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Periostin regulates autophagy through integrin α5β1 or α6β4 and an AKT-dependent pathway in colorectal cancer cell migration. Periostin通过整合素α5β1或α6β4和akt依赖性途径调控结直肠癌细胞迁移中的自噬。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-29 DOI: 10.1111/jcmm.15756
Suyanee Thongchot, Ekapot Singsuksawat, Nuttavut Sumransub, Ananya Pongpaibul, Attaporn Trakarnsanga, Peti Thuwajit, Chanitra Thuwajit

Colorectal cancer (CRC) is one of the most fatal cancers with highly invasive properties. The progression of CRC is determined by the driving force of periostin (PN) from cancer-associated fibroblasts (CAFs) in the tumour microenvironment. This present work aims to investigate autophagy-mediated CRC invasion via the receptor integrin (ITG) by PN. The level of PN in 410 clinical CRC tissues was found increased and was an independent poor prognosis marker (HR = 2.578, 95% CI = 1.218-5.457, P-value = .013) with a significant correlation with overall survival time (P-value < .001). PN activated proliferation, migration and invasion of CRC cells, but with reduced autophagy. Interestingly, the reduction of LC3 autophagic protein corresponded to the increased ability of CRC cell migration. The siITGα5-treated HT-29 and siITGβ4-treated HCT-116 CRC cells attenuated epithelial-to-mesenchymal transitions (EMT)-related genes and pAKT compared with those in siITG-untreated cells. The reduction of pAKT by a PI3K inhibitor significantly restored autophagy in CRC cells. These evidences confirmed the effect of PN through either ITGα5β1 or ITGα6β4 and the AKT-dependent pathway to control autophagy-regulated cell migration. In conclusion, these results exhibited the impact of PN activation of ITGα5β1 or ITGα6β4 through pAKT in autophagy-mediated EMT and migration in CRC cells.

结直肠癌(CRC)是具有高度侵袭性的最致命的癌症之一。结直肠癌的进展是由肿瘤微环境中来自癌症相关成纤维细胞(CAFs)的骨膜蛋白(PN)的驱动力决定的。本研究旨在研究自噬通过受体整合素(ITG)介导的结直肠癌侵袭。410例临床结直肠癌组织中PN水平升高,是独立的不良预后指标(HR = 2.578, 95% CI = 1.218 ~ 5.457, p值= 0.013),与总生存时间(p值为0.013)有显著相关性
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引用次数: 15
A novel role for farnesoid X receptor in the bile acid-mediated intestinal glucose homeostasis. 法内酯X受体在胆汁酸介导的肠道葡萄糖稳态中的新作用。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-10-08 DOI: 10.1111/jcmm.15881
Long Zhao, Zefeng Xuan, Wenfeng Song, Shiyu Zhang, Zequn Li, Guangyuan Song, Xingxin Zhu, Haiyang Xie, Shusen Zheng, Penghong Song

The farnesoid X receptor (FXR), as a bile acid (BA) sensor, plays an important role in the regulation of lipid metabolism. However, the effects and underlying molecular mechanisms of FXR on intestinal glucose homeostasis remain elusive. Herein, we demonstrated that FXR and glucose transporter 2 (GLUT2) are essential for BA-mediated glucose homeostasis in the intestine. BA-activated FXR enhanced glucose uptake in intestinal epithelial cells by increasing the expression of GLUT2, which depended on ERK1/2 phosphorylation via S1PR2. However, it also reduced the cell energy generation via inhibition of oxidative phosphorylation, which is crucial for intestinal glucose transport. Moreover, BA-activated FXR signalling potently inhibited specific glucose flux through the intestinal epithelium to the circulation, which reduced the increase in blood glucose levels in mice following oral glucose administration. This trend was supported by the changed ratio of GLUT2 to SGLT1 in the brush border membrane (BBM), including especially decreased GLUT2 abundance in the BBM. Furthermore, impaired intestinal FXR signalling was observed in the patients with intestinal bile acid deficiency (IBAD). These findings uncover a novel function by which FXR sustains the intestinal glucose homeostasis and provide a rationale for FXR agonists in the treatment of IBAD-related hyperglycaemia.

