Synthesis, Biological Evaluation, and Molecular Modeling of Glycyrrhizin Derivatives as Potent High-Mobility Group Box-1 Inhibitors with Anti-Heart-Failure Activity in Vivo

Abstract The sex-determining region of the Y chromosome (SRY) plays a key role in human sex determination, as mutations in SRY can cause XY sex reversal. Although some SRY missense mutations affect DNA binding and bending activities, it is unclear how others contribute to disease. The high mobility group domain of SRY has two nuclear localization signals (NLS). Sex-reversing mutations in the NLSs affect nuclear import in some patients, associated with defective importin-β binding to the C-terminal NLS (c-NLS), whereas in others, importin-β recognition is normal, suggesting the existence of an importin-β-independent nuclear import pathway. The SRY N-terminal NLS (n-NLS) binds calmodulin (CaM) in vitro, and here we show that this protein interaction is reduced in vivo by calmidazolium, a CaM antagonist. In calmidazolium-treated cells, the dramatic reduction in nuclear entry of SRY and an SRY-c-NLS mutant was not observed for two SRY-n-NLS mutants. Fluorescence spectroscopy studies reveal an unusual conformation of SRY.CaM complexes formed by the two n-NLS mutants. Thus, CaM may be involved directly in SRY nuclear import during gonadal development, and disruption of SRY.CaM recognition could underlie XY sex reversal. Given that the CaM-binding region of SRY is well-conserved among high mobility group box proteins, CaM-dependent nuclear import may underlie additional disease states.

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High mobility group box 1 protein (HMGB1) as biomarker in hypoxia-induced persistent pulmonary hypertension of the newborn: a clinical and in vivo pilot study

International Journal of Medical Sciences ◽

10.7150/ijms.34344 ◽

2019 ◽

Vol 16 (8) ◽

pp. 1123-1131 ◽

Cited By ~ 4

Author(s):

Zhen Tang ◽

Min Jiang ◽

Zhicui Ou-yang ◽

Hailan Wu ◽

Shixiao Dong ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pilot Study ◽

High Mobility ◽

High Mobility Group ◽

Persistent Pulmonary Hypertension

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Changes in quantities of high-mobility-group protein 1 in oviduct cellular fractions after oestrogen stimulation

Biochemical Journal ◽

10.1042/bj1980085 ◽

1981 ◽

Vol 198 (1) ◽

pp. 85-90 ◽

Cited By ~ 6

Author(s):

C T Teng ◽

C S Teng

Keyword(s):

Microsomal Fraction ◽

High Mobility ◽

Quantitative Change ◽

High Mobility Group ◽

Nuclear Fraction ◽

Hmg Proteins ◽

High Mobility Group Protein ◽

Group Protein ◽

Oviduct Cell

Antiserum against chick oviduct high-mobility-group protein 1 (HMG 1) has been induced in the rabbit. With this antiserum, immunobiochemical techniques have been used to probe the quantitative change of HMG 1 in the cellular fractions of chick oviduct before or after oestrogen stimulation. HMG 1 is detectable in the cytosol, microsomal and nuclear fraction of the chick oviduct cell. After administration of oestrogen to young chicks in vivo for 5 days, the quantity of HMG 1 is increased 4-fold in the cytosol, 3.5-fold in the microsomal fraction and 1.6-fold in the nuclear fraction. The finding of large amounts of HMG 1 in cytoplasm of oviduct cell is not likely due to its leakage from the nucleus. We anticipate that HMG 1 is synthesized in the cytoplasm and then transported into the nucleus. The synthesis and transportation of HMG proteins is probably regulated by oestrogen.

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