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BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling. METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP84-104 interactors by mass spectrometry of MBP84-104 pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP84-104-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP84-104 and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression. RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP84-104 interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP84-104-induced pain in females. CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.

[Display omitted] • ● SPS induced NLRP3 inflammasome activation in the hippocampus of rats. • ● The hippocampal region of rats with PTSD showed increased myelin content. • ● MCC950 alleviated myelin alterations in the hippocampal region of PTSD rats. Inflammatory and myelin changes may contribute to the pathophysiology of post-traumatic stress disorder (PTSD). The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3), a brain inflammasome, is activated in the hippocampus of mice with PTSD. In other psychiatric disorders, NLRP3 expression has been associated with axonal myelination and demyelination. However, the association between NLRP3 and myelin in rats with PTSD remains unclear. Therefore, this study aims to investigate the relationship between the NLRP3 inflammasome and myelin in the hippocampus of rats with PTSD. A rat model of post-traumatic stress disorder was established using the single-prolonged stress (SPS) approach. Hippocampal tissues were collected for the detection of NLRP3 inflammasome-associated proteins and myelin basic protein at 3, 7, and 14 days after SPS. To further explore the relationship between NLRP3 and myelin, the NLRP3-specific inhibitor MCC950 was administered intraperitoneally to rats starting 72 h before SPS, and then alterations in NLRP3 inflammasome-associated proteins and myelin were observed in the PTSD and control groups. We found that NLRP3 and downstream related proteins were activated in the hippocampus of rats 3 days after SPS, and the myelin content in the hippocampus increased after SPS stress. MCC950 reduced the expression of NLRP3-related pathway proteins, improved anxiety behaviour and spatial learning memory impairment, and inhibited the increase in myelin content in the hippocampal region of rats after SPS. In conclusion the study indicates that NLRP3 has a significant role in the hippocampal region of rats with PTSD. Inhibition of the NLRP3 inflammasome could be a potential target for treating PTSD. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro‐algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy‐induced peripheral neuropathy (CIPN) in zebrafish larvae.We used zebrafish larvae and a mouse model to test oxaliplatin‐evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin‐induced CIPN model.We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)‐transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co‐expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (Plp1+‐Trpa1 mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin‐evoked nociceptive behaviours.These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro‐allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom. [ABSTRACT FROM AUTHOR]

Chronic stress is a universal condition commonly associated with many psychiatric diseases. An extensive body of evidence discussed hippocampal affection upon chronic stress exposure, however, the underlying molecular pathways still need to be identified. We investigated the impact of chronic stress on miR200/BMP/Olig‐2 signaling and hippocampal myelination. We also compared the effects of chronic administration of amitriptyline and cholecalciferol on chronically stressed hippocampi. Both amitriptyline and cholecalciferol significantly decreased serum cortisol levels, reduced immobility time in the forced swim test, increased the number of crossed squares in open field test, decreased the hippocampal expression of bone morphogenetic protein 4 (BMP4) and its messenger RNA (mRNA) levels, reduced miR200 expression as compared to untreated chronically stressed rats. Also, both drugs amended the hippocampal neuronal damage, enhanced the surviving cell count, and increased the pyramidal layer thickness of Cornu Ammonis subregion 1 (CA1) and granule cell layer of the dentate gyrus. Cholecalciferol was more effective in increasing the area percentage of myelin basic protein (MBP) and Olig‐2 positive cells count in hippocampi of chronic stress‐exposed rats than amitriptyline, thus enhancing myelination. We also found a negative correlation between the expression of BMP4, its mRNA, miR200, and the immunoexpression of MBP and Olig‐2 proteins. This work underscores the amelioration of the stress‐induced behavioral changes, inhibition of miR200/BMP4 signaling, and enhancement of hippocampal myelination following chronic administration of either amitriptyline or cholecalciferol, though cholecalciferol seemed more effective in brain remyelination. [ABSTRACT FROM AUTHOR]

Alterations in the white matter have been implicated in schizophrenia. Myelin basic protein (MBP), a component of the myelin sheath, in the cerebrospinal fluid (CSF) has been suggested as a biomarker for white matter damage in demyelinating diseases. This prompted us to examine the CSF‐MBP levels in patients with schizophrenia. We analyzed the CSF‐MBP levels in 152 patients with schizophrenia and 117 age‐ and sex‐matched controls. A significant positive correlation between age and CSF‐MBP levels was observed both in the patients (p < 0.001) and controls (p = 0.014). No significant difference was observed in the CSF‐MBP levels between the two groups. However, among a subsample of the patients (N = 32), a significantly negative correlation was observed between CSF‐MBP and age‐adjusted motor speed score of the brief assessment of cognition in schizophrenia (ρ = −0.59, p < 0.001). Further, among patients who underwent diffusional magnetic resonance imaging of the brain (N = 27), the CSF‐MBP levels showed a significantly negative correlation with the mean kurtosis value in the right temporo‐parietal region (p < 0.001). Our results suggest that the CSF‐MBP level has limited utility as a diagnostic marker; however, higher CSF‐MBP levels are associated with poorer motor speed, which may be associated with regional white matter damage in the brain in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund's adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats. [ABSTRACT FROM AUTHOR]

Inflammation and autoimmune responses contribute to the pathophysiology of Long COVID, and its affective and chronic fatigue syndrome symptoms, labeled "the physio‐affective phenome." To investigate whether Long COVID and its physio‐affective phenome are linked to autoimmunity to the tight junction proteins, zonulin and occludin (ZOOC), and immune reactivity to lipopolysaccharides (LPS), and whether the latter are associated with signs of human herpes virus‐6 (HHV‐6) reactivation, autoimmunity directed against oligodendrocyte and neuronal proteins, including myelin basic protein. IgA/IgM/IgG responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), HHV‐6, ZOOC, and neuronal proteins, C‐reactive protein (CRP), and advanced oxidation protein products (AOPPs), were measured in 90 Long COVID patients and 90 healthy controls. The physio‐affective phenome was conceptualized as a factor extracted from physical and affective symptom domains. Neural network identified IgA directed to LPS (IgA‐LPS), IgG‐ZOOC, IgG‐LPS, and IgA‐ZOOC as important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio‐affective phenome was explained by CRP, IgA‐myelin basic protein (MBP), and IgG‐MBP. A large part of the variances in both autoimmune responses to MBP (36.3%–39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV‐6 reactivation, which in turn was associated with increased IgM‐SARS‐CoV‐2. Autoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVID's physio‐affective phenome. [ABSTRACT FROM AUTHOR]

Despite significant advancements in the field, the pathophysiology of multiple sclerosis (MS) remains partially understood, with limited therapeutic options available for this debilitating condition. The precise impact of Interleukin-22 (IL-22) in the context of MS is still incompletely elucidated with some evidence suggesting its protective role. To provide a more comprehensive understanding of the role of IL-22, we investigated its effect on remyelination in a mouse model of demyelination induced by Cuprizone. Mice underwent a 6 week regimen of Cuprizone or vehicle, followed or not by intraperitoneal administration of IL-22. Behavioral assessments including tail suspension and inverted screen tests were conducted, alongside histological, histochemical, and quantitative PCR analyses. In Cuprizone-treated mice, IL-22 significantly improved motor and behavioral performance and robustly promoted remyelination in the corpus callosum. Additionally, IL-22 administration led to a significant elevation in MBP transcription in brain biopsies of treated mice. These findings collectively suggest a crucial role for IL-22 in the pathophysiology of MS, particularly in supporting the process of remyelination. These results offer potential avenues for expanding therapeutic strategies for MS treatment. Ongoing experiments aim to further unravel the underlying mechanisms of IL-22 action. [ABSTRACT FROM AUTHOR]

