Journal articles on the topic 'Nogood repairs'
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Yu, Bo, Hongmei Zhang, Jun Hong, Yonggang Lu, and Yajun Zhang. "Promoting Axonal Extension and Repair After Spinal Cord Injury by Inhibiting the Expression of Rho Gene Based on RNA Interference." Journal of Biomaterials and Tissue Engineering 10, no. 7 (July 1, 2020): 1046–51. http://dx.doi.org/10.1166/jbt.2020.2349.
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Spinal cord injury causes central nervous system damage. Rho inhibits axonal regeneration. This study is intended to analyze the effect of inhibition of Rho expression on axonal repair. The oligodendrocytes were isolated and divided into NC group and shRNA-RhoA group followed by analysis of the average length of axon growth and average microtubule fluorescence density by immunofluorescence, Nogo, MAG and RhoA expression were by Real time PCR. Wistar rats were separated into control group; SCI group and shRNA-RhoA group followed by analysis of the BBB scores and the Reuter score of sensory function, RhoA expression by Real time PCR and Western blot, Caspase3 activity as well as Nogo and MAG expression by Real time PCR. Compared with NC group, shRNA-RhoA group showed significantly increased average length of axon growth and average microtubule fluorescence density at the distal axon and reduced expression of RhoA, Nogo and MAG (P < 0 05). In comparison to control group, SCI group presented significantly increased RhoA expression, decreased BBB score, increased Reuter score and Caspase3 activity as well as elevated Nogo and MAG expression (P < 0 05). The shRNA-RhoA group significantly decreased RhoA expression, increased BBB score, decreased Reuter score and Caspase3 activity, and reduced Nogo and MAG expression compared with SCI group (P < 0 05). Inhibiting RhoA expression can promote axon extension and regenerative repair. Targeting RhoA reduces axon growth inhibitory factor expression, inhibits apoptosis and effectively alleviates SCI.
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Rust, Ruslan, Lisa Grönnert, Christina Gantner, Alinda Enzler, Geertje Mulders, Rebecca Z. Weber, Arthur Siewert, et al. "Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke." Proceedings of the National Academy of Sciences 116, no. 28 (June 24, 2019): 14270–79. http://dx.doi.org/10.1073/pnas.1905309116.
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Stroke is a major cause of serious disability due to the brain’s limited capacity to regenerate damaged tissue and neuronal circuits. After ischemic injury, a multiphasic degenerative and inflammatory response is coupled with severely restricted vascular and neuronal repair, resulting in permanent functional deficits. Although clinical evidence indicates that revascularization of the ischemic brain regions is crucial for functional recovery, no therapeutics that promote angiogenesis after cerebral stroke are currently available. Besides vascular growth factors, guidance molecules have been identified to regulate aspects of angiogenesis in the central nervous system (CNS) and may provide targets for therapeutic angiogenesis. In this study, we demonstrate that genetic deletion of the neurite outgrowth inhibitor Nogo-A or one of its corresponding receptors, S1PR2, improves vascular sprouting and repair and reduces neurological deficits after cerebral ischemia in mice. These findings were reproduced in a therapeutic approach using intrathecal anti–Nogo-A antibodies; such a therapy is currently in clinical testing for spinal cord injury. These results provide a basis for a therapeutic blockage of inhibitory guidance molecules to improve vascular and neural repair after ischemic CNS injuries.
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Li, Hengyu, Zhuo Cheng, Pinghua Yang, Wei Huang, Xizhou Li, Daimin Xiang, and Xiaojun Wu. "Endothelial Nogo-B Suppresses Cancer Cell Proliferation via a Paracrine TGF-β/Smad Signaling." Cells 11, no. 19 (September 30, 2022): 3084. http://dx.doi.org/10.3390/cells11193084.
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Nogo-B has been reported to play a critical role in angiogenesis and the repair of damaged blood vessels; however, its role in the tumor microenvironment remains unclear. Here, we observed the differential expression of Nogo-B in endothelial cells from hepatocellular carcinoma (HCC) and glioma samples. Downregulation of Nogo-B expression correlated with the malignant phenotype of cancer and a poor prognosis for patients. In subsequent studies, endothelial Nogo-B inhibition robustly promoted the growth of HCC or glioma xenografts in nude mice. Intriguingly, endothelial Nogo-B silencing dramatically suppressed endothelial cell expansion and tumor angiogenesis, but potently enhanced the proliferation of neighboring HCC and glioma cells. Based on the results of the ELISA assay, Nogo-B silencing reduced TGF-β production in endothelial cells, which attenuated the phosphorylation and nuclear translocation of Smad in neighboring cancer cells. The endothelial Nogo-B silencing-mediated increase in cancer cell proliferation was abolished by either a TGF-β neutralizing antibody or TGF-β receptor inhibitor, indicating the essential role for TGF-β in endothelial Nogo-B-mediated suppression of cancer growth. These findings not only broaden our understanding of the crosstalk between cancer cells and endothelial cells but also provide a novel prognostic biomarker and a therapeutic target for cancer treatments.
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Soto, Altea, Manuel Nieto-Díaz, David Reigada, María Asunción Barreda-Manso, Teresa Muñoz-Galdeano, and Rodrigo M. Maza. "miR-182-5p Regulates Nogo-A Expression and Promotes Neurite Outgrowth of Hippocampal Neurons In Vitro." Pharmaceuticals 15, no. 5 (April 25, 2022): 529. http://dx.doi.org/10.3390/ph15050529.
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Nogo-A protein is a key myelin-associated inhibitor of axonal growth, regeneration, and plasticity in the central nervous system (CNS). Regulation of the Nogo-A/NgR1 pathway facilitates functional recovery and neural repair after spinal cord trauma and ischemic stroke. MicroRNAs are described as effective tools for the regulation of important processes in the CNS, such as neuronal differentiation, neuritogenesis, and plasticity. Our results show that miR-182-5p mimic specifically downregulates the expression of the luciferase reporter gene fused to the mouse Nogo-A 3′UTR, and Nogo-A protein expression in Neuro-2a and C6 cells. Finally, we observed that when rat primary hippocampal neurons are co-cultured with C6 cells transfected with miR-182-5p mimic, there is a promotion of the outgrowth of neuronal neurites in length. From all these data, we suggest that miR-182-5p may be a potential therapeutic tool for the promotion of axonal regeneration in different diseases of the CNS.
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Soto, Altea, Manuel Nieto-Díaz, David Reigada, María Asunción Barreda-Manso, Teresa Muñoz-Galdeano, and Rodrigo M. Maza. "miR-182-5p Regulates Nogo-A Expression and Promotes Neurite Outgrowth of Hippocampal Neurons In Vitro." Pharmaceuticals 15, no. 5 (April 25, 2022): 529. http://dx.doi.org/10.3390/ph15050529.
