Muscle Nerve Suppl. Neurosci. Rev. Opin. Briefly, rats were anesthetized by an injection of mixed narcotics (85 mg/kg trichloroacetaldehyde monohydrate, 42 mg/kg magnesium sulfate, and 17 mg/kg sodium pentobarbital). Accessibility After peripheral nerve injury, axons and their myelin sheaths in the distal nerve stump are disrupted, and Wallerian degeneration takes place. The gene list was loaded, and the source of the organism was filtered as only “Homo Sapiens”, so that the analysis of interactions and pathways was limited to humans. 29, 321–332. RNA samples were converted to cDNA using the Prime-Script reagent Kit (TaKaRa, Dalian, China). Exp. Meanwhile, immune signal molecules and cytokines were also activated rapidly after injury. There has been a previous study which compared the differentially gene expressions in proximal and distal nerves after nerve injury (Jiang et al., 2014). However, the up-regulation of MMP9 was largely compromised in mice with delayed Wallerian degeneration (Shubayev et al., 2006; Barrette et al., 2010). Neurol. Adhesion to and invasion of pulmonary epithelial cells by the F15/LAM4/KZN and Beijing strains of Mycobacterium tuberculosis. doi: 10.1016/j.aanat.2011.02.011, Dubový, P., Jancalek, R., and Kubek, T. (2013). Sonic hedgehog (SHH) was first up-regulated at 6 h post injury and then down-regulated at later time points. Gene networks and their related top diseases and functions are listed in Supplementary Table 4. At 4 days to 4 weeks post injury, which represented a sub-chronic injury stage, less numerous categories of diseases and functions were involved. Data are summarized from 3 independent experiments and values are shown as the means ± SEM. 31:23-34:57 Regulator Effects results. All authors have read and approved the final manuscript. 2021 Feb 4;12:612675. doi: 10.3389/fmicb.2021.612675. 30, 153–179. 119, 1951–1965. 2011 Dec;66(4):531-7. doi: 10.3412/jsb.66.531. Our earlier studies also demonstrated that two other members of the MMP family, MMP7 and MMP12, were kept up-regulated following nerve injury (Jiang et al., 2014; Qin et al., 2016). Clin. Impact Factor 3.921 | CiteScore 5.4More on impact ›. The functional and morphological characteristics of sciatic nerve degeneration and regeneration after crush injury in rats. Anat. The IPA-derived gene network suggested that the category of Nervous System Development and Function was highly scored from 6 h to 4 weeks post nerve injury. Myelin is an important inhibiting factor for neurite growth and nerve repair (Bähr and Przyrembel, 1995; David et al., 1995). doi: 10.1002/jnr.490420417, Donnelly, D. J., and Popovich, P. G. (2008). 24, 1254–1267. Top canonical pathways mapped in IPA (A) and GO terms (B) classified under biological process.In (A) the bar chart on the left represents the percentage of gene Different from the central nervous syst… Stored distal nerve stumps were used for total RNA isolation. PLoS ONE 7:e33664. eCollection 2021. Previous studies also revealed that the MMP9 expression was often elevated following nerve injury. IPA will subdivide your data into slices based on molecule connectivity (networks), cellular functions, and involvement in canonical pathways Spend time surveying the information. 11, 1165–1171. An integrated global view of gene expression patterns during Wallerian degeneration was obtained by performing IPA core analysis, overlaying microarray data to IPKB, and then assigning differentially expressed genes to specific canonical pathways, diseases and biological functions, and networks. Figure 3. 8600 Rockville Pike To gain new molecular insights into Wallerian degeneration, this study aimed to identify differentially expressed genes and elucidate significantly involved pathways and cellular functions in the distal nerve stump following nerve injury. 10:274. doi: 10.3389/fncel.2016.00274. Genomic profiling screens small molecules of metastatic prostate carcinoma. Genes with a fold change greater than 2 (the absolute value of log2 fold change greater than 1) and an adjust p-value less than 0.05 were considered as differentially expressed and were investigated by IPA (Ingenuity Systems Inc., Redwood City, CA). Exp. doi: 10.1371/journal.pone.0033664, Lee, S. K., and Wolfe, S. W. (2000). Res. 40, 99–107. The Supplementary Material for this article can be found online at: https://www.frontiersin.org/article/10.3389/fncel.2016.00274/full#supplementary-material. Neural Regen. 