BACKGROUND: Premature birth is a major global health problem associated with high mortality and morbidity. White matter injury is the most common brain injury in preterm infants. Salvia miltiorrhiza is a traditional herbal plant that is commonly used to treat cardiovascular and cerebrovascular diseases in Asian countries. OBJECTIVE: To investigate the therapeutic effect of Salvia miltiorrhiza on white matter injury in preterm infants. METHODS: Eighteen neonatal male Sprague-Dawley rats at 3-day gestational age were selected and randomized into normal group, white matter injury group, and Salvia miltiorrhiza group. Animal models of preterm white matter injury were established by permanent ligation of the right common carotid artery in the latter two groups. Rats in the Salvia miltiorrhiza group were given intraperitoneal injection of Salvia miltiorrhiza (5 mg/kg•d) for 7 consecutive days. Normal group and white matter injury group were given the same volume of PBS for intervention. On the 14th day after modeling, the rats were sacrificed. Brains were pathologically observed by hematoxylin-eosin staining under microscope, and the expression levels of myelin basic protein and CC1 in brain tissue were visualized using immunofluorescence. Furthermore, liquid chromatography-tandem mass spectrometry was used to analyze possible pathways for the action of Salvia miltiorrhiza. RESULTS AND CONCLUSION: In the white matter injury group, the structure of the corpus callosum was irregular and the cells appeared swollen and necrotic. In addition, induction of white matter injury resulted in significantly reduced myelin formation, with irregular and loosely arranged nerve fibers and significantly decreased myelin sheaths. Interestingly, white matter injury rats treated with Salvia miltiorrhiza had reduced cellular swelling, reduced lesions, and increased myelin sheaths. The expression of myelin basic protein was closely related to myelin formation, and CC1 was a marker of myelin oligodendrocytes. Salvia miltiorrhiza significantly up-regulated the expressions of myelin basic protein and CC1 in white matter injury rats (P < 0.000 1), indicating that Salvia miltiorrhiza alleviated white matter injury. Liquid chromatography-tandem mass spectrometry analysis showed that the therapeutic effect of Salvia miltiorrhiza in the rat model of white matter injury was closely related to the regulation of complement and coagulation cascades. To conclude, Salvia miltiorrhiza may be a potential therapeutic agent for treating preterm white matter injury. [ABSTRACT FROM AUTHOR]

This document is an editorial published in the journal Frontiers in Neurology, discussing new insights and perspectives on traumatic brain injury (TBI). It emphasizes the importance of integration, translation, and multidisciplinary approaches in TBI research. The editorial highlights various aspects of TBI-related research, including basic and translational research, clinical research, and forensic and precision identification research. It mentions several research articles and reviews that contribute to these areas and provide valuable references for understanding TBI. The document also emphasizes the need for further research to improve TBI models, expand clinical studies, and explore biomarkers and imaging techniques for forensic identification. The document concludes a research topic on TBI and related fields, aiming to disseminate high-quality research and bridge the gap between basic neuroscience knowledge and the unmet needs in brain health. It emphasizes the importance of addressing the service provision system, including prevention, care, rehabilitation, and resocialization of TBI victims. The authors express gratitude to the groups that submitted their scientific findings and the reviewers who enhanced the quality of each study. [Extracted from the article]

Leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic Parkinson's disease (PD), controls multiple cellular processes important for GLIA physiology. Interestingly, emerging studies report that LRRK2 is highly expressed in oligodendrocyte precursor cells (OPCs) compared to the pathophysiology of other brain cells and oligodendrocytes (OLs) in PD. Altogether, these observations suggest crucial function(s) of LRRK2 in OPCs/Ols, which would be interesting to explore. In this study, we investigated the role of LRRK2 in OLs. We showed that LRRK2 knock-out (KO) OPC cultures displayed defects in the transition of OPCs into OLs, suggesting a role of LRRK2 in OL differentiation. Consistently, we found an alteration of myelin basic protein (MBP) striosomes in LRRK2 KO mouse brains and reduced levels of oligodendrocyte transcription factor 2 (Olig2) and Mbp in olig2:EGFP and mbp:RFP transgenic zebrafish embryos injected with lrrk2 morpholino (MO). Moreover, lrrk2 knock-down zebrafish exhibited a lower amount of nerve growth factor (Ngf) compared to control embryos, which represents a potent regulator of oligodendrogenesis and myelination. Overall, our findings indicate that LRRK2 controls OL differentiation, affecting the number of mature OLs. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: Knowledge of clitoral neuroanatomy is critical to vulvar surgery. We sought to characterize the density and distribution of autonomic and somatic nerves supplying the clitoris. Methods: Pelvic tissue harvested from female cadavers was sectioned axially at three anatomic levels: the proximal aspect of the clitoral body (CB), the distal CB, and the glans. The CB, glans, and the surrounding connective tissue (dorsal, lateral, and ventral) were outlined microscopically. An area containing large nerve bundles dorsal to the CB, referred to as the dorsal nerve subregion, was analyzed separately. Double-immunofluorescent staining for beta III tubulin (βIIIT), a global axonal marker, and myelin basic protein (MBP), a myelinated nerve marker, was performed. Threshold-based automatic image-segmentation distinguished stained areas. Autonomic and somatic density were calculated as percentage of tissue stained with βIIIT alone, and βIIIT and MBP respectively. Comparisons were made using nonparametric Friedman tests. Results: Seven cadavers, aged 22–81, were examined. Somatic (mean 4.42%, SD ± 1.97) and autonomic (2.14% ± 2.42) nerve density was highest in the dorsal nerve subregion and dorsal region at the distal CB level. Compared with the CB, somatic density was higher in proximal (0.05% ± 0.03 vs 1.27% ± 0.69, p = 0.03) and distal (0.29% ± 0.25 vs 1.09% ± 0.41, p = 0.05) dorsal regions. Somatic density was greater in the glans than in the surrounding lateral (0.78% ± 0.47 vs 0.43% ± 0.23, p = 0.03) and ventral (0.78% ± 0.47 vs 0.52% ± 0.2, p = 0.03) regions. Autonomic density was greater than somatic in all areas, except for the dorsal nerve subregion. Conclusions: Somatic and autonomic nerve density were greatest in a well-defined region dorsal to the CB. Surgical preservation of this region is critical for maintaining nerve supply to the clitoris. [ABSTRACT FROM AUTHOR]

• Adolescent HFD induces neurobehavioral abnormalities and hippocampal structural changes. • Microglial overactivation contributes to the adverse effect of adolescent HFD on behavior and hippocampal structure. • The changes of microglial status induced by early-life HFD is accompanied by an elevated serum FFA concentration. • Augmented microglial lipid accumulation secondary to early-life HFD renders microglial dysfunction. Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders. [ABSTRACT FROM AUTHOR]

Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the molecular basis of antigen presentation and the clinical course of patients with both Adult-Onset MS (AOMS) and Pediatric-Onset MS (POMS). Among the numerous polymorphisms of the Human Leucocyte Antigens (HLA), within MHC II complex, HLA-DRB1*15:01 has been labeled, in Caucasian ethnic groups, as a high-risk allele for MS due to the ability of its structure to increase affinity to Myelin Basic Protein (MBP) epitopes. This characteristic, among others, in the context of the trimolecular complex or immunological synapsis, provides the foundation for autoimmunity triggered by environmental or endogenous factors. As with all professional antigen presenting cells, macrophages are characterized by the expression of MHC II and are often implicated in the formation of MS lesions. Increased presence of M1 macrophages in MS patients has been associated both with progression and onset of the disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic alterations can promote dysregulation of this population's homeostasis in the periphery and the Central Nervous System (CNS). We also explore the potential interconnection in observed pathological macrophage mechanisms and the function of the diverse structure of HLA alleles in neurodegenerative CNS, seen in MS, by comparing available clinical with molecular data through the prism of HLA-immunogenetics. Finally, we discuss available and experimental pharmacological approaches for MS targeting the trimolecular complex that are based on cell phenotype modulation and HLA genotype involvement and try to reveal fertile ground for the potential development of novel drugs. [ABSTRACT FROM AUTHOR]

Background: High‐frequency repetitive transcranial magnetic stimulation (HF‐rTMS) has been found to ameliorate cognitive impairment. However, the effects of HF‐rTMS remain unknown in chronic cerebral hypoperfusion (CCH). Aim: To investigate the effects of HF‐rTMS on cognitive improvement and its potential mechanisms in CCH mice. Materials and methods: Daily HF‐rTMS therapy was delivered after bilateral carotid stenosis (BCAS) and continued for 14 days. The mice were randomly assigned to three groups: the sham group, the model group, and the HF‐rTMS group. The Y maze and the new object recognition test were used to assess cognitive function. The expressions of MAP‐2, synapsis, Myelin basic protein(MBP), and brain‐derived growth factors (BDNF) were analyzed by immunofluorescence staining and western blot to evaluate neuronal plasticity and white matter myelin regeneration. Nissl staining and the expression of caspase‐3, Bax, and Bcl‐2 were used to observe neuronal apoptosis. In addition, the activation of microglia and astrocytes were evaluated by fluorescence staining. The inflammation levels of IL‐1β, IL‐6, and Tumor Necrosis Factor(TNF)‐α were detected by qPCR in the hippocampus of mice in each group. Results: Via behavioral tests, the BCAS mice showed reduced a rate of new object preference and decreased a rate of spontaneous alternations, while HF‐rTMS significantly improved hippocampal learning and memory deficits. In addition, the mice in the model group showed decreased levels of MAP‐2, synapsis, MBP, and BDNF, while HF‐rTMS treatment reversed these effects. As expected, activated microglia and astrocytes increased in the model group, but HF‐rTMS treatment suppressed these changes. HF‐rTMS decreased BCAS‐induced neuronal apoptosis and the expression of pro‐apoptotic protein (Caspase‐3 and Bax) and increased the expression of anti‐apoptotic protein (Bcl‐2). In addition, HF‐rTMS inhibited the expression of inflammatory cytokines (IL‐1β, IL‐6, and TNF‐α). Conclusions: HF‐rTMS alleviates cognitive impairment in CCH mice by enhancing neuronal plasticity and inhibiting inflammation, thus serving as a potential method for vascular cognitive impairment. [ABSTRACT FROM AUTHOR]