farnesoid X受体(FXR)作为胆汁酸(BA)传感器,在调节脂质代谢中起着重要作用。然而,FXR对肠道葡萄糖稳态的影响及其潜在的分子机制尚不清楚。在这里,我们证明了FXR和葡萄糖转运蛋白2 (GLUT2)对于ba介导的肠道葡萄糖稳态至关重要。ba激活的FXR通过增加GLUT2的表达来增强肠上皮细胞的葡萄糖摄取,GLUT2的表达依赖于ERK1/2通过S1PR2磷酸化。然而,它也通过抑制氧化磷酸化减少了细胞能量的产生,氧化磷酸化对肠道葡萄糖运输至关重要。此外,ba激活的FXR信号有效地抑制了通过肠上皮进入循环的特定葡萄糖通量,从而降低了口服葡萄糖给药后小鼠血糖水平的升高。这一趋势与刷缘膜(BBM)中GLUT2与SGLT1比值的变化,特别是BBM中GLUT2丰度的下降有关。此外,在肠胆汁酸缺乏症(IBAD)患者中观察到肠道FXR信号受损。这些发现揭示了FXR维持肠道葡萄糖稳态的新功能,并为FXR激动剂治疗ibad相关高血糖提供了理论依据。
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引用次数: 10
Decreased long non-coding RNA lincFOXF1 indicates poor progression and promotes cell migration and metastasis in osteosarcoma. 长链非编码RNA lincFOXF1的减少表明骨肉瘤进展不良,并促进细胞迁移和转移。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-18 DOI: 10.1111/jcmm.15828
Shengquan Yang, Jian Chen, Bin Lv, Jun Zhang, Deli Li, Mengyuan Huang, Li Yuan, Guoyong Yin

Long non-coding RNAs have been demonstrated to be important regulators of various cancers, though the precise mechanisms remain unclear. Although lincFOXF1 has been reported to act as a tumour suppressor, its function and underlying mechanisms in osteosarcoma have not yet been explored. We employed quantitative real-time polymerase chain reaction (qRT-PCR) to evaluate the expression of lincFOXF1 and GAPDH in osteosarcoma tissues and cell lines, and colony-formation, CCK8, wound-healing, and transwell assays were conducted to analyse the proliferation, migration, and invasion capacity of osteosarcoma cells. Subcellular localization analysis by fractionation and RNA immunoprecipitation assays were performed to elucidate the mechanism responsible for lincFOXF1-mediated phenotypes of osteosarcoma cells. The results revealed that lincFOXF1 expression is significantly decreased and strongly related to Enneking stage as well as metastasis in osteosarcoma patients. Further experiments showed that lincFOXF1 inhibits the migration, invasion and metastasis of cells in vitro and vivo. Mechanistic investigation demonstrated that lincFOXF1 physically binds to EZH2, a polycomb repressive complex 2 (PRC2) component, and a search for downstream targets suggested that G-protein-coupled receptor kinase-interacting protein 1 (GIT1) is involved in the lincFOXF1-mediated repression of osteosarcoma cells migration and invasion. Moreover, GIT1 expression is inversely correlated with lincFOXF1 in osteosarcoma. The present findings indicate that lincFOXF1 is involved in the progression of osteosarcoma through binding with EZH2, further regulating GIT1 expression. Our results suggest that lincFOXF1 may serve as a biomarker and therapeutic target for osteosarcoma patients.

