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A novel strategy for development of glucocorticoids through non-genomic mechanism

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Abstract

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.

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Abbreviations

GCs:

Glucocorticoids

GRE:

Glucocorticoid response element

HH:

Hydrocortisone

HG:

Hydrocortisone-conjugated glycine

HL:

Hydrocortisone-conjugated lysine

HP:

Hydrocortisone-conjugated phenylalanine

RU486:

Mifepristone

ATI:

Actidione

fMLP:

N-Formyl-methionyl-leucylphenylalanine

MPO:

Myeloperoxidase

R L :

Lung resistance

C dyn :

Lung dynamic compliance

RBL-2H3 cell:

Rat basophilic leukemia mast cell

Boc:

Tert-butoxycarbonyl

MMTV-Luc:

Mouse mammary tumor virus-luciferase

cAMP:

Cyclic adenosine monophosphate

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Acknowledgment

The work was supported by grants from National Natural Science Foundation of China (30873077 and 30700344), Shanghai Basic Research Foundation (08JC1404900), Natural Science and Technology Major Project (2009ZX09303002), and Mental Health Program (2010).

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Authors and Affiliations

  1. Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Jian Zhou, Min Li, Lei Liu, Jiang-Rui Zhou & Chun-Lei Jiang

  2. Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Jian Zhou & Zai-Ping Jing

  3. Department of Medicinal Chemistry, College of Pharmacy, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Chun-Quan Sheng

  4. Department of Clinical Pharmacology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Zhen Li

  5. Department of Pathophysiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Yan Wang

  6. Institute of Neuroscience, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Yi-Zhang Chen

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  1. Jian Zhou
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  2. Min Li
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  3. Chun-Quan Sheng
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  6. Yan Wang
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  9. Yi-Zhang Chen
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  10. Chun-Lei Jiang
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Corresponding author

Correspondence to Chun-Lei Jiang.

Additional information

J. Zhou and M. Li contributed equally to this work.

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Zhou, J., Li, M., Sheng, CQ. et al. A novel strategy for development of glucocorticoids through non-genomic mechanism. Cell. Mol. Life Sci. 68, 1405–1414 (2011). https://doi.org/10.1007/s00018-010-0526-0

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