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Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they have been refined under evolutionary pressure to interact with proteins or other biological targets. This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed. [ABSTRACT FROM AUTHOR]

Previous studies have shown that miR-200a is markedly deregulated in various neurodegenerative disorders including Alzheimer's disease (AD), Multiple Sclerosis (MS) and PD. Furthermore, studies have shown the key role of miR-200a on expression of SIRT1 and apoptosis. Therefore, we hypothesized that miR-200a/SIRT1 axis should have a crucial role in apoptosis of dopaminergic (DA)neurons. In this study, human SH-SY5Y cells were treated with MPP+ and expression of miR-200a, SIRT1 and its target genes were assessed. Our results confirmed that expression of miR-200a significantly up-regulated during treating of human SH-SY5Y cells with MPP + in order to induce oxidative stress and apoptosis. Additionally, transcript level of SIRT1 in these cells showed significant down-regulation confirming that SIRT1 is indeed decreased due to miR-200a up-regulation during apoptosis. Moreover, expression of P53, FOXO1 and BCL2 were modulated. In this study, we indicated that miR-200a/ SIRT1 axis directly correlates with apoptosis and P53 signaling pathway. In conclusion, miR-200a and its target gene, SIRT1, may exert a possible role in induction of apoptosis in DA neurons through regulating P53, apoptosis and FOXO signaling pathways. [ABSTRACT FROM AUTHOR]

Recent evidence has shown that neuroinflammation plays a key role in the pathogenesis of Parkinson’s disease (PD). However, different components of the brain’s immune system may exert diverse effects on neuroinflammatory events in PD. The adaptive immune response, especially the T cell response, can trigger type 1 pro-inflammatory activities and suppress type 2 anti-inflammatory activities, eventually resulting in deregulated neuroinflammation and subsequent dopaminergic neurodegeneration. Additionally, studies have increasingly shown that therapies targeting T cells can alleviate neurodegeneration and motor behavior impairment in animal models of PD. Therefore, we conclude that abnormal T cell-mediated immunity is a fundamental pathological process that may be a promising translational therapeutic target for Parkinson’s disease. [ABSTRACT FROM AUTHOR]

Purpose Our goal was to examine how post-void residual urine volume relates to urinary symptoms in patients with multiple sclerosis. Materials and Methods We retrospectively reviewed the records of patients with multiple sclerosis who had lower urinary tract symptoms and presented to a tertiary neurourology clinic. Patients for whom post-void residual volume was recorded at the initial urological assessment were included in our analysis. Results of the AUA (American Urological Association) SI (Symptom Index) and the M-ISI (Michigan Incontinence Symptom Index) completed at this visit were analyzed to assess the severity of lower urinary tract symptoms and incontinence. A chart review was performed to obtain information on demographics and documented urinary tract infections. Results Between 2014 and 2017, 110 patients diagnosed with multiple sclerosis underwent post-void residual volume measurement at our clinic. Average post-void residual volume was 123.4 cc (range 0 to 650 cc). The mean AUA symptom score was 19.1 with an average bother score of 4.1. Analysis of post-void residual volume as a continuous variable did not show an association between increasing post-void residual volume and an increasing AUA SI or bother score (p = 0.53 and 0.44, respectively). When evaluated by post-void residual volume tertile, no relationship was found between post-void residual volume, and the AUA SI and the M-ISI (p = 0.54 and 0.57, respectively). No correlation was also found between increasing post-void residual volume and a recent history of recurrent urinary tract infections (p = 0.27). Conclusions Post-void residual volume was not associated with worsening obstructive lower urinary tract symptoms as assessed by the AUA SI, worsening incontinence as measured by the M-ISI score or an increased risk of recurrent urinary tract infections in select patients with multiple sclerosis and lower urinary tract symptoms. [ABSTRACT FROM AUTHOR]

Purpose The aim of the current study was to determine the outcomes of botulinum toxin A intradetrusor injections in adult patients with spina bifida. Materials and methods All patients with spinal dysraphism who underwent intradetrusor injections of botulinum toxin A from 2002 to 2016 at a total of 14 centers were retrospectively included in analysis. The primary end point was the global success of injections, defined subjectively as the combination of urgency, urinary incontinence and detrusor overactivity/low bladder compliance resolution. Univariate and multivariate analysis was performed to seek predictors of global success. Results A total of 125 patients were included in study. The global success rate of the first injection was 62.3% with resolution of urinary incontinence in 73.5% of patients. All urodynamic parameters had improved significantly by 6 to 8 weeks compared to baseline, including maximum detrusor pressure (–12 cm H 2 O, p <0.001), maximum cystometric capacity (86.6 ml, p <0.001) and compliance (8.9 ml/cm H 2 O, p = 0.002). A total of 20 complications (3.6%) were recorded for the 561 intradetrusor botulinum toxin A injections, including 3 muscular weakness complications. The global success rate of the first injection was significantly lower in patients with poor compliance (34.4% vs 86.9%, OR 0.08, p <0.001). On multivariate analysis poor compliance was associated with a lower global success rate (OR 0.13, p <0.001). Female gender (OR 3.53, p = 0.01) and patient age (OR 39.9, p <0.001) were predictors of global success. Conclusions Intradetrusor botulinum toxin A injections were effective in adult patients with spina bifida who had detrusor overactivity. In contrast, effectiveness was much lower in adult patients with spina bifida who had poor bladder compliance. The other predictors of global success were female gender and older age. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) commonly affects young adults and leads to a decreased quality of life due to different signs and symptoms that induce physical, cognitive, social, and psychological challenges. This disease, an autoimmune neurological disorder, is characterized by chronic inflammatory demyelination and axonal degeneration of the central nervous system (CNS). To date, its etiology is unknown. A large number of physiological functions are regulated by the cholinergic system because the acetylcholine (ACh) is released from cholinergic neurons and acts on other neurons, most of them not cholinergic in the brain, as well as in various nonneuronal cells, such as those of the immune system and blood; thus, it is considered an important modulatory pathway of both the central and peripheral nervous systems. Furthermore, the purinergic system has a significant role in neurotransmission as well as immune and inflammatory responses. Accumulating evidence has suggested the presence of a strong association between these systems and MS. Therefore, this review aims to present and discuss the main mechanisms that potentially explain the influence of the cholinergic and purinergic systems in multiple sclerosis. These mechanisms are discussed in light of available scientific evidence in humans and animal experimental models of MS. We hope that this review provides a better understanding of this subject, helping to guide future research and potential novel therapeutic strategies for patients with MS. [ABSTRACT FROM AUTHOR]

