Myelin Protein Research Articles

Bone marrow stromal cell-conditioned medium regenerates injured sciatic nerve by increasing expression of MPZ and NGF and decreasing apoptosis.

Despite the many benefits of mesenchymal stem cell (MSC) transplantation for tissue regeneration, there are some limitations to using them, including the high costs, applying invasive procedures, the possibility of transplant rejection, and cell malignancy. This study aimed to investigate the effect of secretions of bone marrow stromal cells (BMSCs) with the cell-free strategy on damaged sciatic nerve with an emphasis on the role of apoptosis and the expression of myelin protein zero (MPZ) and nerve growth factor (NGF) proteins. BMSCs were cultured and a 25-fold concentrated conditioned medium (CM) from the cells was provided. After creating a crush injury in the left sciatic nerve of male rats, BMSCs or CM were injected into the injured site of the nerve. Four weeks later, the expression of MPZ, NGF, Bax, and Bcl-2 proteins in the sciatic nerve and histological parameters of the sciatic nerve and gastrocnemius muscle were assessed. The results demonstrated that injection of CM decreased apoptosis and increased expression of MPZ and NGF proteins, improving remyelination and regeneration of the sciatic nerve almost as much as the transplantation of the BMSCs themselves compared to the control group. The results suggest that BMSC secretions may improve remyelination and regeneration of damaged sciatic nerve by increasing the expression of MPZ and NGF and decreasing apoptosis.

Glaucoma, More than Meets the Eye: Patterns of Demyelination Revealed in Human Postmortem Glaucomatous Optic Nerve.

Glaucoma is a neurodegenerative disease affecting millions worldwide, characterised by retinal ganglion cell (RGC) degeneration which leads to blindness in more advanced cases. Although the pathogenesis and underlying mechanisms of glaucoma are not fully understood, there are theories that hint at demyelination playing a role in the disease process. Demyelination, or the degeneration of the myelin sheath surrounding axons, has been found in previous studies using animal models of glaucoma and clinical assessments of glaucoma patients. However, this has not been fully realised or quantified in glaucoma patients. Utilising postmortem optic nerve samples from glaucoma and healthy subjects, various immunohistochemical and morphological assessments were performed to determine the extent, if any, of demyelination in glaucomatous optic nerves. Our findings revealed that alongside nerve shrinkage and degeneration of nerve tissue fascicles, there were significantly less myelin proteins, specifically myelin basic protein (MBP), in glaucoma optic nerves. Additionally, the loss of MBP was correlated with decreased oligodendrocyte (OLG) precursors and increasing glial activity. This further supports previous evidence that demyelination may be a secondary degenerative process associated with glaucoma disease progression. Not only do these results provide evidence for potential disease mechanisms, but this is also the first study to quantify optic nerve demyelination in glaucoma postmortem tissue.

IMPAIRMENT OF AUDITORY FUNCTION IN PERSONS WITH TYPE 2 DIABETES MELLITUS DEPENDING ON THE LEVEL OF PERIPHERAL MYELIN PROTEIN

Introduction: One of the priority tasks of modern medicine is early diagnosis and treatment of micro- and macrovascular complications of diabetes mellitus (DM). Variability of carbohydrate metabolism indicators, metabolic dysfunction are leading factors in the development and progression of complications of type 2 DM with hearing loss due to degenerative changes in nerve fibers. An important aspect of diagnostic and treatment algorithms of SNHL in patients with type 2 DM is early detection of demyelinating processes to prevent neuronal structures damage. The purpose of the study is to determine the relationship between the level of peripheral myelin protein 22 (PMP 22) and the condition of the auditory analyzer according to the data of examination in patients with type 2 DM combined with hearing impairment. Material and methods: There were examined 30 patients with type 2 DM (15 men and 15 women aged 56,28±4,54 years) associated with degree I–II sensorineural disorders; 15 persons with signs of sensorineural hearing loss (SNHL) (8 men, 7 women aged 59,33±2,65 years) without diabetes and 15 controls. During the examination the studied patients were divided into groups: the 1st group (n=15) without or with isolated microvascular complications of type 2 DM, the 2nd group (n = 15) with neuro-, nephro- and retinopathy. All patients underwent a set of laboratory tests, clinical and instrumental diagnostics of auditory function. The obtained data subjected to statistical processing and correlations identified. Results: The analysis revealed that in patients both groups with type 2 DM and SNHL the level of PMP22 significantly increased compared to controls and the comparison group and more significantly in those with microangiopathies. Conclusions: A significant increase was revealed in the content of PMP 22 and manifestations of SNHL in patients with type 2 DM associated with microangiopathies that indicate demyelinating processes in the neural structures of the auditory analyzer.