[Display omitted] • We developed an aggressive multiple system atrophy-cerebellar variant mouse model. • In mice, human α-synuclein was expressed in oligodendrocytes via Tet-Off regulation. • We observed age-dependent phosphorylated α-synuclein deposition in glia and neurons. • Marked microglial and astrocytic reaction with inflammation in demyelinated lesions. • α-Synuclein oligomers spread from oligodendrocytes to astrocytes and neurons. Multiple system atrophy (MSA) is a severe α-synucleinopathy facilitated by glial reactions; the cerebellar variant (MSA-C) preferentially involves olivopontocerebellar fibres with conspicuous demyelination. A lack of aggressive models that preferentially involve olivopontocerebellar tracts in adulthood has hindered our understanding of the mechanisms of demyelination and neuroaxonal loss, and thus the development of effective treatments for MSA. We therefore aimed to develop a rapidly progressive mouse model that recaptures MSA-C pathology. We crossed Plp1 -tTA and tetO- SNCA*A53T mice to generate Plp1 -tTA::tetO- SNCA*A53T bi-transgenic mice, in which human A53T α-synuclein—a mutant protein with enhanced aggregability—was specifically produced in the oligodendrocytes of adult mice using Tet-Off regulation. These bi-transgenic mice expressed mutant α-synuclein from 8 weeks of age, when doxycycline was removed from the diet. All bi-transgenic mice presented rapidly progressive motor deterioration, with wide-based ataxic gait around 22 weeks of age and death around 30 weeks of age. They also had prominent demyelination in the brainstem/cerebellum. Double immunostaining demonstrated that myelin basic protein was markedly decreased in areas in which SM132, an axonal marker, was relatively preserved. Demyelinating lesions exhibited marked ionised calcium-binding adaptor molecule 1-, arginase-1-, and toll-like receptor 2-positive microglial reactivity and glial fibrillary acidic protein-positive astrocytic reactivity. Microarray analysis revealed a strong inflammatory response and cytokine/chemokine production in bi-transgenic mice. Neuronal nuclei-positive neuronal loss and patchy microtubule-associated protein 2-positive dendritic loss became prominent at 30 weeks of age. However, a perceived decrease in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta in bi-transgenic mice compared with wild-type mice was not significant, even at 30 weeks of age. Wild-type, Plp1 -tTA, and tetO- SNCA*A53T mice developed neither motor deficits nor demyelination. In bi-transgenic mice, double immunostaining revealed human α-synuclein accumulation in neurite outgrowth inhibitor A (Nogo-A)-positive oligodendrocytes beginning at 9 weeks of age; its expression was further increased at 10 to 12 weeks, and these increased levels were maintained at 12, 24, and 30 weeks. In an α-synuclein-proximity ligation assay, α-synuclein oligomers first appeared in brainstem oligodendrocytes as early as 9 weeks of age; they then spread to astrocytes, neuropil, and neurons at 12 and 16 weeks of age. α-Synuclein oligomers in the brainstem neuropil were most abundant at 16 weeks of age and decreased thereafter; however, those in Purkinje cells successively increased until 30 weeks of age. Double immunostaining revealed the presence of phosphorylated α-synuclein in Nogo-A-positive oligodendrocytes in the brainstem/cerebellum as early as 9 weeks of age. In quantitative assessments, phosphorylated α-synuclein gradually and successively accumulated at 12, 24, and 30 weeks in bi-transgenic mice. By contrast, no phosphorylated α-synuclein was detected in wild-type, tetO- SNCA*A53T , or Plp1 -tTA mice at any age examined. Pronounced demyelination and tubulin polymerisation, promoting protein-positive oligodendrocytic loss, was closely associated with phosphorylated α-synuclein aggregates at 24 and 30 weeks of age. Early inhibition of mutant α-synuclein expression by doxycycline diet at 23 weeks led to fully recovered demyelination; inhibition at 27 weeks led to persistent demyelination with glial reactions, despite resolving phosphorylated α-synuclein aggregates. In conclusion, our bi-transgenic mice exhibited progressively increasing demyelination and neuroaxonal loss in the brainstem/cerebellum, with rapidly progressive motor deterioration in adulthood. These mice showed marked microglial and astrocytic reactions with inflammation that was closely associated with phosphorylated α-synuclein aggregates. These features closely mimic human MSA-C pathology. Notably, our model is the first to suggest that α-synuclein oligomers may spread from oligodendrocytes to neurons in transgenic mice with human α-synuclein expression in oligodendrocytes. This model of MSA is therefore particularly useful for elucidating the in vivo mechanisms of α-synuclein spreading from glia to neurons, and for developing therapies that target glial reactions and/or α-synuclein oligomer spreading and aggregate formation in MSA. [ABSTRACT FROM AUTHOR]

Purpose: During the course of demyelinating inflammatory diseases, myelin-derived proteins, including myelin basic protein(MBP), are secreted into extracellular space. MBP shows extensive post-translational modifications, including deimination/citrullination. Deiminated MBP is structurally less ordered, susceptible to proteolytic attack, and more immunogenic than unmodified MBP. This study investigated the effect of the deiminated/citrullinated isomer of MBP(C8) and the unmodified isomer of MBP(C1) on cultured primary astrocytes. Methods: MBP charge isomers were isolated/purified from bovine brain. Primary astrocyte cultures were prepared from the 2-day-old Wistar rats. For evaluation of glutamate release/uptake a Fluorimetric glutamate assay was used. Expression of peroxisome proliferator-activated receptor-gamma(PPAR-γ), excitatory amino acid transporter 2(EAAT2), the inhibitor of the nuclear factor kappa-B(ikB) and high mobility group-B1(HMGB1) protein were assayed by Western blot analysis. IL-17A expression was determined in cell medium by ELISA. Results: We found that MBP(C8) and MBP(C1) acted differently on the uptake/release of glutamate in astrocytes: C1 increased glutamate uptake and did not change its release, whereas C8 decreased glutamate release but did not change its uptake. Both isomers increased the expression of PPAR-γ and EAAT2 to the same degree. Western blots of cell lysates revealed decreased expression of ikB and increased expression of HMGB1 proteins after treatment of astrocytes by C8. Moreover, C8-treated cells released more nitric oxide and proinflammatory IL-17A than C1-treated cells. Conclusions: These data suggest that the most immunogenic deiminated isomer C8, in parallel to the decreases in glutamate release, elicits an inflammatory response and enhances the secretion of proinflammatory molecules via activation of nuclear factor kappa B(NF-kB). Summary statement: The most modified-citrullinated myelin basic protein charge isomer decreases glutamate release, elicits an inflammatory response and enhances the secretion of proinflammatory molecules via activation of nuclear factor kappa B in astrocytes.

