ABSTRACT
BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelinating lesions in the white matter of the central nervous system. Studies have shown that exercise is beneficial for multiple sclerosis (MS). However, the molecular basis is largely unknown. MATERIALS AND METHODS: We integrated multiple blood and hippocampus transcriptome data from subjects with physical activity or MS. Transcription change associations between physical activity and MS were analyzed with bioinformatic methods including GSEA (Gene Set Enrichment Analysis) and GO (Gene Ontology) analysis. RESULTS: We find that exercise can specifically reverse immune-related genes in the hippocampus of MS patients, while this effect is not observable in blood. Moreover, many of these reversed genes encode immune-related receptors. Interestingly, higher levels of physical activity have more pronounced effects on the reversal of MS-related transcripts. CONCLUSIONS: The immune-response related genes or pathways in the hippocampus may be the targets of exercise in alleviating MS conditions, which may offer new therapeutic clues for MS.
Subject(s)
Autoimmune Diseases , Multiple Sclerosis , White Matter , Humans , Multiple Sclerosis/genetics , Hippocampus , ExerciseABSTRACT
Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.
ABSTRACT
The synthesis of 4-triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienone (13), bicyclo[2.2.2]octenones 1a-j and 15a-j, and bicyclo[2.2.2]octadienones 2a-f, 6a-d, and 11a-f is described. The 2,4-cyclohexadienones 4 and 13 were used for the first time as nondimerizing and easily accessible alternatives to 2,6,6-trimethyl-2,4-cyclohexadienone 12 in Diels-Alder reactions with acetylene derivatives 5a-d to prepare the adducts 6a-d and 11a-e in excellent yields. Compounds 11a-d were initially prepared by the alcoholysis of 6a-d to afford bicyclo[2.2.2]octene-2,5-diones 7a-dfollowed by treatment of 7a-d with N-phenyltriflimide in the presence of LHMDS at -78 degrees C. Diels-Alder reaction of 13 with an acetylene equivalent, phenyl vinyl sulfoxide, was also studied. A detailed study of the Diels-Alder reactions of various olefinic dienophiles 14a-j with 13 has been carried out to furnish cycloadducts 15a-j in high yields. Reductive removal of triflyloxy group of vinyl triflates 11a-f and 15a-j was performed in the presence of [Pd(PPh(3))(2)Cl(2)-Bu(3)N-HCO(2)H] to obtain the desired bicyclo[2.2.2]octadienones 2a-f and bicyclo[2.2.2]octenones 1a-j, respectively, in good overall yields.