Diverse Responses of Oligodendrocytes to Different FGF-Family Members: Uncoupling Structure-Function Relationship Within FGF Subfamilies.

The fifteen canonical paracrine fibroblast growth factors (FGFs) are organized in five subfamilies that interact with four FGF-receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co-receptors. Many of these FGFs are expressed in CNS regions where oligodendrocyte (OL) progenitors originate, migrate or differentiate. FGF2 (basic FGF) is considered a prototype FGF and the information about the effects of FGF signaling on OL-lineage cells has evolved largely from the study of FGF2. However, other FGFs from four subfamilies ((FGF1 (FGF1,-2), FGF4 (FGF4,-5,-6), FGF8 (FGF8,-17,-18) and FGF9 (FGF9,-16,-20)) that can interact with the isoforms of FGFRs expressed in OL-lineage cells may also play important roles. We previously reported OL-responses to FGF8 family members. Here, we investigate the effects of members of the FGF1,-4, and -9 subfamilies on proliferation and differentiation of OL progenitors (OPCs), and on cell cycle re-entry and down-regulation of myelin proteins by mature OLs. We found that while FGF2 induced all these responses strongly, FGF4,-6,-9 could do so only transiently and in the presence of exogenous HSPGs, and that FGF5,-16,-20 could not do so even in the presence of heparin or at higher concentrations. Furthermore, we noted that structurally similar FGFs within subfamilies did not always show similarities in their biological effects on OL-lineage cells. Taken together, these studies reveal that FGFs differ in the way they regulate the OL-lineage cells, emphasizes the selectivity and importance of HSPGs as FGF co-receptors in OL-lineage cells and suggests that structural similarity among FGF-subfamily members may not always predict their overlapping biological functions.

Effect of Melatonin Administration on Nerve Regeneration after Recurrent Laryngeal Nerve Injury.

Recurrent Laryngeal Nerve (RLN) injury is a complication in neck surgery. The aim of this study is to evaluate the effect of primary suture repair with melatonin treatment on nerve regeneration after RLN damage. After the RLN damage, nerve repair was performed in the first and fourth groups. The third and fourth groups were given intraperitoneal melatonin therapy daily for six weeks. EMG was applied to all subjects and vocal cord movements were evaluated endoscopically. At the end of the sixth week, all subjects were sacrificed, and their larynx were examinedhistologically. Vocal cord paralysis (VCP) was observed in all subjects after RLN damage. In the sixth week, improvement was observed in the first and fourth group who underwent nerve repair, whereas none in the second and third group, who did not undergo nerve repair, improved. With EMG, the highest MUP was in the fourth group. Histologically, an increase in Schwann cells, a decrease in axon damage, and cytoplasmic vacuolization were in the fourth group. Myelin protein zero and Ki-67 staining were the most in the fourth group. In our study, laryngoscopic, electrophysiological and histopathological findings show that melatonin contributes to nerve healing but this could not translate into functional recovery.

Unveiling the biological effects of radio-frequency and extremely-low frequency electromagnetic fields on the central nervous system performance.