This letter discusses the importance of molecular mimicry in understanding and treating human diseases. Molecular mimicry occurs when pathogenic microbes express antigens that closely resemble those found in humans, allowing them to evade the immune system. The letter presents a bibliometric analysis of research on molecular mimicry, identifying trends and hotspots in the field. The analysis reveals that the United States is the leading country in molecular mimicry research, and the Journal of Autoimmunity is one of the most active journals in publishing this research. The letter also highlights three main areas of molecular mimicry research: its function in autoimmune diseases, its role in vaccine development, and the discovery of mimics through specificity and computational tools. The analysis suggests a shift in research focus towards specificity and computational tools in recent years. Overall, the letter emphasizes the potential of molecular mimicry in improving our understanding of diseases and developing therapeutic interventions. [Extracted from the article]

Multiple sclerosis (MS) is a pathological condition characterized by the demyelination of nerve fibers, primarily attributed to the destruction of oligodendrocytes and subsequent motor neuron impairment. Ethidium bromide (EB) is a neurotoxic compound that induces neuronal degeneration, resulting in demyelination and symptoms resembling those observed in experimental animal models of multiple sclerosis (MS). The neurotoxic effects induced by EB in multiple sclerosis (MS) are distinguished by the death of oligodendrocytes, degradation of myelin basic protein (MBP), and deterioration of axons. Neurological complications related to MS have been linked to alterations in the signaling pathway known as smo-shh. Purmorphine (PUR) is a semi-synthetic compound that exhibits potent Smo-shh agonistic activity. It possesses various pharmacological properties, including antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory effects. Hence, the current investigation was conducted to assess the neuroprotective efficacy of PUR (at doses of 5 and 10 mg/kg, administered intraperitoneally) both individually and in conjunction with Fingolimod (FING) (at a dose of 0.5 mg/kg, administered intraperitoneally) in the experimental model of MS induced by EB. The administration of EB was conducted via the intracerebropeduncle route (ICP) over a period of seven days in the brain of rats. The Wistar rats were allocated into six groups using randomization, each consisting of eight rats (n = 8 per group). The experimental groups in this study were categorized as follows: (I) Sham Control, (II) Vehicle Control, (III) PUR per se, (IV) EB, (V) EB + PUR5, (VI) EB + PUR10, (VII) EB + FING 0.5, and (VIII) EB + PUR10 + FING 0.5. On the final day of the experimental timeline, all animal subjects were euthanized, and subsequent neurochemical estimations were conducted on cerebrospinal fluid, blood plasma, and brain tissue samples. In addition, we conducted neurofilament (NFL) analysis and histopathological examination. We utilized the luxol myelin stain to understand better the degeneration associated with MS and its associated neurological complications. The findings of our study indicate that the activation of SMO-Shh by PUR has a mitigating effect on neurobehavioral impairments induced by EB, as well as a restorative effect on cellular and neurotransmitter abnormalities in an experimental model of MS. [ABSTRACT FROM AUTHOR]

Introduction: Neurological impairment is a big concern in the development of patients with congenital heart defects (CHD). A number of neuromarkers have been studied in search of a diagnostic or prognostic marker for brain injury during the vulnerable perioperative period. Our aim was to assess two novel neuromarkers, myelin basic protein (MBP) and protein Tau (pTau), as diagnostic markers for brain injury in perioperative period in children with CHD. Methods: Forty patients were enrolled and dichotomized based on peripheric oxygen saturation in cyanotic and non-cyanotic group. Blood samples were collected preoperative, after the induction of anesthesia, and in postoperative day 1. Neuromarker concentrations were measured using commercially available ELISA kits. Results: Neuromarkers' values were increased postoperative, with statistical significance reached only in non-cyanotic group (p < 0.0001). A significant positive correlation was observed between preoperatory MBP and albumin level, hemoglobin level, height, and weight of patients. Association with cerebral saturations were analyzed by a coefficient defined as ≥ 20% reduction in cerebral saturation measured by near-infrared spectroscopy during perioperative period. An acceptable predicting model was observed with pTau in cyanotic group (AUC = 0.7). Conclusion: We evaluated MBP and pTau as potential biomarkers of brain injury in children with CHD undergoing cardiac surgery. Elevated postoperative pTau and MBP concentrations were observed in both groups. Elevated pTau values were associated with perioperative hypoxemia. [ABSTRACT FROM AUTHOR]

The Hypothalmic-Pituitary-Adrenal axis also known as the HPA axis is central to stress response. It also acts as the relay center between the body and the brain. We analysed hypothalamic proteome from mice subjected to chronic social defeat paradigm using iTRAQ based quantitative proteomics to identify changes associated with stress response. We identified greater than 2000 proteins after processing our samples analysed through Q-Exactive (Thermo) and Orbitrap Velos (Thermo) at 5% FDR. Analysis of data procured from the runs showed that the proteins whose levels were affected belonged primarily to mitochondrial and metabolic processes, translation, complement pathway among others. We also found increased levels of fibrinogen, myelin basic protein (MBP) and neurofilaments (NEFL, NEFM, NEFH) in the hypothalamus from socially defeated mice. Interestingly, research indicates that these proteins are upregulated in blood and CSF of subjects exposed to trauma and stress. Since hypothalamus secreted proteins can be found in blood and CSF, their utility as biomarkers in depression holds an impressive probability and should be validated in clinical samples. [ABSTRACT FROM AUTHOR]

The study of peptide repertoires presented by major histocompatibility complex (MHC) molecules and the identification of potential T-cell epitopes contribute to a multitude of immunopeptidome-based treatment approaches. Epitope mapping is essential for the development of promising epitope-based approaches in vaccination as well as for innovative therapeutics for autoimmune diseases, infectious diseases, and cancer. It also plays a critical role in the immunogenicity assessment of protein therapeutics with regard to safety and efficacy concerns. The main challenge emerges from the highly polymorphic nature of the human leukocyte antigen (HLA) molecules leading to the requirement of a peptide mapping strategy for a single HLA allele. As many autoimmune diseases are linked to at least one specific antigen, we established FASTMAP, an innovative strategy to transiently co-transfect a single HLA allele combined with a diseasespecific antigen into a human cell line. This approach allows the specific identification of HLA-bound peptides using liquid chromatography--tandem mass spectrometry (LC-MS/MS). Using FASTMAP, we found a comparable spectrum of endogenous peptides presented by the most frequently expressed HLA alleles in the world's population compared to what has been described in literature. To ensure a reliable peptide mapping workflow, we combined the HLA alleles with well-known human model antigens like coagulation factor VIII, acetylcholine receptor subunit alpha, protein structures of the SARS-CoV-2 virus, and myelin basic protein. Using these model antigens, we have been able to identify a broad range of peptides that are in line with already published and in silico predicted T-cell epitopes of the specific HLA/model antigen combination. The transient co-expression of a single affinity-tagged MHC molecule combined with a disease-specific antigen in a human cell line in our FASTMAP pipeline provides the opportunity to identify potential T-cell epitopes/endogenously processed MHC-bound peptides in a very cost-effective, fast, and customizable system with high-throughput potential. [ABSTRACT FROM AUTHOR]

HIV-associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression through antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV protein Nef has been implicated in HAND pathogenesis, but its effect on white matter damage has not been well characterized. Here, utilizing in vivo, ex vivo, and in vitro methods, we demonstrate that Nef-containing extracellular vesicles (Nef EVs) disrupt myelin sheaths and inflict damage upon oligodendrocytes within the murine central nervous system. Intracranial injection of Nef EVs leads to reduced myelin basic protein (MBP) staining and a decreased number of CC1 + oligodendrocytes in the corpus callosum. Moreover, cerebellar slice cultures treated with Nef EVs exhibit diminished MBP expression and increased presence of unmyelinated axons. Primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures exposed to Nef EVs display a decreased number of O4 + cells, indicative of oligodendrocyte impairment. These findings underscore the potential contribution of Nef EV-mediated damage to oligodendrocytes and myelin maintenance in the pathogenesis of HAND. [ABSTRACT FROM AUTHOR]

This article explores the role of the WAK3 gene in Arabidopsis plants' immune responses to harpins, proteins produced by certain bacteria that activate plant defenses. The researchers used T-DNA insertion mutants to study WAK3 and found that it is essential for the necrosis and acquired resistance responses triggered by harpins. They also discovered that genetic variation in harpin perception may impact plant fitness. The study benefited from the use of the 1001 Genomes data, which eliminated the need for lengthy genetic mapping. This research provides valuable insights into the genetic basis of plant immune responses and its potential implications for crop protection. [Extracted from the article]