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Nogo-A protein is a key myelin-associated inhibitor of axonal growth, regeneration, and plasticity in the central nervous system (CNS). Regulation of the Nogo-A/NgR1 pathway facilitates functional recovery and neural repair after spinal cord trauma and ischemic stroke. MicroRNAs are described as effective tools for the regulation of important processes in the CNS, such as neuronal differentiation, neuritogenesis, and plasticity. Our results show that miR-182-5p mimic specifically downregulates the expression of the luciferase reporter gene fused to the mouse Nogo-A 3′UTR, and Nogo-A protein expression in Neuro-2a and C6 cells. Finally, we observed that when rat primary hippocampal neurons are co-cultured with C6 cells transfected with miR-182-5p mimic, there is a promotion of the outgrowth of neuronal neurites in length. From all these data, we suggest that miR-182-5p may be a potential therapeutic tool for the promotion of axonal regeneration in different diseases of the CNS.
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Kim, Min, Jung Kang, Paschalis Theotokis, Nikolaos Grigoriadis, and Steven Petratos. "Can We Design a Nogo Receptor-Dependent Cellular Therapy to Target MS?" Cells 8, no. 1 (December 20, 2018): 1. http://dx.doi.org/10.3390/cells8010001.
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The current landscape of therapeutics designed to treat multiple sclerosis (MS) and its pathological sequelae is saturated with drugs that modify disease course and limit relapse rates. While these small molecules and biologicals are producing profound benefits to patients with reductions in annualized relapse rates, the repair or reversal of demyelinated lesions with or without axonal damage, remains the principle unmet need for progressive forms of the disease. Targeting the extracellular pathological milieu and the signaling mechanisms that drive neurodegeneration are potential means to achieve neuroprotection and/or repair in the central nervous system of progressive MS patients. The Nogo-A receptor-dependent signaling mechanism has raised considerable interest in neurological disease paradigms since it can promulgate axonal transport deficits, further demyelination, and extant axonal dystrophy, thereby limiting remyelination. If specific therapeutic regimes could be devised to directly clear the Nogo-A-enriched myelin debris in an expedited manner, it may provide the necessary CNS environment for neurorepair to become a clinical reality. The current review outlines novel means to achieve neurorepair with biologicals that may be directed to sites of active demyelination.
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Sozmen, Elif G., Shira Rosenzweig, Irene L. Llorente, David J. DiTullio, Michal Machnicki, Harry V. Vinters, Lief A. Havton, Roman J. Giger, Jason D. Hinman, and S. Thomas Carmichael. "Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice." Proceedings of the National Academy of Sciences 113, no. 52 (December 12, 2016): E8453—E8462. http://dx.doi.org/10.1073/pnas.1615322113.
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White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis. In these areas of only partial damage, local white matter progenitors respond to injury, as oligodendrocyte progenitors (OPCs) proliferate. However, OPCs fail to mature into oligodendrocytes (OLs) even in regions of demyelination with intact axons and instead divert into an astrocytic fate. Local axonal sprouting occurs, producing an increase in unmyelinated fibers in the corpus callosum. The OPC maturation block after white matter stroke is in part mediated via Nogo receptor 1 (NgR1) signaling. In both aged and young adult mice, stroke induces NgR1 ligands and down-regulates NgR1 inhibitors during the peak OPC maturation block. Nogo ligands are also induced adjacent to human white matter stroke in humans. A Nogo signaling blockade with an NgR1 antagonist administered after stroke reduces the OPC astrocytic transformation and improves poststroke oligodendrogenesis in mice. Notably, increased white matter repair in aged mice is translated into significant poststroke motor recovery, even when NgR1 blockade is provided during the chronic time points of injury. These data provide a perspective on the role of NgR1 ligand function in OPC fate in the context of a specific and common type of stroke and show that it is amenable to systemic intervention to promote recovery.
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Pernet, Vincent, and Martin E. Schwab. "The role of Nogo-A in axonal plasticity, regrowth and repair." Cell and Tissue Research 349, no. 1 (May 17, 2012): 97–104. http://dx.doi.org/10.1007/s00441-012-1432-6.
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Elliott Donaghue, Irja, Charles H. Tator, and Molly S. Shoichet. "Local Delivery of Neurotrophin-3 and Anti-NogoA Promotes Repair After Spinal Cord Injury." Tissue Engineering Part A 22, no. 9-10 (May 2016): 733–41. http://dx.doi.org/10.1089/ten.tea.2015.0471.
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Yu, J., C. Fernandez-Hernando, Y. Suarez, M. Schleicher, Z. Hao, P. L. Wright, A. DiLorenzo, T. R. Kyriakides, and W. C. Sessa. "Reticulon 4B (Nogo-B) is necessary for macrophage infiltration and tissue repair." Proceedings of the National Academy of Sciences 106, no. 41 (September 25, 2009): 17511–16. http://dx.doi.org/10.1073/pnas.0907359106.
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Gonzenbach, R. R., and M. E. Schwab. "Disinhibition of neurite growth to repair the injured adult CNS: Focusing on Nogo." Cellular and Molecular Life Sciences 65, no. 1 (November 3, 2007): 161–76. http://dx.doi.org/10.1007/s00018-007-7170-3.
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Ahuja, Christopher S., Satoshi Nori, Lindsay Tetreault, Jefferson Wilson, Brian Kwon, James Harrop, David Choi, and Michael G. Fehlings. "Traumatic Spinal Cord Injury—Repair and Regeneration." Neurosurgery 80, no. 3S (February 21, 2017): S9—S22. http://dx.doi.org/10.1093/neuros/nyw080.
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Abstract BACKGROUND: Traumatic spinal cord injuries (SCI) have devastating consequences for the physical, financial, and psychosocial well-being of patients and their caregivers. Expediently delivering interventions during the early postinjury period can have a tremendous impact on long-term functional recovery. PATHOPHYSIOLOGY: This is largely due to the unique pathophysiology of SCI where the initial traumatic insult (primary injury) is followed by a progressive secondary injury cascade characterized by ischemia, proapoptotic signaling, and peripheral inflammatory cell infiltration. Over the subsequent hours, release of proinflammatory cytokines and cytotoxic debris (DNA, ATP, reactive oxygen species) cyclically adds to the harsh postinjury microenvironment. As the lesions mature into the chronic phase, regeneration is severely impeded by the development of an astroglial-fibrous scar surrounding coalesced cystic cavities. Addressing these challenges forms the basis of current and upcoming treatments for SCI. MANAGEMENT: This paper discusses the evidence-based management of a patient with SCI while emphasizing the importance of early definitive care. Key neuroprotective therapies are summarized including surgical decompression, methylprednisolone, and blood pressure augmentation. We then review exciting neuroprotective interventions on the cusp of translation such as Riluzole, Minocycline, magnesium, therapeutic hypothermia, and CSF drainage. We also explore the most promising neuroregenerative strategies in trial today including Cethrin™, anti-NOGO antibody, cell-based approaches, and bioengineered biomaterials. Each section provides a working knowledge of the key preclinical and patient trials relevant to clinicians while highlighting the pathophysiologic rationale for the therapies. CONCLUSION: We conclude with our perspectives on the future of treatment and research in this rapidly evolving field.