Radiofrequency electromagnetic radiation (RF-EMR) and extremely low-frequency electromagnetic fields (ELF-EMF) have emerged as noteworthy sources of environmental pollution in the contemporary era. The potential biological impacts of RF-EMR and ELF-EMF exposure on human organs, particularly the central nervous system (CNS), have garnered considerable attention in numerous research studies. This article presents a comprehensive yet summarized review of the research on the explicit/implicit effects of RF-EMR and ELF-EMF exposure on CNS performance. Exposure to RF-EMR can potentially exert adverse effects on the performance of CNS by inducing changes in the permeability of the blood-brain barrier (BBB), neurotransmitter levels, calcium channel regulation, myelin protein structure, the antioxidant defense system, and metabolic processes. However, it is noteworthy that certain reports have suggested that RF-EMR exposure may confer cognitive benefits for various conditions and disorders. ELF-EMF exposure has been associated with the enhancement of CNS performance, marked by improved memory retention, enhanced learning ability, and potential mitigation of neurodegenerative diseases. Nevertheless, it is essential to acknowledge that ELF-EMF exposure has also been linked to the induction of anxiety states, oxidative stress, and alterations in hormonal regulation. Moreover, ELF-EMR exposure alters hippocampal function, notch signaling pathways, the antioxidant defense system, and synaptic activities. The RF-EMR and ELF-EMF exposures exhibit both beneficial and adverse effects. Nevertheless, the precise conditions and circumstances under which detrimental or beneficial effects manifest (either individually or simultaneously) remain uncertain.

Utility of cerebrospinal fluid protein biomarkers in predicting the outcome of Guillain-Barre syndrome

Objectives The study aimed to investigate the potential of peripheral myelin protein 2 (P2) and Alpha B-crystallin (αBC) as predictive biomarkers in Guillain-Barré syndrome (GBS). Given the unpredictability of GBS prognosis, the need for specific and reliable biomarkers for disease development and intensity assessment is crucial. Material and Methods A prospective observational study was conducted on a cohort of 220 individuals diagnosed with GBS at a tertiary general hospital in South India. P2 and αBC levels in cerebrospinal fluid (CSF) were quantified using ELISA assay kits. The study spanned from March 2021 to April 2023, with participants aged 18–60 years. The study protocol adhered to ethical standards, and the Brighton criteria were employed for GBS diagnosis. CSF samples were collected at admission and two weeks post-onset. Data analysis utilised SPSS, and statistical significance was set at p < 0.05. Results Upon admission, mean P2 levels were 2.2 ± 0.5 ng/mL, and αBC levels were 9.8 ± 2.3 ng/mL. After two weeks, P2 increased to 4.8 ± 0.8 ng/mL, and αBC increased to 15.1 ± 2.3 ng/mL. A positive correlation was observed between the rise in P2 and αBC levels and enhanced muscle strength at 4 weeks and 6 months. Conclusion The study suggests a significant increase in P2 and αBC levels in GBS patients, correlating with improved muscle strength. P2 and αBC ratios in CSF between the second and first weeks may serve as prognostic markers for GBS. Limitations include a small sample size and the absence of a control group, necessitating caution in generalizability.

Enriched environment enhanced the astrocyte-derived BDNF and VEGF expression and alleviate white matter injuries of rats with ischemic stroke

ABSTRACT Objectives Numerous studies have shown that an enriched environment can promote ischemic stroke and improve cognitive function. In addition, white matter is closely related to cognitive function. The effects and mechanisms of the enriched environment on white matter recovery after stroke have not been elucidated. This study will analyse the effects of the enriched environment on white matter and cognitive function in the post-stroke brain from the perspective of astrocytes and their secretions. Methods Stroke models were used for middle cerebral artery occlusion model. post-operative rats were divided into sham-operated, standard and enriched environment groups. The degree of cerebral infarction was assessed by TTC staining and the degree of white matter damage was assessed by Luxol-Fast Blue staining. The prognosis after stroke was assessed using the longa score and Morris water maze test. Western Blot and immunofluorescence were used to quantify and localize astrocytes and their associated secretory factors and myelin protein markers. Results We found that ischemic stroke can cause severe demyelination. After EE treatment, there was a significant increase in cerebral remyelination and a significant improvement in neurological and cognitive functions. Astrocyte, BDNF, and VEGF expression were significantly higher than in rats in the standard circumstances of stroke model. Conclusion These data suggest that the enriched environment contributes to brain white matter recovery and improvement of cognitive function after stroke. The mechanism is related to astrocytes and their secretions. EE can activate astrocytes to secrete BDNF and VEGF, which may be crucial to promote white matter recovery.