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Objective To compare the repair effects of different doses of human umbilical cord mesenchymal stem cells (hUC-MSCs) on white matter injury (WMI) in neonatal rats. Methods Two-day-old Sprague-Dawley neonatal rats were randomly divided into five groups: sham operation group, WMI group, and hUC-MSCs groups (low dose, medium dose, and high dose), with 24 rats in each group. Twenty-four hours after successful establishment of the neonatal rat white matter injury model, the WMI group was injected with sterile PBS via the lateral ventricle, while the hUC-MSCs groups received injections of hUC-MSCs at different doses. At 14 and 21 days post-modeling, hematoxylin and eosin staining was used to observe pathological changes in the tissues around the lateral ventricles. Real-time quantitative polymerase chain reaction was used to detect the quantitative expression of myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) mRNA in the brain tissue. Immunohistochemistry was employed to observe the expression levels of GFAP and neuron-specific nuclear protein (NeuN) in the tissues around the lateral ventricles. TUNEL staining was used to observe cell apoptosis in the tissues around the lateral ventricles. At 21 days post-modeling, the Morris water maze test was used to observe the spatial learning and memory capabilities of the neonatal rats. Results At 14 and 21 days post-modeling, numerous cells with nuclear shrinkage and rupture, as well as disordered arrangement of nerve fibers, were observed in the tissues around the lateral ventricles of the WMI group and the low dose group. Compared with the WMI group, the medium and high dose groups showed alleviated pathological changes; the arrangement of nerve fibers in the medium dose group was relatively more orderly compared with the high dose group. Compared with the WMI group, there was no significant difference in the expression levels of MBP and GFAP mRNA in the low dose group (P>0.05), while the expression levels of MBP mRNA increased and GFAP mRNA decreased in the medium and high dose groups. The expression level of MBP mRNA in the medium dose group was higher than that in the high dose group, and the expression level of GFAP mRNA in the medium dose group was lower than that in the high dose group (P<0.05). Compared with the WMI group, there was no significant difference in the protein expression of GFAP and NeuN in the low dose group (P>0.05), while the expression of NeuN protein increased and GFAP protein decreased in the medium and high dose groups. The expression of NeuN protein in the medium dose group was higher than that in the high dose group, and the expression of GFAP protein in the medium dose group was lower than that in the high dose group (P<0.05). Compared with the WMI group, there was no significant difference in the number of apoptotic cells in the low dose group (P>0.05), while the number of apoptotic cells in the medium and high dose groups was less than that in the WMI group, and the number of apoptotic cells in the medium dose group was less than that in the high dose group (P<0.05). Compared with the WMI group, there was no significant difference in the escape latency time in the low dose group (P>0.05); starting from the third day of the latency period, the escape latency time in the medium dose group was less than that in the WMI group (P<0.05). The medium and high dose groups crossed the platform more times than the WMI group (P<0.05). Conclusions Low dose hUC-MSCs may yield unsatisfactory repair effects on WMI in neonatal rats, while medium and high doses of hUC-MSCs have significant repair effects, with the medium dose demonstrating superior efficacy. [ABSTRACT FROM AUTHOR]

Voltage gated calcium channels (VGCCs) play a critical role in neural transmission. Antibodies that target these ion channels can disrupt cellular signal transmission resulting in various clinical presentations. VGCC antibodies are most commonly associated with paraneoplastic syndromes such as Lambert-Eatons myasthenic syndrome. Here, we report a 47-year-old female with Stage IV appendiceal adenocarcinoma status post appendectomy and right hemicolectomy, who presented with progressive memory impairment, aphasia, ataxia, weakness, and headache. Neurologic exam was notable for right-sided parietal drift, decreased right arm swing, and ataxia of the bilateral upper extremities, more prominent on the right side. MRI of the brain with and without contrast was unremarkable. Cerebrospinal fluid (CSF) was notable for an elevated myelin basic protein (4.9 ng/mL, normal reference 0.0-3.7 ng/mL) with normal cell count, flow cytometry, and cytology. An extensive serum autoimmune neurology antibody evaluation revealed elevated VGCC autoantibodies (observed value: 96.1 pmol/L, normal range 0.0-30.0 pmol/L). A diagnosis of paraneoplastic voltage gated calcium channel antibodies secondary to appendiceal adenocarcinoma was made. The patient was treated with five exchanges with plasmapheresis over 10 days with significant clinical improvement in her symptoms. Upon literature review, this would be the first reported case of VGCC antibodies associated with appendiceal adenocarcinoma. [ABSTRACT FROM AUTHOR]

The X-chromosome-linked cell adhesion molecule L1 (L1CAM), a glycoprotein mainly expressed by neurons in the central and peripheral nervous systems, has been implicated in many neural processes, including neuronal migration and survival, neuritogenesis, synapse formation, synaptic plasticity and regeneration. L1 consists of extracellular, transmembrane and cytoplasmic domains. Proteolytic cleavage of L1's extracellular and transmembrane domains by different proteases generates several L1 fragments with different functions. We found that myelin basic protein (MBP) cleaves L1's extracellular domain, leading to enhanced neuritogenesis and neuronal survival in vitro. To investigate in vivo the importance of the MBP-generated 70 kDa fragment (L1-70), we generated mice with an arginine to alanine substitution at position 687 (L1/687), thereby disrupting L1's MBP cleavage site and obliterating L1-70. Young adult L1/687 males showed normal anxiety and circadian rhythm activities but enhanced locomotion, while females showed altered social interactions. Older L1/687 males were impaired in motor coordination. Furthermore, L1/687 male and female mice had a larger hippocampus, with more neurons in the dentate gyrus and more proliferating cells in the subgranular layer, while the thickness of the corpus callosum and the size of lateral ventricles were normal. In summary, subtle mutant morphological changes result in subtle behavioral changes. [ABSTRACT FROM AUTHOR]

Non ketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by mutations in the genes encoding glycine cleavage system proteins. Classic NKH has a neonatal onset, and patients present with severe neurodegeneration. Although glycine accumulation has been implicated in NKH pathophysiology, the exact mechanisms underlying the neurological damage and white matter alterations remain unclear. We investigated the effects of glycine in the brain of neonatal rats and MO3.13 oligodendroglial cells. Glycine decreased myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in the corpus callosum and striatum of rats on post-natal day (PND) 15. Glycine also reduced neuroglycan 2 (NG2) and N-methyl- d -aspartate receptor subunit 1 (NR1) in the cerebral cortex and striatum on PND15. Moreover, glycine reduced striatal glutamate aspartate transporter 1 (GLAST) content and neuronal nucleus (NeuN), and increased glial fibrillary acidic protein (GFAP) on PND15. Glycine also increased DCFH oxidation and malondialdehyde levels and decreased GSH concentrations in the cerebral cortex and striatum on PND6, but not on PND15. Glycine further reduced viability but did not alter DCFH oxidation and GSH levels in MO3.13 cells after 48- and 72-h incubation. These data indicate that impairment of myelin structure and glutamatergic system and induction of oxidative stress are involved in the neuropathophysiology of NKH. Glycine administration impairs myelin and alters glial and neuronal cell markers in the brain of neonatal rats (postnatal day 1 - PND1) possibly mediated by glutamatergic system disturbances and oxidative stress. Glycine also reduces the viability of undifferentiated and differentiated MO3.13 cells as well as during differentiation. [Display omitted] • Glycine administration impairs myelin in the brain of neonatal rats. • Glycine alters glial and neuronal cell markers. • Glycine disturbs glutamatergic system and induces oxidative stress. • Glycine reduces the viability of differentiated and undifferentiated MO3.13 cells. [ABSTRACT FROM AUTHOR]

This preliminary study aimed to investigate an ActiGraft blood clot implant (RedDress Ltd., Pardes-Hanna, Israel) attempting to treat and induce the regeneration of a completely injured peripheral nerve with a massive loss defect. The tibial portion of the sciatic nerve in 11 rabbits was transected, and a 25 mm nerve gap was reconnected using a collagen tube. A comparison was performed between the treatment group (eight rabbits; reconnection using a tube filled with ActiGraft blood clot) and the control group (three rabbits; gap reconnection using an empty tube). The post-operative follow-up period lasted 18 weeks and included electrophysiological and histochemical assessments. The pathological severity score was high in the tube cross sections of the control group (1.33) compared to the ActiGraft blood clot treatment group (0.63). Morphometric analysis showed a higher percentage of the positive myelin basic protein (MBP) stained area in the ActiGraft blood clot group (19.57%) versus the control group (3.67%). These differences were not statistically significant due to the small group sizes and the large intra-group variability. The results of this preliminary study suggest that the application of an ActiGraft blood clot (into the collagen tube) can enable nerve recovery. However, a future study using a larger animal group is required to achieve objective statistical results. [ABSTRACT FROM AUTHOR]

