Interference of interleukin-1β mediated by lentivirus promotes functional recovery of spinal cord contusion injury in rats via the PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Yi-li Wang ◽  
Xi Hu ◽  
Qin-xuan Li ◽  
Li-xin Zhang ◽  
Qing-jie Xia ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signaling Pathway ◽  
Motor Function ◽  
Akt Signaling ◽  
Inflammatory Factors ◽  
Akt Signaling Pathway ◽  
Cord Injury ◽  
Spinal Cord Contusion ◽  
Recovery Of Motor Function

Abstract Background: Spinal cord contusion (SCC) results in a series of pathophysiologic consequences such as edema, apoptosis, and inflammation. However, inflammation may also be beneficial for the recovery of motor function after SCC, but the underlying mechanisms remain incompletely elucidated. Interleukin-1 beta (IL-1β) is a pro-inflammatory factor that has synergistic effects with other inflammatory factors to aggravate spinal cord injury. Inflammatory factors have been found to activate the serine/threonine-specific protein kinase, protein kinase B (AKT) and to inhibit cell survival, but it is not clear whether inflammation upregulates the expression of IL-1β in the rat model of SCC and subsequently interferes in the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway. Therefore, this study explored whether IL-1β affects the recovery of motor function in spinal cord injury by interfering with the PI3K/AKT signaling pathway. Method: SCC rats were established by the Allen method. The Basso Beattie Bresnahan (BBB) scoring was used to assess motor function in the spinal cord of injured rats. Quantitative polymerase chain reaction and Western blot were used to determine the expression of genes and proteins of IL-1β, PI3K, and AKT1. Immunohistochemistry and immunofluorescence were used to locate and detect IL-1β and AKT1 proteins in spinal cord tissue. To further explore the underlying mechanism of IL-1β, lentivirus was constructed by RNA interfering (RNAi) technique to inhibit the expression of IL-1β, and bioinformatics was applied to show the relationship between IL-1β and AKT1. Results: BBB scores decreased after SCC, and IL-1β and AKT1 was located in the cytoplasm of spinal cord anterior horn neurons. In the early stage of SCC, the expression level of IL-1β gene and protein in the experimental group was higher than that in the sham operated group. At the same time, expression of the AKT1 gene decreased. After expression of IL-1β mediated by lentivirus was inhibited, BBB scores increased significantly, and spinal cord motor function improved. Bioinformatic analysis revealed a relationship between IL-1β and AKT1. In addition, AKT1 gene expression was upregulated and PI3K expression was unchanged in the PI3K/AKT signaling pathway. Conclusion IL-1β not only exacerbates the inflammatory response after SCC, but also interferes with motor function. Inhibition of IL-1β may promote recovery of spinal cord injury by upregulating AKT1 in the PI3K/AKT signaling pathway, which provides a new perspective for future clinical practice in treating spinal cord injury

scholarly journals Local delivery of USC-derived Exosome Carrying ANGPTL3 Enhance Spinal Cord Functional Recovery After Injury by Promoting Angiogenesis

2020 ◽  
Author(s):  
Xu Yan ◽  
Yong Cao ◽  
Chunyuan Chen ◽  
Hui Xie ◽  
Hongbin Lu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Signaling Pathway ◽  
Functional Recovery ◽  
Umbilical Vein ◽  
Motor Evoked Potential ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Cord Injury

Abstract Background: Spinal cord injury (SCI) is a devastating clinical diseasewithout effectivetherapeuticapproach recently. In this study, we aim to investigate the effect of locally injection with exosome derived human urine stem cell (USC) embedding with hydrogelcould improve the spinal cord functional recovery after injury and the underlying mechanism.Methods:Exosome were isolate from USC andidentified by transmission electron microscopy and western blot. Functional assays using human umbilical vein endothelial cell (HUVEC) in vitro were performed to assess the effects of USC-Exosdeliverythe angiopoietin-like protein 3 (ANGPTL3) on tube formation and migration as well as their regulatory role in the PI3K/AKT signaling pathway activation. In vivo experiment we locally injection with exosome derived USC embedding with hydrogel for treatment of SCI. The effects of USC-Exos on functional recovery in spinal cord injury mice were tested by measuring motor evoked potential, histological and neovascular numbers. Meanwhile, the role of the candidate protein ANGPTL3 in USC-Exo for promoting angiogenesisin SCI was assessed.Results:In current study, we demonstrate that when given locallyinjection with exosomederivedhuman urine stem cell (USC) embeddingwith hydrogelcould pass the spinal cord blood brain barrier and delivery the angiopoietin-like protein 3 (ANGPTL3) to the injured spinal cord region. In addition, the administration of exosome derived from human USC could enhance spinal cord neurological functional recovery by promoting angiogenesis.The mechanism studies revealed that ANGPTL3 are enriched in USCexosome(USC-Exo) and required for USC exosome promoting angiogenesis. Functional studies further confirmed the effects caused by exosome derived from USC on angiogenesis wasmediated by PI3K/AKT signaling pathway. Conclusion:Collectively, our results indicated that USC derived exosome serve as a critical regulator of angiogenesis by transferring ANGPTL3 and may represent a promising novel therapeutic agent for SCI repair.