Generation of a fluorescent oligodendrocyte reporter line in human induced pluripotent stem cells

Human brain organoids can serve as models to study myelination, a process orchestrated by oligodendrocytes. Real-time imaging provides new insights on the communication of oligodendrocytes with neurons as well as demyelination processes in patient derived organoids. PLP1, a prominent myelin protein within the central nervous system, is associated with demyelinating diseases, such as Pelizaeus-Merzbacher. In this study, we generated a stable PLP1-Citrine reporter line (fPLP1) in human induced pluripotent stem cells (iPSCs) by CRISPR/Cas9 editing. fPLP1 facilitates visualization of PLP1 expression in living brain organoids, allowing time-lapse imaging of pre-myelinating and myelinating oligodendrocytes.

Preclinical Efficacy of Peripheral Nerve Regeneration by Schwann Cell-like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells in C22 Mice.

Charcot-Marie-Tooth disease (CMT) is a hereditary disease with heterogeneous phenotypes and genetic causes. CMT type 1A (CMT1A) is a type of disease affecting the peripheral nerves and is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene. Human tonsil-derived mesenchymal stem cells (TMSCs) are useful for stem cell therapy in various diseases and can be differentiated into Schwann cell-like cells (TMSC-SCs). We investigated the potential of TMSC-SCs called neuronal regeneration-promoting cells (NRPCs) for peripheral nerve and muscle regeneration in C22 mice, a model for CMT1A. We transplanted NRPCs manufactured in a good manufacturing practice facility into the bilateral thigh muscles of C22 mice and performed behavior and nerve conduction tests and histological and ultrastructural analyses. Significantly, the motor function was much improved, the ratio of myelinated axons was increased, and the G-ratio was reduced by the transplantation of NRPCs. The sciatic nerve and gastrocnemius muscle regeneration of C22 mice following the transplantation of NRPCs downregulated PMP22 overexpression, which was observed in a dose-dependent manner. These results suggest that NRPCs are feasible for clinical research for the treatment of CMT1A patients. Research applying NRPCs to other peripheral nerve diseases is also needed.

Lobe‐specific changes in white matter volume and myelination following 6‐month 40 Hz gamma sensory stimulation in patients on the Alzheimer’s disease spectrum

AbstractBackgroundAlthough morphometric changes in Alzheimer’s Disease (AD) occur both in gray and white matter, gray matter changes had been the primary focus of previous work. Recent studies have highlighted the importance of pathological changes in white matter and myelination in AD patients, including early changes to oligodendrocytes and transcription of myelin protein genes in the white matter prior to symptoms of cognitive decline, even in subjects with AD but without other neurological comorbidities (Ferrer et al., 2020). Since neuronal activities, particularly network oscillations have been shown to promote myelination, the present study examined how 40Hz gamma stimulation affected white matter volume and myelination in different cortical lobes in patients with AD.MethodData were obtained from the Overture trial (NCT03555281) in which treatment participants received daily, at‐home, 40Hz gamma sensory stimulation for six months, while placebo participants received sham stimulation (treatment‐to‐placebo ratio 2:1). Magnetic resonance imaging (MRI) data were collected at 1.5 Tesla at baseline, month 3, and month 6. MRI T1 images and T1w/T2w ratios were used to estimate volume (N = 38) and myelination (N = 36), respectively. Using Bayesian linear mixed effects modeling, we estimated white matter volume and myelination percent changes with respect to baseline. Treatment group results were reported in relation to the placebo group.ResultWith respect to the placebo group: In the left hemisphere, the treatment group exhibited reduced white matter atrophy in the frontal lobe (‐3.27±1.4, p = 0.0225), in the temporal lobe (‐3.9±1.76, p = 0.0306), in the parietal lobe (‐3.32±1.43, p = 0.0236), in the occipital lobe (‐4.1±1.72, p = 0.0195) and reduced demyelination in the frontal lobe (‐5.13±2.12, p = 0.0186), in the temporal lobe (‐5.33±2.42, p = 0.0321), in the parietal lobe (‐5.7±2.07 (p = 0.0079), in the occipital lobe (‐5.65±2.52, p = 0.0296). In the right hemisphere, the treatment group trended towards reduced white matter volume loss and demyelination in all lobes, however, demyelination was significantly reduced in the parietal lobe (‐4.48±2.09, p = 0.037), and in the occipital lobe (‐5.5±2.22, p = 0.0165).ConclusionWhite matter atrophy and demyelination were statistically significantly reduced in all lobes of the left hemisphere and trended towards reduction in the right hemisphere, demonstrating that 40Hz sensory stimulation can reduce the neurodegeneration associated with AD.

