show that KIAA1199 is transcriptionally activated by IL6/STAT3 pathway,thereby accelerating the deterioration of EOC.KIAA1199 could also be used as a poor prognosis factor and potential target in treatment.

Skin derived precursors induced Schwann cells mediated tissue engineering-aided neuroregeneration across sciatic nerve defect

A central question in neural tissue engineering is how the tissue-engineered nerve(TEN)translates detailed transcriptional signals associated with peripheral nerve regeneration into meaningful biological processes.Here,we report a skin-derived precursor-induced Schwann cell(SKP-SC)-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft(SKP-SCs-TEN)that can promote sciatic nerve regeneration and functional restoration nearly to the levels achieved by autologous nerve grafts according to behavioral,histological,and electrophysiological evidence.For achieving better effect of neuroregeneration,this is the first time to jointly apply a dynamic perfusion bioreactor and the ascorbic acid to stimulate the SKP-SCs secretion of extracellular matrix(ECM).To overcome the limitation of traditional tissue-engineered nerve grafts,jointly utilizing SKP-SCs and their ECM components were motivated by the thought of prolongating the effect of support cells and their bioactive cues that promote peripheral nerve regeneration.To further explore the regulatory model of gene expression and the related molecular mechanisms involved in tissue engineering-aided peripheral nerve regeneration,we performed a cDNA microarray analysis of gene expression profiling,a comprehensive bioinformatics analysis and a validation study on the grafted segments and dorsal root ganglia tissues.A wealth of transcriptomic and bioinformatics data has revealed complex molecular networks and orchestrated functional regulation that may be responsible for the effects of SKP-SCs-TEN on promoting peripheral nerve regeneration.Our work provides new insights into transcriptomic features and patterns of molecular regulation in nerve functional recovery aided by SKP-SCs-TEN that sheds light on the broader possibilities for novel repair strategies of peripheral nerve injury.

Spatiotemporal Dynamics of the Molecular Expression Pattern

Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors–the glial scar is triggered by injury and inhibits or promotes regeneration.Recent technological advances in spatial transcriptomics(ST)provide a unique opportunity to decipher most genes systematically throughout scar formation,which remains poorly understood.Here,we frst constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples.Locally,we profled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment,such as neurotransmitter disorders,activation of the pro-infammatory response,neurotoxic saturated lipids,angiogenesis,obstructed axon extension,and extracellular structure re-organization.In addition,we described 21 cell transcriptional states during scar formation and delineated the origins,functional diversity,and possible trajectories of subpopulations of fbroblasts,glia,and immune cells.Specifcally,we found some regulators in special cell types,such as Thbs1 and Col1a2 in macrophages,CD36 and Postn in fbroblasts,Plxnb2 and Nxpe3 in microglia,Clu in astrocytes,and CD74 in oligodendrocytes.Furthermore,salvianolic acid B,a blood–brain barrier permeation and CD36 inhibitor,was administered after surgery and found to remedy fbrosis.Subsequently,we described the extent of the scar boundary and profled the bidirectional ligand-receptor interactions at the neighboring cluster boundary,contributing to maintain scar architecture during gliosis and fbrosis,and found that GPR37L1_PSAP,and GPR37_PSAP were the most signifcant gene-pairs among microglia,fbroblasts,and astrocytes.Last,we quantifed the fraction of scar-resident cells and proposed four possible phases of scar formation:macrophage infltration,proliferation and diferentiation of scar-resident cells,scar emergence,and scar stationary.Together,these profles delineated the spatial heterogeneity of the scar,confrmed the previous concepts about scar architecture,provided some new clues for scar formation,and served as a valuable resource for the treatment of central nervous system injury.

