Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). The present study examined whether recombinant human GGF2 (rhGGF2) could effect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis. Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases. Clinically, GGF2 treatment delayed signs, decreased severity, and resulted in statistically significant reductions in relapse rate. rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased mRNA expression of myelin basic protein exon 2, a marker for remyelination, and with an increase in the CNS of the regulatory cytokine, interleukin 10, at both the RNA and protein levels. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated on the clinical, pathologic, and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a T helper 2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of multiple sclerosis.Most therapeutic strategies in the human demyelinating disease, multiple sclerosis (MS), have been based on modulating the immune response, and the animal model of MS, experimental autoimmune encephalomyelitis (EAE), has been particularly useful for testing potential therapeutic agents (1, 2). EAE, a CD4 ϩ T helper 1 (Th1) T cell-mediated disease of the central nervous system (CNS), involves autosensitization to myelin antigens and in the SJL mouse is a chronic relapsing neurologic disease with inflammatory demyelinated CNS lesions highly reminiscent of MS (3-5). Relatively unexplored in demyelinating conditions has been the therapeutic potential of neurotrophic factors with known regulatory effects on the myelinating cell. Prominent among these factors are members of the neuregulin family of soluble and transmembrane proteins belonging to the epidermal growth factor superfamily (6). Recombinant human glial growth factor 2 (rhGGF2) is a secreted isoform of neuregulin with documented stimulatory effects on oligodendrocytes and Schwann cells (7-10). Because oligodendrocytes are a major target in the MS lesion and because remyelination occurs in MS and EAE (3,4), it was hypothesized that administration of rhGGF2 to animals with EAE might ameliorate the disease. This report presents the findings from a large series of experiments in which rhGGF2 was given to mice at different stages of adoptively transferred chronic relapsing EAE. The results have shown that not only does rhGGF2 have marked beneficial effects at the acute and relapsing phases of the disease but it is also associated with structural and molecular evidence for enhanced remyelination of CNS lesions in long-term rhGGF2-treated animals.

No abstract

Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI), a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE) in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS) as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS.

Autism is one of the most common neurological developmental disorder associated with social isolation and restricted interests in children. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. To search for biomarkers for early detection and exploration of the disease mechanisms, here, we investigated the protein expression signatures of peripheral blood mononuclear cells (PBMCs) in autistic children compared with healthy controls by using isobaric tags for relative and absolute quantitation (iTRAQ) proteomics approach. The results showed a total of 41 proteins as differentially expressed in autistic group as compared to control. These proteins are found associated with metabolic pathways, endoplasmic reticulum (ER) stress and protein folding, endocytosis, immune and inflammatory response, plasma lipoprotein particle organization, and cell adhesion. Among these, 17 proteins (13 up-regulated and four down-regulated) are found to be linked with mitochondria. Eight proteins including three already reported proteins in our previous studies were selected to be verified. Five already reported autism associated pro-inflammatory cytokines [interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-12, and tumor necrosis factor-α (TNF-α)] were detected in plasma by enzyme-linked immunosorbent assay (ELISA) analysis. The results were consistent with proteomic results and reports from previous literature. These results proposed that PBMCs from autistic children might be activated, and ER stress, unfolded protein response (UPR), acute-phase response (APR), inflammatory response, and endocytosis may be involved in autism occurrence. These reported proteins may serve as potential biomarkers for early diagnosis of autism. More specifically, simultaneous detection of three proteins [complement C3 (C3), calreticulin (CALR), and SERPINA1] in the plasma and PBMCs could increase the authenticity of detection.

Background: Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces signi cant challenges due to the existence of heterogeneity.Methods: In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out.Results: The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, PBMCs, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focus on several common and previously reported mechanisms of ASD.Limitations: The number of samples carrying risk genes in omics research is limited. In further research, a large sample size is required. A group of children who have been diagnosed with ASD but have not been detected to carry risk genes should also be included. Conclusion:The biomarkers for ASD diagnosis could be found by taking DEPs and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.