There are global efforts in developing therapeutic strategies for central nervous system (CNS) injuries using multimodal approaches. Nogo receptor type 1 (NgR1) has been known as a primary molecule limiting neuronal regeneration in the adult CNS. We identified lateral olfactory tract usher substance (LOTUS) as an endogenous NgR1 antagonist. Membrane-bound LOTUS interacts with NgR1 and inhibits its function by blocking its ligand binding. Five molecules including Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), B lymphocyte stimulator (BLyS) and chondroitin sulfate proteoglycans (CSPGs) have been identified as NgR1 ligands. These ligands bind to NgR1 and activate NgR1 signaling, leading to axon growth inhibition such as growth cone collapse and neurite outgrowth inhibition. We have recently reported that the soluble form of LOTUS (s-LOTUS) also suppressed NgR1-mediated signaling induced by myelin axonal inhibitors (MAIs) including Nogo, MAG and OMgp by binding with both NgR1 and its co-receptor p75 neurotrophin receptor (p75 NTR ). Though s-LOTUS has been reported to suppress MAIs, whether s-LOTUS also suppresses NgR1 signaling induced by BLyS and CSPGs remains to be elucidated. Here, we show that s-LOTUS inhibits NgR1-mediated signaling induced by BLyS and CSPGs. Although treatment with s-LOTUS did not suppress BLyS-NgR1 interaction, s-LOTUS inhibited growth cone collapse and neurite outgrowth inhibition induced by BLyS and CSPGs in chick dorsal root ganglion (DRG) neurons. Furthermore, s-LOTUS compensated for the suppressive function of endogenous LOTUS in NgR1-mediated signaling in olfactory bulb neurons of lotus -knockout mice. These findings suggest that s-LOTUS is a potent therapeutic agent for neuronal regeneration in the CNS injuries. [ABSTRACT FROM AUTHOR]

Recently, environmental nonylphenol (NP) exposure in the fetus and child has received increasing attention because of its potentially deleterious effects on the central nervous system (CNS). Microglia (MG), resident immune cells in the CNS, are vital to CNS homeostasis and defense against exogenous chemicals, which makes them a potentially sensitive target of NP. The present study aims to explore the effects of maternal NP exposure during pregnancy and lactation on MG in offspring hippocampus, the production of pro-inflammatory cytokines by MG, and associated underlying mechanisms. We found that maternal NP exposure increased the production of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in offspring hippocampus. Increases in both activation and number of MG were observed in offspring hippocampus. Increased phosphorylation of Akt was found to co-localize with hippocampal MG, while increased phosphorylation of c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) were observed in offspring hippocampus. Activator protein 1 (AP-1), an inflammatory transcription factor, was also activated in the hippocampus of pups subjected to maternal NP exposure. These results suggest that maternal NP exposure might activate MG in offspring hippocampus. This activation seems to subsequently increase the production of IL-1β, IL-6, and TNF-α. Furthermore, Akt/MAPK/AP-1 signaling may be involved in this activation of MG and increased production of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Introduction The flavonoid kurarinone suppresses CD4+ T-cell-mediated chronic inflammatory dermatitis. However, kurarinone's effects upon autoimmune central nervous system (CNS) disease remain unknown. We investigated the potential therapeutic effects and molecular mechanism(s) of kurarinone in an experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis (MS). Materials and methods Myelin oligodendrocyte glycoprotein (MOG 35-55 ) peptide-induced EAE was constructed in wild-type mice. Effects of kurarinone (100 mg/kg/day) upon clinical scores were assessed based on physical traits and signs. Spinal cord sections were extracted to assess inflammation, demyelination, and mRNA expression of key pro-inflammatory cytokines and chemokines. CNS-infiltrating mononuclear cells (MNCs) and splenocytes were harvested; flow cytometry was then applied to determine CD4+ and CD8+ T-cell percentages as well as Th1/Th2/Th17 subset percentages. Purified naïve CD4+ T-cells underwent in vitro T-cell polarization and proliferation to assess kurarinone's effects. Results Prophylactic and treatment regimens of kurarinone significantly improved clinical scores in the MOG 35-55 peptide-induced EAE model ( P   <  0.05). Kurarinone significantly lowered CNS inflammation and demyelination (61% and 83% decreases, respectively; P   <  0.05), significantly decreased MNC infiltration into CNS tissue (42% decrease; P   <  0.05), and significantly inhibited levels of several pro-inflammatory cytokines and chemokines ( P   <  0.05). Kurarinone significantly lowered CD4+ and CD8+ CNS T-cell counts (51% and 80% decreases, respectively; P  < 0.05) and significantly reduced CNS Th1 and Th17 cell percentages (24% and 44% decreases, respectively; P   <  0.05). Kurarinone significantly inhibited in vitro Th1, Th2, and Th17 cell differentiation and proliferation ( P   <  0.05). Conclusions Kurarinone significantly inhibits the clinical progression of EAE through the inhibition of Th1 and Th17 cell differentiation and proliferation. Kurarinone may show promise as an immunomodulatory therapeutic agent in treating MS. [ABSTRACT FROM AUTHOR]

Age related neurodegenerative disorders (ARND) are presented as the most debilitating and challenging diseases associated with the central nervous system. Despite the advent of active molecules with a positive role on neurodegenerative mechanisms, many of the current therapeutic strategies remain ineffective in treating or preventing ARND. Lipid nanocarriers have emerged as efficient delivery systems with the capability to cross biological barriers, especially the blood brain barrier (BBB). Also, when associated to natural compounds, lipid nanocarriers have demonstrated to be an interesting alternative to ARND therapies with multiple beneficial effects. This comprehensive review focus on state-of-the-art lipid based nanocarriers for the delivery of natural compounds targeting neurodegeneration. A critical analysis of published reports will be also provided giving indications to researchers about the most promising ARND nanotherapy strategies. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this paper is to examine the role of UVR at birth and its relationship to lifespan and determine whether there are significant differential effects on sex and race. We test if variation in UVR, as determined by solar cycles (long-term variation), is related to survival as measured by age at death. Methods The data used 78 million death records from the National Center for Health Statistics (NCHS) from 1979 to 2013 with accidents, suicides, and war casualties deleted resulted in ~63 million records. Records of persons ≤ 47 years old were also scrubbed because we could not show an effect on lifespan based upon the intensity of solar energy as reflected by sunspot number (SSN). This we hypothesize is due to the protective effect of the hormones associated with growth and reproduction. Also selected were persons afflicted with multiple sclerosis (MS). Results Males of all races born with a UVR intensity as estimated by sunspot number (SSN) ≤ 90 had an average lifespan of 74.4 years, for females of all races, 78.1 years; males born with >90 had an average lifespan of 66.3 years, for females of all races, 70.2 years, resulting in a lifespan decrease of 8.1 years for males and 8.5 years for females. For African-American males born ≤ 90 SSN, 70.8 years and for >90 SSN, 62.5 years, an 8.3-year decrease; similarly, for African-American females ≤ 90 SSN, 75.0, for >90 SSN, 65.4 years, a 9.6-year decrease. Higher solar energy at birth had an adverse effect on human lifespan. We also found that there were twice as many persons with MS born in >80–90 SSN as in the general population. Conclusions There is a statistically significant inverse relationship between exposure to solar energy at birth and average human lifespan. Solar energy by some mechanism alters the epigenome at birth, but the effect of higher solar energy becomes apparent after the age of natural selection. [ABSTRACT FROM AUTHOR]

