A novel strategy for development of glucocorticoids through non-genomic mechanism.
Glucocorticoids (GCs) are routinely believed to take effect through genomic mechanisms, which are also largely responsible for GCs' side effects. Beneficial non-genomic effects of GCs have been reported as being independent of the genomic pathway. Here, we synthesized a new type of GCs, which took effect mainly via non-genomic mechanisms. Hydrocortisone was conjugated with glycine, lysine and phenylalanine to get a bigger molecular structure, which could hardly go through the cell membrane. Evaluation of the anti-inflammatory efficacy showed that hydrocortisone-conjugated glycine (HG) and lysine could inhibit neutrophil degranulation within 15 min. HG could inhibit IgE-mediated histamine release from mast cells via a non-genomic pathway, and rapidly alleviate allergic reaction. Luciferase reporter assay showed that HG would not activate the glucocorticoid response element within 30 min, which verified the rapid effects independent of the genomic pathway. The work proposes a novel insight into the development of novel GCs, and provides new tools for experimental study on non-genomic mechanisms.
Zhou
Jian
J
Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, Shanghai, People's Republic of China.
Li
Min
M
Sheng
Chun-Quan
CQ
Liu
Lei
L
Li
Zhen
Z
Wang
Yan
Y
Zhou
Jiang-Rui
JR
Jing
Zai-Ping
ZP
Chen
Yi-Zhang
YZ
Jiang
Chun-Lei
CL
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D016678:Genome; D005938:Glucocorticoids / Q000138:chemical synthesis*; D006168:Guinea Pigs; D006632:Histamine / Q000032:analysis; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009195:Peroxidase / Q000032:analysis; D010649:Phenylalanine / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D005938:Glucocorticoids; D010649:Phenylalanine; D006632:Histamine; D009195:Peroxidase; D006854:Hydrocortisone