28:28-31:22 Diseases & Functions results. List of primer pairs for real-time quantitative qPCR. Red color indicates the increased expression whereas green color indicates the decreased expression as compared to control (expression at 0 h). Build custom pathways and gene or chemical list libraries Create custom pathways with My Pathways and gene or chemical list libraries from a range of input data: gene lists from IPA search results, existing IPA networks or canonical pathways, uploaded lists of targets or biomarkers, or imported pathways using XGMML, BioPax, SBML, or GPML. In addition to canonical pathways, differentially expressed genes were also categorized to related diseases and functions. Nerve injury disturbs signal transmission, causes loss or alteration of sensation, impairs the power and function of target organs, and leads to disability and even mortality of victims. Total RNA was extracted with Trizol reagent (Life technologies, Carlsbed, CA) and cleaned with RNeasy spin columns (Qiagen, Valencia, CA). Therefore, genes involved in this function category were further analyzed. IPA provides two powerful tools to understand the pathway analysis results: the networks and canonical pathways that showed several pathways related to an adaptative immune response. (2007). Genes that were first up-regulated and then down-regulated are boxed in the red frame while genes that were first down-regulated and then up-regulated are boxed in the green frame. Detected global gene expressions at each time point following sciatic nerves transection were compared with the control group. IPA University: Examining Canonical Pathway results in QIAGEN Ingenuity Pathway Analysis software video tutorial video Active Link Making your RNAseq, microarray, proteomics and metabolomics datasets work for you webpage Inactive Link Pathway/Tox List 搜尋 IPA內建有 Ingenuity Canonical Pathways 與 Toxicity Lists Library資料。例如可以找到Hepatic Cholestasis相關的毒物以及Signaling Pathway資料。此搜尋是針對該內建資料庫，您需要輸入 pathway的名稱作為關鍵字搜尋。 IV. doi: 10.1016/j.neulet.2013.01.008, Li, M., Zhang, P., Guo, W., Li, H., Gu, X., and Yao, D. (2014). Rats were randomly divided into 11 groups according to different observation points and went through surgical transection of sciatic nerves as previously described (Yu et al., 2012). The IPA system (version 42012434, Ingenuity Systems; Qiagen China Co., Ltd.) was used for subsequent bioinformatics analysis, which included canonical pathway analysis, disease and function, regulator effects, upstream regulators and molecular networks. In this study we used microarray and bioinformatic analysis to examine dynamic molecular changes in the distal nerve stump following peripheral nerve injury. It has been known that after peripheral nerve injury, Schwann cells not only proliferate to form the bands of Bungner, but also produce a range of neurotrophic factors, including BDNF (Frostick et al., 1998; Faroni et al., 2013; Jang et al., 2016). Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents. Matrix metalloproteinases in wound repair (review). To investigate peripheral nerve injury-induced molecular changes during Wallerian degeneration, microarray analysis was performed to detect the expression levels of more than 30,000 genes at 0, 0.5, 1, 6, 12, and 24 h, 4 days, and 1, 2, 3, and 4 weeks in the distal nerve stumps post sciatic nerve transection. Int. 25, 1179–1187. Privacy, Help J. Neurol. Immun. Ingenuity pathway analysis indicated that inflammation and immune response, cytokine signaling, cellular growth and movement, as well as tissue development and function were significantly activated following sciatic nerve injury. Consistent with the results of canonical pathway analysis, following sciatic nerve transection, the number of categories of diseases and functions first increased and then progressively declined. 6, 391–407. doi: 10.1097/00005072-199507000-00002, Lykissas, M. G., Batistatou, A. K., Charalabopoulos, K. A., and Beris, A. E. (2007). f4-ijmm-35-06-1511: Ingenuity Pathway Analysis (IPA) canonical pathways most significantly changed in third-trimester peripheral blood NK (pNK) cells compared to first-trimester pNK cells. The representative differentially expressed genes in the canonical pathway are listed to the right. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The expression levels of genes were indicated by the color bar (attached to the raster plot). Changes in pathways, networks and transcriptional factors were identified using Ingenuity Pathway Analysis (IPA). Timely inflammatory and immune reactions are highly relevant with Wallerian degeneration, and benefit subsequent nerve repair and functional recovery (Dubový, 2011; Gaudet et al., 2011). Differentially expressed genes involved in nervous system development and function at 4 weeks post sciatic nerve transection are listed in the network. Figure 2. From 4 days post nerve injury, the scores of top networks were even higher and networks with a score value higher than 30 are presented in Table 1. Neurosci. Supplementary Table 3. The differentially expressed genes involved in Nervous System Development and Function are listed in Supplementary Table 5. Despite these findings, it is still required to further investigate the molecular changes of Wallerian degeneration from a genetic perspective. Anat. Differentially expressed genes involved in Nervous System Development and Function at 0.5, 1, 6, 12, and 24 h, 4 days, and 1, 2, and 3 weeks post sciatic nerve transection. Top enriched diseases and functions following sciatic nerve transection. Regulation of Schwann cell proliferation and migration by miR-1 targeting brain-derived neurotrophic factor after peripheral nerve injury. 24, 577–583. Differentially expressed genes in Nervous System Development and Function at 4 weeks post sciatic nerve transection. 27 The Upstream Analysis feature of IPA was used to predict the activation or inhibition of transcriptional regulators based on the direction of gene expression changes in our data set. It should be known that the proximal and the distal nerve stumps may share many common genes but have different spatiotemporal expression patterns after nerve injury. Myelin-associated glycoprotein (MAG) and myelin and lymphocyte protein (MAL) were down-regulated at 4 days and 1 week post nerve injury, respectively. 2016 Dec;65:321-329. doi: 10.1016/j.dci.2016.07.022. doi: 10.1242/jcs.098996, Zochodne, D. W. (2000). Therefore, it is a common and severe clinical problem worldwide. Careers. Table 1. 10, 1402–1408. Mucosal Immunol. 31, 407–415. Protein expression profiling during Wallerian degeneration after rat sciatic nerve injury. doi: 10.1093/nar/gkv007, Shubayev, V. I., Angert, M., Dolkas, J., Campana, W. M., Palenscar, K., and Myers, R. R. (2006). Ann. The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration. Supplementary Table 5. Biomaterials 35, 6143–6156. doi: 10.4103/1673-5374.187059, Raimondo, S., Fornaro, M., Tos, P., Battiston, B., Giacobini-Robecchi, M. G., and Geuna, S. (2011). doi: 10.1002/glia.22957, Jiang, N., Li, H., Sun, Y., Yin, D., Zhao, Q., Cui, S., et al. Nerves are fragile tissues that are susceptible to traumatic injuries, such as penetration, crushing, and stretch tractions (Campbell, 2008). At 0.5, 1, 6, 12, and 24 h, 4 days, and 1, 2, 3, and 4 weeks after surgery, rats were sacrificed by decapitation. The interferon signalling and hepatic fibrosis/hepatic stellate cell activation pathways were among the top 5 canonical pathways in all strains. 87, 27–46. Am. Nihon Saikingaku Zasshi. B., Archer, D. R., Li, Y., and Griffin, J. W. (2005). Heatmap and hierarchical cluster analysis were used to demonstrate the expression patterns of these differentially expressed genes. COVID-19 is an emerging, rapidly evolving situation. 2018 Apr;104:53-64. doi: 10.1016/j.cyto.2017.09.027. Compared with the expressed genes at 0 h post injury, only a small number of genes were differentially expressed at 0.5 and 1 h after nerve injury. Wrote the manuscript: SY. 2010 May;59(Pt 5):528-533. doi: 10.1099/jmm.0.016006-0. doi: 10.1002/mus.24082, Li, S., Liu, Q., Wang, Y., Gu, Y., Liu, D., Wang, C., et al. Only a signaling pathway, called Agranulocyte Adhesion and Diapedesis, was activated during nearly whole post-injury period. Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. (2016). Microarray analysis showed that a few genes were differentially expressed at 0.5 and 1 h post nerve injury and later on a relatively larger number of genes were up-regulated or down-regulated. To further identify key genes involved in this cellular function and establish the connections in-between these genes, the gene network diagrams were made based on IPKB. Neurosci. Neural Regenerat. Certainly, the gene expression patterns and activated biological processes in the distal nerve stump showed different characteristics compared to those in the proximal nerve stump. In contrast, many of these biological processes were also detected in the distal nerve stump after peripheral nerve injury, as revealed by this study. Differential gene expression profiling and biological process analysis in proximal nerve segments after sciatic nerve transection. Starting from 6 h post injury, a larger number of canonical pathways were activated, which were mainly related to inflammation and immune response, cytokine signaling, diseases, nuclear receptor signaling, and intracellular and second messenger signaling. Methods 222, 189–198. Prevention and treatment information (HHS). BDNF is a well-known neurotrophic factor that promotes neuronal survival and activity and stimulates axon growth (Braun et al., 1996; Lykissas et al., 2007). These top networks are generally associated with cellular morphology, assembly, organization, and organ development. doi: 10.1007/s12031-012-9813-6, Frostick, S. P., Yin, Q., and Kemp, G. J. Neurosci. 34:58-36:16 Network results. J. Mol. Res. This product is not intended for the diagnosis, prevention, or treatment of a disease. Int. The heapmap suggested that nearly 2/3 of genes involved in this cellular function were firstly up-regulated and then down-regulated while a little bit less than 1/3 of differentially genes were first down-regulated and then up-regulated. Ingenuity® Pathway Analysis (IPA) software was used to conduct pathway enrichment based on the recruited gene datasets mentioned above. 49, 233–243. Neurosci. The quality and quantity of isolated RNA were checked by Agilent Bioanalyzer 2100 (Agilent technologies, Santa Clara, CA) and NanoDrop ND-1000 spectrophotometer (Infinigen Biotechnology Inc., City of Industry, CA), respectively. At 1 h post nerve transection, canonical pathways related to immune response and cytokine signaling were activated. 96, 1441–1457. Cell. Why is Wallerian degeneration in the CNS so slow? Schwann cell properties: 3. Analyzed the data: JY and SY. The expression patterns of SHH, solute carrier family 6 member 17 (SLC6A17), and ret proto-oncogene RET were also in agreement with microarray results. Limited knowledge exists on pathways, networks and transcriptional factors regulated within epithelial cells by diverse Mycobacterium tuberculosis genotypes. We analyzed the global differential gene expression of a GBM cell line HTB15 in comparison to normal human Astrocytes, and established a few canonical pathways that are important in determining the molecular mechanisms of cancer using global gene expression microarray, coupled with the Ingenuity Pathway Analysis (IPA®). An Overview of the Canonical Pathways in IPA Causal Networks Ingenuity Pathway Analysis (IPA) | Advanced Analytics - Generate virtual upstream regulators which are networks of regulators Upstream Regulators Analysis Tutorial Ingenuity Pathway Analysis (IPA) Figure 6. qPCR analysis of genes involved in Nervous System Development and Function following sciatic nerve transection. Supplementary Table 1. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. 4, 143–151. doi: 10.1371/journal.pone.0143491, Yu, B., Zhou, S., Wang, Y., Qian, T., Ding, G., Ding, F., et al. Peripheral regeneration. (2013). Notably, a cellular function called Nervous System Development and Function was drastically stimulated at 6, 12, and 24 h post injury, and was enriched during nearly whole post-injury period. Learn how to navigate through the Canonical Pathway results in a QIAGEN Ingenuity Pathway Analysis (IPA) Core Analysis. These top networks were mainly connected to the functions: Cellular Movement and Cell-To-Cell Signaling. Curr. IPA読み取り専用ライセンス 【解析データの内容】 Canonical Pathway インプットデータと既知のパスウェイを比較し、p-value の低いパスウェイを抽出します。 