Objective The present study evaluated ankle stiffness in adults with and without neurological disorders and investigated the accuracy and reproducibility of a clinically applicable method using a dynamometer. Methods Measurements were obtained from 8 healthy subjects (age 39.3), 9 subjects with spastic cerebral palsy (CP) (age 39.8) and 8 subjects with multiple sclerosis (MS) (age 49.9). Slow and fast dorsiflexion stretches of the ankle joint were performed to evaluate passive muscle-tendon-joint stiffness, reflex mediated stiffness and range of movement (ROM), respectively. Intra/inter-rater reliability for passive and reflex mediated ankle muscle stiffness was assessed for all groups. Results Subjects with CP and MS showed significantly larger values of passive stiffness in the triceps surae muscle tendon complex and smaller ROM compared to healthy individuals, while no significant difference in reflex mediated stiffness. Measurements of passive muscle-tendon-joint stiffness and reflex mediated stiffness showed good to excellent inter- and intra-rater reliability (ICC: 0.62–0.91) in all groups. Conclusion Increased stiffness was found in subjects with CP and MS with a clinically applicable method that provides valid and reproducible measurement of passive ankle muscle-tendon-joint stiffness and reflex mediated stiffness. Significance The present technique may provide important supplementary information for the clinician. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches. In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed. Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background Immune complexes (ICs) may clearly reflect immunological abnormalities caused by disease, especially for autoimmune diseases. Although ICs have been detected in cerebrospinal fluid (CSF) from patients with CNS autoimmune diseases, identities of antigens in such ICs have not been comprehensively determined. Methods We used immune complexome analysis, in which nano-liquid chromatography-tandem mass spectrometry is employed to comprehensively identify antigens incorporated into ICs in biological fluids, to characterize ICs in CSF samples from patients with CNS autoimmune diseases, and to find disease-specific IC antigen to a certain CNS autoimmune disease. Also, we compared the IC antigens we identified with the reported CSF proteome or with the published plasma proteome to examine if the method is distinguished from the conventional CSF proteome analysis. Results We identified 176 antigens in 78 CSF samples. We then assessed the overlaps among these antigens, the CSF proteome, and the plasma proteome; 140 of the 176 antigens were found to be exclusively detected by our method. Notably, IC-associated suprabasin in CSF was 100% specific to neuropsychiatric systemic lupus erythematosus (NPSLE). Conclusions This report is the first to comprehensively identify the antigens incorporated into ICs in CSF. There was limited overlap between the antigens we identified and the CSF proteome or the plasma proteome; therefore, our method can be distinguished from the conventional CSF proteome analysis. Although the sensitivity of disease-specific IC-antigens detected in immune complexome analysis screening, the sensitivity may be improved by developing an ELISA method specifically for detecting the ICs. Immune complexome analysis of CSF may be a new and promising path to biomarker discovery for diagnosis and study for CNS autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objective To determine the extent to which the content of the Quality of Life in Neurological Disorders (Neuro-QoL) covers the International Classification of Functioning, Disability and Health (ICF) Core Sets for multiple sclerosis (MS), stroke, spinal cord injury (SCI), and traumatic brain injury (TBI) using summary linkage indicators. Design Content analysis by linking content of the Neuro-QoL to corresponding ICF codes of each Core Set for MS, stroke, SCI, and TBI. Setting Three academic centers. Participants None. Interventions None. Main Outcome Measures Four summary linkage indicators proposed by MacDermid et al were estimated to compare the content coverage between Neuro-QoL and the ICF codes of Core Sets for MS, stroke, MS, and TBI. Results Neuro-QoL represented 20% to 30% Core Set codes for different conditions in which more codes in Core Sets for MS (29%), stroke (28%), and TBI (28%) were covered than those for SCI in the long-term (20%) and early postacute (19%) contexts. Neuro-QoL represented nearly half of the unique Activity and Participation codes (43%–49%) and less than one third of the unique Body Function codes (12%−32%). It represented fewer Environmental Factors codes (2%−6%) and no Body Structures codes. Absolute linkage indicators found that at least 60% of Neuro-QoL items were linked to Core Set codes (63%−95%), but many items covered the same codes as revealed by unique linkage indicators (7%−13%), suggesting high concept redundancy among items. Conclusions The Neuro-QoL links more closely to ICF Core Sets for stroke, MS, and TBI than to those for SCI, and primarily covers activity and participation ICF domains. Other instruments are needed to address concepts not measured by the Neuro-QoL when a comprehensive health assessment is needed. [ABSTRACT FROM AUTHOR]

Action observation is known to enhance sensorimotor system activation, and such effect has been linked to neural priming and response facilitation mechanisms. This facilitation effect, however, has been primarily studied by focusing on high-level motor proficiency, whereas evidence on the effect of observing poorly performed actions is still lacking. We then devised a study to investigate neural correlates of the observation of suboptimal motor acts as mirrored by corticospinal activation (via transcranial magnetic stimulation (TMS), Experiment 1) and by modulation of cortical oscillatory activity (via electroencephalography (EEG), Experiment 2). 40 participants were presented with four randomly reiterated videos. Videos depicted a healthy confederate, a minimally impaired multiple sclerosis (MS) patient, a mildly impaired MS patient, or a confederate trying to simulate mild motor difficulties performing a test concerning fine motor abilities. In Experiment 1 we analyzed TMS-induced motor-evoked potentials during the observation of videos. In Experiment 2 EEG data were analyzed in the frequency-domain. Analyses highlighted both increased corticospinal excitability and desynchronized alpha-beta oscillations during the observation of poorly performed motor acts performed by the mildly impaired MS patient. Further, we observed gradually increasing beta activity across videos reiterations, specifically for the minimally impaired patient’s video. Reported findings corroborate the hypotheses that the action-observation network and the motor system might be involved in processes evoked in the attempt to understand and predict observed actions which do not belong to the onlookers’ motor repertoire, reflecting in an increased sensorimotor activity. [ABSTRACT FROM AUTHOR]

The gut microbiota – the trillions of bacteria that reside within the gastrointestinal tract – has been found to not only be an essential component immune and metabolic health, but also seems to influence development and diseases of the enteric and central nervous system, including motility disorders, behavioral disorders, neurodegenerative disease, cerebrovascular accidents, and neuroimmune-mediated disorders. By leveraging animal models, several different pathways of communication have been identified along the “gut-brain-axis” including those driven by the immune system, the vagus nerve, or by modulation of neuroactive compounds by the microbiota. Of the latter, bacteria have been shown to produce and/or consume a wide range of mammalian neurotransmitters, including dopamine, norepinephrine, serotonin, or gamma-aminobutyric acid (GABA). Accumulating evidence in animals suggests that manipulation of these neurotransmitters by bacteria may have an impact in host physiology, and preliminary human studies are showing that microbiota-based interventions can also alter neurotransmitter levels. Nonetheless, substantially more work is required to determine whether microbiota-mediated manipulation of human neurotransmission has any physiological implications, and if so, how it may be leveraged therapeutically. In this review this exciting route of communication along the gut-brain-axis, and accompanying data, are discussed. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that clozapine and quetiapine (atypical antipsychotics), tamoxifen (selective-estrogen receptor modulator) and pioglitazone (PPARγ agonist) may improve functional recovery in multiple sclerosis (MS). We have compared the effectiveness of oral administration of these drugs, beginning at peak disease, at reducing ascending paralysis, motor deficits and demyelination in mice subjected to experimental autoimmune encephalomyelitis (EAE). Mice were immunized with an immunogenic peptide corresponding to amino acids 35–55 of the myelin oligodendrocyte glycoprotein (MOG 35–55 ) in complete Freund's adjuvant and injected with pertussis toxin to induce EAE. Unlike clozapine, quetiapine and tamoxifen, administration of pioglitazone beginning at peak disease decreased both clinical scores and lumbar white matter loss in EAE mice. Using kinematic gait analysis, we found that pioglitazone also maintained normal movement of the hip, knee and ankle joints for at least 44 days after MOG 35–55 immunization. This long-lasting preservation of hindleg joint movements was accompanied by reduced white matter loss, microglial and macrophage activation and the expression of pro-inflammatory genes in the lumbar spinal cords of EAE mice. These results support clinical findings that suggest pioglitazone may reduce the progressive loss of motor function in MS by decreasing inflammation and myelin damage. [ABSTRACT FROM AUTHOR]