Impairment of auditory function in persons with type 2 diabetes mellitus depending on the level of peripheral myelin protein 22

Background. One of the priority tasks of modern medicine is early diagnosis and treatment of micro- and macrovascular complications of diabetes mellitus (DM) which cause a decrease in the quality of life of working age people and an increase in mortali­ty. Variability of carbohydrate metabolism indicators, metabolic dysfunction are leading factors in the development and progression of disabling complications of type 2 DM with hearing loss due to degenerative changes in nerve fibers. An important aspect of diagnostic and treatment algorithms of sensorineural hearing disorders in patients with type 2 DM is early detection of demyelinating processes to prevent damage to neuronal structures. The purpose of the study is to determine the relationship between the level of peripheral myelin protein 22 (PMP 22) and the condition of the auditory analyzer according to the data of instrumental examination in patients with type 2 DM combined with hearing impairment. Materials and methods. There were examined 30 patients with type 2 DM (15 men and 15 women aged 56.28 ± 4.54 years) associated with degree I–II sensorineural disorders of the auditory function; 15 people with signs of sensorineural hearing loss (SNHL) (8 men, 7 women aged 59.33 ± 2.65 years) without diabetes and 15 controls. During the examination, the patients with type 2 DM and SNHL, depending on the severity of the underlying disease, were divided into groups: the first group (n = 15) with or without isolated microvascular complications of type 2 DM, the second group (n = 15) with neuro-, nephro- and retinopathy. All patients underwent a set of laboratory tests to determine the content of PMP 22 in the blood serum, clinical and instrumental diagnosis of the auditory function. The obtained data were processed statistically, and correlations were identified. Results. The analysis of the results revealed that in patients with type 2 DM and SNHL (groups 1 and 2), the level of peripheral myelin protein 22 significantly increased compared to both controls and the comparison group, and more significantly in those with microangiopathies. The correlations were found bet­ween the most informative indicators reflecting the state of various structures of the hearing analyzer and the content of PMP 22 in the blood serum. Conclusions. A significant increase was revealed in the content of PMP 22 and manifestations of sensorineural hearing loss in patients with type 2 diabetes mellitus associated with microangiopathies that indicate demyelinating processes in the neural structures of the auditory analyzer.

AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells

BackgroundCharcot-Marie-Tooth disease type 1A (CMT1A) is one of the most common hereditary peripheral neuropathies caused by duplication of 1.5 Mb genome region including PMP22 gene. We aimed to correct the duplication in human CMT1A patient-derived iPS cells (CMT1A-iPSCs) by genome editing and intended to analyze the effect on Schwann cells differentiated from CMT1A-iPSCs.MethodsWe designed multiple gRNAs targeting a unique sequence present at two sites that sandwich only a single copy of duplicated peripheral myelin protein 22 (PMP22) genes, and selected one of them (gRNA3) from screening their efficiencies by T7E1 mismatch detection assay. AAV2-hSaCas9-gRNAedit was generated by subcloning gRNA3 into pX601-AAV-CMV plasmid, and the genome editing AAV vector was infected to CMT1A-iPSCs or CMT1A-iPSC-derived Schwann cell precursors. The effect of the genome editing AAV vector on myelination was evaluated by co-immunostaining of myelin basic protein (MBP), a marker of mature myelin, and microtubule-associated protein 2(MAP2), a marker of neurites or by electron microscopy.ResultsHere we show that infection of CMT1A-iPS cells (iPSCs) with AAV2-hSaCas9-gRNAedit expressing both hSaCas9 and gRNA targeting the tandem repeat sequence decreased PMP22 gene duplication by 20–40%. Infection of CMT1A-iPSC-derived Schwann cell precursors with AAV2-hSaCas9-gRNAedit normalized PMP22 mRNA and PMP22 protein expression levels, and also ameliorated increased apoptosis and impaired myelination in CMT1A-iPSC-derived Schwann cells.ConclusionsIn vivo transfer of AAV2-hSaCas9-gRNAedit to peripheral nerves could be a potential therapeutic modality for CMT1A patient after careful examinations of toxicity including off-target mutations.