Posttranslational modifications (PTMs), particularly phosphorylation, play a pivotal role in expanding the complexity of the proteome and regulating diverse cellular processes. In this study, we present an efficient Escherichia coli phosphorylation system designed to streamline the evaluation of potential substrates for Arabidopsis thaliana plant kinases, although the technology is amenable to any. The methodology involves the use of IPTG-inducible vectors for co-expressing kinases and substrates, eliminating the need for radioactive isotopes and prior protein purification. We validated the system's efficacy by assessing the phosphorylation of well-established substrates of the plant kinase SnRK1, including the rat ACETYL-COA CARBOXYLASE 1 (ACC1) and FYVE1/FREE1 proteins. The results demonstrated the specificity and reliability of the system in studying kinase-substrate interactions. Furthermore, we applied the system to investigate the phosphorylation cascade involving the A. thaliana MKK3-MPK2 kinase module. The activation of MPK2 by MKK3 was demonstrated to phosphorylate the Myelin Basic Protein (MBP), confirming the system's ability to unravel sequential enzymatic steps in phosphorylation cascades. Overall, this E. coli phosphorylation system offers a rapid, cost-effective, and reliable approach for screening potential kinase substrates, presenting a valuable tool to complement the current portfolio of molecular techniques for advancing our understanding of kinase functions and their roles in cellular signaling pathways. [ABSTRACT FROM AUTHOR]

Objective: Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro‐diffusely abnormal white matter, mDAWM). Methods: We used an in‐depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. Results: mDAWM‐defined areas exhibit ill‐defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. Interpretation: We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo‐myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components. [ABSTRACT FROM AUTHOR]

Microribonucleic acids (miRNAs) comprising miR-23a/b clusters, specifically miR-23a and miR-27a, are recognized for their divergent roles in myelination within the central nervous system. However, cluster-specific miRNA functions remain controversial as miRNAs within the same cluster have been suggested to function complementarily. This study aims to clarify the role of miR-23a/b clusters in myelination using mice with a miR-23a/b cluster deletion (KO mice), specifically in myelin expressing proteolipid protein (PLP). Inducible conditional KO mice were generated by crossing miR-23a/b clusterflox/flox mice with PlpCre-ERT2 mice; the offspring were injected with tamoxifen at 10 days or 10 weeks of age to induce a myelin-specific miR-23a/b cluster deletion. Evaluation was performed at 10 weeks or 12 months of age and compared with control mice that were not treated with tamoxifen. KO mice exhibit impaired motor function and hypoplastic myelin sheaths in the brain and spinal cord at 10 weeks and 12 months of age. Simultaneously, significant decreases in myelin basic protein (MBP) and PLP expression occur in KO mice. The percentages of oligodendrocyte precursors and mature oligodendrocytes are consistent between the KO and control mice. However, the proportion of oligodendrocytes expressing MBP is significantly lower in KO mice. Moreover, changes in protein expression occur in KO mice, with increased leucine zipper-like transcriptional regulator 1 expression, decreased R-RAS expression, and decreased phosphorylation of extracellular signal-regulated kinases. These findings highlight the significant influence of miR-23a/b clusters on myelination during postnatal growth and aging. [ABSTRACT FROM AUTHOR]

Introduction: Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive. Methods: The cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA‐sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection. Results: In this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)‐2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2‐mediated ferroptosis. Ferroptosis‐related genes were analyzed in vivo and DRG cells further validated the reliability of RNA‐sequencing results, suggesting HDAC2‐H4K12ac axis participated in epigenetic modulation of ferroptosis‐related genes. Conclusion: HDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2‐mediated ferroptosis. [ABSTRACT FROM AUTHOR]

This article describes how methylcobalamin (MeCbl) restores nerve myelination in a moderate-grade hepatic encephalopathy (MoHE) model of ammonia neurotoxicity. The comparative profiles of myelin basic protein (MBP), homocysteine (Hcy) and methionine synthase (MS: a MeCbl- dependent enzyme) activity versus nerve myelination status were studied in the hippocampus of the control, the MoHE (developed by administering 100 mg/kg bw thioacetamide i.p. for 10 days) and the MoHE rats treated with MeCbl (500 μµg/kg BW i.p.) for 7 days. Compared to those of control rats, the hippocampal CA1 and CA3 regions of the MoHE rats showed significantly lower myelinated areas and MBP immunostaining. This coincided with the deranged myelin layering in TEM images, decreased MBP protein and its transcript levels in hippocampus of MoHE rats. However, all these parameters recovered to normal levels after MeCbl treatment. MeCbl is a cofactor of MS that catalyzes the conversion of Hcy to methionine as a feeder step of methylation reactions. We observed significantly increased serum and hippocampal Hcy levels in MoHE rats, however, these levels were restored to control values with a concordant activation of MS due to MeCbl treatment. A significant recovery in neurobehavioral impairments in the MoHE rats due to MeCbl treatment was also observed. These findings suggest that MoHE pathogenesis is associated with deranged nerve myelination in the hippocampus and that MeCbl treatment is able to restore it mainly by activating MS, a MeCbl-dependent Hcy-metabolizing enzyme. [ABSTRACT FROM AUTHOR]

Despite significant advancements in the field, the pathophysiology of multiple sclerosis (MS) remains partially understood, with limited therapeutic options available for this debilitating condition. The precise impact of Interleukin-22 (IL-22) in the context of MS is still incompletely elucidated with some evidence suggesting its protective role. To provide a more comprehensive understanding of the role of IL-22, we investigated its effect on remyelination in a mouse model of demyelination induced by Cuprizone. Mice underwent a 6 week regimen of Cuprizone or vehicle, followed or not by intraperitoneal administration of IL-22. Behavioral assessments including tail suspension and inverted screen tests were conducted, alongside histological, histochemical, and quantitative PCR analyses. In Cuprizone-treated mice, IL-22 significantly improved motor and behavioral performance and robustly promoted remyelination in the corpus callosum. Additionally, IL-22 administration led to a significant elevation in MBP transcription in brain biopsies of treated mice. These findings collectively suggest a crucial role for IL-22 in the pathophysiology of MS, particularly in supporting the process of remyelination. These results offer potential avenues for expanding therapeutic strategies for MS treatment. Ongoing experiments aim to further unravel the underlying mechanisms of IL-22 action.

Background: A bioactive myelin basic protein (MBP) fragment, comprising MBP84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling. Methods: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP84-104 interactors by mass spectrometry of MBP84-104 pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP84-104-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP84-104 and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression. Results: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP84-104 interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP84-104-induced pain in females. Conclusion: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.

Elastic neutron scattering from proteins reflects the motional amplitudes resulting from their internal collective and single-atom dynamics and is observable if the global diffusion of whole molecules is either blocked or cannot be resolved by the spectrometer under consideration. Due to finite instrumental resolution, the measured elastic scattering amplitude always contains contaminations from quasielastic neutron scattering and some model must be assumed to extract the resolution-corrected counterpart from corresponding experimental spectra. Here, we derive a quasi-analytical method for that purpose, assuming that the intermediate scattering function relaxes with a "stretched" Mittag-Leffler function, Eα(−(t/τ)α) (0 < α < 1), toward the elastic amplitude and that the instrumental resolution function has Gaussian form. The corresponding function can be integrated into a fitting procedure and allows for eliminating the elastic intensity as a fit parameter. We illustrate the method for the analysis of two proteins in solution, the intrinsically disordered Myelin Basic Protein, confirming recently published results [Hassani et al., J. Chem. Phys. 156, 025102 (2022)], and the well-folded globular protein myoglobin. We also briefly discuss the consequences of our findings for the extraction of mean square position fluctuations from elastic scans. [ABSTRACT FROM AUTHOR]

PurposeThe purpose of this study was to test if optic nerve head (ONH) myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptor molecule 1 (Iba1) proteins are altered in non-human primate (NHP) early/moderate experimental glaucoma (EG).MethodsFollowing paraformaldehyde perfusion, control and EG eye ONH tissues from four NHPs were paraffin embedded and serially (5 µm) vertically sectioned. Anti-MBP, CNPase, GFAP, Iba1, and nuclear dye-stained sections were imaged using sub-saturating light intensities. Whole-section images were segmented creating anatomically consistent laminar (L) and retrolaminar (RL) regions/sub-regions. EG versus control eye intensity/pixel-cluster density data within L and two RL regions (RL1 [1-250 µm]/RL2 [251-500 µm] from L) were compared using random effects models within the statistical program "R."ResultsEG eye retinal nerve fiber loss ranged from 0% to 20%. EG eyes' MBP and CNPase intensity were decreased within the RL1 (MBP = 31.4%, P < 0.001; CNPase =62.3%, P < 0.001) and RL2 (MBP = 19.6%, P < 0.001; CNPase = 56.1%, P = 0.0004) regions. EG eye GFAP intensity was decreased in the L (41.6%, P < 0.001) and RL regions (26.7% for RL1, and 28.4% for RL2, both P < 0.001). Iba1+ and NucBlue pixel-cluster density were increased in the laminar (28.2%, P = 0.03 and 16.6%, P = 0.008) and both RL regions (RL1 = 37.3%, P = 0.01 and 23.7%, P = 0.0002; RL2 = 53.7%, P = 0.002 and 33.2%, P < 0.001).ConclusionsRetrolaminar myelin disruption occurs early in NHP EG and may be accompanied by laminar and retrolaminar decreases in astrocyte process labeling and increases in microglial/ macrophage density. The mechanistic and therapeutic implications of these findings warrant further study.