Primary angiitis of the central nervous system (PACNS) is a rare and heterogeneous inflammatory disease of the CNS vasculature with poorly understood pathophysiology. Comprehensive immune-cell phenotyping revealed increased frequencies of leukocytes in the cerebrospinal fluid (CSF) of PACNS patients compared to patients with multiple sclerosis, ischemic stroke, and somatoform disorders (n = 18 per group). Changes in the intrathecal immune-cell profile were heterogeneous in PACNS. While proportions of T-cell subsets remained unaltered, some PACNS patients showed a shift toward NK- or B cells. Intrathecal immunoglobulin synthesis was observed in a subgroup of PACNS patients with an increased frequency of antibody producing plasma cells. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Aloysia citrodora Paláu ( Lippia citriodora Kunth), commonly known as "lemon verbena" is a medicinal plant native to South America, North Africa, and South of Europe which is used by native people for several indications such as diarrhea, flatulence, insomnia, and rheumatism. Aim of the review Despite the wide biological activities of lemon verbena, there is no current review summarizing medicinal properties of the plant; thus, this paper aims to discuss current state of the art regarding the phytochemistry, pharmacology, and therapeutic applications of A. citrodora considering in vitro , in vivo , and clinical studies. Materials and methods Electronic databases including PubMed, Scifinder, Cochrane library, Scopus, and Science direct were searched with the scientific name of the plant and its synonyms, as well as the common name. All studies on the ethnobotany, phytochemistry, pharmacology, and clinical application of the plant until October 2017 were included in this review. Results Despite the few number of studies on the ethnopharmacology of the plant, A. citrodora is widely assessed regarding its phytochemistry and biological activities. Neral and geranial are the main ingredients of the essential oil; whereas verbascoside is the most significant component of the extract. Biological activities such as antioxidant, anxiolytic, neuroprotective, anticancer, anesthetic, antimicrobial, and sedative effects are proved in cell cultures, as well as animal studies. Conclusions Several pharmacological activities have been reported for A. citrodora ; however, the plant is not fully assessed regarding its safety and efficacy in human. Future well-designed human studies are essential to confirm the therapeutic benefits of this plant in clinical settings. [ABSTRACT FROM AUTHOR]

Fibrosis is defined as the thickening and scarring of connective tissue, usually as a consequence of tissue damage. The central nervous system (CNS) is special in the sense that fibrogenic cells are restricted to vascular and meningeal areas. Inflammation and the disruption of the blood-brain barrier can lead to the infiltration of fibroblasts and trigger fibrotic response. While the initial function of the fibrotic tissue is to restore the blood-brain barrier and to limit the site of injury, it also demolishes the structure of extracellular matrix and impedes the healing process by producing inhibitory molecules and forming a physical and biochemical barrier that prevents axon regeneration. As a major constituent in the extracellular matrix, proteoglycans participate in the neuro-inflammation, modulating the fibrotic process. In this review, we will discuss the pathophysiology of fibrosis during acute injuries of the CNS, as well as during chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and age-related neurodegeneration with focus on the functional roles of proteoglycans. [ABSTRACT FROM AUTHOR]

Following lesions to the central nervous system, scar tissue forms at the lesion site. Injury often severs axons and scar tissue is thought to block axonal regeneration, resulting in permanent functional deficits. While scar-forming astrocytes have been extensively studied, much less attention has been given to the fibrotic, non-glial component of the scar. We here review recent progress in understanding fibrotic scar formation following different lesions to the brain and spinal cord. We specifically highlight recent evidence for pericyte-derived fibrotic scar tissue formation, discussing the origin, recruitment, function and therapeutic relevance of fibrotic scarring. [ABSTRACT FROM AUTHOR]

Naltrexone, a non-selective antagonist of opioid receptors, is mainly used as rehabilitation therapy for discharged opiate addicts to eliminate addiction in order to maintain a normal life and prevent or reduce relapse. In recent years, there have been some novel and significant findings on the off-label usage of naltrexone. Within a specific dosage window, LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders. The results of increasing studies indicate that LDN exerts its immunoregulatory activity by binding to opioid receptors in or on immune cells and tumor cells. These new discoveries indicate that LDN may become a promising immunomodulatory agent in the therapy for cancer and many immune-related diseases. In this article, we review the pharmacological functions and mechanisms of LDN as well as its clinical therapeutic potential as revealed by our team and other researchers. [ABSTRACT FROM AUTHOR]

Background The term “tumor-to-lesion metastasis” is an extension of “tumor-to-tumor metastasis,” which is a rare but well-documented phenomenon. Tumor metastasis to the meninges and/or central nervous system (CNS) is rare in patents with multiple sclerosis (MS), although MS lesions bear many similarities to the primary tumor microenvironment and metastatic niche. We present the first case of malignant tumor metastasis to MS lesions with immunophenotyping of inflammatory cells in the metastatic foci. Case Description A 45-year-old male patient with a 6-year history of MS and newly diagnosed lung carcinoma developed carcinoma metastases in the meninges and CNS, as well as into mixed active/inactive MS lesions. The carcinoma-hosting MS lesions exhibited abundant macrophages/microglia with ongoing demyelination but rare T cells. In comparison, a 46-year-old female patient with a 21-month history of MS and newly diagnosed gastric carcinoma was found to have leptomeningeal carcinomatosis and separate active MS lesions containing not only frequent macrophages/microglia but also T cells. Conclusions The carcinoma-hosting MS lesions are unlike typical active lesions but recapitulate the CNS metastatic niche. Our observations suggest that metastasis-hosting MS lesions might require a distinct immune microenvironment to be permissive to the seeding and growth of metastatic tumors. [ABSTRACT FROM AUTHOR]

