Perineural invasion (PNI) by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma (OSCC). Since Schwann cells (SCs) and fibroblasts maintain the physiological homeostasis of the peripheral nervous system, and we have focused on cancer-associated fibroblasts (CAFs) for decades, it's imperative to elucidate the impact of CAFs on SCs in PNI⁺ OSCCs. We describe a disease progression-driven shift of PNI^- towards PNI⁺ during the progression of early-stage OSCC (31%, n = 125) to late-stage OSCC (53%, n = 97), characterized by abundant CAFs and nerve demyelination. CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro, and this involved up-regulated ER stress and decreased MAPK signals. Moreover, CAFs also aggravated the paralysis of the hind limb and PNI in vivo. Unexpectedly, leukemia inhibitory factor (LIF) was exclusively expressed on CAFs and up-regulated in metastatic OSCC. The LIF inhibitor EC330 restored CAF-induced SC inactivation. Thus, OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
Schwann Cells/metabolism* ; Mouth Neoplasms/metabolism* ; Humans ; Cancer-Associated Fibroblasts/metabolism* ; Animals ; Carcinoma, Squamous Cell/metabolism* ; Neoplasm Invasiveness/pathology* ; Male ; Female ; Mice ; Cell Movement/physiology* ; Cell Proliferation/physiology* ; Cell Line, Tumor ; Leukemia Inhibitory Factor/metabolism* ; Middle Aged

Demyelination and remyelination play key roles in spinal cord injury (SCI), affecting the recovery of motor and sensory functions. Research in rodent models is extensive, but the study of these processes in non-human primates is limited. Therefore, our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis. In a previous study, we created an SCI model in M. fascicularis by controlling the contusion displacement. We used Eriochrome Cyanine staining, immunohistochemical analysis, and toluidine blue staining to evaluate demyelination and remyelination. The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally, the former mainly impacting sensory pathways, while the latter primarily affected motor pathways. Toluidine blue staining showed myelin loss and axonal distension at the injury site. Schwann cell-derived myelin sheaths were only found at the center, while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas. Our study showed that long-lasting demyelination occurs in the spinal cord of M. fascicularis after SCI, with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.
Animals ; Spinal Cord Injuries/physiopathology* ; Demyelinating Diseases/etiology* ; Remyelination/physiology* ; Macaca fascicularis ; Disease Models, Animal ; Myelin Sheath/pathology* ; Oligodendroglia/pathology* ; Schwann Cells/pathology* ; Female ; Spinal Cord/pathology* ; Axons/pathology*

Diabetic peripheral neuropathy(DPN) is a chronic complication resulted from peripheral nerve injury in the late stage of diabetes. It involves a variety of pathological changes such as oxidative stress, endoplasmic reticulum stress, neuroinflammation, and apoptosis of Schwann cells(SCs). DPN is the main factor leading to lower limb disability or amputation in diabetic patients, with high incidence, long disease course, and poor prognosis. The modern medicine treatment of DPN mainly focuses on controlling blood glucose and improving microcirculation and nerve nutrition, which can only mitigate the clinical symptoms and not fundamentally reverse the pathological changes of peripheral nerves. Autophagy is a self-clearing mechanism that maintains cellular homeostasis by removing excess metabolites. Traditional Chinese medicine(TCM), featuring the holistic concept and syndrome differentiation, can treat chronic diseases in a multi-target, multi-pathway, and wide-range manner. Modern studies have shown that the occurrence and development of DPN are related to a variety of pathological changes, and autophagy is a key mechanism associated with DPN. The environment with persistent high glucose can lead to the inhibition or over-activation of peripheral nerve cells, which causes irreversible damage of nerve cells and the occurrence and development of DPN. Therefore, restoring autophagy balance and reducing nerve damage is one of the key ways to treat DPN. The recent studies have confirmed that some active ingredients in traditional Chinese medicines and TCM compound prescriptions can inhibit the oxidative stress, endoplasmic reticulum stress, mitochondrial damage, inflammation, and apoptosis of SCs in DPN by regulating the autophagy pathway, thus playing a role in the prevention and treatment of DPN. However, the systematic induction in this field remains to be carried out. This paper reviewed the relevant literature, explained the mechanism of TCM in the prevention and treatment of DPN by regulating autophagy, and summarized the potential targets of TCM in the treatment of DPN, with a view to providing new ideas for clinical research and drug development.
Humans ; Autophagy ; Diabetes Mellitus ; Diabetic Neuropathies/complications* ; Medicine, Chinese Traditional ; Oxidative Stress ; Schwann Cells/pathology*

Hamartoma/pathology* ; Humans ; Intestinal Mucosa/pathology* ; Schwann Cells/pathology*

