scholarly journals Transection injury differentially alters the proteome of the human sural nerve

2021 ◽  
Author(s):  
Monica J Chau ◽  
Jorge E Quintero ◽  
Eric Blalock ◽  
Christopher Samaan ◽  
Greg Gerhardt ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Sural Nerve ◽  
Epithelial Mesenchymal Transition ◽  
Post Injury ◽  
Mesenchymal Transition ◽  
Before And After ◽  
Human Nerve ◽  
Key Pathways

Regeneration after severe peripheral nerve injury is often poor. Knowledge of human nerve regeneration and the growth microenvironment is greatly lacking. We aimed to identify the regenerative proteins in human peripheral nerve by comparing the proteome before and after a transection injury. In a unique study design, we collected from the same participants, samples from naïve and degenerating sural nerve. Naïve and degenerating (two weeks after injury) samples were analyzed using mass spectrometry and immunoassays. Using a correlation matrix, we found significantly altered levels following the nerve injury. Mass spectrometry revealed that post-injury samples had 672 proteins significantly upregulated and 661 significantly downregulated compared to naïve samples (q < 0.05, |FC| > 2). We used Gene Ontology pathways to highlight groups of proteins that were significantly upregulated or downregulated with injury-induced degeneration and regeneration. Significant protein changes in key pathways were identified including growth factor levels, Schwann cell de-differentiation, myelination downregulation, epithelial-mesenchymal transition, and axonal regeneration pathways. Having proteome signatures of human peripheral nerves of both the uninjured and the degenerating/regenerating state may serve as biomarkers to aid in the future development of repair strategies and in monitoring neural tissue regeneration.

MiR-597 Targeting 14-3-3σ Enhances Cellular Invasion and EMT in Nasopharyngeal Carcinoma Cells

2019 ◽  
Vol 12 (2) ◽  
pp. 105-114 ◽  
Author(s):  
Lisha Xie ◽  
Tao Jiang ◽  
Ailan Cheng ◽  
Ting Zhang ◽  
Pin Huang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Downstream Target ◽  
Before And After

Background: Alterations in microRNAs (miRNAs) are related to the occurrence of nasopharyngeal carcinoma (NPC) and play an important role in the molecular mechanism of NPC. Our previous studies show low expression of 14-3-3σ (SFN) is related to the metastasis and differentiation of NPC, but the underlying molecular mechanisms remain unclear. Methods: Through bioinformatics analysis, we find miR-597 is the preferred target miRNA of 14-3-3σ. The expression level of 14-3-3σ in NPC cell lines was detected by Western blotting. The expression of miR-597 in NPC cell lines was detected by qRT-PCR. We transfected miR-597 mimic, miR-597 inhibitor and 14-3-3σ siRNA into 6-10B cells and then verified the expression of 14-3-3σ and EMT related proteins, including E-cadherin, N-cadherin and Vimentin by western blotting. The changes of migration and invasion ability of NPC cell lines before and after transfected were determined by wound healing assay and Transwell assay. Results: miR-597 expression was upregulated in NPC cell lines and repaired in related NPC cell lines, which exhibit a potent tumor-forming effect. After inhibiting the miR-597 expression, its effect on NPC cell line was obviously decreased. Moreover, 14-3-3σ acts as a tumor suppressor gene and its expression in NPC cell lines is negatively correlated with miR-597. Here 14-3-3σ was identified as a downstream target gene of miR-597, and its downregulation by miR-597 drives epithelial-mesenchymal transition (EMT) and promotes the migration and invasion of NPC. Conclusion: Based on these findings, our study will provide theoretical and experimental evidences for molecular targeted therapy of NPC.

scholarly journals 4-Aminopyridine as a Single Agent Diagnostic and Treatment for Severe Nerve Crush Injury

2019 ◽  
Vol 184 (Supplement_1) ◽  
pp. 379-385 ◽  
Author(s):  
Mark Noble ◽  
Kuang-Ching (Chris) Tseng ◽  
Haiyan Li ◽  
John C Elfar
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Enhanced Recovery ◽  
Treatment Options ◽  
Single Agent ◽  
Medical Problem ◽  
Post Injury ◽  
Electron Microscopic ◽  
Nerve Crush

Abstract Background Traumatic peripheral nerve injury (TPI) is a major medical problem without effective treatment options. There is no way to diagnose or treat an incomplete injury and delays contribute to morbidity. We examined 4-aminopyridine (4-AP), a potassium-channel blocker as a possible treatment for TPI. Methods We used standard mouse models of TPI with functional outcomes including sciatic-functional-index, sensory indices, and electrodiagnostics; in addition to standard immunohistochemical, and electron microscopic correlates of axon and myelin morphology. Results Sustained early 4-AP administration increased the speed and extent of behavioral recovery too rapidly to be explained by axonal regeneration. 4-AP also enhanced recovery of nerve conduction velocity, promoted remyelination, and increased axonal area post-injury. 4-AP treatment also enabled the rapid distinction between incomplete and complete nerve lesions. Conclusion 4-AP singularly provides both a new potential therapy to promote durable recovery and remyelination in acute peripheral nerve injury and a means of identifying lesions in which this therapy would be most likely to be of value. The ability to distinguish injuries that may respond to extended therapy without intervention can offer benefit to wounded soldiers.