Background and Purpose: Gadolinium-based contrast agents (GBCAs) administration have drastically improved the accuracy of Multiple Sclerosis (MS) diagnosis by highlighting any damage to the brain blood barrier, thereby differentiating between active and non-active lesions. Following multiple administrations of GBCAs, several MS studies have reported a signal intensity (SI) increase on unenhanced T1-weighted images in certain brain regions such as the dentate nucleus (DN) and the globus pallidus (GP). Our aim was therefore to determine the accumulation of macrocyclic GBCAs on enhanced T1-weighted images SI in the DN and the GP of MS patients injected eight times.Materials and Methods: Five MS patients underwent eight weekly consecutive MRI scans. Enhanced 3D T1-weighted images with Gadobutrol as a macrocyclic GBCA, were acquired. A ROI-based approach was applied for the evaluation of SI in the DN to middle cerebellar peduncle (DN-MCP) and GP to semi-oval white matter (GP-SOWM) ratios. An analysis of variance on repeated measures was used for the statistical analysis of each ratio.Results: No DN-MCP and GP-SOWM SI ratio differences were observed over the eight-weeks period using the macrocyclic GBCA.Conclusion: Iterative and weekly injections of macrocyclic GBCAs are not associated with T1 signal increase in the DN and GP of MS patients. These results would suggest a no gadolinium accumulation in the brain using macrocyclic GBCA even after several close injections and promote the use of a macrocylcic GBCA rather than linear agents for MS patients. [ABSTRACT FROM AUTHOR]

Phosphatidylserine (PS) exposure during apoptosis leads to silent clearance of cells without adverse immune reactions to self-proteins. Given the biological functions of PS in cellular cleanup and global immunosuppression, we hypothesized that administration of PS-protein complexes would reduce immunogenicity. Here, we report that exposing Pompe disease mice to acid alpha glucosidase (rhGAA) with PS or immunosuppressant dexamethasone resulted in lower anti-rhGAA antibodies than in animals receiving rhGAA alone. However, upon rechallenge with rhGAA, only PS-rhGAA pre-exposed mice displayed a durable hyporesponsiveness even after PS administration was ceased. Thus, pre-exposure of antigens administered together with PS were not silently cleared, but the immune system acquired memory about the antigen that averted mounting of a response during rechallenge. In hemophilia A mice, PS hyporesponsiveness toward Factor VIII was reversed by administration of function-blocking antibody against the PS receptor T-cell immunoglobulin and mucin 4, implicating this receptor in PS's effect. Moreover, pre-exposure of myelin oligodendrocyte glycoprotein peptide with PS delayed the onset and reduced the severity of experimental autoimmune encephalomyelitis. These observations suggest that PS's function in apoptosis is not limited to silent antigen clearance without immune responses toward self-proteins but shows that PS reduces immune response during rechallenge to several antigens that also involves initiation of antigen tolerance. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factors (PDGF) promotes cell proliferation, survival and migration, primarily of cells of mesenchymal origin. Dysfunction of PDGF signaling has been observed in a wide array of pathological conditions, such as cancer, fibrosis, neurological conditions and atherosclerosis. Reported abnormalities of the PDGF pathway include overexpression or amplification of PDGF receptors (PDGFRs), gain of function point mutations or activating chromosomal translocations. Current development of therapeutic drugs often aims at producing compounds that specifically target interaction between PDGFs and their receptors by specific DNA aptamers and ligand traps, or downregulate PDGFRs with blocking antibodies, or inhibit tyrosine kinase activity of PDGFRs with small molecules. In this review, we discuss some of the approaches taken to interfere with PDGF signaling, review a panel of existing therapeutic drugs, and consider clinically successful cases and remaining challenges. [ABSTRACT FROM AUTHOR]

Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA) is a glycosaminoglycan that is found in extracellular tissue in many parts of the body. It is a material of increasing importance to biomaterials science and is finding applications in diverse areas ranging from tissue culture scaffolds to cosmetic materials. This paper reviews the recent research on the role of HA as a immunoprotective and immunomodulatory biomaterial and the importance of HA in combating immune related diseases such as type 1 diabetes, cancer, and autoimmunity. The chemical modifications and processing methods employed to produce HA-modified materials are discussed, thus giving a better understanding of the structure-function-property relationships that influence immunomodulation, immunoprotection and stability. The article concludes with a discussion on the latest progress in HA materials science which is enabling the realisation of new therapies such as vaccine delivery, immunotherapy, cell encapsulation and transplantation. [ABSTRACT FROM AUTHOR]

Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K–dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAMs are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K–dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6 −/− and TAM mutant mice models. [ABSTRACT FROM AUTHOR]

Objective: Since during pregnancy and lactation women tend to develop autoimmune processes, characterization of placenta immunoglobulins and their possible catalytic functions is a very important step towards understanding the function of placenta.Methods: ELISA, affinity chromatography, SDS-PAGE and MALDI mass spectrometry were used.Results: It was shown, that ten placentas contain in average 1.1 ± 0.33 mg IgGs/g of placenta and 0.11 ± 0.1 mЕ anti-DNA antibodies/g of placenta. All ten individual IgG preparations were characterized by a specific ratio and various combinations of heavy (47.5-51.7 kDa) and light (22.2-33.3 kDa) chains with different molecular masses. All intact IgGs demonstrate DNase but have not amylase activity. Several strict criteria have been used to show that the DNase activity is an intrinsic property of placenta IgGs. The heavy chains of antibodies were catalytically inactive. The light chains of 22-24 kDa of all IgGs demonstrated maximal DNase activity, while the chains of approximately 25-33.2 kDa were significantly less active. IgGs were completely inactive after dialysis against EDTA. The optimal external cofactors of placenta DNase abzymes are Mg2+ and Cu2+ ions, while, activity in the presence of Mn2+ and Ca2+ is approximately 3-4-fold lower. Activation of DNase abzymes by Cu2+ ions was revealed for the first time. Placental antibodies possess selective cytotoxicity against cancer cells.Conclusion: It was shown previously, that appearance of serum DNase abzymes is the good indicator of the beginning and obvious spontaneous or induced autoimmune diseases. The detection of placenta DNase antibodies indicates that during pregnancy, autoimmune processes can affect this organ. [ABSTRACT FROM AUTHOR]

Objective To identify predictors for employment status after 10 years in a cohort of people with multiple sclerosis (MS), with the aim to increase knowledge concerning factors present at an early stage that are important for working life and work-life balance. Design A 10-year longitudinal observational cohort study. Setting University hospital. Participants A consecutive sample of people with MS (N=154) of working age were included at baseline, of which a total of 116 people participated in the 10-year follow-up; 27 people declined participation and 11 were deceased. Interventions Not applicable. Main Outcome Measures Baseline data on personal factors and functioning were used as independent variables. Employment status 10 years after baseline, categorized as full-time work, part-time work, and no work, was used as the dependent variable. A generalized ordinal logistic regression was used to analyze the predictive value of the independent variables. Results Predictors for full- or part-time work after 10 years were young age ( P =.002), low perceived physical impact of MS ( P =.02), fatigue ( P =.03), full-time work ( P =.001), and high frequency of social/lifestyle activities ( P =.001) at baseline. Low perceived physical impact of MS ( P =.02) at baseline also predicted full-time work after 10 years. Conclusions This study underlines the complexity of working life for people with MS, and indicates that it may be valuable to give more attention to the balance between working and private life, both in clinical practice and future research, to achieve a sustainable working life over time. [ABSTRACT FROM AUTHOR]

Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress (OS). It is well documented that equilibration status of OS plays fundamental roles in human reproductive medicine, and the physiological role of Nrf2 in ovarian granulosa cells (GCs) has not been determined yet. Herein we aimed to study the function of Nrf2 in GCs. Human ovarian tissues were subjected to immunohistochemistry to localize Nrf2 and Keap1 and we detected the expression of Nrf2 and Keap1 in the human GCs. Human luteinized GCs were isolated and cultured, and hydrogen peroxide (H 2 O 2 ) or Dimethylfumarates (DMF), an activator of Nrf2, were added to GCs to analyze the relationship between Nrf2 and antioxidants by quantitative RT-PCR. The mRNA levels of Nrf2, catalase, superoxide dismutase 1 (SOD1), and 8-Oxoguanine DNA glycosylase (OGG1) were elevated by H 2 O 2 , and DMF treatment showed similar but pronounced effects through activation of Nrf2. To determine the relationship of Nrf2 and the generation of antioxidants, siRNAs were used and quantitative RT-PCR were conducted. Decreased expression of Nrf2 resulted in a decreased level of these antioxidant mRNA. Intracellular levels of ROS were investigated by fluorescence of 8-hydroxy-2′-deoxyguanosine and fluorescent dye, 2′,7′-dichlorodihydrofluorescein diacetate after H 2 O 2 and/or DMF treatment, and DMF treatment quenched intracellular ROS generation by H 2 O 2 . These results show that activation of Nrf2 might lead to alleviate OS in human GCs, and this could provide novel insight to conquer the age-related fertility decline that is mainly attributed to the accumulation of aberrant OS. [ABSTRACT FROM AUTHOR]

The putative strong anti-nociceptive properties of the antidepressant phenelzine (PLZ) have not been widely explored as a treatment for pain. Antinociceptive effects of PLZ were identified in the formalin model of tonic pain (Mifflin et al., 2016) and in allodynia associated with experimental autoimmune encephalomyelitis, (EAE) a mouse model of multiple sclerosis (Potter et al., 2016). Here, we further clarify the specific types of stimuli and contexts in which PLZ modulates nociceptive sensitivity. Our findings indicate that PLZ selectively inhibits ongoing inflammatory pain while sparing transient reflexive and acute nociception. We also investigated the cellular mechanisms of action of PLZ in the dorsal horn, and as expected of a monoamine-oxidase inhibitor, PLZ increased serotonin (5HT) immunoreactivity. We next used two approaches to test the hypothesis that PLZ inhibits the activation of spinal nociresponsive neurons. First, we evaluated the formalin-evoked protein expression of the immediate early gene, c- fos . PLZ reduced Fos expression in the superficial dorsal horn. Second, we evaluated the effects of PLZ on intracellular calcium responses to superfusion of glutamate (0.3–1.0 mM) in an ex vivo lumbar spinal cord slice preparation. Superfusion with PLZ (100–300 μM) reduced 1 mM glutamate-evoked calcium responses. This was blocked by pretreatment with the 5HT1A-receptor antagonist WAY-100,635, but not the alpha-2 adrenergic antagonist idazoxan. We conclude that PLZ exerts antinociceptive effects through a 5-HT/5HT1AR-dependent inhibition of neuronal responses within nociceptive circuits of the dorsal horn. [ABSTRACT FROM AUTHOR]

In recent years, inactivation of A 2A adenosine receptors has been emerged as a novel strategy for treatment of several neurodegenerative diseases. Although numerous studies have shown the beneficial effects of A 2A receptors blockade on spatial memory, the impacts of selective adenosine A 2A receptors on memory performance has not yet been examined in the context of demyelination. In the present study, we evaluated the effect of A 2A receptor antagonist SCH58261 on spatial memory and myelination in an experimental model of focal demyelination in rat fimbria. Demyelination was induced by local injection of lysolecithin (LPC) 1% (2 μl) into the hippocampus fimbria. SCH58261 (20 μg/0.5 μl or 40 μg/0.5 μl) was daily injected intracerebroventricularly (i.c.v.) for 10 days post LPC injection. The Morris water maze test was used to assess the spatial learning and memory on day 6 post lesion. Myelin staining and immunostaining against astrocytes/microglia were carried out 10 days post LPC injection. The administration of adenosine A 2A receptor antagonist prevented the spatial memory impairment in LPC receiving animals. Myelin staining revealed that application of SCH58261 reduces the extent of demyelination areas in the fimbria. Furthermore, the level of astrocytes and microglia activation was attenuated following administration of A 2A receptor antagonist. Collectively, the results of this study suggest that A 2A receptor blockade can improve the spatial memory and protect myelin sheath, which might be considered as a novel therapeutic approach for multiple sclerosis disease. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a demyelinating disease in which neurological deficits result from damage to myelin, axons, and neuron cell bodies. Prolonged or repeated episodes of demyelination impair remyelination. We hypothesized that augmenting Sonic hedgehog (Shh) signaling in chronically demyelinated lesions could enhance oligodendrogenesis and remyelination. Shh regulates oligodendrocyte development during postnatal myelination, and maintains adult neural stem cells. We used genetic approaches to detect Shh expression and Shh responding cells in vivo. Shh CreERT2 or Gli1 CreERT2 mice were crossed to reporter mice for genetic fate-labeling of cells actively transcribing Shh or Gli1 , an effective readout of canonical Shh signaling. Tamoxifen induction enabled temporal control of recombination at distinct stages of acute and chronic cuprizone demyelination of the corpus callosum. Gli1 fate-labeled cells were rarely found in the corpus callosum with tamoxifen given during acute demyelination stages to examine activated microglia, reactive astrocytes, or remyelinating cells. Gli1 fate-labeled cells, mainly reactive astrocytes, were observed in the corpus callosum with tamoxifen given after chronic demyelination. However, Shh expressing cells were not detected in the corpus callosum during acute or chronic demyelination. Finally, SAG, an agonist of both canonical and type II non-canonical Hedgehog signaling pathways, was microinjected into the corpus callosum after chronic demyelination. Significantly, SAG delivery increased proliferation and enhanced remyelination. SAG did not increase Gli1 fate-labeled cells in the corpus callosum, which may indicate signaling through the non-canonical Hedgehog pathway. These studies demonstrate that Hedgehog pathway interventions may have therapeutic potential to modulate astrogliosis and to promote remyelination after chronic demyelination. [ABSTRACT FROM AUTHOR]