Deciphering glial scar after spinal cord injury

Spinal cord injury(SCI)often leads to permanent disability,which is mainly caused by the loss of functional recovery.In this review,we aimed to investigate why the healing process is interrupted.One of the reasons for this interruption is the formation of a glial scar around the severely damaged tissue,which is usually covered by reactive glia,macrophages and fibroblasts.Aiming to clarify this issue,we summarize the latest research findings pertaining to scar formation,tissue repair,and the divergent roles of blood-derived monocytes/macrophages,ependymal cells,fibroblasts,microglia,oligodendrocyte progenitor cells(OPCs),neuron-glial antigen 2(NG2)and astrocytes during the process of scar formation,and further analyse the contribution of these cells to scar formation.In addition,we recapitulate the development of therapeutic treatments targeting glial scar components.Altogether,we aim to present a comprehensive decoding of the glial scar and explore potential therapeutic strategies for improving functional recovery after SCI.

miR-20a Promotes the Axon Regeneration of DRG Neurons by Targeting Nr4a3

Dear Editor,The peripheral nervous system(PNS)regenerates more easily after injury than the central nervous system(CNS)[1].Sensory neurons in the L4–L6 dorsal root ganglia(DRGs)extend axons to form the sciatic nerve along with motor axons.The DRG neuron is one of the exceptional mature neurons whose axons can regenerate after injury.

Non-coding RNAs as Emerging Regulators of Neural Injury Responses and Regeneration

Non-coding RNAs（ncRNAs） are a large cluster of RNAs that do not encode proteins,but have multiple functions in diverse cellular processes.Mounting evidence indicates the involvement of nc RNAs in the physiology and pathophysiology of the central and peripheral nervous systems.It has been shown that numerous ncRNAs,especially micro RNAs and long non-coding RNAs,are differentially expressed after insults such as acquired brain injury,spinal cord injury,and peripheral nerve injury.These ncRNAs affect neuronal survival,neurite regrowth,and glial phenotype primarily by targeting specific mRNAs,resulting in translation repression or degradation of the mRNAs.An increasing number of studies have investigated the regulatory roles of micro RNAs and long non-coding RNAs in neural injury and regeneration,and thus a new research field is emerging.In this review,we highlight current progress in the field in an attempt to provide further insight into post-transcriptional changes occurring after neural injury,and to facilitate the potential use of ncRNAs for improving neural regeneration.We also suggest potential directions for future studies.

Transcriptome Analysis of Schwann Cells at Various Stages of Myelination Implicates Chromatin Regulator Sin3A in Control of Myelination Identity

Enhancing remyelination after injury is of utmost importance for optimizing the recovery of nerve function.While the formation of myelin by Schwann cells(SCs)is critical for the function of the peripheral nervous system,the temporal dynamics and regulatory mechanisms that control the progress of the s lineage through myelination require further elucidation.Here,using in vitro co-culture models,gene expression profiling of laser capture-microdissected SCs at various stages of myelination,and multilevel bioinformatic analysis,we demonstrated that SCs exhibit three distinct transcriptional characteristics duringmyelination:the immature,promyelinating,and myelinating states.We showed that suppressor interacting 3a(Sin3A)and 16 other transcription factors and chromatin regulators play important roles in the progress of myelination.Sin3A knockdown in the sciatic nerve or specifically in SCs reduced or delayed the myelination of regenerating axons in a rat crushed sciatic nerve model,while overexpression of Sin3A greatly promoted the remyelination of axons.Further,in vitro experiments revealed that Sin3A silencing inhibited SC migration and differentiation at the promyelination stage and promoted SC proliferation at the immature stage.In addition,SC differentiation and maturation may be regulated by the Sin3A/histone deacetylase2(HDAC2)complex functionally cooperating with Sox10,as demonstrated by rescue assays.Together,these results complement the recent genome and proteome analyses of SCs during peripheral nerve myelin formation.The results also reveal a key role of Sin3A-dependent chromatin organization in promoting myelinogenic programs and SC differentiation to control peripheral myelination and repair.These findings may inform new treatments for enhancing remyelination and nerveregeneration.