Upstream Analysis The Wallerian degeneration process, since its first observation by Augustus Volney Waller in 1850, has been widely studied. J. Neurobiol. All these results highlight the central roles of the MMP family in nerve regeneration. Int. Ratio Calculations for Pathways Go Back Ratio Calculations for Pathways. QIAGEN Ingenuity Pathway Analysis 5 Glossary of Terms . Canonical pathways; Epithelial cells; Mycobacterium tuberculosis; Networks; RNA sequencing; Transcriptional factors. IPA allows you to compare analysis results from multiple experimental groups to identify similarities, differences, and trends. Laminin overrides the inhibitory effects of peripheral nervous system and central nervous system myelin-derived inhibitors of neurite growth. The ratio is calculated as follows: The number of molecules in a given pathway that meet cutoff criteria, divided by total number of molecules that make up that pathway and that are in the reference set (see Defining the Reference Set). Notably, a cellular function highly related to nerve regeneration, which is called Nervous System Development and Function, was continuously activated from 4 days until 4 weeks post injury. Macrophage recruitment in different models of nerve injury: lysozyme as a marker for active phagocytosis. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. The stacked bar chart displays the percentage of genes that were upregulated (red), downregulated (green), and genes not overlapping with our data set (white) in each canonical pathway. 9, 1186–1194. Consistent with the gene network diagram, MMP9 and BDNF were up-regulated post nerve injury while MAG and MAL were down-regulated. Acad. *Correspondence: Sheng Yi, syi@ntu.edu.cn, Front. Clipboard, Search History, and several other advanced features are temporarily unavailable. limma powers differential expression analyses for RNA-sequencing and microarray studies. Improved understanding of pathogenesis from protein interactions in Mycobacterium tuberculosis. Sci. Neurobiol. The role of neurotrophins in axonal growth, guidance, and regeneration. Similar as the results from canonical pathway analysis, diseases and functions with a p-value less than 10−5 as well as involved representative genes are listed in Figure 3. For instance, matrix metalloproteinase 9 (MMP9) and brain derived neurotrophic factor (BDNF) were drastically up-regulated starting from 6 h post injury and remained at high expression levels until 4 weeks post injury. Anat. doi: 10.1016/j.jneumeth.2013.11.012, Vargas, M. E., and Barres, B. 2019 Nov 20;20(1):878. doi: 10.1186/s12864-019-6265-1. Signal flow and pathways in response to early Wallerian degeneration after rat sciatic nerve injury. Cell. All categories of diseases and functions and their associated genes are listed in Supplementary Table 3. doi: 10.1002/neu.480230507, Campbell, W. W. (2008). Keywords: doi: 10.1016/B978-0-12-410499-0.00007-1, Faroni, A., Calabrese, F., Riva, M. A., Terenghi, G., and Magnaghi, V. (2013). 2020 Feb;113(2):504-520. doi: 10.1111/mmi.14436. 42, 594–602. Analysis using Ingenuity Pathway Analysis (IPA) software revealed that 466 network and 423 functions-pathways eligible genes were up-regulated, and 363 network and 342 functions-pathways … Epub 2017 Oct 9. During tissue remodeling, MMPs mediate the breakdown of the extracellular matrix (ECM), a key network containing physical and biochemical cues for tissue regeneration (Ravanti and Kähäri, 2000; Dubový, 2004; Chen et al., 2007). Figure 5. 9, S33–S38. We have previously reported on the up-regulation of the mRNA expression of BDNF at 1, 4, 7, and 14 days post nerve crush injury (Yi et al., 2016). The microenvironment of injured and regenerating peripheral nerves. (2014). The thermal setting was 5 min at 95°C; 40 cycles of 30 seconds at 95°C, 45 seconds at the annealing temperature, 30 seconds at 72°C; and 5 min at 72°C. Expert Rev Proteomics. Copyright © 2016 Yu, Gu and Yi. Schwann cells, neurotrophic factors, and peripheral nerve regeneration. The representative differentially expressed genes in the disease and function are listed to the right. In a few previous studies in our group, microarray was used to investigate the expression profiles in the distal nerve stump following peripheral nerve injury, and a number of up-regulated or down-regulated molecules were identified during Wallerian degeneration (Yao et al., 2012, 2013; Li M. et al., 2013; Li et al., 2014). List of the gene networks at 0.5, 1, 6, 12, and 24 h, 4 days, and 1, 2, 3, and 4 weeks post sciatic nerve transection. Strain-specific behavior of Mycobacterium tuberculosis in A549 lung cancer cell line. Bioinformatic analysis was performed to analysis differentially expressed genes at 0.5, 1, 6, 12, and 24 h, 4 days, and 1, 2, 3, and 4 weeks post sciatic nerve transection.
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