Quercetin is reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet has attracted the attention of the scientific community, resulting in a huge output of in vitro and in vivo (preclinical) studies. Therefore, we hypothesized that quercetin can protect Na + ,K + -ATPase activity in the central nervous system, reestablish the peripheral cholinesterases activities, and reduce oxidative stress during demyelination events in rats. In line with this expectation, our study aims to find out how quercetin acts on the Na + ,K + -ATPase activity in the central nervous system, peripheral cholinesterases, and stress oxidative markers in an experimental model of demyelinating disease. Wistar rats were divided into 4 groups: vehicle, quercetin, ethidium bromide (EB), and EB plus quercetin groups. The animals were treated once a day with vehicle (ethanol 20%) or quercetin 50 mg/kg for 7 (demyelination phase, by gavage) or 21 days (remyelination phase) after EB (0.1%, 10 μL) injection (intrapontine).The encephalon was removed, and the pons, hypothalamus, cerebral cortex, hippocampus, striatum, and cerebellum were dissected to verify the Na + ,K + -ATPase activity. Our results showed that quercetin protected against reduction in Na + ,K + -ATPase in the pons and cerebellum in the demyelination phase, and it increased the activity of this enzyme in the remyelination phase. During the demyelination, quercetin promoted the increase in acetylcholinesterase activity in whole blood and lymphocytes induced by EB, and it reduced the increase in acetylcholinesterase activity in lymphocytes in the remyelination phase. On day 7, EB increased the superoxide dismutase and decreased catalase activities, as well as increased the thiobarbituric acid–reactive substance levels. Taken together, these results indicated that quercetin regulates the Na + ,K + -ATPase activity, affects the alterations of redox state, and participates in the reestablishment of peripheral cholinergic activity during demyelinating and remyelination events. [ABSTRACT FROM AUTHOR]

Objective To examine moderators of treatment effects in a randomized controlled trial comparing a telehealth self-management intervention with a telehealth multiple sclerosis (MS) education intervention for fatigue, pain, and mood in adults with MS. Design Secondary analysis of a single-blind randomized controlled trial. Setting Community. Participants Adults with MS and chronic fatigue, chronic pain, and/or moderate depressive symptoms (N=163) recruited from across the United States. Interventions Two 8-week, telephone-delivered symptom interventions delivered 1:1: a self-management intervention (n=75) and an MS education intervention (n=88). Main Outcome Measures Outcome measures were fatigue impact pain interference, and depressive symptom severity assessed at baseline and posttreatment. Potential moderators of treatment effects assessed at baseline were demographics (age, sex, and education), clinical characteristics (disease duration and disability severity), symptoms (perceived cognitive impairment and pain intensity), baseline levels of the treatment outcomes (pain interference, fatigue impact and depressive symptom severity), and cognitive behavioral factors (pain catastrophizing, fatigue catastrophizing, self-efficacy, and patient activation). Results Moderation analyses found significant moderation for fatigue impact but not for pain intensity or depressive symptom severity. Baseline patient activation interacted with treatment group to predict fatigue impact at posttreatment ( P =.049). Among participants with high baseline patient activation, the self-management group reported significantly less fatigue at posttreatment than the education group. No other variables moderated the study outcomes. Conclusions At the group level, participants responded to both interventions, regardless of disease characteristics, demographics, symptom levels, and cognitive behavioral factors. Self-management and education are both potentially beneficial symptom treatments that may be recommended to individuals with MS and chronic pain, fatigue, and/or depressive symptoms. [ABSTRACT FROM AUTHOR]

Background Multiple sclerosis is an immune-mediated inflammatory disease of central nervous system. MicroRNAs play important roles in autoimmune diseases such as MS. Objectives The aim was to evaluate the expression pattern of miR-34a, miR-199a, miR-30c and miR-19a in peripheral blood derived CD4+ T lymphocytes of both relapsing and remitting phases of MS. Methods Blood samples from 40 RRMS patients (20 in relapsing and 20 in remitting phase) and 20 healthy volunteers were taken. CD4+ T cells were isolated. The expression level of miR-34a, miR-199a, miR-30c and miR-19a, and the percentage of Th17 and Treg cells were measured. Expression of master transcription factors of Th17 and Treg cells and several targets of these miRNAs were also evaluated. Results Data indicated an increased expression of miR-34a, miR-30c and miR-19a in relapsing phase and decreased expression of miR-199a in remitting phase. ROC curve data add other prestigious information of miR-34a, miR-199a, miR-30c and miR-19a by defining relapsing and remitting phase and also healthy cases with high specificity and sensitivity at a proposed optimum cut-off point. Conclusion Collectively, we showed a correlation between the four miRNAs with different phases of MS and their possible involvement in differentiation pathways of Th17 cells, as the most important players in MS. [ABSTRACT FROM AUTHOR]

Experimental autoimmune encephalomyelitis (EAE) is primarily used as an animal model of autoimmune demyelinating disease, multiple sclerosis. In this study, we found the proliferative rate of oligodendrocyte progenitor cells (OPCs) in the medulla elevated twofold above control levels during EAE and new generation of mature oligodendrocytes was increased as well. Although astrocytes showed hypertrophic reactive phenotype, a new generation of them was rare. Astrocyte- and tanycyte-like neural stem cells (NSCs), multipotent NSCs, did not augment their low proliferative rate. Thus, the present study demonstrates that resident OPCs derived from NSCs contribute to remyelination in the medulla oblongata in EAE mice. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a high prevalence degenerative disease characterized at the cellular level by glial and neuronal cell death. The causes of cell death during the disease course are not fully understood. In this work we demonstrate that in a MS model induced by Theiler’s murine encephalomyelitis virus (TMEV) infection, the inward rectifier (Kir) 4.1 potassium channel subunit is overexpressed in astrocytes. In voltage clamp experiments the inward current density from TMEV-infected astrocytes was significantly larger than in mock-infected ones. The cRNA hybridization analysis from mock- and TMEV-infected cells showed an upregulation of a potassium transport channel coding sequence. We validated this mRNA increase by RT-PCR and quantitative PCR using Kir 4.1 specific primers. Western blotting experiments confirmed the upregulation of Kir 4.1, and alignment between sequences provided the demonstration that the over-expressed gene encodes for a Kir family member. Flow cytometry showed that the Kir 4.1 protein is located mainly in the cell membrane in mock and TMEV-infected astrocytes. Our results demonstrate an increase in K + inward current in TMEV-infected glial cells, this increment may reduce the neuronal depolarization, contributing to cell resilience mechanisms. [ABSTRACT FROM AUTHOR]

Background: Common methods of gait analyses measure step length/width, gait velocity and gait variability to name just a few. Those parameters tend to be changing with fitness and skill of the subjects. But, do stable subject characteristic parameters in walking exist? Does the Limit-Cycle-Attractor qualify as such a parameter?.Research Question: The attractor method is a new approach focusing on the dynamics of human motion. It classifies the fundamental walking pattern by calculating the Limit-Cycle-Attractor and its variability from acceleration data of the feet. Our hypothesis is that the fundamental walking pattern in healthy controls and in people with Multiple Sclerosis (pwMS) is stable, but can be altered through acute interventions or rehabilitation.Methods: For this purpose, two investigations were conducted involving 113 subjects. The short-term stability was tested pre and post a 15 min passive/active MOTOmed (ergometer) session as well as up to 20 min afterwards. The long-term stability was tested over five weeks of rehabilitation once a week in pwMS. The main parameter of interest describes the velocity normalized average difference between two attractors (δM), which is an indicator for the change in movement pattern.Results: The Friedman's two-way ANOVA by ranks did not reveal any significant difference in δM. However, the conventional walking tests (6 min.10 m) improved significantly (p < 0.05) during rehabilitation. Contrary to our original hypothesis, the fundamental walking pattern was highly stable against controlled motor-assisted movement initiation via MOTOmed and rehabilitation treatment. Movement characteristics appeared to be independent of the improved fitness as indicated by the enhanced walking speed and distance.Significance: The individual Limit-Cycle-Attractor is extremely robust and might indeed qualify as an (almost) invariable characteristic in human walking. This opens up the possibility to encode the individual walking characteristics. Conditions as Parkinson, Multiple Sclerosis etc., might display disease specific distinctions via the Limit-Cycle-Attractor. [ABSTRACT FROM AUTHOR]