长链非编码rna已被证明是多种癌症的重要调节因子,尽管其确切机制尚不清楚。虽然lincFOXF1已被报道作为肿瘤抑制因子,但其在骨肉瘤中的功能和潜在机制尚未被探索。我们采用实时定量聚合酶链反应(qRT-PCR)技术检测lincFOXF1和GAPDH在骨肉瘤组织和细胞系中的表达,并通过集落形成、CCK8、创面愈合和transwell检测分析骨肉瘤细胞的增殖、迁移和侵袭能力。通过分离亚细胞定位分析和RNA免疫沉淀分析来阐明lincfoxf1介导的骨肉瘤细胞表型的机制。结果显示,在骨肉瘤患者中,lincFOXF1的表达显著降低,且与Enneking分期及转移密切相关。进一步的实验表明,lincFOXF1在体外和体内均能抑制细胞的迁移、侵袭和转移。机制研究表明,lincFOXF1物理结合多梳抑制复合体2 (PRC2)组分EZH2,寻找下游靶点提示g蛋白偶联受体激酶相互作用蛋白1 (GIT1)参与了lincFOXF1介导的骨肉瘤细胞迁移和侵袭的抑制。此外,GIT1在骨肉瘤中的表达与lincFOXF1呈负相关。本研究结果表明,lincFOXF1通过与EZH2结合参与骨肉瘤的进展,进而调控GIT1的表达。我们的研究结果表明,lincFOXF1可能作为骨肉瘤患者的生物标志物和治疗靶点。
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引用次数: 5
Serum sCD14, PGLYRP2 and FGA as potential biomarkers for multidrug-resistant tuberculosis based on data-independent acquisition and targeted proteomics. 基于数据独立获取和靶向蛋白质组学的血清sCD14、PGLYRP2和FGA作为耐多药结核病的潜在生物标志物
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-23 DOI: 10.1111/jcmm.15796
Jing Chen, Yu-Shuai Han, Wen-Jing Yi, Huai Huang, Zhi-Bin Li, Li-Ying Shi, Li-Liang Wei, Yi Yu, Ting-Ting Jiang, Ji-Cheng Li

Multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis (TB) resistant to at least isoniazid and rifampicin, is a major concern of TB control worldwide. However, the diagnosis of MDR-TB remains a huge challenge to its prevention and control. To identify new diagnostic methods for MDR-TB, a mass spectrometry strategy of data-independent acquisition and parallel reaction monitoring was used to detect and validate differential serum proteins. The bioinformatic analysis showed that the functions of differential serum proteins between the MDR-TB group and the drug-sensitive tuberculosis group were significantly correlated to the complement coagulation cascade, surface adhesion and extracellular matrix receptor interaction, suggesting a disorder of coagulation in TB. Here, we identified three potential candidate biomarkers such as sCD14, PGLYRP2 and FGA, and established a diagnostic model using these three candidate biomarkers with a sensitivity of 81.2%, a specificity of 90% and the area under the curve value of 0.934 in receiver operation characteristics curve to diagnose MDR-TB. Our study has paved the way for a novel method to diagnose MDR-TB and may contribute to elucidate the mechanisms underlying MDR-TB.

耐多药结核病(MDR-TB)被定义为至少对异烟肼和利福平具有耐药性的结核病,是世界范围内结核病控制的一个主要问题。然而,耐多药结核病的诊断仍然是其预防和控制的巨大挑战。为了确定耐多药结核病的新诊断方法,采用了数据独立获取和平行反应监测的质谱策略来检测和验证差异血清蛋白。生物信息学分析显示,耐多药结核组与药敏结核组血清差异蛋白功能与补体凝血级联、表面粘附和细胞外基质受体相互作用显著相关,提示结核患者存在凝血功能紊乱。本研究确定了sCD14、PGLYRP2和FGA 3种潜在候选生物标志物,并利用这3种候选生物标志物建立了诊断耐多药结核病的诊断模型,其灵敏度为81.2%,特异性为90%,受试者操作特征曲线曲线下面积为0.934。我们的研究为一种诊断耐多药结核病的新方法铺平了道路,并可能有助于阐明耐多药结核病的潜在机制。
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引用次数: 11
Commentary on 'Metabolic reprogramming-associated genes predict overall survival for rectal cancer'. 对“代谢重编程相关基因预测直肠癌总生存率”的评论。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-10-22 DOI: 10.1111/jcmm.15938
Ruihuan Shen

The current paper is a commentary on the Metabolic reprogramming-associated genes predict overall survival for rectal cancer (Jian-Qing Lin et al 2020). The authors concluded that 'Patients with high-risk demonstrated significantly poorer survival outcomes than patients with low-risk in the TCGA database. Also, patients with high-risk still showed significantly poorer survival outcomes than patients with low-risk in the GEO database'. But the figure 3 in their published paper, 'Survival analyses for the prognostic metabolic genes in rectal cancer', presented that there was type I error in their study during the hypothesis testing process, obviously.

