Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following early embryonic germ cell migration, oocytes are surrounded by somatic cells and remain arrested at diplotene stage until luteinizing hormone (LH) surge. Strict regulation of both meiotic arrest and meiotic resumption during dormant stage are critical for future fertility. Inter-cellular signaling system between the somatic compartment and oocyte regulates these meiotic events and determines the follicle quality. As well as the collected number of eggs, their qualities are also important for in vitro fertilization (IVF) outcome. In spontaneous and IVF cycles, germinal vesicle (GV)-stage oocytes, premature GV breakdown, and persistence of first meiotic arrest limit the reproductive performance. Likewise, both women with premature ovarian aging and young cancer women are undergoing chemoradiotherapy under the risk of follicle loss because of unregulated meiotic events. Understanding of oocyte meiotic events is therefore critical for the prevention of functional ovarian reserve. High levels of cyclic guanosine monophophate (cGMP), cyclic adenosine monophophate (cAMP) and low phosphodiesterase (PDE) 3A enzyme activity inside the oocyte are responsible for maintaining of meiotic arrest before the LH surge. cGMP is produced in the somatic compartment, and natriuretic peptide precursor C (Nppc) and natriuretic peptide receptor 2 (Npr2) regulate its production. cGMP diffuses into the oocyte and reduces the PDE3A activity, which inhibits the conversion of cAMP to the 5'AMP, and cAMP levels are enhanced. In addition, oocyte itself has the ability to produce cAMP. Taken together, accumulation of cAMP inside the oocyte induces protein kinase activity, which leads to the inhibition of maturation-promoting factor and meiotic arrest also continues. By stimulating the expression of epidermal growth factor, LH inhibits the Nppc/Npr2 system, blocks cGMP synthesis, and initiates meiotic resumption. Oocytes lacking the functional of this pathway may lead to persistence of the GV oocyte, which reduces the number of good quality eggs. Selective regulation of somatic cell signals and oocyte meiotic events enhance progress in fertility preservation methods, which may give us the opportunity to prevent follicle loss in prematurely aging women and young women with cancer are undergoing chemoradiotherapy.
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PMID:Selective Regulation of Oocyte Meiotic Events Enhances Progress in Fertility Preservation Methods. 2641 5

Cyclic adenosine monophosphate (cAMP) is a key intracellular second messenger, which is degraded by phosphodiesterase 4 (PDE4). PDE4 suppresses cAMP levels, and thus stimulates the activity of inflammatory cells. Therefore, PDE4 has been considered as a therapeutic target for airway inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). Roflumilast, an approved PDE4 inhibitor, has been shown to have clinical benefits in COPD. However, central nervous system-related side effects including nausea and vomiting have limited the therapeutic index of roflumilast. Moreover, although airway mucus hypersecretion is the characteristic feature, which is associated with the severity and prognosis, the inhibitory effect of roflumilast on sputum production is limited to a minority of patients. In this study, we demonstrate the inhibitory effects of TAS-203, which is an orally active PDE4 inhibitor associated with a lowered emetic effect, on airway inflammation and mucus hypersecretion. A cell-based assay showed TAS-203 treatment suppressed epidermal growth factor (EGF)-induced mucin MUC5AC expression. TAS-203 also suppressed monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-5 and IL-13 production in a Sephadex-induced airway inflammation model, and the number of infiltrating cells in bronchoalveolar lavage (BAL) fluid. TAS-203 caused marked reduction of goblet cell hyperplasia in a histopathological analysis of airway epithelium. Furthermore, TAS-203 suppressed 5-hydroxytryptamine (5-HT)-induced airway hyperresponsiveness (AHR). In addition, we preliminarily confirmed TAS-203 prevents airway MUC5AC production in BAL fluid, and shows lower specific airway resistance (sRaw) in a cigarette smoke-induced COPD-like model. Our data suggest that TAS-203 might be useful in the treatment of airway inflammatory disease.
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PMID:TAS-203, an oral phosphodiesterase 4 inhibitor, exerts anti-inflammatory activities in a rat airway inflammation model. 3071 15


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