PURPOSE: Wallerian degeneration (WD) is an antegrade degenerative process distal to peripheral nerve injury. Numerous genes are differentially regulated in response to the process. However, the underlying mechanism is unclear, especially the early response. We aimed at investigating the effects of sciatic nerve injury on WD via CLDN 14/15 interactions in vivo and in vitro. METHODS: Using the methods of molecular biology and bioinformatics analysis, we investigated the molecular mechanism by which claudin 14/15 participate in WD. Our previous study showed that claudins 14 and 15 trigger the early signal flow and pathway in damaged sciatic nerves. Here, we report the effects of the interaction between claudin 14 and claudin 15 on nerve degeneration and regeneration during early WD. RESULTS: It was found that claudin 14/15 were upregulated in the sciatic nerve in WD. Claudin 14/15 promoted Schwann cell proliferation, migration and anti-apoptosis in vitro. PKCα, NT3, NF2, and bFGF were significantly upregulated in transfected Schwann cells. Moreover, the expression levels of the β-catenin, p-AKT/AKT, p-c-jun/c-jun, and p-ERK/ERK signaling pathways were also significantly altered. CONCLUSION Claudin 14/15 affect Schwann cell proliferation, migration, and anti-apoptosis via the β-catenin, p-AKT/AKT, p-c-jun/c-jun, and p-ERK/ERK pathways in vitro and in vivo. The results of this study may help elucidate the molecular mechanisms of the tight junction signaling pathway underlying peripheral nerve degeneration.
Animals ; Claudins ; Nerve Regeneration ; Peripheral Nerve Injuries ; Rats ; Schwann Cells/pathology* ; Sciatic Nerve ; Wallerian Degeneration/pathology*

Charcot-Marie-Tooth disease (CMT) is the commonest form of inherited neuropathy and has an incidence of 1/2500. CMT1A is the commonest subtype of CMT, which is caused by duplication of peripheral myelin protein 22 (PMP22) gene and accounts for approximately 50% of CMT diagnosed by genetic testing. Duplication of PMP22 may influence the production of PMP22 mRNA and protein, and interfere with the proliferation, differentiation and apoptosis of Schwann cells. In addition, deregulation of NRG1/ErbB pathway and lipid metabolism can also lead to dysfunction of Schwann cells. Such factors may disturb the myelination process, leading to axon degeneration, muscle weakness, and atrophy subsequently. Accordingly, drug therapies for CMT1A are developed by targeting such factors. PXT3003, antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are supposed to down-regulate the level of PMP22 mRNA, while recombinant human NRG-1 (rhNRG1) and neurotrophin-3 (NT-3) may enhance Schwann cells survival and differentiation. In addition, lipid-supplemented diet may remedy the defect of lipid metabolism and maintain the proper structure of myelin. Other targeting drugs include ascorbic acid, progesterone antagonists, IFB-088, ADX71441, and ACE-083. This review is to sum up the pathogenesis of CMT1A and promising targeting drug therapies for further research.
Cell Differentiation ; Charcot-Marie-Tooth Disease ; genetics ; pathology ; therapy ; Genetic Testing ; Humans ; Schwann Cells ; cytology

OBJECTIVETo observe the deregulation of autophagy in diabetic peripheral neuropathy (DPN) and investigate whether Jinmaitong ( JMT) alleviates DPN by inducing autophagy.

METHODSDPN models were established by streptozotocin-induced diabetic rats and Schwann cells (SCs) cultured in high glucose medium. The pathological morphology was observed by the improved Bielschowsky's nerve fiber axonal staining and the Luxol fast blue-neutral red myelin staining. The ultrastructure was observed by the transmission electron microscopy. Beclin1 level was detected by immunohistochemistry and Western blot. The proliferation of cultured SCs was detected by methylthiazolyldiphenyl-tetrazolium bromide.

RESULTSDiabetic peripheral nerve tissues demonstrated pathological morphology and reduced autophagic structure, accompanied with down-regulation of Beclin1. JMT apparently alleviated the pathological morphology change and increased the autophagy [in vivo, Beclin1 integral optical density (IOD) value of the control group 86.6±17.7, DM 43.9±8.8, JMT 73.3 ±17.8, P<0.01 or P<0.05, in vitro Beclin1 IOD value of the glucose group 0.47±0.25 vs the control group 0.88±0.29, P<0.05]. Consequently, inhibition of autophagy by 3-methyladenine resulted in a time- and concentration-dependent decrease of the proliferation of SCs (P<0.05, P<0.01).

CONCLUSIONSDown-regulation of autophagy in SCs might contribute to the pathogenesis of DPN. JMT alleviates diabetic peripheral nerve injury at least in part by inducing autophagy.