目前这篇论文是对代谢重编程相关基因预测直肠癌总生存率的一篇评论(jianqing Lin et al 2020)。作者得出结论:“在TCGA数据库中,高风险患者的生存结果明显低于低风险患者。”此外,在GEO数据库中,高风险患者的生存结果仍明显低于低风险患者。但在他们发表的论文《直肠癌预后代谢基因的生存分析》中,图3显示,在假设检验过程中,他们的研究显然存在I型错误。
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引用次数: 2
Host pre-conditioning improves human adipose-derived stem cell transplantation in ageing rats after myocardial infarction: Role of NLRP3 inflammasome. 宿主预处理改善心肌梗死后衰老大鼠的人脂肪干细胞移植:NLRP3炎性体的作用
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-10-06 DOI: 10.1111/jcmm.15403
Tsung-Ming Lee, Horng-Jyh Harn, Tzyy-Wen Chiou, Ming-Hsi Chuang, Chun-Hung Chen, Chi-Hsuan Chuang, Po-Cheng Lin, Shinn-Zong Lin

Functional decline of stem cell transplantation in ageing hosts is well documented. The mechanism for this is poorly understood, although it is known that advancing age does not provide an optimal milieu for exogenous stem cells to survive, engraft and differentiate. We showed that n-butylidenephthalide improved human adipose-derived stem cell (hADSC) engraftment via attenuating the production of reactive oxygen species (ROS). It remained unclear whether pre-treated hosts with n-butylidenephthalide can rejuvenate the ageing heart and improve hADSC engraftment by regulating the ROS/NLRP3 inflammasome-mediated cardiac fibrosis after myocardial infarction. One hour after coronary ligation, hADSCs were transplanted into the hearts of young and ageing Wistar rats that were pre-treated with or without n-butylidenephthalide for 3 days. At day 3 after infarction, myocardial infarction was associated with an increase in ROS levels and NLRP3 inflammasome activity with age. hADSC transplant effectively provided a significant decrease in ROS levels, NLRP3 inflammasome activity, IL-1β levels and cardiac fibrosis in either young or old infarcted rats. However, the beneficial effects of hADSCs were greater in young compared with old rats in terms of NLRP3 inflammasome activity. The infarcted ageing rats pre-conditioned by n-butylidenephthalide improved engraftment and differentiation of hADSCs and additionally attenuated cardiac fibrosis compared with hADSCs alone. The anti-inflammation effects of n-butylidenephthalide were reversed by SIN-1. In conclusions, the increased NLRP3 inflammasome activity plays the pathogenesis of ageing-related functional hADSC decline in the ageing hosts. n-butylidenephthalide-pre-treated ageing hosts reversibly ameliorate the harsh microenvironments, improve stem cell engraftment and attenuate cardiac fibrosis after myocardial infarction.

