- 作者: Joanna Jakobkiewicz-Banecka; Ewa Piotrowska; Magdalena Narajczyk; Sylwia Baranska; Grzegorz Wegrzyn
- 作者服務機構: Department of Molecular Biology, University of Gdansk, Ktadki 24, 80-822 Gdansk, Poland
- 中文摘要: --
- 英文摘要:
Background:
Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by mutations leading
to dysfunction of one of enzymes involved in degradation of glycosaminoglycans (GAGs).
Due to their impaired degradation, GAGs accumulate in cells of patients, which results in
dysfunction of tissues and organs. Substrate reduction therapy is one of potential treatment of
these diseases. It was demonstrated previously that genistein (4', 5, 7-trihydroxyisoflavone)
inhibits synthesis and reduces levels of GAGs in cultures of fibroblasts of MPS patients.
Recent pilot clinical study indicated that such a therapy may be effective in MPS III
(Sanfilippo syndrome).
Methods:
To learn on details of the molecular mechanism of genistein-mediated inhibition of GAG
synthesis, efficiency of this process was studied by measuring of incorporation of labeled
sulfate, storage of GAGs in lysosomes was estimated by using electron microscopic
techniques, and efficiency of phosphorylation of epidermal growth factor (EGF) receptor was
determined by using an ELISA-based assay with fluorogenic substrates.
Results:
Effects of genistein on inhibition of GAG synthesis and accumulation in fibroblasts from
patients suffering from various MPS types were abolished in the presence of an excess of
EGF, and were partially reversed by an increased concentration of genistein. No such effects
were observed when an excess of 17β-estradiol was used instead of EGF. Moreover, EGFmediated
stimulation of phsophorylation of the EGF receptor was impaired in the presence of
genistein in both wild-type and MPS fibroblasts. - 中文關鍵字: --
- 英文關鍵字: --