Deletion of voltage-gated calcium channels in astrocytes decreases neuroinflammation and demyelination in a murine model of multiple sclerosis

The experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis was used in combination with a Cav1.2 conditional knock-out mouse (Cav1.2KO) to study the role of astrocytic voltage-gated Ca++ channels in autoimmune CNS inflammation and demyelination. Cav1.2 channels were specifically ablated in Glast-1-positive astrocytes by means of the Cre-lox system before EAE induction. After immunization, motor activity was assessed daily, and a clinical score was given based on the severity of EAE symptoms. Cav1.2 deletion in astrocytes significantly reduced the severity of the disease. While no changes were found in the day of onset and peak disease severity, EAE mean clinical score was lower in Cav1.2KO animals during the chronic phase of the disease. This corresponded to better performance on the rotarod and increased motor activity in Cav1.2KO mice. Furthermore, decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes were found in the lumbar section of the spinal cord of Cav1.2KO mice 40 days after immunization. The degree of myelin protein loss and size of demyelinated lesions were also attenuated in Cav1.2KO spinal cords. Similar results were found in EAE animals treated with nimodipine, a Cav1.2 Ca++ channel inhibitor with high affinity to the CNS. Mice injected with nimodipine during the acute and chronic phases of the disease exhibited lower numbers of reactive astrocytes, activated microglial, and infiltrating immune cells, as well as fewer demyelinated lesions in the spinal cord. These changes were correlated with improved clinical scores and motor performance. In summary, these data suggest that antagonizing Cav1.2 channels in astrocytes during EAE alleviates neuroinflammation and protects the spinal cord from autoimmune demyelination.

PATH-02. NOVEL SOX10 INDEL MUTATIONS DRIVE SCHWANNOMAS THROUGH IMPAIRED TRANSACTIVATION OF MYELINATION GENE PROGRAMS

Abstract Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity due to their stereotypic intracranial and paraspinal locations. However, the molecular drivers responsible for a substantial subset remain unknown. Through genomic profiling of 96 schwannomas, we identified novel in-frame insertion/deletion mutations in the SOX10 gene in 29% of sporadic tumors which uniformly lacked alterations in known nerve sheath tumor genes including NF1, NF2, LZTR1, and SMARCB1. These indel mutations clustered at the C-terminal end of the HMG-box domain, the DNA binding motif of the SOX10 transcription factor critical for Schwann cell differentiation. Schwannomas arising from non-vestibular cranial nerves (e.g. facial, trigeminal, vagus) were highly enriched for SOX10 mutations, whereas the vast majority of vestibular schwannomas had NF2 inactivation. DNA methylation profiling revealed that SOX10 mutant schwannomas clustered together with schwannomas harboring NF2 mutation or SH3PXD2A-HTRA1 fusion, indicating that SOX10 indel mutations define a novel schwannoma molecular subtype and not a distinct nerve sheath tumor entity. To investigate the mechanism by which SOX10 indel mutations promote schwannoma development, we stably transduced human fetal glial cells with either wildtype SOX10 or two different tumor-derived insertion mutants. RNA sequencing revealed that both SOX10 indel mutants, in contrast to wildtype SOX10, failed to activate expression of myelination and glial differentiation gene programs, including PMP2 which encodes the major peripheral myelin protein in mature Schwann cells. Electrophoretic mobility shift assay revealed that the indel mutants retained their DNA binding capacity to the SOX10 binding site in the PMP2 promoter, while a luciferase reporter assay revealed transactivation at the PMP2 promoter by wildtype SOX10 but not by the mutants. In summary, we identified a new recurrent genetic event in 29% of sporadic schwannomas that we speculate drives schwannoma development through impaired transactivation of myelination gene expression programs causing blocked differentiation of immature Schwann cells.