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Ineichen, Benjamin V., Sandra Kapitza, Christiane Bleul, Nicolas Good, Patricia S. Plattner, Maryam S. Seyedsadr, Julia Kaiser, et al. "Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology." Acta Neuropathologica 134, no. 3 (June 23, 2017): 423–40. http://dx.doi.org/10.1007/s00401-017-1745-3.
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Syed, Yasir A., Alexandra S. Baer, Gert Lubec, Harald Hoeger, Georg Widhalm, and Mark R. Kotter. "Inhibition of oligodendrocyte precursor cell differentiation by myelin-associated proteins." Neurosurgical Focus 24, no. 3-4 (March 2008): E5. http://dx.doi.org/10.3171/foc/2008/24/3-4/e4.
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Object Promoting repair of central nervous system (CNS) white matter represents an important approach to easing the course of a number of tragic neurological diseases. For this purpose, strategies are currently being evaluated for transplanting cells capable of generating new oligodendrocytes into areas of demyelination and/or enhancing the potential of endogenous stem/precursor cells to give rise to new oligodendrocytes. Emerging evidence, however, indicates that increasing the presence of cells capable of forming new myelin sheaths is not sufficient to promote repair because of unknown inhibitors that accumulate in lesions as a consequence of myelin degeneration and impair the generation of new oligodendrocytes. The aim of the present study was to characterize the nature of the inhibitory molecules present in myelin. Methods Differentiation of primary rat oligodendrocyte precursor cells (OPCs) in the presence of CNS and peripheral nervous system myelin was assessed by immunocytochemical methods. The authors further characterized the nature of the inhibitors by submitting myelin membrane preparations to biochemical precipitation and digestion. Finally, OPCs were grown on purified Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein, the most prominent inhibitors of axon regeneration. Results Myelin membrane preparations induced a differentiation block in OPCs that was associated with down-regulation of expression of the transcription factor Nkx2.2. The inhibitory activity in myelin was restricted to the CNS and was predominantly associated with white matter. Furthermore, the results demonstrate that myelin proteins that are distinct from the most prominent inhibitors of axon outgrowth are specific inhibitors of OPC differentiation. Conclusions The inhibitory effect of unknown myelin-associated proteins should be considered in future treatment strategies aimed at enhancing CNS repair.
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Zullo, Kelly, Yingbiao Ji, Yun Wei, Karl Herbine, Nicole Maloney, Rachel Cohen, Christopher Pastore, et al. "Lingo3 interacts with TFF2 to control mucosal integrity, Type 1 inflammation, and colitic tissue repair." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 192.8. http://dx.doi.org/10.4049/jimmunol.202.supp.192.8.
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Abstract Constant exposure of intestinal epithelial cells (IEC) to potentially damaging stimuli makes mucosal repair programs essential for gut homeostasis, immunological quiescence and resistance to colitis. Trefoil factor 2 (TFF2) is a mucus associated protein that promotes epithelial barrier integrity in the lung and intestine, but whether a bona-fide TFF2 receptor exists remains controversial. Herein, we provide evidence that leucine rich repeat nogo interacting protein 3 (LINGO3) is a transmembrane component of TFF2 signaling and proliferation within IEC. TFF2 requires LINGO3 for barrier recovery in scratch-wound assays and mice lacking LINGO3 (LINGO3KO) have impaired intestinal barrier function under steady state conditions. Interestingly, LINGO3KO mice phenocopy TFF2KO mice, with both having a significant accumulation of mucosal CD4+TH1 cells expressing IFNg+ TNFa+ under steady-state conditions and impaired recovery from DSS-induced colitis. Impaired recovery in LINGO3KO animals was marked by reduced intestinal crypt regeneration and reduced expression of the stem cell marker LGR5 compared to WT counterparts. Additionally, TFF2 agonist administration (TFF2-Fc) promoted enhanced recovery and limited inflammatory cell recruitment in WT mice during DSS-induced colitis whereas TFF2-Fc treatment was ineffective in LINGO3KO animals. Combined, these data support our contention that a TFF2-LINGO3 ligand/receptor axis regulates tissue repair and inflammation within the gastrointestinal tract through regulation of IEC function.
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Douglas Baumann, M., James W. Austin, Michael G. Fehlings, and Molly S. Shoichet. "A quantitative ELISA for bioactive anti-Nogo-A, a promising regenerative molecule for spinal cord injury repair." Methods 47, no. 2 (February 2009): 104–8. http://dx.doi.org/10.1016/j.ymeth.2008.07.007.
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Li, Zhiyuan, Zhanxiu Zhang, Lili Zhao, Hui Li, Suxia Wang, and Yong Shen. "Bone marrow mesenchymal stem cells with Nogo-66 receptor gene silencing for repair of spinal cord injury." Neural Regeneration Research 9, no. 8 (2014): 806. http://dx.doi.org/10.4103/1673-5374.131595.
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Wu, Chengjie, Yuxin Zhou, Pengcheng Tu, Guanglu Yang, Suyang Zheng, Yalan Pan, Jie Sun, Yang Guo, and Yong Ma. "Jisuikang Promotes the Repair of Spinal Cord Injury in Rats by Regulating NgR/RhoA/ROCK Signal Pathway." Evidence-Based Complementary and Alternative Medicine 2020 (November 28, 2020): 1–13. http://dx.doi.org/10.1155/2020/9542359.
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Jisuikang (JSK) is an herbal formula composed of many kinds of traditional Chinese medicine, which has been proved to be effective in promoting the rehabilitation of patients with spinal cord injury (SCI) after more than ten years of clinical application. However, the mechanisms of JSK promoting nerve regeneration are yet to be clarified. The aim of this study was to investigate the effects of JSK protecting neurons, specifically the regulation of NgR/RhoA/ROCK signal pathway. The motor function of rats was evaluated by the BBB score and inclined plate test, Golgi staining and transmission electron microscope were used to observe the microstructure of nerve tissue, and fluorescence double-labeling method was used to detect neuronal apoptosis. In this study, we found that JSK could improve the motor function of rats with SCI, protect the microstructure (mitochondria, endoplasmic reticulum, and dendritic spine) of neurons, and reduce the apoptosis rate of neurons in rats with SCI. In addition, JSK could inhibit the expression of Nogo receptor (NgR) in neurons and the NgR/RhoA/ROCK signal pathway in rats with SCI. These results indicated JSK could improve the motor function of rats with SCI by inhibiting the NgR/RhoA/ROCK signal pathway, which suggests the potential applicability of JSK as a nerve regeneration agent.
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Brochier, Camille, James I. Jones, Dianna E. Willis, and Brett Langley. "Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration." Proceedings of the National Academy of Sciences 112, no. 49 (November 23, 2015): 15220–25. http://dx.doi.org/10.1073/pnas.1509754112.
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Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules—such as myelin-derived Nogo and myelin-associated glycoprotein—or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration.
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Argueta, Donovan A., Hanan Chweih, Bryant Avalos, Huy Tran, Aithanh Nguyen, Anupam Aich, Nicholas V. DiPatrizio, and Kalpna Gupta. "Palmitoylethanolamide-Mediated Inhibition of Nogo-a Signaling Attenuates Pain in Sickle Mice." Blood 136, Supplement 1 (November 5, 2020): 15–16. http://dx.doi.org/10.1182/blood-2020-138617.