干细胞移植在衰老宿主中的功能下降是有充分证据的。尽管已知年龄增长不能为外源干细胞的存活、移植和分化提供最佳环境,但其机制尚不清楚。我们发现,正丁基酞通过减少活性氧(ROS)的产生,改善了人脂肪源性干细胞(hADSC)的植入。目前尚不清楚正丁苯酞预处理的宿主是否可以通过调节心肌梗死后ROS/NLRP3炎症小体介导的心脏纤维化,使老化的心脏恢复活力,改善hADSC的植入。冠状动脉结扎1小时后,将hascs移植到幼龄和老龄Wistar大鼠心脏中,分别给予或不给予正丁基苯酞预处理3天。梗死后第3天,心肌梗死与ROS水平和NLRP3炎性体活性随年龄增加相关。hADSC移植有效地降低了年轻或年老梗死大鼠的ROS水平、NLRP3炎性体活性、IL-1β水平和心脏纤维化。然而,在NLRP3炎性体活性方面,年轻大鼠与老年大鼠相比,hscs的有益作用更大。与单独使用hADSCs相比,经正丁苯酞预处理的梗死老化大鼠可改善hADSCs的植入和分化,并减轻心脏纤维化。正丁基苯酞的抗炎作用被SIN-1逆转。综上所述,NLRP3炎性体活性的升高在衰老宿主衰老相关的功能性hADSC下降中起着重要的发病机制作用。n-丁二苯酞预处理衰老宿主可逆转改善恶劣的微环境,改善干细胞植入,减轻心肌梗死后的心肌纤维化。
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引用次数: 6
Resolvin D1 attenuates the inflammatory process in mouse model of LPS-induced keratitis. Resolvin D1可减轻lps诱导的小鼠角膜炎模型的炎症过程。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-10-15 DOI: 10.1111/jcmm.15633
Francesco Petrillo, Maria Consiglia Trotta, Claudio Bucolo, Anca Hermenean, Arianna Petrillo, Rosa Maisto, Gorizio Pieretti, Michela Pietropaolo, Franca Ferraraccio, Caterina Gagliano, Marilena Galdiero, Michele D'Amico

The aim of this study was to investigate the effects of the lipid mediator Resolvin D1 in experimental keratitis. C57BL/6J mice were injected with lipopolysaccharide (2 µg/eye), and after 24 hours, the corneal damage was assessed. Clinical score was quantified, and corneal inflammatory biomarkers were detected by immunohistochemistry. A robust accumulation of sub-epithelial macrophages and polymorphonuclear leucocytes, chemokine (C-X-C motif) ligand 1 (also known as keratinocyte-derived chemokine), interleukin-10 and promoters of apoptosis was also observed in lipopolysaccharide-treated mice. Formyl peptide receptor 2 corneal expression was also assessed. The corneal stroma treated with lipopolysaccharide was characterized by presence of macrophages of M1-like subtype and immature fibroblastic cells, marked with Ki67, not fully differentiated in fibroblasts. Indeed, the staining of the cornea with anti-vimentin antibodies, a marker of differentiated myofibroblasts, was very faint. Resolvin D1 attenuated all the inflammatory parameters assessed in the present study, except for IL-10. In conclusion, the data presented here seem to be consistent with the hypothesis that Resolvin D1 protected the cornea from the lipopolysaccharide-induced keratitis by acting on several inflammatory components of this damage, pivoted by Formyl peptide receptor 2 (FPR2) activation and macrophages-leucocytes activity.

本研究的目的是探讨脂质介质Resolvin D1在实验性角膜炎中的作用。给C57BL/6J小鼠注射脂多糖(2µg/眼),24h后评估角膜损伤情况。量化临床评分,免疫组织化学检测角膜炎症生物标志物。在脂多糖处理的小鼠中也观察到亚上皮巨噬细胞和多形核白细胞、趋化因子(C-X-C基序)配体1(也称为角化细胞来源的趋化因子)、白细胞介素-10和凋亡启动子的大量积累。还评估了甲酰基肽受体2角膜表达。脂多糖处理后的角膜基质存在m1样亚型巨噬细胞和未成熟成纤维细胞,标记Ki67,未完全分化为成纤维细胞。的确,角膜的抗vimentin抗体(分化的肌成纤维细胞的标记物)染色非常微弱。Resolvin D1降低了本研究中评估的除IL-10外的所有炎症参数。总之,这里的数据似乎与以下假设一致:Resolvin D1通过作用于这种损伤的几种炎症成分,以甲酰基肽受体2 (FPR2)激活和巨噬细胞-白细胞活性为中心,保护角膜免受脂多糖诱导的角膜炎的伤害。
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引用次数: 11
miR-30b Promotes spinal cord sensory function recovery via the Sema3A/NRP-1/PlexinA1/RhoA/ROCK Pathway. miR-30b通过Sema3A/NRP-1/PlexinA1/RhoA/ROCK通路促进脊髓感觉功能恢复。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-25 DOI: 10.1111/jcmm.15591
Xin Wang, Bo Li, Zhijie Wang, Fengyan Wang, Jing Liang, Chuanjie Chen, Lei Zhao, Bo Zhou, Xiaoling Guo, Liqun Ren, Xin Yuan, Xueming Chen, Tianyi Wang

