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Articles by Y Gu
Total Records ( 4 ) for Y Gu
  Y Yao , H Li , Y Gu , N. E Davidson and Q. Zhou
 

Estrogen receptor (ER) mediates estrogen-dependent gene transcription, which plays a critical role in mammary gland development, reproduction and homeostasis. Histone acetyltransferases and class I and class II histone deacetylases (HDACs) cause posttranscriptional modification of histone proteins that participate in ER signaling. Here, we report that human SIRT1, a class III HDAC, regulates ER expression. Inhibition of SIRT1 activity by sirtinol suppresses ER expression through disruption of basal transcriptional complexes at the ER promoter. This effect leads to inhibition of estrogen-responsive gene expression. Our in vitro observations were further extended that SIRT1 knockout reduces ER protein in mouse mammary gland. Finally, ER-mediated estrogen response genes are also decreased in mouse embryonic fibroblasts derived from SIRT1-knockout mice. These results suggest that inhibition of SIRT1 deacetylase activity by either pharmacological inhibitors or genetic depletion impairs ER-mediated signaling pathways.

  Y Gu , X Liang , W Wu , M Liu , S Song , L Cheng , L Bo , C Xiong , X Wang , X Liu , L Peng and K. Yao
 

Context: Hormonal male contraceptive regimens effectively and reversibly suppress sperm production, but there are few large-scale efficacy studies.

Objective: The safety, contraceptive efficacy, reversibility, and feasibility of injectable testosterone undecanoate (TU) in tea seed oil as a hormonal male contraceptive was assessed.

Design: This was a multicenter, phase III, contraceptive efficacy clinical trial.

Participants: A total of 1045 healthy fertile Chinese men were recruited throughout China into the study.

Intervention(s): Injections of 500 mg TU were administered monthly for 30 months. A definition of severe oligozoospermia (≤1 x 106/ml) was used as a criterion of spermatogenic suppression and as the threshold for entering the contraceptive efficacy phase.

Main Outcome Measure(s): The primary outcome was pregnancy rate in the partner. Other outcomes include: semen parameters, testis volumes, reproductive hormone levels, and safety laboratory tests.

Results: Forty-three participants (4.8%) did not achieve azoospermia or severe oligozoospermia within the 6-month suppression phase. A total of 855 participants entered into the efficacy phase, and 733 participants completed monthly TU treatment and follow-up. There were nine pregnancies in 1554.1 person-years of exposure in the 24-month efficacy phase for a cumulative contraceptive failure rate of 1.1 per 100 men. The combined method failure rate was 6.1%, comprising 4.8% with inadequate suppression and 1.3% with postsuppression sperm rebound. No serious adverse events were reported. Spermatogenesis returned to the normal fertile reference range in all but two participants.

Conclusions: Monthly injection of 500 mg TU provides safe, effective, reversible, and reliable contraception in a high proportion of healthy fertile Chinese men.

  L. A MacFarlane , Y Gu , A. G Casson and P. R. Murphy
 

We have previously reported that elevated fibroblast growth factor-2 (FGF-2) expression is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer and that these risks are reduced in tumors coexpressing an endogenous antisense (FGF-AS) RNA. In the present study, we examined the role of the endogenous FGF-AS transcript in the regulation of FGF-2 expression in the human lung adenocarcinoma cell line Seg-1. FGF-2 and FGF-AS were temporally and spatially colocalized in the cytoplasm of individual cells, and knockdown of either FGF-2 or FGF-AS by target-specific siRNAs resulted in dose-dependent up-regulation of the complementary transcript and its encoded protein product. Using a luciferase reporter system, we show that these effects are mediated by interaction of the endogenous antisense RNA with the 3'-untranslated region of the FGF-2 mRNA. Deletion mapping identified a 392-nucleotide sequence in the 5823-nucleotide FGF-2 untranslated tail that is targeted by FGF-AS. Small interfering RNA-mediated knockdown of either FGF-AS or FGF-2 significantly increased the stability of the complementary partner mRNA, demonstrating that these mRNAs are mutually regulatory. Knockdown of FGF-AS also resulted in reduced expression of argonaute-2 (AGO-2) and a number of other elements of the endogenous micro-RNA/RNA interference pathways. Conversely, small interfering RNA-mediated knockdown of AGO-2 significantly increased the stability of the FGF-2 mRNA transcript and the steady-state levels of both FGF-2 mRNA and protein, suggesting a role for AGO-2 in the regulation of FGF-2 expression.

  R Pardossi Piquard , S. P Yang , S Kanemoto , Y Gu , F Chen , C Bohm , J Sevalle , T Li , P. C Wong , F Checler , G Schmitt Ulms , P St. George Hyslop and P. E. Fraser
 

Complexes involved in the /-secretase-regulated intramembranous proteolysis of substrates such as the amyloid-β precursor protein are composed primarily of presenilin (PS1 or PS2), nicastrin, anterior pharynx defective-1 (APH1), and PEN2. The presenilin aspartyl residues form the catalytic site, and similar potentially functional polar transmembrane residues in APH1 have been identified. Substitution of charged (E84A, R87A) or polar (Q83A) residues in TM3 had no effect on complex assembly or activity. In contrast, changes to either of two highly conserved histidines (H171A, H197A) located in TM5 and TM6 negatively affected PS1 cleavage and altered binding to other secretase components, resulting in decreased amyloid generating activity. Charge replacement with His-to-Lys substitutions rescued nicastrin maturation and PS1 endoproteolysis leading to assembly of the formation of structurally normal but proteolytically inactive -secretase complexes. Substitution with a negatively charged side chain (His-to-Asp) or altering the structural location of the histidines also disrupted -secretase binding and abolished functionality of APH1. These results suggest that the conserved transmembrane histidine residues contribute to APH1 function and can affect presenilin catalytic activity.

 
 
 
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