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Sickle cell disease (SCD) is characterized by multiple comorbidities including pain. SCD patients often use cannabinoids to alleviate pain, but their psychoactive effects and social stigma impose major challenges. Strategies to elevate endogenous cannabinoids (eCBs) are devoid of such challenges, but pharmacologic approaches showed adverse-effects in clinical trials. Therefore, we examined the potential of non-pharmacologic integrative approaches to elevate eCBs. Enriched high-energy diet has been shown to increase levels of eCBs (Argueta et al., Front Physiol 2019) and when combined with companionship reduced hyperalgesia in sickle mice (Tran et al., Blood 2016). We hypothesized that enriched diet and companionship would enhance eCBs without adverse effects and reduce hyperalgesia by inhibiting peripheral and central pro-nociceptive mechanisms. We fed male homozygous-BERK (sickle) mice, regular Rodent Diet (RD; 2018, Harlan) or customized high calorie enriched Sickle Mouse Diet (SD; 59M3, TestDiet), housed with or without a female companion (C+ or C-, respectively) for 3-weeks. RD/SD contain 18.6/26.4% protein, 6.2/11.1% fat, 24/27.5% carbohydrates and 18/26% kcal/g, respectively; and SD contains higher minerals, vitamins and ω-3 fatty acids compared to RD. Control HbAA-BERK and sickle mice were divided into 4 groups: [i] R/C-, RD, no companion, [ii] S/C-, SD without companion, [iii] R/C+, RD with companion, and [iv] S/C+, SD with companion. After 3-weeks of treatment, spinal cord eCBs were analyzed using targeted lipid quantitation with liquid chromatography mass spectrometry (LCMS). We observed a 20% decrease in palmitoylethanolamide (PEA), in sickle mice compared to control mice, in R/C- group (p<0.05). Further, we observed increased spinal PEA in S/C+ compared to R/C- sickle mice (~40%, p<0.05), which was concomitant with reduced mechanical, heat, and cold hyperalgesia in S/C+ sickle mice group (~80%, p<0.001; ~60%, p<0.01; & ~30%, p<0.001, respectively). Therefore, sickle diet and companionship enhances endogenous spinal PEA which has an inhibitory effect on hyperalgesia in sickle mice. Treatment of control and sickle mice in R/C- group with PEA (i.p. 20 mg/kg/day) led to acute (1 hour) reduction of mechanical- (~40%, p<0.01) and cold-hyperalgesia (~40%, p<0.001) in sickle mice compared to pre-treatment, which was sustained during 3 day treatment, but had no effect on control mice which do not have hyperalgesia. PEA inhibits substance P (SP)-induced mast cell activity, and sickle mice show increased spinal SP, neuronal sensitization, peripheral nerve injury and mast cell activation (Tran et al., Blood 2017). Pain in SCD is both neuropathic and inflammatory. We examined if PEA inhibited the mechanisms that underlie spinal nerve repair by neurite outgrowth inhibitor, NOGO-A/reticulon-4, which regulates nerve regeneration via Rho Kinase (ROCK) signaling. NOGO-A contributes to inflammatory pain and hyperalgesia following spinal cord injury via NOGO receptor 1 in spinal cord. We observed that spinal NOGO-A expression and ROCK activity are upregulated (20% & 100%, respectively) in sickle mice compared to control mice (all R/C-), which were inhibited upon 3-day treatment with PEA. We validated ROCK activity downstream of NOGO-A using SH-SY5Y neuroblastoma cells, simulating a sickle microenvironment with hemin (40 µM) and TNFα (1 ng/ml)(H+T). ROCK activity increased in H+T-treated SH-SY5Y cells compared to vehicle (~30%, p=0.05). In parallel, we analyzed the effect of PEA on extracellular traps (ET) in cutaneous mast cells from sickle mice induced by H+T in vitro. PEA treatment inhibited ET formation and extravasation of nuclear contents in H+T induced mast cells. Thus, PEA has the potential to attenuate neuropathic and inflammatory pain by inhibiting neuronal NOGO-A/ROCK pathway and mast cell activation in a sickle milieu. PEA has analgesic and anti-inflammatory effects on chronic pain in several clinical conditions. Therefore, our data suggest that diet and pleasure have the potential to upregulate pro-analgesic PEA that inhibits NOGO-A signaling and mast cell activation, leading to attenuation of hyperalgesia in sickle mice. Disclosures Gupta: Grifols: Research Funding; Cyclerion: Research Funding; 1910 Genetics: Research Funding; Novartis: Honoraria; Tautona Group: Honoraria; CSL Behring: Honoraria.
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Eftekharpour, Eftekhar, Soheila Karimi-Abdolrezaee, and Michael G. Fehlings. "Current status of experimental cell replacement approaches to spinal cord injury." Neurosurgical Focus 24, no. 3-4 (March 2008): E19. http://dx.doi.org/10.3171/foc/2008/24/3-4/e18.
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✓ Despite advances in medical and surgical care, the current clinical therapies for spinal cord injury (SCI) are largely ineffective. During the last 2 decades, the search for new therapies has been revolutionized by the discovery of stem cells, which has inspired scientists and clinicians to search for a stem cell–based reparative approaches to many diseases, including neurotrauma. In the present study, the authors briefly summarize current knowledge related to the pathophysiology of SCI, including the concepts of primary and secondary injury and the importance of posttraumatic demyelination. Key inhibitory obstacles that impede axonal regeneration include the glial scar and a number of myelin inhibitory molecules including Nogo. Recent advancements in cell replacement therapy as a therapeutic strategy for SCI are summarized. The strategies include the use of pluripotent human stem cells, embryonic stem cells, and a number of adult-derived stem and progenitor cells such as mesenchymal stem cells, Schwann cells, olfactory ensheathing cells, and adult-derived neural precursor cells. Although current strategies to repair the subacutely injured cord appear promising, many obstacles continue to render the treatment of chronic injuries challenging. Nonetheless, the future for stem cell–based reparative strategies for treating SCI appears bright.
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Steinbach, Karin, Claire L. McDonald, Markus Reindl, Rüdiger Schweigreiter, Christine Bandtlow, and Roland Martin. "Nogo-Receptors NgR1 and NgR2 Do Not Mediate Regulation of CD4 T Helper Responses and CNS Repair in Experimental Autoimmune Encephalomyelitis." PLoS ONE 6, no. 11 (November 11, 2011): e26341. http://dx.doi.org/10.1371/journal.pone.0026341.
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Babur, Özgün, Anh T. P. Ngo, Rachel A. Rigg, Jiaqing Pang, Zhoe T. Rub, Ariana E. Buchanan, Annachiara Mitrugno, et al. "Platelet procoagulant phenotype is modulated by a p38-MK2 axis that regulates RTN4/Nogo proximal to the endoplasmic reticulum: utility of pathway analysis." American Journal of Physiology-Cell Physiology 314, no. 5 (May 1, 2018): C603—C615. http://dx.doi.org/10.1152/ajpcell.00177.2017.