Platinum-based chemotherapy induces demyelination of Schwann cells in oral squamous cell carcinoma treatment

BackgroundCisplatin, carboplatin, and oxaliplatin are the only three platinum-based antineoplastic drugs that have been accepted worldwide for treating various cancers. Up to 83.6% of patients treated with platinum-based antineoplastic drugs will develop chemotherapy-induced peripheral neuropathy (CIPN), manifesting as sensory paresthesias, dysesthesias, and hypoesthesias that can cause significant adverse impact to daily activities. AimTo investigate how these three platinum-based drugs affect mitochondrial function and myelination state of Schwann cells and the signalling pathway involved. Method2 μM Cisplatin, 20 μM carboplatin, and 1 μM oxaliplatin were used to inhibit the growth of CAL-27 by 20% respectively. These drugs were then used to induce chemotherapy-induced peripheral neuropathy in Rat Schwann Cells (RSC96). The changes in cell metabolism and myelin formation in RSC96 were investigated. ResultCisplatin and carboplatin, but not oxaliplatin increased intracellular and mitochondrial reactive oxygen species in RSC96. Only Cisplatin and carboplatin decreased mitochondrial membrane potential (ΔΨm) and ATP production in RSC96. Both Cisplatin and carboplatin led to demyelination of RSC96, characterized by increased expression of p75NTR and decreased expression of myelin protein zero (MPZ). ConclusionCisplatin and carboplatin, but not oxaliplatin, caused mitochondrial dysfunction and induced demyelination in RSC96 while showing similar toxicity to head and neck cancer cells. Oxaliplatin may be a potential chemotherapy drug to prevent CIPN in patients with head and neck cancer.

Voluntary wheel running prevents formation of membrane attack complexes and myelin degradation after peripheral nerve injury

Regular aerobic activity is associated with a reduced risk of chronic pain in humans and rodents. Our previous studies in rodents have shown that prior voluntary wheel running can normalize redox signaling at the site of peripheral nerve injury, attenuating subsequent neuropathic pain. However, the full extent of neuroprotection offered by voluntary wheel running after peripheral nerve injury is unknown. Here, we show that six weeks of voluntary wheel running prior to chronic constriction injury (CCI) reduced the terminal complement membrane attack complex (MAC) at the sciatic nerve injury site. This was associated with increased expression of the MAC inhibitor CD59. The levels of upstream complement components (C3) and their inhibitors (CD55, CR1 and CFH) were altered by CCI, but not increased by voluntary wheel running. Since MAC can degrade myelin, which in turn contributes to neuropathic pain, we evaluated myelin integrity at the sciatic nerve injury site. We found that the loss of myelinated fibers and decreased myelin protein which occurs in sedentary rats following CCI was not observed in rats with prior running. Substitution of prior voluntary wheel running with exogenous CD59 also attenuated mechanical allodynia and reduced MAC deposition at the nerve injury site, pointing to CD59 as a critical effector of the neuroprotective and antinociceptive actions of prior voluntary wheel running. This study links attenuation of neuropathic pain by prior voluntary wheel running with inhibition of MAC and preservation of myelin integrity at the sciatic nerve injury site.

Astrocyte ensheathment of calyx-forming axons of the auditory brainstem precedes accelerated expression of myelin genes and myelination by oligodendrocytes.

Early postnatal brain development involves complex interactions among maturing neurons and glial cells that drive tissue organization. We previously analyzed gene expression in tissue from the mouse medial nucleus of the trapezoid body (MNTB) during the first postnatal week to study changes that surround rapid growth of the large calyx of Held (CH) nerve terminal. Here, we present genes that show significant changes in gene expression level during the second postnatal week, a developmental timeframe that brackets the onset of airborne sound stimulation and the early stages of myelination. Gene Ontology analysis revealed that many of these genes are related to the myelination process. Further investigation of these genes using a previously published cell type-specific bulk RNA-Seq data set in cortex and our own single-cell RNA-Seq data set in the MNTB revealed enrichment of these genes in the oligodendrocyte lineage (OL) cells. Combining the postnatal day (P)6-P14 microarray gene expression data with the previously published P0-P6 data provided fine temporal resolution to investigate the initiation and subsequent waves of gene expression related to OL cell maturation and the process of myelination. Many genes showed increasing expression levels between P2 and P6 in patterns that reflect OL cell maturation. Correspondingly, the first myelin proteins were detected by P4. Using a complementary, developmental series of electron microscopy 3D image volumes, we analyzed the temporal progression of axon wrapping and myelination in the MNTB. By employing a combination of established ultrastructural criteria to classify reconstructed early postnatal glial cells in the 3D volumes, we demonstrated for the first time that astrocytes within the mouse MNTB extensively wrap the axons of the growing CH terminal prior to OL cell wrapping and compaction of myelin. Our data revealed significant expression of several myelin genes and enrichment of multiple genes associated with lipid metabolism in astrocytes, which may subserve axon wrapping in addition to myelin formation. The transition from axon wrapping by astrocytes to OL cells occurs rapidly between P4 and P9 and identifies a potential new role of astrocytes in priming calyceal axons for subsequent myelination.