Background: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. Methods: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. Results: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. Conclusions: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI. [ABSTRACT FROM AUTHOR]

Background: Offspring of hypertensive disorders of pregnancy are at an increased risk of developing neurodevelopmental and neurobehavioral disorders compared to offspring from non-affected pregnancies. Using rodent models of Preeclampsia (PreE; new onset of hypertension after 20 weeks gestation) and HELLP (hemolysis, elevated liver enzymes, and low platelets), we studied the behavioral outcome of their offspring in adolescence. Methods: A subset of dams received Orencia, a T-cell activation inhibitor, as T cells have been associated with the induction of hypertension and inflammation during pregnancy. We hypothesized that offspring from hypertensive dams would experience adverse behavioral outcomes in social, cognitive, locomotor, and anxiety tests, and offspring from dams treated with Orencia would demonstrate less adverse behaviors. Results: Male offspring of PreE + Orencia dams (p < 0.05) and female offspring from HELLP + Orencia dams (p < 0.05) spent more time playing compared to normal pregnant offspring. All offspring from hypertensive and Orencia-treated dams performed worse on the Barnes Maze test compared to normal pregnant. We also measured adult (postnatal day > 60) myelin basic protein (MBP) and NeuN expression in both the prefrontal cortex and hippocampus. In the hippocampus and prefrontal cortex, there was no difference in expression of either MBP or NeuN in all groups regardless of sex. Conclusion: The results from this study suggest that offspring of hypertensive disorders of pregnancy have behavioral changes, specifically cognitive differences. This study has shown that there is a sex dependent difference in offspring neurobehavioral development, influenced in part by the type of hypertensive disorder of pregnancy, and alterations in the maternal immune system. Highlights: Female offspring from HELLP dams treated with or without Orencia (Abatacept, prevents T cell activation) have decreased locomotion. Male offspring from PreE dams and females from HELLP dams that have been treated with Orencia have increased social play. Offspring of both hypertensive and Orencia treated dams have spatial memory deficits. Male offspring from PreE dams treated with Orencia show evidence of anxiety-like behavior in marble burying tasks. Plain language summary: Children of pregnancies that are complicated by hypertensive disorders of pregnancy (HDP) such as Preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome have an increased risk of having behavioral deficits and changes in brain development. Both Preeclampsia and HELLP have been shown to activate the immune and inflammation systems in the body of the mother. In this study, we used offspring of rat models of Preeclampsia and HELLP to study their behavior including anxiety-like behaviors and memory deficits. We also compared offspring of rat models of Preeclampsia and HELLP that were given Orencia, which minimizes immune responses by blocking the activation of T cells. We also studied two regions of the brain (prefrontal cortex and hippocampus) to measure two proteins (myelin basic protein (MBP) and NeuN) involved in brain function. Our study found that offspring from dams that were treated with Orencia during pregnancy with HDP had sex differences in time playing. All offspring, regardless of the HDP dam being treated with or without Orencia, had evidence of spatial learning deficits. When sexes and groups were compared there was no difference in MBP or NeuN expression in the prefrontal cortex or hippocampus. [ABSTRACT FROM AUTHOR]

The exact mechanisms of MS (multiple sclerosis) evolution are still unknown. However, the development of EAE (experimental autoimmune encephalomyelitis simulating human MS) in C57BL/6 mice occurs due to the violation of bone marrow hematopoietic stem cell differentiation profiles, leading to the production of toxic for human autoantibody splitting MBP (myelin basic protein), MOG (mouse oligodendrocyte glycoprotein), five histones, DNA, and RNA. Here, we first analyzed the changes in the relative phosphatase activity of IgGs from C57BL/6 mice blood over time, corresponding to three stages of EAE: onset, acute, and remission. Antibodies have been shown to catalyze the hydrolysis of p-nitrophenyl phosphate at several optimal pH values, mainly in the range of 6.5–7.0 and 8.5–9.5. During the spontaneous development of EAE, the most optimal value is pH 6.5. At 50 days after the birth of mice, the phosphatase activity of IgGs at pH 8.8 is 1.6-fold higher than at pH 6.5. During spontaneous development of EAE from 50 to 100 days, an increase in phosphatase activity is observed at pH 6.5 but a decrease at pH 8.8. After mice were immunized with DNA–histone complex by 20 and 60 days, phosphatase activity increased respectively by 65.3 and 109.5 fold (pH 6.5) and 128.4 and 233.6 fold (pH 8.8). Treatment of mice with MOG at the acute phase of EAE development (20 days) leads to a maximal increase in the phosphatase activity of 117.6 fold (pH 6.5) and 494.7 fold (pH 8.8). The acceleration of EAE development after mice treatment with MOG and DNA–histone complex results in increased production of lymphocytes synthesizing antibodies with phosphatase activity. All data show that IgG phosphatase activity could be essential in EAE pathogenesis. [ABSTRACT FROM AUTHOR]

Understanding the intricate nanoscale architecture of neuronal myelin during central nervous system development is of utmost importance. However, current visualization methods heavily rely on electron microscopy or indirect fluorescent method, lacking direct and real-time imaging capabilities. Here, we introduce a breakthrough near-infrared emissive curcumin-BODIPY derivative (MyL-1) that enables direct visualization of myelin structure in brain tissues. The remarkable compatibility of MyL-1 with stimulated emission depletion nanoscopy allows for unprecedented super-resolution imaging of myelin ultrastructure. Through this innovative approach, we comprehensively characterize the nanoscale myelinogenesis in three dimensions over the course of brain development, spanning from infancy to adulthood in mouse models. Moreover, we investigate the correlation between myelin substances and Myelin Basic Protein (MBP), shedding light on the essential role of MBP in facilitating myelinogenesis during vertebral development. This novel material, MyL-1, opens up new avenues for studying and understanding the intricate process of myelinogenesis in a direct and non-invasive manner, paving the way for further advancements in the field of nanoscale neuroimaging. [ABSTRACT FROM AUTHOR]

White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether dipyridamole could alleviate WMLs by regulating the phenotype of disease-associated microglia (DAM) through equilibrative nucleoside transporter 2 (ENT2) and adenosine A2A receptor (Adora2a) and to clarify the underlying molecular mechanisms. CCH rat models were constructed to mimic VaD. Morris water maze and Luxol Fast Blue staining were employed to assess cognitive function and quantify the severity of WMLs, respectively. Immunofluorescent staining was performed to analyze the activation of glial cells and the phenotypic transformation of DAM. Additionally, levels of ENT2, proteins in the NF-κB and ERK1/2 pathways and inflammatory cytokines were detected. The results indicated that dipyridamole diminished the activation and proliferation of microglia and astrocytes, increased the expression of myelin basic protein and ameliorated WMLs and cognitive decline in CCH rats. Further study revealed that dipyridamole decreased the expression of ENT2 and inhibited the activation of ERK1/2 and NF-κB signaling pathways, which ultimately converted DAM to anti-inflammatory phenotype and suppressed the levels of TNF-α, IL-1β, IL-6 in WMLs. However, Adora2a inhibitor (SCH58261) attenuated above effects. Our study demonstrates that dipyridamole facilitates the conversion of DAM to the anti-inflammatory phenotype through ENT2/Adora2a pathway and inhibits the activation of ERK1/2 and NF-κB signaling pathways, thereby alleviating neuroinflammation in WMLs. The current findings establish the basis for using dipyridamole to treat VaD. [ABSTRACT FROM AUTHOR]

Background: The high number of accidents and traumatic brain injuries, especially in the productive age group, causes a lot of morbidity and mortality. A fast and accurate examination method is needed for the diagnosis and treatment of traumatic brain injury. Nerve damage biomarkers such as Neuron Specific Enolase, S100B, Glial Fibrillary Acidic Protein, and Myelin Basic Protein, have been used globally both for research and daily use to determine the severity of traumatic brain injury. Methods: Searches and journal searches were carried out from Science Direct, Scopus, Springer Link, and PubMed, with the keywords "Neuron Specific Enolase", "S100B", "Glial Fibrillary Acidic Protein", "Myelin Basic Protein", and "Traumatic Brain Injury ". Screening was carried out using PRISMA 2021 to look for studies that met the criteria and were of sufficient study quality according to the Newcastle-Ottawa Scale. Results: Twenty-three studies were collected and further grouped based on outcomes, both prognostic and survival outcomes. Neuron Specific Enolase, S100B, and Glial Fibrillary Acidic Protein values were higher in poor outcomes (all p values < 0.001) and poor survival (all p values < 0.001) in traumatic brain injury. Myelin Basic Protein was not significant in poor outcome (p = 0.35), but was higher in poor survival (p < 0.001) in traumatic brain injury. Conclusion: Neuron Specific Enolase, S100B, and Glial Fibrillary Acidic Protein, can be used as markers for prognostic and survival value in traumatic brain injury. Myelin Basic Protein can be used as a marker for survival value in traumatic brain injury. [ABSTRACT FROM AUTHOR]

