The possible involvement of sema3A and sema4A in the pathogenesis of multiple sclerosis.

BACKGROUND: Immune semaphorins are widely accepted to have functional impact on autoimmune diseases. OBJECTIVES: To assess the status of sema3A and sema4A in the pathogenesis of Multiple Sclerosis (MS). RESULTS: Sema3A expression on (T regulatory cells)Tregs was decreased in MS patients, compared to healthy controls (35.85 ± 16.7% vs 88.27 ± 3.8%; p ≤ 0.001). Serum levels of sema3A were decreased in MS patients 2.95 ± 0.43 vs 18.67 ± 5.7 ng/ml in healthy individuals; p ≤ 0.001. Sema4A serum levels were increased in MS patients compared to healthy individuals (12.99 ± 8.6 vs 5.83 ± 3.91 ng/ml; p ≤ 0.001). Sema3A and sema4A serum levels were found to be in negative/positive correlation with MS disease severity (rs = 0.62, rs = -0.49, respectively). CONCLUSION: We show that sema3A is a regulatory molecule in MS, whereas sema4A is a stimulatory one. Targeting sema3A and sema4A could become a potential therapeutic approach in MS.

HDL-cholesterol elevation associated with fingolimod and dimethyl fumarate therapies in multiple sclerosis.

BACKGROUND: Patients with Multiple Sclerosis (PwMS) display altered lipoproteins levels and function, which seem to affect disease risk and progress. Whether disease-modifying therapies affect the lipoprotein profile in PwMS has scarcely been studied. OBJECTIVE: The study aims to assess whether fingolimod and dimethyl fumarate (DMF) affect lipoproteins in PwMS. METHODS: We compared retrospectively the blood lipoprotein levels of 29 fingolimod-treated and 41 DMF-treated patients before and after 3 and 12 months of therapy. Patients treated with cholesterol-reducing medications were not included. Data on weight change and disease activity during 1-year follow-up were obtained. RESULTS: HDL level, HDL/LDL ratio and HDL/total cholesterol ratio were increased in both treatment groups after 3 months' therapy and sustained, with no change in LDL or triglycerides. While at baseline only 26% of patients met the recommended minimum of HDL 60 mg/dl, after 3 months' therapy, 43% of fingolimod-treated and 47% of DMF-treated patients reached the recommended level. The majority of patients had no weight reduction. CONCLUSIONS: Fingolimod and DMF therapies are associated with a specific increase in HDL in PwMS. Further studies are required to validate these findings and their potential implication as biomarker of reduced inflammatory state and/or reduced risk of neurodegeneration or cardiovascular comorbidity.

p53 Mediates epidermal growth factor (EGF) induction of MMP-2 transcription and trophoblast invasion.

Trophoblast invasion is a highly restricted process, regulated by growth factors, hormones and cytokines. Trophoblast invasion is attainable due to proteolytic degradation of the epithelial basement membrane and the extracellular matrix by proteolytic enzymes like the matrix metalloproteinases (MMPs) particularly MMP-2. Epidermal growth factor (EGF), a major mediator of implantation, has been documented to induce MMP-2 and trophoblast invasion. The aim of this study was to investigate the transcriptional regulation of MMP-2 in EGF- stimulated invasive trophoblast cells, using JAR choriocarcinoma cell line and 6-8w 1st trimester trophoblasts. MMP-2 expression was induced by EGF within 1 hour. Gelshift and supershift assay were used to explore transcription factors involved in MMP-2 regulation. EGF induced binding activity and expression of phophorylated p53, AP-2alpha and -gamma, C/EBPepsilon and -lambda to their responding sequences, found in the MMP-2 promoter. Additionally EGF induced binding activity to SP-1, but reduced the expression of SP-1 and SP-4. Inhibition of p53 by antisense reduced both basic and EGF- induced MMP-2 expression. In summary: MMP-2 transcriptional regulation by EGF in invasive trophoblasts is mediated through several binding sites and transcription factors including p53, AP-2alpha and -gamma, C/EBPepsilon and -lambda and SP-1. p53 mediates both basic and EGF-induced MMP-2 transcription.