scholarly journals Metadherin–PRMT5 complex enhances the metastasis of hepatocellular carcinoma through the WNT–β-catenin signaling pathway

2019 ◽  
Vol 41 (2) ◽  
pp. 130-138 ◽  
Author(s):  
Kai Zhu ◽  
Yuanfei Peng ◽  
Jinwu Hu ◽  
Hao Zhan ◽  
Liuxiao Yang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Arginine Methyltransferase ◽  
Mesenchymal Transition ◽  
Functional Assays ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Accumulating data suggest that metadherin (MTDH) may function as an oncogene. Our previous study showed that MTDH promotes hepatocellular carcinoma (HCC) metastasis via the epithelial-mesenchymal transition. In this study, we aim to further elucidate how MTDH promotes HCC metastasis. Using Co-immunoprecipitation (co-IP) and mass spectrometry, we found that MTDH can specifically bind to protein arginine methyltransferase 5 (PRMT5). Further functional assays revealed that PRMT5 overexpression promoted the proliferation and motility of HCC cells and that knockout of PRMT5 impeded the effect of MTDH. The immunohistochemistry assay/tissue microarray results showed that when MTDH was overexpressed in HCC cells, PRMT5 translocated from the nucleus to the cytoplasm, with the subsequent translocation of β-catenin from the cytoplasm to the nucleus and upregulation of the WNT–β-catenin signaling pathway. Further in vivo experiments suggested that PRMT5 and β-catenin played a pivotal role in MTDH-mediated HCC metastasis. We therefore concluded that the MTDH–PRMT5 complex promotes HCC metastasis by regulating the WNT–β-catenin signaling pathway.

scholarly journals A Review on the Role of Endogenous Neurotrophins and Schwann Cells in Axonal Regeneration

2021 ◽  
Author(s):  
Samyak Pandey ◽  
Jayesh Mudgal
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Treatment Option ◽  
Functional Recovery ◽  
Peripheral Nerve Injury ◽  
Pharmacological Intervention ◽  
Post Injury ◽  
Diverse Range ◽  
Physical Trauma

AbstractInjury to the peripheral nerve is traditionally referred to acquired nerve injury as they are the result of physical trauma due to laceration, stretch, crush and compression of nerves. However, peripheral nerve injury may not be completely limited to acquired physical trauma. Peripheral nerve injury equally implies clinical conditions like Guillain-Barré syndrome (GBS), Carpal tunnel syndrome, rheumatoid arthritis and diabetes. Physical trauma is commonly mono-neuropathic as it engages a single nerve and produces focal damage, while in the context of pathological conditions the damage is divergent involving a group of the nerve causing polyneuropathy. Damage to the peripheral nerve can cause a diverse range of manifestations from sensory impairment to loss of function with unpredictable recovery patterns. Presently no treatment option provides complete or functional recovery in nerve injury, as nerve cells are highly differentiated and inert to regeneration. However, the regenerative phenotypes in Schwann cells get expressed when a signalling cascade is triggered by neurotrophins. Neurotrophins are one of the promising biomolecules that are released naturally post-injury with the potential to exhibit better functional recovery. Pharmacological intervention modulating the expression of these neurotrophins such as brain-derived neurotrophic factor (BDNF) and pituitary adenylyl cyclase-activating peptide (PACAP) can prove to be a significant treatment option as endogenous compounds which may have remarkable innate advantage showing maximum ‘biological relevance’. Graphical abstract

scholarly journals Ral Overactivation in Malignant Peripheral Nerve Sheath Tumors

2009 ◽  
Vol 29 (14) ◽  
pp. 3964-3974 ◽  
Author(s):  
Vidya Bodempudi ◽  
Farnaz Yamoutpoor ◽  
Weihong Pan ◽  
Arkadiusz Z. Dudek ◽  
Tuba Esfandyari ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Cell Cycle Progression ◽  
Epithelial Mesenchymal Transition ◽  
Neurofibromatosis Type ◽  
Dominant Negative ◽  
Nerve Sheath Tumor ◽  
Mesenchymal Transition ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

