The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the core clock gene period (Per) and cryptochrome (Cry) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein-1 (Bmal1). By binding to E-box sequences in the promoters of Per1/2 and Cry1/2 genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock’s circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.
Recently, it was demonstrated that the expression of BMAL1 was decreased in the endometrium of women suffering from recurrent spontaneous abortion. To investigate the pathological roles of uterine clock genes during pregnancy, we produced conditional deletion of uterine Bmal1 (cKO) mice and found that cKO mice could receive embryo implantation but not sustain pregnancy. Gene ontology analysis of microarray suggested that uterine NK (uNK) cell function was suppressed in cKO mice. Histological examination revealed the poor formation of maternal vascular spaces in the placenta. In contrast to WT mice, uNK cells in the spongiotrophoblast layer, where maternal uNK cells are directly in contact with fetal trophoblast, hardly expressed an immunosuppressive NK marker, CD161, in cKO mice. By progesterone supplementation, pregnancy could be sustained until the end of pregnancy in some cKO mice. Although this treatment did not improve the structural abnormalities of the placenta, it recruited CD161-positive NK cells into the spongiotrophoblast layer in cKO mice. These findings indicate that the uterine clock system may be critical for pregnancy maintenance after embryo implantation.
Objective: Ranolazine is an anti-ischaemic agent with additional electrophysiological properties by inhibiting the cardiac late Na+ current and reducing the Ca2+ overload; it does not produce a change in heart rate or blood pressure. This study aimed to know if Ranolazine was added to Angiotensin Receptor Blockers plus Mineralocorticoid Receptor Antagonists (ARB+MRA) therapy in hypertensive with normal kidney function can reduce or avoid ventricular extrasystoles without the use of antiarrhythmics drugs such as flecainide or propafenone.Design & Methods: For developing this study, one first group of 45 hypertensive patients was entered, females 17 with an average age of 64.8 (SD 14.0) and males 28 with an average age of 68.4 (SD 12.8) in a regime of ARB+MRA therapy. All patients were assessed with a 24hs-monitoring Holter, pre and post Ranolazine (375/500 mg, 2xd), with an average therapy time-length on females-males by 12.4 (SD 10.0) -12.8 (SD 12.0) months. Also, the second group of 73 patients was registered, females-males (43-30) with an average age (SD) 67.1 (12.2) -66.8 (13.5) assessed with a 24hs-monitoring Holter only once at 12.2-16.7 months after ARB+MRA+Ranolazine therapy. All patients achieved normal levels of the central hemodynamic parameters, principally augmentation index (surrogate value of arterial stiffness) and end-systolic pressure measured with applanation tonometry (SphygmoCor System-PVX AtCor-Australia) used according to standard methods.
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