The cryopreservation of mammalian embryos is an important technology in embryo engineering. The discovery and application of the embryo's own high freezing resistance factors are the main methods to improve the utilization of mammalian embryos in cryopreservation. Cathepsin L gene expression in the frozen and thawed dormant embryos displayed a significant difference from those normal hatched ones. The aim of the present study was to dig out the potential role of Cathepsin L in anti-freezing capacity of murine blastocysts by investigating the location and expression of Cathepsin L in frozen and thawed both activated and dormant hatching blastocysts. Different concentrations of Cathepsin L recombinant protein and E-64d were then respectively added into the embryo cryoprotectant and pre-cryo culture medium. Our results found that down-regulation of Cathepsin L improves the freezing resistance of murine normal hatching embryos by reducing apoptosis. Cathepsin L inhibitors can be used to improve the efficiency of cryopreservation and recovery of blastocysts in vitro. Our study provides a theoretical basis for the further development and application of Cathepsin L.

2014-10-01·The Journal of Steroid Biochemistry and Molecular Biology2区 · 生物学

Novel roles of 1α,25(OH)2D3 on DNA repair provide new strategies for breast cancer treatment

2区 · 生物学

Review

作者: Gonzalo, Susana

Breast cancers classified as triple-negative (TNBC) and BRCA1-deficient, are particularly aggressive and difficult to treat. A major breakthrough was the finding that these tumors are exquisitely sensitive to inhibitors of poly(ADP-ribose) polymerase (PARPi). Phase II clinical trials have shown encouraging outcomes, with tolerable side effects. However, a significant fraction of these cancers acquire resistance. Elegant studies demonstrated that loss of the DNA repair protein 53BP1 contributes to the resistance of BRCA1-deficient cells and tumors to PARPi. Thus, raising the levels of 53BP1 in these aggressive tumors could potentially restore their sensitivity to PARPi and other genotoxic agents. We will review here our studies revealing that 1α,25(OH)2D3, an active form of vitamin D, stabilizes 53BP1 levels in tumor cells. Breast tumor cells that become BRCA1-deficient activate cathepsin L-mediated degradation of 53BP1 to ensure genome stability and proliferation. Importantly, 1α,25(OH)2D3 treatment restores the levels of 53BP1 as efficiently as cathepsin L inhibitors, which results in increased genomic instability in response to PARPi or radiation, and reduced proliferation. Furthermore, analysis of human breast tumors identified nuclear cathepsin L as a positive biomarker for TNBC, which correlates inversely with 53BP1 when vitamin D receptor (VDR) nuclear levels are low. The major findings of these studies are: (1) identification of a new pathway contributing to breast cancers with the poorest prognosis; (2) discovery of the ability of 1α,25(OH)2D3 to inhibit this pathway; and (3) discovery of a triple biomarker signature for identification of patients that could benefit from the treatment. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

2014-07-01·Antimicrobial Agents and Chemotherapy2区 · 医学

Characterization of a Respiratory Syncytial Virus L Protein Inhibitor

2区 · 医学

Article

作者: Xiong, Hui ; Fan, Jun ; Challa, SreeRupa ; Aschenbrenner, Lisa ; McLaughlin, Robert E. ; Tiong-Yip, Choi-Lai ; Johnson, Kenneth D. ; Yu, Qin

ABSTRACTThe respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function.

100 项与 Cathepsin L抑制剂(LGM) 相关的药物交易

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