Myelin basic protein (MBP) is the second most abundant protein in the central nervous system and is responsible for structural maintenance of the myelin sheath covering axons. Previously, we showed that MBP has a more proactive role in the oligodendrocyte homeostasis, interacting with membrane-associated proteins, including integral membrane protein 2B (ITM2B or Bri2) that is associated with familial dementias. Here, we report that the molecular dynamics of the in silico-generated MBP-Bri2 complex revealed that MBP covers a significant portion of the Bri2 ectodomain, assumingly trapping the furin cleavage site, while the surface of the BRICHOS domain, which is responsible for the multimerization and activation of the Bri2 high-molecular-weight oligomer chaperone function, remains unmasked. These observations were supported by the co-expression of MBP with Bri2, its mature form, and disease-associated mutants, which showed that in mammalian cells, MBP indeed modulates the post-translational processing of Bri2 by restriction of the furin-catalyzed release of its C-terminal peptide. Moreover, we showed that the co-expression of MBP and Bri2 also leads to an altered cellular localization of Bri2, restricting its membrane trafficking independently of the MBP-mediated suppression of the Bri2 C-terminal peptide release. Further investigations should elucidate if these observations have physiological meaning in terms of Bri2 as a MBP chaperone activated by the MBP-dependent postponement of Bri2 membrane trafficking. [ABSTRACT FROM AUTHOR]

Abstract—The aim of the study was to identify patterns of change in certain neurospecific proteins (BDNF, S100β, MBP) in the serum of patients with chronic mercury intoxication after stopping exposure to the toxicant. In clinical conditions, men with an established diagnosis of chronic mercury intoxication (CMI) were examined in a distant period after isolation from a toxicant in chemical production. Serum concentrations of neurospecific proteins (BDNF, S100β, MBP) were determined by solid-phase enzyme-linked immunosorbent assay using a commercial test-systems of ChemiKine (United States), CanAg (Sweden), and AnshLabs (United States), respectively. The obtained results indicate and confirm the progression of the disease in the distant, post-exposure period of chronic mercury intoxication, which corresponds to the clinical manifestation of the disease. Elevated serum concentrations of BDNF, S100β protein, and MBP were reported in patients with CMI 5 years after exposure to the toxicant. Long-lasting high levels of neurotrophic proteins may reflect the course of neurodestructive processes occurring in the nervous tissue and the progression of the disease. BDNF deficiency in CMI individuals examined in a linked sample at 8 years post-exposure may be indicative of attenuation of neurogenesis. Further studies will contribute to a more accurate definition and understanding of the use of serum concentrations of BDNF, S100β protein, MBP as markers of pathological process activity and a specific target for effective treatment. [ABSTRACT FROM AUTHOR]

Introduction: Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS). Recently, we showed that one year after the initiation of cladribine treatment, T and B cell crosstalk was impaired, reducing potentially pathogenic effector functions along with a specific reduction of autoreactivity to RAS guanyl releasing protein 2 (RASGRP2). In the present study we conducted a longitudinal analysis of the effect of cladribine treatment in patients with RRMS, focusing on the extent to which the effects observed on T and B cell subsets and autoreactivity after one year of treatment are maintained, modulated, or amplified during the second year of treatment. Methods: In this case-control exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 52 (W52), 60 (W60), 72 (W72) and 96 (W96) weeks, were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. Results: We found a substantial reduction in circulating memory B cells and proinflammatory B cell responses. Furthermore, we observed reduced T cell responses to autoantigens possibly presented by B cells (RASGRP2 and a-B crystallin (CRYAB)) at W52 and W96 and a further reduction in responses to the myelin antigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) after 96 weeks. Conclusion: We conclude that the effects of cladribine observed after year one are maintained and, for some effects, even increased two years after the initiation of a full course of treatment with cladribine tablets. [ABSTRACT FROM AUTHOR]

Objective. Electroacupuncture (Ea) is a useful complementary and alternative therapy for intracerebral hemorrhage (ICH). However, the neurobiological basis for the Ea treatment of ICH is still unclear. The primary aim of the present study was to explore whether Ea prevents brain edema, apoptosis, excitotoxicity, and neuroinflammation in rats after hemorrhagic stroke. Methods. Rats were randomly divided into Sham, Control, and Ea groups. We used modified neurological severity score (mNSS) and gait analysis to estimate neurological function in rats, and PET/CT to assess glucose uptake and the hemorrhagic focus volume. Measurement of the brain water content and TUNEL staining were used to evaluate brain edema and cell apoptosis, respectively. The serum myelin basic protein (MBP), neuron-specific enolase (NSE), calcium-binding protein B (S100B), and tumor necrosis factor-α (TNF-α) concentrations were examined with ELISA. The expression levels of the CD68, GALC, Arg-1, iNOS, NR2A, Glu2R, AQP4, MAP2, GFAP, AQP9, Bcl-2, Bax, and Glu proteins around the hematoma were detected via immunohistochemistry staining. Western blot was used to analyze the levels of the AQP4, AQP9, Bax, Bcl-2, iNOS, and Arg-1 proteins. Results. Ea treatment improved neurological function and reduced the hemorrhagic area and brain water content in rats after ICH. The serum concentrations of MBP, NSE, S100B, and TNF-α all decreased significantly in the Ea group compared with the Control group. Expression levels of the Glu, NR2A, AQP4, AQP9, Bax, GFAP, iNOS, and CD68 proteins in brain tissue surrounding the hematoma were obviously suppressed in ICH rats following Ea treatment. Moreover, Ea stimulation increased the levels of the MAP2, GALC, Glu2R, Arg-1, and Bcl-2 proteins, but reduced the number of TUNEL-positive cells in rats after ICH. Conclusion. The results of this study suggest that Ea may exert neuroprotective effects by suppressing brain edema, apoptosis, excitotoxicity, and neuroinflammation. [ABSTRACT FROM AUTHOR]

Many biochemical, immunological, and neuropsychiatric changes are associated with end-stage renal disease (ESRD). Neuronal damage biomarkers such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), S100 calcium-binding protein B (S100B), ionized calcium-binding adaptor molecule-1 (IBA1), and myelin basic protein (MBP) are among the less-studied biomarkers of ESRD. We examined the associations between these neuro-axis biomarkers, inflammatory biomarkers, e.g., C-reactive protein (CRP), interleukin (IL-6), IL-10, and zinc, copper, and neuropsychiatric symptoms due to ERSD. ELISA techniques were used to measure serum levels of neuronal damage biomarkers in 70 ESRD patients, and 46 healthy controls. ESRD patients have higher scores of depression, anxiety, fatigue, and physiosomatic symptoms than healthy controls. Aberrations in kidney function tests and the number of dialysis interventions are associated with the severity of depression, anxiety, fibro-fatigue and physiosomatic symptoms, peripheral inflammation, nestin, and NFL. Serum levels of neuronal damage biomarkers (NFL, MBP, and nestin), CRP, and interleukin (IL)-10 are elevated, and serum zinc is decreased in ESRD patients as compared with controls. The neuronal damage biomarkers NFL, nestin, S100B and MBP are associated with the severity of one or more neuropsychiatric symptom domains. Around 50 % of the variance in the neuropsychiatric symptoms is explained by NFL, nestin, S00B, copper, and an inflammatory index. The severity of renal dysfunction and/or the number of dialysis interventions may induce peripheral inflammation and, consequently, neurotoxicity to intermediate filament proteins, astrocytes, and the blood-brain barrier, leading to the neuropsychiatric symptoms of ESRD. • ESRD patients have higher scores of depression, anxiety, and fatigue. • Kidney function decline and dialysis treatments cause peripheral inflammation. • NFL, MBP, and nestin are associated with the severity of neuropsychiatric symptoms. • Serum levels of NFL, MBP, nestin, CRP, and IL-10 are elevated in ESRD patients. [ABSTRACT FROM AUTHOR]