Spinal cord injury (SCI) induces both motor and sensory dysfunctions. We wondered whether miR-30b could promote primary sensory neuron (PSN) axon growth in inhibitory microenvironment. The neurite growth was promoted by miR-30b agomir and inhibited by antagomir. MiR-30b targeted and degraded sema3A mRNA. MiR-30b regulated the formation of sema3A-NRP-1-PlexinA1 complex via targeting sema3A. The neurite length was induced by the miR-30b agomir, and the application of sema3A protein could reverse the effect of agomir. GTP-RhoA and ROCK expression were down-regulated by miR-30b. Neurite outgrowth that inhibited by sema3A and the miR-30b antagomir was increased by Y-27632. Agomir promoted neurite growth in NogoA inhibitory conditions, which indicated miR-30b could both enhance neuronal intrinsic regenerative ability and promote neurite growth against inhibitory microenvironment via Sema3A/NRP-1/PlexinA1/RhoA/ROCK axis. The agomir could also regulate Sema3A/NRP-1/PlexinA1/RhoA/ROCK axis in vivo and restore spinal cord sensory conductive function. In conclusion, miR-30b could be a novel target for sensation recovery after SCI.

脊髓损伤(SCI)可引起运动和感觉功能障碍。我们想知道miR-30b是否可以促进初级感觉神经元(PSN)轴突在抑制性微环境中的生长。miR-30b阿戈莫可促进神经突生长,安塔戈莫可抑制神经突生长。MiR-30b靶向并降解sema3A mRNA。MiR-30b通过靶向sema3A调控sema3A- nrp -1- plexina1复合物的形成。miR-30b agomir诱导神经突长度,sema3A蛋白的应用可以逆转agomir的作用。miR-30b下调GTP-RhoA和ROCK的表达。被sema3A和miR-30b拮抗莫抑制的神经突生长被Y-27632增加。Agomir促进NogoA抑制条件下的神经突生长,说明miR-30b可以通过Sema3A/ nnp -1/PlexinA1/RhoA/ROCK轴增强神经元内在再生能力,促进神经突生长。agomir还能在体内调节Sema3A/NRP-1/PlexinA1/RhoA/ROCK轴,恢复脊髓感觉传导功能。总之,miR-30b可能是脊髓损伤后感觉恢复的新靶点。
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引用次数: 14
Mechanical stress regulates autophagic flux to affect apoptosis after spinal cord injury. 机械应力调节自噬通量影响脊髓损伤后细胞凋亡。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-17 DOI: 10.1111/jcmm.15863
Xin Zhang, Yingli Jing, Chuan Qin, Changbin Liu, Degang Yang, Feng Gao, Mingliang Yang, Liangjie Du, Jianjun Li

Increased mechanical stress after spinal cord injury (SCI) expands the scope of nerve tissue damage and exacerbates nerve function defects. Surgical decompression after SCI is a conventional therapeutic strategy and has been proven to have neuroprotective effects. However, the mechanisms of the interaction between mechanical stress and neurons are currently unknown. In this study, we monitored intramedullary pressure (IMP) and investigated the therapeutic benefit of decompression (including durotomy and piotomy) after injury and its underlying mechanisms in SCI. We found that decreased IMP promotes the generation and degradation of LC3 II, promotes the degradation of p62 and enhances autophagic flux to alleviate apoptosis. The lysosomal dysfunction was reduced after decompression. Piotomy was better than durotomy for the histological repair of spinal cord tissue after SCI. However, the autophagy-lysosomal pathway inhibitor chloroquine (CQ) partially reversed the apoptosis inhibition caused by piotomy after SCI, and the structural damage was also aggravated after CQ administration. An antibody microarray analysis showed that decompression may reverse the up-regulated abundance of p-PI3K, p-AKT and p-mTOR caused by SCI. Our findings may contribute to a better understanding of the mechanism of decompression and the effects of mechanical stress on autophagy after SCI.