ABSTRACT Ras leads an important signaling pathway that is deregulated in neurofibromatosis type 1 and malignant peripheral nerve sheath tumor (MPNST). In this study, we show that overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines. RalA, however, was overactivated in all MPNST cells and tumor samples compared to nontransformed Schwann cells. Silencing Ral or inhibiting it with a dominant-negative Ral (Ral S28N) caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells. Silencing Ral also reduced the expression of epithelial mesenchymal transition markers. Expression of the NF1-GTPase-related domain (NF1-GRD) diminished the levels of Ral activation, implicating a role for neurofibromin in regulating RalA activation. NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, but cell death increased. We propose Ral overactivation as a novel cell signaling abnormality in MPNST that leads to important biological outcomes with translational ramifications.

scholarly journals Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors

2021 ◽  
Author(s):  
Shivaani Kummar ◽  
Apurva K. Srivastava ◽  
Tony Navas ◽  
Fabiola Cecchi ◽  
Young H. Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Solid Tumors ◽  
Epithelial Mesenchymal Transition ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Common Adverse Event ◽  
Expansion Phase ◽  
Mesenchymal Transition ◽  
Before And After ◽  
Vegf Inhibition

SummaryThe vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors.

scholarly journals The progress of biomaterials in peripheral nerve repair and regeneration

2020 ◽  
Vol 8 (4) ◽  
pp. 252-269
Author(s):  
Yimeng Wang ◽  
Yuan Zhang ◽  
Xuemin Li ◽  
Qiqing Zhang
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Nerve Repair ◽  
Repair Process ◽  
Development Strategies ◽  
Post Injury ◽  
Peripheral Nerve Repair ◽  
Advantages And Disadvantages ◽  
Challenging Issue ◽  
Nerve Conduits

Repair and regeneration of the injured peripheral nerve (PN) is a challenging issue in clinics. Although the regeneration outcome of large PN defects is currently unsatisfactory, recently, the study of PN repair has considerably progressed. In particular, biomaterials for repairing PNs, such as nerve guidance conduits and nerve repair membranes, have been well developed. Herein, we summarize the anatomy of the PN, the pathophysiological features of the nerve injury, and the repair process post injury. Then, we highlight the progress in the development of natural and synthetic biomaterials and summarize the applications, advantages, and disadvantages of these materials. These materials can be used as nerve repair membranes and nerve conduits in the field of PN repair. Finally, we discuss the challenges encountered and development strategies for PN repair in the future.

scholarly journals Anesthetic Block of Pain-related Cortical Activity in Patients with Peripheral Nerve Injury Measured by Magnetoencephalography

2011 ◽  
Vol 115 (2) ◽  
pp. 375-386 ◽  
Author(s):  
Peter J. Theuvenet ◽  
Jan C. de Munck ◽  
Maria J. Peters ◽  
Jan M. van Ree ◽  
Fernando L. Lopes da Silva ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Ulnar Nerve ◽  
Peripheral Nerve Injury ◽  
Cortical Activation ◽  
Control Group ◽  
Global Field Power ◽  
Before And After ◽  
Local Block

Background This study examined whether chronic neuropathic pain, modulated by a local anesthetic block, is associated with cortical magnetic field changes. Methods In a group of 20 patients with pain caused by unilateral traumatic peripheral nerve injury, a local block with lidocaine 1% was administered and the cortical effects were measured and compared with a control group. The global field power (GFP), describing distribution of cortical activation after median and ulnar nerve stimulation, was plotted and calculated. The effects on the affected hemisphere and the unaffected hemisphere (UH) before and after a block of the injured nerve were statistically evaluated. Results Major differences based on the GFP curves, at a component between 50 ms - 90 ms (M70), were found in patients: in the affected hemisphere the M70 GFP peak values were statistically significantly larger in comparison with the UH, and the GFP curves differed morphologically. Interestingly, the mean UH responses were reduced in comparison with the control group, a finding suggesting that the UH is also part of the cortical changes. At M70, the GFP curves and values in the affected hemisphere were modulated by a local block of the median or the ulnar nerve. The most likely location of cortical adaptation is in the primary somatosensory cortex. Conclusions Cortical activation is enhanced in the affected hemisphere compared with the UH and is modulated by a local block. The UH in neuropathic pain changes as well. Evoked fields may offer an opportunity to monitor the effectiveness of treatments of neuropathic pain in humans.

Tendon Transfer in Partially Anaesthetic Hands

1987 ◽  
Vol 12 (1) ◽  
pp. 14-18
Author(s):  
N. CITRON ◽  
JANE TAYLOR
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Marked Improvement ◽  
Tendon Transfer ◽  
Dominant Hand ◽  
Before And After

Stereognosis and sensory localisation were studied in hands of patients with partial anaesthesia due to peripheral nerve injury both before and after tendon transfer to impart movement to the anaesthetic part. One patient showed a marked improvement in stereognosis and localisation, but in general little was gained in terms of improved sensation. Function was improved more in the dominant than in the non-dominant hand. Earlier tendon transfer in cases of peripheral nerve injury might decrease cortical exclusion.

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