Animals ; Autophagy ; drug effects ; Axons ; drug effects ; pathology ; Beclin-1 ; metabolism ; Cell Proliferation ; drug effects ; Cells, Cultured ; Diabetes Mellitus, Experimental ; complications ; drug therapy ; pathology ; Diabetic Neuropathies ; complications ; drug therapy ; pathology ; Down-Regulation ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Glucose ; pharmacology ; Immunohistochemistry ; Male ; Rats, Wistar ; Schwann Cells ; drug effects ; pathology ; Sciatic Nerve ; drug effects ; pathology ; ultrastructure ; Staining and Labeling

Schwannomas are the most common benign nerve sheath tumors originating in Schwann cells. With special conditions like neurofibromatosis type 2 or entity called schwannomatosis, patients develop multiple schwannomas. But in clinical setting, distinguishing schwannomatosis from neurofibromatosis type 2 is challengeable. We describe 58-year-old male who presented with severe neuropathic pain, from schwannomatosis featuring multiple schwannomas of spine and trunk, and underwent surgical treatment. We demonstrate his radiologic and clinical findings, and discuss about important clinical features of this condition. To confirm schwannomatosis, we performed brain magnetic resonance imaging, and took his familial history. Staged surgery was done for pathological confirmation and relief of the pain. Schwannomatosis and neurofibromatosis type 2 are similar but different disease. There are diagnostic hallmarks of these conditions, including familial history, pathology, and brain imaging. Because of different prognosis, the two diseases must be distinguished, so diagnostic tests that are mentioned above should be performed in caution.
Brain ; Diagnostic Tests, Routine ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Nerve Sheath Neoplasms ; Neuralgia ; Neurilemmoma* ; Neurofibromatosis 2 ; Neuroimaging ; Pathology ; Prognosis ; Schwann Cells ; Spine*

PURPOSE: Charcot-Marie-Tooth disease (CMT) is a peripheral neuropathy mainly divided into CMT type 1 (CMT1) and CMT2 according to the phenotype and genotype. Although molecular pathologies for each genetic causative have not been revealed in CMT2, the correlation between cell death and accumulation of misfolded proteins in the endoplasmic reticulum (ER) of Schwann cells is well documented in CMT1. Establishment of in vitro models of ER stress-mediated Schwann cell death might be useful in developing drug-screening systems for the treatment of CMT1. MATERIALS AND METHODS: To develop high-throughput screening (HTS) systems for CMT1, we generated cell models using transient expression of mutant proteins and chemical induction. RESULTS: Overexpression of wild type and mutant peripheral myelin protein 22 (PMP22) induced ER stress. Similar results were obtained from mutant myelin protein zero (MPZ) proteins. Protein localization revealed that expressed mutant PMP22 and MPZ proteins accumulated in the ER of Schwann cells. Overexpression of wild type and L16P mutant PMP22 also reduced cell viability, implying protein accumulation-mediated ER stress causes cell death. To develop more stable screening systems, we mimicked the ER stress-mediated cell death in Schwann cells using ER stress inducing chemicals. Thapsigargin treatment caused cell death via ER stress in a dose dependent manner, which was measured by expression of ER stress markers. CONCLUSION: We have developed genetically and chemically induced ER stress models using Schwann cells. Application of these models to HTS systems might facilitate the elucidation of molecular pathology and development of therapeutic options for CMT1.
Cell Death ; Cell Survival ; Charcot-Marie-Tooth Disease* ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Genotype ; Mass Screening* ; Mutant Proteins ; Myelin P0 Protein ; Myelin Sheath ; Pathology, Molecular ; Peripheral Nervous System Diseases ; Phenotype ; Schwann Cells ; Thapsigargin

BACKGROUND: Schwannomas are benign tumors of ectodermal origin derived from Schwann cells of the nerve sheath. Approximately less than 4% of these tumors are found in the paranasal sinuses and there has been little information reported concerning the presentation and surgical management of sinonasal schwannomas. The purpose of this study was to analyze the clinical data, management, and long-term outcomes of sinonasal schwannomas. METHODS: Retrospective chart review of patients with sinonasal schwannomas treated from January 2001 to March 2012 was performed. Clinical data and follow-up information were obtained from a review of the patients' charts and the operative, anesthesia, and pathology reports. RESULTS: There were 4 females and 4 males included in this study. The mean age was 37.5 years (range, 22-51 years). The mean tumor size was 3.1 cm (range 1.0-6.0 cm). The origin of the tumors included: nasal septum (n = 2), nasal vestibule (n = 2), pterygopalatine fossa (n = 2), ethmoid sinus (n = 1), and inferior turbinate (n = 1). Seven patients had endoscopic resections and one patient with a schwannoma in the nasal vestibule underwent a sublabial approach. The mean follow-up was 59 months. There were no tumor recurrences during the study period. CONCLUSIONS: Schwannomas in sinonasal cavity can be treated effectively with the endoscopic approach with minimal morbidity and long-term disease control.
Anesthesia ; Ectoderm ; Ethmoid Sinus ; Female ; Follow-Up Studies ; Humans ; Male ; Nasal Septum ; Neurilemmoma* ; Paranasal Sinuses ; Pathology ; Pterygopalatine Fossa ; Recurrence ; Retrospective Studies ; Schwann Cells ; Turbinates