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Upon encountering physiological cues associated with damaged or inflamed endothelium, blood platelets set forth intracellular responses to ultimately support hemostatic plug formation and vascular repair. To gain insights into the molecular events underlying platelet function, we used a combination of interactome, pathway analysis, and other systems biology tools to analyze associations among proteins functionally modified by reversible phosphorylation upon platelet activation. While an interaction analysis mapped out a relative organization of intracellular mediators in platelet signaling, pathway analysis revealed directional signaling relations around protein kinase C (PKC) isoforms and mitogen-activated protein kinases (MAPKs) associated with platelet cytoskeletal dynamics, inflammatory responses, and hemostatic function. Pathway and causality analysis further suggested that platelets activate a specific p38-MK2 axis to phosphorylate RTN4 (reticulon-4, also known as Nogo), a Bcl-xl sequestration protein and critical regulator of endoplasmic reticulum (ER) physiology. In vitro, we find that platelets drive a p38-MK2-RTN4-Bcl-xl pathway associated with the regulation of the ER and platelet phosphatidylserine exposure. Together, our results support the use of pathway tools in the analysis of omics data sets as a means to help generate novel, mechanistic, and testable hypotheses for platelet studies while uncovering RTN4 as a putative regulator of platelet cell physiological responses.
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Slomovitz, Brian, Bradley Monk, Katherine Moxley, Nadeem Ghali, Justyna Fronczek Sokol, Chuan Tian, Nawel Bourayou, and Jalid Sehouli. "348 A phase 2 umbrella study of retifanlimab (INCMGA00012) alone or in combination with other therapies in patients with advanced or metastatic endometrial cancer (POD1UM-204, GOG 3038, ENGOT-en12/NOGGO)." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A374. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0348.
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BackgroundManagement of advanced endometrial cancer after failure with platinum therapy remains a challenge. Tumors characterized by DNA repair abnormalities are associated with high numbers of neoantigens; immunotherapy is promising in this setting as demonstrated in studies with checkpoint inhibitors (CPI). 1–6 Overcoming emerging resistance to CPI through novel combinations is a focus of research. Retifanlimab is an investigational humanized immunoglobulin G4 monoclonal antibody against programmed cell death 1 (PD 1). In POD1UM-101, retifanlimab monotherapy demonstrated acceptable tolerability and durable clinical benefit in multiple advanced tumor types, including pretreated endometrial cancer.7 POD1UM-204 is designed to further investigate efficacy and safety of retifanlimab alone or in combination with other immunotherapy or targeted agents in patients with advanced/metastatic endometrial cancer.MethodsPOD1UM-204 is a phase 2, multicenter, nonrandomized, open-label, umbrella study in women =18 years of age, with histologically confirmed diagnosis of advanced/metastatic endometrial cancer that has progressed on or after platinum-based chemotherapy. Patients must have an ECOG performance status =1, at least 1 measurable tumor lesion by Response Evaluation Criteria in Solid Tumors v1.1, and provide tumor tissue at baseline.Approximately 220 patients will be enrolled into 4 treatment groups: Group A–patients with MSI-H (microsatellite instability high) endometrial cancer and no prior CPI therapy (up to 100 patients) receiving retifanlimab monotherapy; Group B–patients with dMMR (deficient DNA mismatch repair) or POLE (DNA polymerase epsilon) endometrial cancer and no prior CPI therapy (up to 40 patients) receiving retifanlimab monotherapy; Group C–patients with unselected endometrial cancer and regardless of prior CPI treatment (up to 40 patients) receiving retifanlimab plus epacadostat (indoleamine 2,3-dioxygenase inhibitor); and Group D–patients with endometrial cancer and activating fibroblast growth factor receptor (FGFR1, 2 or 3) mutations or alterations outside of the kinase domain and regardless of prior CPI treatment (up to 40 patients) receiving retifanlimab plus pemigatinib (FGFR1, 2, 3 inhibitor) (figure 1). Patients can receive up to 26 treatment cycles if they continue to derive benefit and have not met criteria for withdrawal.The primary study objective is evaluating retifanlimab monotherapy antitumor activity (objective response rate [ORR] determined by independent central review [ICR]) in Group A. Secondary study objectives include assessing additional efficacy measures (duration of response, disease control rate and progression-free survival by ICR, and overall survival) in Group A; determining clinical activity (ORR by the investigator) in Groups B, C and D; and evaluating safety and tolerability of retifanlimab.Abstract 348 Figure 1POD1UM-204 study designResultsN/AConclusionsN/AAcknowledgementsThis study is sponsored by Incyte Corporation (Wilmington, DE).Trial RegistrationClinicalTrials. gov Identifier: NCT04463771; EudraCT 2020-000496-20Ethics ApprovalThe study was approved by institutional review boards or independent ethics committees of participating institutions.ConsentN/AReferencesMittica G, Ghisoni E, Giannone G, et al. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. Oncotarget 2017;8:90532–544.Di Tucci C, Capone C, Galati G, et al. Immunotherapy in endometrial cancer: new scenarios on the horizon. J Gynecol Oncol 2019;30:e46.Brooks R, Fleming G, Lastra R, et al. Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin 2019;69:258–79.Makker V, Rasco D, Vogelzang N, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019;20:711–8.Marabelle A, Le D, Ascierto P, et al. Efficacy of Pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1–10.Oaknin, A, Duska L, Sullivan R, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-h and MSS endometrial cancer. Gynecol Oncol 2019;154(suppl 1):17 [Abstract 33].Mehnert JM, Joshua AM, Lakhani N, et al. First-in-human phase 1 study of INCMGA00012 in patients with advanced solid tumors: interim results of the cohort expansion phase. J Immunother Cancer 2018;6(suppl 1):115 [Abstract P669].
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Hawryluk, Gregory W. J., James Rowland, Brian K. Kwon, and Michael G. Fehlings. "Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury." Neurosurgical Focus 25, no. 5 (November 2008): E14. http://dx.doi.org/10.3171/foc.2008.25.11.e14.
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Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed. Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials) also showed some promise, but we are unaware of plans for future trials with these agents. These studies have, however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who are understandably desperate for any intervention that might improve their function. Taken together, recent advances suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective therapies for SCI may become available over the next decade.
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Lim, Peter AC, and Adela M. Tow. "Recovery and Regeneration after Spinal Cord Injury: A Review and Summary of Recent Literature." Annals of the Academy of Medicine, Singapore 36, no. 1 (January 15, 2007): 49–57. http://dx.doi.org/10.47102/annals-acadmedsg.v36n1p49.