We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II + ) CD11b + Ly-6G + neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II + , CD11b + Ly-6C + mature monocytes increased modestly throughout the disease course. Amelioration of the clinical disease by TSA treatment was accompanied by diminished abundance of CD11b + Ly-6G dim activated neutrophils in secondary lymphoid organs and their influx into the spinal cord without affecting monocytes. Interestingly, the co-inhibitory ligand CD274 + (PD-L1 + ) but not CD275 + (ICOS-L + ), CD39 + or CD11c + dendritic cells were decreased in the peripheral lymphoid compartment of drug treated mice. Thus, in addition to myelin-specific T cell tolerance induction observed previously, selective repression of mature neutrophils and PD-L1 + cells is critically involved in the epigenetic regulation of P-EAE. [ABSTRACT FROM AUTHOR]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease. [ABSTRACT FROM AUTHOR]

Brain direct current (DC) potentials denote sustained shifts and slow deflections of cerebral potentials superimposed with conventional electroencephalography (EEG) waves and reflect alterations in the excitation level of the cerebral cortex and subcortical structures. Using galvanometers, such sustained displacement of the EEG baseline was recorded in the early days of EEG recordings. To stabilize the EEG baseline and eliminate artefacts, EEG was performed later by voltage amplifiers with high-pass filters that dismiss slow DC potentials. This left slow DC potential recordings as a neglected diagnostic source in the routine clinical setting over the last few decades. Brain DC waves may arise from physiological processes or pathological phenomena. Recordings of DC potentials are fundamental electro-clinical signatures of some neurological and psychological disorders and may serve as diagnostic, prognostic, and treatment monitoring tools. We here review the utility of both physiological and pathological brain DC potentials in different aspects of neurological and psychological disorders. This may enhance our understanding of the role of brain DC potentials and improve our fundamental clinical and research strategies for brain disorders. [ABSTRACT FROM AUTHOR]

We previously reported that S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, attenuated T H 17-mediated immune responses in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Cellular GSNO homeostasis is regulated via its synthesis by reaction between nitric oxide and glutathione and its enzymatic catabolism by GSNO reductase (GSNOR). In this study, we evaluated potential of reversible inhibitor of GSNOR (N6022) in comparison with exogenous GSNO in immunopathogenesis of EAE. Daily treatment of EAE mice with N6022 or exogenous GSNO significantly attenuated the clinical disease of EAE, but N6022 treatment showed greater efficacy than GSNO. Both N6022 and exogenous GSNO treatments increased the spleen levels of GSNO, as documented by increased protein-associated S-nitrosothiols, and inhibited polarization and CNS effector function of proinflammatory T H 17 cells while inducing the polarization and CNS effector function of anti-inflammatory CD4 + CD25 + FOXP3 - regulatory T (Treg) cells. Moreover, N6022 further attenuated T H 1 while inducing T H 2 and CD4 + CD25 + FOXP3 + Treg in their polarization and CNS effector functions. Similar to GSNO, the N6022 treatment protected against the EAE disease induced demyelination. However, neither exogenous GSNO nor N6022 treatment did not cause significant systemic lymphopenic effect as compared to FTY720. Taken together, these data document that optimization of cellular GSNO homeostasis by GSNOR inhibitor (N6022) in NO metabolizing cells attenuates EAE disease via selective inhibition of pro-inflammatory subsets of CD4 + cells (T H 1/T H 17) while upregulating anti-inflammatory subsets of CD4 + cells (T H 2/Treg) without causing lymphopenic effects and thus offers a potential treatment option for MS/EAE. [ABSTRACT FROM AUTHOR]

Myelin is a membrane wrapped around the axon of the nerve cell, which is composed of the mature oligodendrocytes. The role of myelin is to insulate and prevent the nerve electrical impulses from the axon of the neurons to the axons of the other neurons, which is essential for the proper functioning of the nervous system. Minor changes in myelin thickness could lead to substantial changes in conduction speed and may thus alter neural circuit function. Demyelination is the myelin damage, which characterized by the loss of nerve sheath and the relative fatigue of the neuronal sheath and axon. Studies have shown that myelin injury may be closely related to neurodegenerative diseases and may be an early diagnostic criteria and therapeutic target. Thus this review summarizes the recent result of pathologic effect and signal pathways of myelin injury in neurodegenerative diseases, especially the Alzheimer's disease to provide new and effective therapeutic targets. [ABSTRACT FROM AUTHOR]

Scutellaria comprises many species traditionally used for cognitive and neurological conditions. In vitro and in vivo studies have supported the value of bioactive compounds of the genus Scutellaria for CNS disorders such as Alzheimer, cerebral ischemia, depression and anxiety. In particular, the effects of plants belonging to the genus Scutellaria and their components are detailed on cognitive ability such as memory, attention and learning. In this review, the pharmacology of CNS effect and the related molecular mechanisms of the plants belonging to the genus Scutellaria and active constituents have been discussed. [ABSTRACT FROM AUTHOR]

Aims To investigate the association of the Nectin/Necl family genes with the risk of developing NMOSD. Methods Whole-exome sequencing was performed on two familial NMOSD cases and two unaffected family members. Additionally, 106 patients with sporadic NMOSD and 212 healthy controls (HCs) underwent screening for mutant Necl2 . Finally, the molecular weight and cellular localization of mutant NECL2 was examined in transfected HeLa cells. Results We identified a novel deletion mutation in Necl2 (c.1052_1060delCCACCACCA; p. Thr351_Thr353del), which was associated with disease manifestation in the NMOSD familial cases. The frequency at which the mutation occurred in patients with sporadic NMOSD was significantly higher than for HCs (5.7% and 0, respectively; p < 0.01). The mutation was located in the extracellular domain close to the transmembrane region, at a point in the protein sequence characterized by threonine enrichment. The mutant NECL2 had a lower molecular weight and exhibited defective trafficking to the cell surface. Conclusions Our results suggest that the Necl2 mutation identified herein may be associated with the risk of developing NMOSD. Furthermore, mutated NECL2 may play a role in the pathogenesis of the disease, potentially through its roles in axonal regeneration and/or via neuron-glia interactions that are relevant to myelination. [ABSTRACT FROM AUTHOR]