脊髓损伤后机械应力的增加扩大了神经组织损伤的范围,加重了神经功能缺损。脊髓损伤后手术减压是一种传统的治疗策略,已被证明具有神经保护作用。然而,机械应力与神经元相互作用的机制目前尚不清楚。在这项研究中,我们监测髓内压(IMP),并研究脊髓损伤后减压(包括硬膜切开和脊柱切开)的治疗效果及其潜在机制。我们发现IMP的减少促进LC3 II的生成和降解,促进p62的降解,增强自噬通量以减轻细胞凋亡。减压后溶酶体功能障碍减轻。脊髓损伤后脊髓组织的组织学修复效果优于硬膜切开术。然而,自噬-溶酶体途径抑制剂氯喹(chloroquine, CQ)部分逆转了脊髓损伤后截骨引起的细胞凋亡抑制,且给药后结构损伤也加重。抗体芯片分析显示,减压可以逆转脊髓损伤引起的p-PI3K、p-AKT和p-mTOR丰度上调。我们的研究结果可能有助于更好地理解脊髓损伤后的减压机制和机械应力对自噬的影响。
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引用次数: 13
Substance P enhances the therapeutic effect of MSCs by modulating their angiogenic potential. P物质通过调节间充质干细胞的血管生成潜能来增强其治疗效果。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-28 DOI: 10.1111/jcmm.15804
Hyun Sook Hong, Suna Kim, Yinji Jin, Youngsook Son

Bone marrow mesenchymal stem cell (MSC) therapy acts through multiple differentiations in damaged tissue or via secretion of paracrine factors, as demonstrated in various inflammatory and ischaemic diseases. However, long-term ex vivo culture to obtain a sufficient number of cells in MSC transplantation leads to cellular senescence, deficiency of the paracrine potential, and loss of survival rate post-transplantation. In this study, we evaluated whether supplementation of MSCs with substance P (SP) can improve their therapeutic potential. SP treatment elevated the secretion of paracrine/angiogenic factors, including VEGF, SDF-1a and PDGF-BB, from late passage MSCs in vitro. MSCs supplemented with SP accelerated epidermal/dermal regeneration and neovascularization and suppressed inflammation in vivo, compared to MSCs transplanted alone. Importantly, supplementation with SP enabled the incorporation of transplanted human MSCs into the host vasculature as pericytes via PDGF signalling, leading to the direct engagement of transplanted cells in compact vasculature formation. Our results showed that SP is capable of restoring the cellular potential of senescent stem cells, possibly by modulating the generation of paracrine factors from MSCs, which might accelerate MSC-mediated tissue repair. Thus, SP is anticipated to be a potential beneficial agent in MSC therapy for inflammatory or ischaemic diseases and cutaneous wounds.

骨髓间充质干细胞(MSC)治疗通过损伤组织中的多种分化或通过分泌旁分泌因子起作用,这在各种炎症和缺血性疾病中得到证实。然而,在骨髓间充质干细胞移植中,为了获得足够数量的细胞而进行的长期离体培养会导致细胞衰老、旁分泌电位不足、移植后存活率下降。在这项研究中,我们评估了补充P物质(SP)是否可以提高MSCs的治疗潜力。SP处理可提高体外晚传代MSCs的旁分泌/血管生成因子(包括VEGF、SDF-1a和PDGF-BB)的分泌。与单独移植的MSCs相比,补充SP的MSCs在体内加速了表皮/真皮的再生和新生血管的形成,并抑制了炎症。重要的是,补充SP能够使移植的人间充质干细胞通过PDGF信号传导进入宿主血管作为周细胞,导致移植细胞直接参与致密血管的形成。我们的研究结果表明,SP能够恢复衰老干细胞的细胞潜能,可能是通过调节MSCs中旁分泌因子的产生,这可能加速MSCs介导的组织修复。因此,SP有望成为MSC治疗炎症性或缺血性疾病和皮肤伤口的潜在有益剂。
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引用次数: 5
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Journal of Cellular and Molecular Medicine
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