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Introduction: Spinal cord injury (SCI) often results in significant neurologic dysfunction and disability. An annual incidence of 15 to 40 traumatic SCI cases per million population has been reported worldwide, and a conservative estimate for Singapore would be 23 cases per million. With continued improvements in medical care, an increasing prevalence of SCI patients is expected, with corresponding need for comprehensive rehabilitation services led by specialist rehabilitation physicians. Methods: A literature search, review, and summary of findings of recent studies relating to factors associated with recovery, as well as interventions for rehabilitation and promotion of healing of the injured spinal cord was performed. Conclusions: Many SCI patients show improvements in motoric and neurologic level, but those with complete injuries have poor chance of improving American Spinal Injury Association (ASIA) scores. SCI of violent aetiology tends to be more neurologic complete, and those without sacral sparing less likely to improve. Older patients generally do well in activities of daily living. Women have better motor score improvement, although men have better Functional Independence Measure (FIM) scores generally. Electrodiagnostic tests such as somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) can help with prognostication, as can imaging techniques such as magnetic resonance imaging (MRI). Immediate surgery for spinal decompression may improve recovery, but whether routine surgery after SCI improves function remains unclear, as does the timing. Methylprednisolone and similar agents appear to help limit secondary injury processes. Rehabilitation interventions such as functional electrical stimulation (FES) and body-weight supported treadmill ambulation training may be effective, as may neural-controlled prostheses and devices. Substances that promote repair and regeneration of the injured spinal cord such as GM-1, 4-AP, BDNG, GDNF, Nogo and MAG-inhibitors, have been studied. Transplanted tissues and cells, such as blood macrophages, bone marrow transplant with GM-CSF, olfactory ensheathing cells, fetal tissues, stem or progenitor cells, have been reported to produce neurological improvements. Key words: Prognosis, Regeneration, Rehabilitation, Spinal cord injuries
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Zheng, Yanjun, Jingrong Lin, Dingsheng Liu, Guoqing Wan, Xuefeng Gu, and Jian Ma. "Nogo-B promotes angiogenesis and improves cardiac repair after myocardial infarction via activating Notch1 signaling." Cell Death & Disease 13, no. 4 (April 2022). http://dx.doi.org/10.1038/s41419-022-04754-4.
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AbstractNogo-B (Reticulon 4B) is reportedly a regulator of angiogenesis during the development and progression of cancer. However, whether Nogo-B regulates angiogenesis and post-myocardial infarction (MI) cardiac repair remains elusive. In the present study, we aimed to explore the role and underlying mechanisms of Nogo-B in cardiac repair during MI. We observed an increased expression level of Nogo-B in the heart of mouse MI models, as well as in isolated cardiac microvascular endothelial cells (CMECs). Moreover, Nogo-B was significantly upregulated in CMECs exposed to oxygen-glucose deprivation (OGD). Nogo-B overexpression in the endothelium via cardiotropic adeno-associated virus serotype 9 (AAV9) with the mouse endothelial-specific promoter Tie2 improved heart function, reduced scar size, and increased angiogenesis. RNA-seq data indicated that Notch signaling is a deregulated pathway in isolated CMECs along the border zone of the infarct with Nogo-B overexpression. Mechanistically, Nogo-B activated Notch1 signaling and upregulated Hes1 in the MI hearts. Inhibition of Notch signaling using a specific siRNA and γ-secretase inhibitor abolished the promotive effects of Nogo-B overexpression on network formation and migration of isolated cardiac microvascular endothelial cells (CMECs). Furthermore, endothelial Notch1 heterozygous deletion inhibited Nogo-B-induced cardioprotection and angiogenesis in the MI model. Collectively, this study demonstrates that Nogo-B is a positive regulator of angiogenesis by activating the Notch signaling pathway, suggesting that Nogo-B is a novel molecular target for ischemic disease.
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Rust, Ruslan, Rebecca Z. Weber, Lisa Grönnert, Geertje Mulders, Michael A. Maurer, Anna-Sophie Hofer, Andrea M. Sartori, and Martin E. Schwab. "Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke." Scientific Reports 9, no. 1 (December 2019). http://dx.doi.org/10.1038/s41598-019-56634-1.
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AbstractAngiogenesis is a key restorative process following stroke but has also been linked to increased vascular permeability and blood brain barrier (BBB) disruption. Previous pre-clinical approaches primarily focused on the administration of vascular endothelial growth factor (VEGF) to promote vascular repair after stroke. Although shown to improve angiogenesis and functional recovery from stroke, VEGF increased the risk of blood brain barrier disruption and bleedings to such an extent that its clinical use is contraindicated. As an alternative strategy, antibodies against the neurite growth inhibitory factor Nogo-A have recently been shown to enhance vascular regeneration in the ischemic central nervous system (CNS); however, their effect on vascular permeability is unknown. Here, we demonstrate that antibody-mediated Nogo-A neutralization following stroke has strong pro-angiogenic effects but does not increase vascular permeability as opposed to VEGF. Moreover, VEGF-induced vascular permeability was partially prevented when VEGF was co-administered with anti-Nogo-A antibodies. This study may provide a novel therapeutic strategy for vascular repair and maturation in the ischemic brain.
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Jia, Bo, Wei Huang, Yu Wang, Peng Zhang, Zhiwei Wang, Ming Zheng, and Tianbing Wang. "Nogo-C Inhibits Peripheral Nerve Regeneration by Regulating Schwann Cell Apoptosis and Dedifferentiation." Frontiers in Neuroscience 14 (January 21, 2021). http://dx.doi.org/10.3389/fnins.2020.616258.
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While Nogo protein demonstrably inhibits nerve regeneration in the central nervous system (CNS), its effect on Schwann cells in peripheral nerve repair and regeneration following sciatic nerve injury remains unknown. In this research, We assessed the post-injury expression of Nogo-C in an experimental mouse model of sciatic nerve-crush injury. Nogo-C knockout (Nogo-C–/–) mouse was generated to observe the effect of Nogo-C on sciatic nerve regeneration, Schwann cell apoptosis, and myelin disintegration after nerve injury, and the effects of Nogo-C on apoptosis and dedifferentiation of Schwann cells were observed in vitro. We found that the expression of Nogo-C protein at the distal end of the injured sciatic nerve increased in wild type (WT) mice. Compared with the injured WT mice, the proportion of neuronal apoptosis was significantly diminished and the myelin clearance rate was significantly elevated in injured Nogo-C–/– mice; the number of nerve fibers regenerated and the degree of myelination were significantly elevated in Nogo-C–/– mice on Day 14 after injury. In addition, the recovery of motor function was significantly accelerated in the injured Nogo-C–/– mice. The overexpression of Nogo-C in primary Schwann cells using adenovirus-mediated gene transfer promoted Schwann cells apoptosis. Nogo-C significantly reduced the ratio of c-Jun/krox-20 expression, indicating its inhibition of Schwann cell dedifferentiation. Above all, we hold the view that the expression of Nogo-C increases following peripheral nerve injury to promote Schwann cell apoptosis and inhibit Schwann cell dedifferentiation, thereby inhibiting peripheral nerve regeneration.
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Silveira, Isabelle Andrade, Beatriz Guitton Renaud Baptista de Oliveira, Magali Rezende de Carvalho, Nelson Carvalho Andrade, and Bruno Utzeri Peixoto. "Eletroterapia em úlceras venosas: uma revisão integrativa." Revista Enfermagem Atual In Derme 77, no. 15 (April 8, 2019). http://dx.doi.org/10.31011/reaid-2016-v.77-n.15-art.373.