Exploration of the common pathogenic link between COVID-19 and diabetic foot ulcers: An in silico approach.

The Coronavirus Disease-19 (COVID-19) is posing an ongoing threat to human health. Patients of diabetic foot ulcer (DFU) are susceptible to COVID-19-induced adverse outcomes. Nevertheless, investigations into their mutual molecular mechanisms have been limited to date. In the present work, we tried to uncover the shared pathogenesis and regulatory gene targets of COVID-19 and DFU. In this study, we chose GSE161281 as the COVID-19 data set, which contained severe acute respiratory syndrome coronavirus 2 infected human induced embryonic stem cell-derived peripheral neurons (n = 2) with uninfected controls (n = 2). The GSE134431 designated as the DFU data set, comprising full-thickness DFU (n = 13) and diabetic foot skin (n = 8) samples from diabetic patients. The differential expressed genes (DEGs) were identified from GSE161281 and GSE134431, and the common DEGs between COVID-19 and DFU were extracted. Multifactor regulatory network and co-expression network of the common DEGs were analyzed, along with candidate drug prediction. Altogether, six common DEGs (dickkopf-related protein 1 [DKK1], serine proteinase inhibitor A3 [SERPINA3], ras homolog family member D [RHOD], myelin protein zero like 3 [MPZL3], Claudin-11 [CLDN11], and epidermal growth factor receptor pathway substrate 8-like 1 [EPS8L1]) were found between COVID-19 and DFU. Functional analyses indicated that pathways of apoptotic and Wnt signaling may contribute to progression of COVID-19. Gene co-expression network implied the shared pathways of immune regulation and cytokine response participated collectively in the development of DFU and COVID-19. A multifactor regulatory network was constructed integrating the corresponding microRNAs (miRNAs) and transcription factors. Additionally, we proposed potential drug objects for the combined therapy. Our study revealed the shared molecular mechanisms underlying COVID-19 and DFU. The identified pivotal targets and common pathways can provide new perspectives for further research and assist the development of management strategies in patients of DFU complicated with COVID-19.

Proteomic analysis of peripheral nerve myelin during murine aging.

Aging of the peripheral nervous system (PNS) is associated with structural and functional changes that lead to a reduction in regenerative capacity and the development of age-related peripheral neuropathy. Myelin is central to maintaining physiological peripheral nerve function and differences in myelin maintenance, degradation, formation and clearance have been suggested to contribute to age-related PNS changes. Recent proteomic studies have elucidated the complex composition of the total myelin proteome in health and its changes in neuropathy models. However, changes in the myelin proteome of peripheral nerves during aging have not been investigated. Here we show that the proteomes of myelin fractions isolated from young and old nerves show only subtle changes. In particular, we found that the three most abundant peripheral myelin proteins (MPZ, MBP, and PRX) do not change in old myelin fractions. We also show a tendency for high-abundance myelin proteins other than these three to be downregulated, with only a small number of ribosome-related proteins significantly downregulated and extracellular matrix proteins such as collagens upregulated. In addition, we illustrate that the peripheral nerve myelin proteome reported in this study is suitable for assessing myelin degradation and renewal during peripheral nerve degeneration and regeneration. Our results suggest that the peripheral nerve myelin proteome is relatively stable and undergoes only subtle changes in composition during mouse aging. We proffer the resultant dataset as a resource and starting point for future studies aimed at investigating peripheral nerve myelin during aging. Said datasets are available in the PRIDE archive under the identifier PXD040719 (aging myelin proteome) and PXD041026 (sciatic nerve injury proteome).