Curcumin Promotes Recovery of Motor Function After Spinal Cord Injury in Rats Through Mammalian Target of Rapamycin (mTOR)-Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway

2020 ◽  
Vol 10 (4) ◽  
pp. 562-568
Author(s):  
Xianfeng Jiang ◽  
Fengwu Tang ◽  
Guang Han ◽  
Chen Yun ◽  
Xuyi Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signaling Pathway ◽  
Motor Function ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Cord Injury ◽  
Recovery Of Motor Function

Objective: Curcumin possesses extensive therapeutic effects on several diseases and tumor cells, which has inhibitory effects on mammalian target of rapamycin (mTOR)-STAT3 signaling. Our study aims to explore the influences of curcumin on promoting the recovery of motor function after spinal cord injury (SCI) in rats through the mTOR-STAT3 signaling pathway. Methods : SCI rats were treated with rapamycin and curcumin followed by establishing rat models of SCI. The influences of rapamycin and curcumin on the protein expressions of PTEN, Akt, phosphorylated S6 and chondroitin sulphate proteoglycans (CSPGs) were measured by western blot. Means of Basso, Beattie and Bresnahan (BBB) locomotor rating scale was used to assess motor function. Results: After SCI, curcumin promoted the expression of PTEN, reduced the proliferation of neuroglia cells, affected the expressions of CSPGs and improved the motor function. Conclusion: Curcumin can promote motor function recovery after SCI which is possibly by up-regulating the PTEN expression via the mTOR-STAT3 signaling pathway.

Bone marrow mesenchymal stem cells-derived exosomes reduce apoptosis and inflammatory response during spinal cord injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway

2021 ◽  
pp. 096032712110033
Author(s):  
Liying Fan ◽  
Jun Dong ◽  
Xijing He ◽  
Chun Zhang ◽  
Ting Zhang
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Motor Function ◽  
Inflammatory Factors ◽  
Cord Injury ◽  
Marrow Mesenchymal Stem Cells ◽  
Apoptosis And Inflammation

Spinal cord injury (SCI) is one of the most common destructive injuries, which may lead to permanent neurological dysfunction. Currently, transplantation of bone marrow mesenchymal stem cells (BMSCs) in experimental models of SCI shows promise as effective therapies. BMSCs secrete various factors that can regulate the microenvironment, which is called paracrine effect. Among these paracrine substances, exosomes are considered to be the most valuable therapeutic factors. Our study found that BMSCs-derived exosomes therapy attenuated cell apoptosis and inflammation response in the injured spinal cord tissues. In in vitro studies, BMSCs-derived exosomes significantly inhibited lipopolysaccharide (LPS)-induced PC12 cell apoptosis, reduced the secretion of pro-inflammatory factors including tumor necrosis factor (TNF)-α and IL (interleukin)-1β and promoted the secretion of anti-inflammatory factors including IL-10 and IL-4. Moreover, we found that LPS-induced protein expression of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear transcription factor-κB (NF-κB) was significantly downregulated after treatment with BMSCs-derived exosomes. In in vivo studies, we found that hindlimb motor function was significantly improved in SCI rats with systemic administration of BMSCs-derived exosomes. We also observed that the expression of pro-apoptotic proteins and pro-inflammatory factors was significantly decreased, while the expression of anti-apoptotic proteins and anti-inflammatory factors were upregulated in SCI rats after exosome treatment. In conclusion, BMSCs-derived exosomes can inhibit apoptosis and inflammation response induced by injury and promote motor function recovery by inhibiting the TLR4/MyD88/NF-κB signaling pathway, which suggests that BMSCs-derived exosomes are expected to become a new therapeutic strategy for SCI.

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