Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An adequate vascular supply is important to provide endocrine and paracrine signals during follicular development. We evaluated the direct in vivo effects of both the GnRH-agonist Leuprolide acetate (LA) and the GnRH-antagonist Antide (Ant) on the expression of VEGF-A and ANPT-1 and their receptors in ovarian follicles from prepubertal eCG-treated rats. We also examined whether the changes observed in apoptosis by GnRH-I analogs have an effect on the caspase cascade. LA significantly decreased the levels of VEGF-A, its receptor Flk-1, and ANPT-1 when compared to controls, while the co-injection of Ant interfered with this effect. No changes were observed in the levels of Tie-2 after treatment with these analogs. When we measured the follicular content of caspase-3 protein, we observed that LA significantly increased the level of the active form. The co-injection of Ant interfered with this effect and Ant alone significantly decreased caspase-3 cleavage. IHC analyses corroborated these data. Notably, while LA increased caspase-3 activity levels, Ant decreased them when compared to controls. In follicles obtained from LA-treated rats, cleavage of PARP (a substrate of caspase-3) from the intact 113-kDa protein showed a significant enhancement in an 85-kDa fragment. The co-injection of Ant interfered with this effect. Ant alone significantly decreased PARP cleavage as compared to controls. We conclude that the decrease in VEGF-A, its receptor Flk-1/KDR, and ANPT-1 produced by the administration of GnRH-I agonist is one of the mechanisms involved in ovarian cell apoptosis. This suggests an intraovarian role of an endogenous GnRH-like peptide in gonadotropin-induced follicular development.
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PMID:Regulation of ovarian angiogenesis and apoptosis by GnRH-I analogs. 1787 66

Three-layered milli-capsules (3LMC), diameter of 1.85+/-0.07 and 0.15+/-0.09 mm thickness, were designed for the long-term subcutaneous (sc) administration of drugs. 3LMCs composed of (1) surface membrane (release rate control membrane), (2) drug-carrying layer and (3) base membrane were prepared by dispensing each solution in series. As surface membrane, poly-(epsilon-caprolactone) having MW of 70 kDa (PCL70) was used in combination with plasticizer, polysorbate 60 (Tween60). Base membrane was prepared with PCL70. Fluorescein isothiocyanate labeled dextrans (FD-4, MW=4 kDa and FD-20, MW=20 kDa) were used as model drug and in vitro release experiment was performed with PCL70 surface membrane containing Tween60 with 0.3, 1.0 and 3.0% (w/w). As the amount of Tween60 increased, release rate of FD-4 was increased. PCL70+0.3% Tween60 membrane showed a good sustained release property for 5 weeks; 50.3+/-6.0% of FD-4 was released during 5 weeks. When FD-20 was encapsulated, long-term sustained release was not obtained, 10.7+/-3.6% was released during 5 weeks. However, when lower MW drug, leuprolide acetate, was encapsulated, 3LMC composed of PCL70+0.3% Tween60 showed a good sustained release property, 63.0+/-5.9% released for 5 weeks. Leuprolide acetate encapsulated 3LMC was evaluated in rat experiment. After sc administration to rats, 0.5 and 1.0 mg, plasma leuprolide concentration showed its maximum concentration at day 1, thereafter gradually decreased and maintained the effective concentration for 14 weeks. Plasma leuprolide concentration vs. time curve showed a good dose-dependency. When surface membrane prepared by blending PCL70 and poly(lactic acid) (PLA) in the molar ratio of 5:1 was used, long-term sustained release property was not obtained. Instead, lower MW PCL, PCL40, was blended with PLA (5:1) to prepare surface membrane, sustained release of leuprolide was observed for 5 weeks. Through those studies, 3LMC has been shown to be a long-term sustained release preparation by properly selecting the surface membrane.
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PMID:Three-layered microcapsules as a long-term sustained release injection preparation. 1978 37

Impaired immune reconstitution after hematopoietic stem cell transplantation (HSCT) is attributed in part to impaired thymopoiesis. Recent data suggest that precursor input may be a point of regulation for the thymus. We hypothesized that administration of FLT3 ligand (FLT3L) would enhance thymopoiesis after adoptive transfer of aged, FLT3L-treated bone marrow (BM) to aged, Lupron-treated hosts by increasing murine HSC (Lin[minus]Sca1+c-Kit+ [LSK] cells) trafficking and survival. In murine models of aged and young hosts, we show that FLT3L enhances thymopoiesis in aged, Lupron-treated hosts through increased survival and export of LSK cells via CXCR4 regulation. In addition, we elucidate an underlying mechanism of FLT3L action on BM LSK cells-FLT3L drives LSK cells into the stromal niche using Hoescht (Ho) dye perimortem. In summary, we show that FLT3L administration leads to: (1) increased LSK cells and early thymocyte progenitor precursors that can enhance thymopoiesis after transplantation and androgen withdrawal, (2) mobilization of LSK cells through downregulation of CXCR4, (3) enhanced BM stem cell survival associated with Bcl-2 upregulation, and (4) BM stem cell enrichment through increased trafficking to the BM niche. Therefore, we show a mechanism by which FLT3L activity on hematopoeitic and thymic progenitor cells may contribute to thymic recovery. These data have potential clinical relevance to enhance thymic reconstitution after cytoreductive therapy.
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PMID:FLT3 ligand regulates thymic precursor cells and hematopoietic stem cells through interactions with CXCR4 and the marrow niche. 2855 33