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Objetivos: Descrever e analisar as evidências científicas encontradas na literatura sobre o uso da eletroterapiano reparo tecidual de úlceras venosas. Método: Revisão integrativa nas bases de dados: LILACS e MEDLINE viaPUBMED, utilizando os descritores: terapia por estimulação elétrica, úlceras venosas e cicatrização. Após a seleção,foi realizada leitura analítica, destacando: ano, título, local, autor, objetivos, método e resultados. A qualidade dosestudos foi avaliada de acordo com o Centro de Medicina Baseada em Evidências Oxford quanto ao nível de evidênciae grau de recomendação. Para análise, optou-se pela categorização temática. Resultados: Existem diferentes tiposde eletroterapias, porém não existe um padrão ouro de forma de onda e frequência de estimulação que seja omais efetivo; os estudos incluídos apresentaram resultados benéficos do uso da eletroterapia, bem como eficáciana redução do quadro álgico dos indivíduos com poucas semanas de intervenção. Conclusões: A eletroterapiaapresenta bons resultados na cicatrização de úlceras venosas, porém ainda existem lacunas importantes queprecisam ser preenchidas sobre seu uso, gerando uma demanda por estudos clínicos controlados para melhorverificar sua efetividade.Palavras-chave: Terapia por estimulação elétrica; Úlceras venosas; Cicatrização.
ABSTRACTObjectives: To describe and analyze the scientific evidence in the literature on the use of electrotherapy fortissue repair venous ulcers. Method: Integrative review in databases: LILACS and MEDLINE via PubMed, using thekeywords: electrical stimulation therapy, venous ulcers and healing. After selecting analytical reading was held,highlighting: year, title, location, author, objectives, methods and results. Study quality was assessed accordingto the Medical Center Evidence-based Oxford as level of evidence and grade of recommendation. For analysisopted up the thematic categorization. Results: There are different types of electrotherapies, but there is nogold standard wave form and stimulation frequency that is the most effective; the included studies showedbeneficial results of the use of electrotherapy and efficacy in the pain reduction of individuals with few weeksof intervention. Conclusions: Electrotherapy gives good results in the healing of venous ulcers, but there are stillimportant gaps that need to be filled on its use, generating a demand for controlled clinical studies to furtherverify its effectiveness.Keywords: Electrical stimulation therapy; Venous ulcers; Healing.
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Tsujioka, Hiroshi, and Toshihide Yamashita. "Neural circuit repair after central nervous system injury." International Immunology, December 3, 2020. http://dx.doi.org/10.1093/intimm/dxaa077.
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Abstract Central nervous system injury often causes lifelong impairment of neural function, because the regenerative ability of axons is limited, making a sharp contrast to the successful regeneration that is seen in the peripheral nervous system. Nevertheless, partial functional recovery is observed, because axonal branches of damaged or undamaged neurons sprout and form novel relaying circuits. Using a lot of animal models such as the spinal cord injury model or the optic nerve injury model, previous studies have identified many factors that promote or inhibit axonal regeneration or sprouting. Molecules in the myelin such as myelin-associated glycoprotein, Nogo-A or oligodendrocyte-myelin glycoprotein, or molecules found in the glial scar such as chondroitin sulfate proteoglycans, activate Ras homolog A (RhoA) signaling, which leads to the collapse of the growth cone and inhibit axonal regeneration. By contrast, axonal regeneration programs can be activated by many molecules such as regeneration-associated transcription factors, cyclic AMP, neurotrophic factors, growth factors, mechanistic target of rapamycin or immune-related molecules. Axonal sprouting and axonal regeneration largely share these mechanisms. For functional recovery, appropriate pruning or suppressing of aberrant sprouting are also important. In contrast to adults, neonates show much higher sprouting ability. Specific cell types, various mouse strains and different species show higher regenerative ability. Studies focusing on these models also identified a lot of molecules that affect the regenerative ability. A deeper understanding of the mechanisms of neural circuit repair will lead to the development of better therapeutic approaches for central nervous system injury.
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Ricciardi, Carlo Alberto, David Long, and Luigi Gnudi. "MO630SNOGO-B IS AN IMPORTANT CONTRIBUTOR TO GLOMERULAR ENDOTHELIAL CELL STABILITY AND VASCULAR REMODELLING INTERVENING ON VEGFA/VEGFR2 SIGNALLING." Nephrology Dialysis Transplantation 36, Supplement_1 (May 1, 2021). http://dx.doi.org/10.1093/ndt/gfab093.0011.
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Abstract Background and Aims Nogo-B is an endoplasmic reticulum protein present as a full length and circulating soluble isoform (sNogo-B) corresponding to the first ∼200aa of the N-terminus. Nogo-B is expressed in glomerular endothelial cells (GECs) and is downregulated in the diabetic glomeruli; its repletion, ameliorates diabetic glomerulopathy. However, the precise biological role of Nogo-B and its soluble form in GEC is not well understood. We hypothesise that sNogo-B could modulate VEGFA/VEGFR2 signalling, and vascular remodelling resulting in improved GECs health and vascular remodelling (vessel repair/new vessel formation). We predict that this effect may be mediated by changes in VEGFA/VEGFR2 signalling; a critical signalling pathway which regulates blood vessel function in physiology and disease. Method For this experiment we used human conditionally immortalised GECs. Cells were used after differentiation at 37°. GECs were infected with adenovirus vector expressing sNogo-B or identical vector lacking sNogo-B cDNA (control vector). Cells were serum starved (4 hours, FBS 2%) and exposed to VEGFA (50 ng/ml) for 5’ 10’ 15’ min and VEGFR2 phosphorylation assessed with western immunoblotting. Results VEGFA-Mediated VEGFR2 phosphorylation was upregulated in wild-type GECs after 15 min VEGFA incubation (P<0.05) n=4. sNogo-B overexpression upregulated the sNogo-B protein level in the supernatant by 10 fold and prevented VEGFA/VEGFR2 phosphorylation in human immortalized glomerular endothelial cells(P<0.05). Conclusion sNogo-B prevents the VEGFA mediated VEGFR2 phosphorylation in GECs. Upregulation of VEGFA/VEGFR2 signalling has been implicated in diabetic glomerulopathy. sNogo-B inhibition of VEGFA/VEGFR2 signalling opens new investigations looking at the potential role of sNogo-B as therapeutic target in diabetic nephropathy.
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Jiang, Junjie, Yuanchen Yu, Zhiwu Zhang, Yuan Ji, Hong Guo, Xiaohua Wang, and Shengjun Yu. "Effects of Nogo-A and its receptor on the repair of sciatic nerve injury in rats." Brazilian Journal of Medical and Biological Research 54, no. 9 (2021). http://dx.doi.org/10.1590/1414-431x2020e10842.
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Averyanov, I. N. "THE PROCESS OF SELECTING A RATIONAL METHOD OF REPAIR OF AIRCRAFT ENGINES AND GAS TURBINES BASED ON GOST R ISO 9001–2008." Spravochnik. Inzhenernyi zhurnal, 2014, 57–64. http://dx.doi.org/10.14489/hb.2014.07.pp.057-064.
