Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The heparan sulfate-cleaving enzyme heparanase (HPSE) plays an important role in remodeling of the basement membrane and extracellular matrix during inflammation. Inducible HPSE enzymatic activity has been reported in leukocytes; however, little is known of the molecular mechanisms that regulate HPSE gene expression during inflammatory disease. In this study, HPSE expression and regulation in the T cell-mediated disease model, experimental autoimmune encephalomyelitis (EAE), were investigated. Expression analysis showed that HPSE mRNA is induced in rat CD4+ antigen-specific T lymphocytes upon activation and correlates with the encephalitogenicity of the cells. Examination of the kinetics and cell type-specific expression of HPSE throughout the progression of active EAE in rats, indicated that HPSE was highly expressed in CD4+ T cells infiltrating the central nervous system (CNS) during clinical disease. Little or no HPSE expression was observed in CD8+ T cells, macrophages, or astrocytes during disease progression. To investigate the mechanism of inducible HPSE gene regulation in T cells, studies were extended into human primary T cells. HPSE mRNA, protein, and enzymatic activity were induced upon activation. Functional analysis of the human HPSE promoter identified an EGR1 binding motif that contained high inducible activity and was transactivated by EGR1. Furthermore, the treatment of primary T lymphocytes with an EGR1 siRNA inhibited inducible HPSE mRNA expression. These data provide evidence to suggest that inducible HPSE expression in primary T lymphocytes is regulated at the transcriptional level by EGR1 and is important in facilitating CD4+ T cell infiltration into the CNS to promote EAE.
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PMID:Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4+ T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene 1. 1765 51

The heparan sulfate-cleaving enzyme heparanase (HPSE) plays an important role in remodeling of the basement membrane and extracellular matrix during inflammation. Inducible HPSE enzymatic activity has been reported in leukocytes; however, little is known of the molecular mechanisms that regulate HPSE gene expression during inflammatory disease. In this study, HPSE expression and regulation in the T cell-mediated disease model, experimental autoimmune encephalomyelitis (EAE), were investigated. Expression analysis showed that HPSE mRNA is induced in rat CD4+ antigen-specific T lymphocytes upon activation and correlates with the encephalitogenicity of the cells. Examination of the kinetics and cell type-specific expression of HPSE throughout the progression of active EAE in rats, indicated that HPSE was highly expressed in CD4+ T cells infiltrating the central nervous system (CNS) during clinical disease. Little or no HPSE expression was observed in CD8+ T cells, macrophages, or astrocytes during disease progression. To investigate the mechanism of inducible HPSE gene regulation in T cells, studies were extended into human primary T cells. HPSE mRNA, protein, and enzymatic activity were induced upon activation. Functional analysis of the human HPSE promoter identified an EGR1 binding motif that contained high inducible activity and was transactivated by EGR1. Furthermore, the treatment of primary T lymphocytes with an EGR1 siRNA inhibited inducible HPSE mRNA expression. These data provide evidence to suggest that inducible HPSE expression in primary T lymphocytes is regulated at the transcriptional level by EGR1 and is important in facilitating CD4+ T cell infiltration into the CNS to promote EAE.
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PMID:Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4+ T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene. 2935 Aug 61

The number of FDA-approved protein drugs (biologics), such as antibodies, antibody-drug conjugates, hormones, and enzymes, continues to grow at a rapid rate; most of these drugs are used to treat diseases of the peripheral body. Unfortunately, most of these biologics cannot be used to treat brain diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), and brain tumors in a noninvasive manner due to their inability to permeate the blood-brain barrier (BBB). Therefore, there is a need to develop an effective method to deliver protein drugs into the brain. Here, we report a proof of concept to deliver a recombinant brain-derived neurotrophic factor (BDNF) to the brains of healthy and experimental autoimmune encephalomyelitis (EAE) mice via intravenous (iv) injections by co-administering BDNF with a BBB modulator (BBBM) peptide ADTC5. Western blot evaluations indicated that ADTC5 enhanced the brain delivery of BDNF in healthy SJL/elite mice compared to BDNF alone and triggered the phosphorylation of TrkB receptors in the brain. The EAE mice treated with BDNF + ADTC5 suppressed EAE relapse compared to those treated with BDNF alone, ADTC5 alone, or vehicle. We further demonstrated that brain delivery of BDNF induced neuroregeneration via visible activation of oligodendrocytes, remyelination, and ARC and EGR1 mRNA transcript upregulation. In summary, we have demonstrated that ADTC5 peptide modulates the BBB to permit noninvasive delivery of BDNF to exert its neuroregeneration activity in the brains of EAE mice.
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PMID:Noninvasive Brain Delivery and Efficacy of BDNF to Stimulate Neuroregeneration and Suppression of Disease Relapse in EAE Mice. 3184 44