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Xiao, Peiyi, Jinmin Gu, Wei Xu, Xingyang Niu, Jian Zhang, Jingjing Li, Yicong Chen, Zhong Pei, Jinsheng Zeng, and Shihui Xing. "RTN4/Nogo-A-S1PR2 negatively regulates angiogenesis and secondary neural repair through enhancing vascular autophagy in the thalamus after cerebral cortical infarction." Autophagy, March 9, 2022, 1–20. http://dx.doi.org/10.1080/15548627.2022.2047344.
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Feng, Xue-Feng, Jian-Feng Lei, Man-Zhong Li, Yu Zhan, Le Yang, Yun Lu, Ming-Cong Li, Yu-Ming Zhuang, Lei Wang, and Hui Zhao. "Magnetic Resonance Imaging Investigation of Neuroplasticity After Ischemic Stroke in Tetramethylpyrazine-Treated Rats." Frontiers in Pharmacology 13 (April 26, 2022). http://dx.doi.org/10.3389/fphar.2022.851746.
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Ischemic stroke elicits white matter injury typically signed by axonal disintegration and demyelination; thus, the development of white matter reorganization is needed. 2,3,5,6-Tetramethylpyrazine (TMP) is widely used to treat ischemic stroke. This study was aimed to investigate whether TMP could protect the white matter and promote axonal repair after cerebral ischemia. Male Sprague–Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO) and treated with TMP (10, 20, 40 mg/kg) intraperitoneally for 14 days. The motor function related to gait was evaluated by the gait analysis system. Multiparametric magnetic resonance imaging (MRI) was conducted to noninvasively identify gray-white matter structural integrity, axonal reorganization, and cerebral blood flow (CBF), followed by histological analysis. The expressions of axonal growth-associated protein 43 (GAP-43), synaptophysin (SYN), axonal growth-inhibitory signals, and guidance factors were measured by Western blot. Our results showed TMP reduced infarct volume, relieved gray-white matter damage, promoted axonal remodeling, and restored CBF along the peri-infarct cortex, external capsule, and internal capsule. These MRI findings were confirmed by histopathological data. Moreover, motor function, especially gait impairment, was improved by TMP treatment. Notably, TMP upregulated GAP-43 and SYN and enhanced axonal guidance cues such as Netrin-1/DCC and Slit-2/Robo-1 but downregulated intrinsic growth-inhibitory signals NogoA/NgR/RhoA/ROCK-2. Taken together, our data indicated that TMP facilitated poststroke axonal remodeling and motor functional recovery. Moreover, our findings suggested that TMP restored local CBF, augmented guidance cues, and restrained intrinsic growth-inhibitory signals, all of which might improve the intracerebral microenvironment of ischemic areas and then benefit white matter remodeling.
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Feng, Xue-Feng, Jian-Feng Lei, Man-Zhong Li, Yu Zhan, Le Yang, Yun Lu, Ming-Cong Li, Yu-Ming Zhuang, Lei Wang, and Hui Zhao. "Magnetic Resonance Imaging Investigation of Neuroplasticity After Ischemic Stroke in Tetramethylpyrazine-Treated Rats." Frontiers in Pharmacology 13 (April 26, 2022). http://dx.doi.org/10.3389/fphar.2022.851746.
Full textAbstract:
Ischemic stroke elicits white matter injury typically signed by axonal disintegration and demyelination; thus, the development of white matter reorganization is needed. 2,3,5,6-Tetramethylpyrazine (TMP) is widely used to treat ischemic stroke. This study was aimed to investigate whether TMP could protect the white matter and promote axonal repair after cerebral ischemia. Male Sprague–Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO) and treated with TMP (10, 20, 40 mg/kg) intraperitoneally for 14 days. The motor function related to gait was evaluated by the gait analysis system. Multiparametric magnetic resonance imaging (MRI) was conducted to noninvasively identify gray-white matter structural integrity, axonal reorganization, and cerebral blood flow (CBF), followed by histological analysis. The expressions of axonal growth-associated protein 43 (GAP-43), synaptophysin (SYN), axonal growth-inhibitory signals, and guidance factors were measured by Western blot. Our results showed TMP reduced infarct volume, relieved gray-white matter damage, promoted axonal remodeling, and restored CBF along the peri-infarct cortex, external capsule, and internal capsule. These MRI findings were confirmed by histopathological data. Moreover, motor function, especially gait impairment, was improved by TMP treatment. Notably, TMP upregulated GAP-43 and SYN and enhanced axonal guidance cues such as Netrin-1/DCC and Slit-2/Robo-1 but downregulated intrinsic growth-inhibitory signals NogoA/NgR/RhoA/ROCK-2. Taken together, our data indicated that TMP facilitated poststroke axonal remodeling and motor functional recovery. Moreover, our findings suggested that TMP restored local CBF, augmented guidance cues, and restrained intrinsic growth-inhibitory signals, all of which might improve the intracerebral microenvironment of ischemic areas and then benefit white matter remodeling.
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Feng, Xue-Feng, Jian-Feng Lei, Man-Zhong Li, Yu Zhan, Le Yang, Yun Lu, Ming-Cong Li, Yu-Ming Zhuang, Lei Wang, and Hui Zhao. "Magnetic Resonance Imaging Investigation of Neuroplasticity After Ischemic Stroke in Tetramethylpyrazine-Treated Rats." Frontiers in Pharmacology 13 (April 26, 2022). http://dx.doi.org/10.3389/fphar.2022.851746.
Full textAbstract:
Ischemic stroke elicits white matter injury typically signed by axonal disintegration and demyelination; thus, the development of white matter reorganization is needed. 2,3,5,6-Tetramethylpyrazine (TMP) is widely used to treat ischemic stroke. This study was aimed to investigate whether TMP could protect the white matter and promote axonal repair after cerebral ischemia. Male Sprague–Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO) and treated with TMP (10, 20, 40 mg/kg) intraperitoneally for 14 days. The motor function related to gait was evaluated by the gait analysis system. Multiparametric magnetic resonance imaging (MRI) was conducted to noninvasively identify gray-white matter structural integrity, axonal reorganization, and cerebral blood flow (CBF), followed by histological analysis. The expressions of axonal growth-associated protein 43 (GAP-43), synaptophysin (SYN), axonal growth-inhibitory signals, and guidance factors were measured by Western blot. Our results showed TMP reduced infarct volume, relieved gray-white matter damage, promoted axonal remodeling, and restored CBF along the peri-infarct cortex, external capsule, and internal capsule. These MRI findings were confirmed by histopathological data. Moreover, motor function, especially gait impairment, was improved by TMP treatment. Notably, TMP upregulated GAP-43 and SYN and enhanced axonal guidance cues such as Netrin-1/DCC and Slit-2/Robo-1 but downregulated intrinsic growth-inhibitory signals NogoA/NgR/RhoA/ROCK-2. Taken together, our data indicated that TMP facilitated poststroke axonal remodeling and motor functional recovery. Moreover, our findings suggested that TMP restored local CBF, augmented guidance cues, and restrained intrinsic growth-inhibitory signals, all of which might improve the intracerebral microenvironment of ischemic areas and then benefit white matter remodeling.