Effects of leonurine hydrochloride on medically induced incomplete abortion in early pregnancy rats

Objectives

To determine the effect of leonurine hydrochloride (LH) on abnormal bleeding induced by medical abortion.

Study design

Rats had incomplete abortions induced in early pregnancy using mifepristone in combination with misoprostol. After abortion, rats were treated with LH for 7 days, and the duration and volume of uterine bleeding were observed. Approximately 30 min after the last treatment, the animals were killed and the uterine shape was observed. The sinistro-uteri were suspended in organ baths to record the contraction curves, including the frequency and tension for 10 min; the dextro-uteri were fixed with formaldehyde for pathologic evaluation. In addition, blood samples were collected from the femoral artery for the measurement of estradiol (E₂) and progesterone (P) levels by radioimmunoassay.

Results

In in vivo experiments, compared with the model group, LH treatment markedly reduced the volume of bleeding and intrauterine residual, and significantly shortened the duration of bleeding. From the contraction curve, LH notably reinforced the frequency and tension of uterine contractions. LH remarkably elevated the serum estradiol level in rats, but had no obvious effect on progesterone level.

Conclusions

LH has an inhibitory effect on bleeding caused by incomplete abortion; the mechanism may be related to up-regulation of the E₂ level, leading to an increase in uterine contractions and evacuation of intrauterine residuum.     

Prostaglandin F2alpha increases the sensitivity of the contractile proteins to Ca2+ in human myometrium

It is not known whether agonists (other than oxytocin) increase the contractile protein sensitivity to intracellular calcium ([Ca2+]i) in human myometrium. We determined the calcium-tension relationship in the presence and absence of prostaglandin F2alpha (PGF2alpha). PGF2alpha increased the calcium sensitivity during both the contractile (rising) and relaxation (falling) phases of a contraction.     

Effects of L- and T-type Ca<Superscript>2+</Superscript> channel blockers on spermatogenesis and steroidogenesis in the prepubertal mouse testis

Purpose  

To assess the involvement of L-type and T-type Ca²⁺ channel blockers in inducing male infertility.     

Effect of estrogen and 1alpha,25(OH)2- vitamin D3 on the activity and growth of human primary osteoblast-like cells in vitro

OBJECTIVE: To evaluate effects of 17beta-E(2) and 1alpha,25(OH)(2)-vitamin D(3) on human osteoblast-like (hOB) cells. DESIGN: Controlled, experimental study. SETTING: University hospital. PATIENT(S): hOB cell cultures were prepared from the upper femur of postmenopausal patients undergoing bipolar endoprosthesis arthroplasty for a fractured femoral neck. INTERVENTION(S): hOB cells were subcultured with either 17beta-E(2) or 1alpha,25(OH)(2)-vitamin D(3), or both. MAIN OUTCOME MEASURE(S): Cell proliferation and activity of alkaline phosphatase, osteocalcin, and interleukin-6. RESULT(S): 17beta-E(2) significantly reduced interleukin-6 and osteocalcin to 34% and 60% of control value but induced alkaline phosphatase and cell proliferation to 183% and 150% of control value. 1alpha,25(OH)(2)-vitamin D(3) significantly decreased cell proliferation to 88% of that of control group, but 1alpha,25(OH)(2)-vitamin D(3) plus 17beta-E(2) showed no difference from the control group. Alkaline phosphatase and osteocalcin were significantly increased by 1alpha,25(OH)(2)-vitamin D(3) alone or combined with 17beta-E(2), to 169% and 198% and to 144% and 144% of control value, respectively. 1alpha,25(OH)(2)-vitamin D(3), with or without 17beta-E(2), decreased interleukin-6 levels to 27% and 38% of control group, respectively. CONCLUSION(S): 17beta-E(2) and 1alpha,25(OH)(2)-vitamin D(3) have effects on osteoblasts. The prevention of osteoporosis by estrogen may be related not only to direct effects on osteoblastic activity and proliferation but also to indirect effects on osteoclasts by the decrease of interleukin-6 secretion.     

Effects of Labetalol on the Releas of Prostacyclin and Endothelin-1 by Cultured Human Umbilical Vein Endothelial Cells and on the Excretion of Prostacyclin and Thromboxane Metabolites in Preeclamptic Patients

Objective: Labetalol reduces blood pressure primarily by blocking alpha-and beta-receptors, but other mechanisms of action may also be possible. We studied the effects of labetalol on the synthesis of vasodilatory prostacyclin (PGI₂) and vasoconstrictory endothelin-1 (ET-1) by cultured human umbilical vein endothelial cells (HUVECs). We also studied the effect of oral labetalol treatment on PGI, and thromboxane A₂ (TxA.₂) production in preeclamptic patients.

Methods: HUVECs were incubated in the absence (control) and presence of labetalol (10^?8-10-⁵ mol/L) and the release of PGI-, as measured by its metabolite 6-keto-PGF_1α, and that of ET-1, were assessed by radioimmuno- assays. Because the presence of serum strongly affects endothelial cell function, we studied the effect of labetalol in HUVECs incubated with or without serum. In the in vivo part of the study, urine samples collected before and during oral labetalol intake were assessed for 2,3-dinor-6-keto-PGF, a metab-olite of PGI.1_α and for 2,3-dinor-thromboxane-B., a metabolite of TxA,₂ with high-pressure liquid chromatography and radioimmunoassay.

Results: HUVECs incubated in the presence of serum (10%) produced 8 times more 6-keto-PGF_loi and 5 times more ET-1 than HUVECs incubated without serum. Labetalol (10^?8-10^?5 mol/L) did not affect the production of PGL, although the highest labetalol level (not achievable in vivo, 10^?5 mol/L) was accompanied by a drop in PG1-, release in both serum-free (– 21%) and serum conditions (- 14%); this was probably a sign of toxic effect. Labetalol caused no consistent change in the release of ET-1 in HUVECs. Oral labetalol treatment did not affect urinary excretion of PGI, and TxA., metabolites.

Conclusions: No clinically relevant effects of labetalol were found on endothelial cell PG1-, or ET-1 production. Labetalol at therapeutic doses and concentrations does not affect the production of vasoactive PGI₂ and TxA₂ in preeclamptic patients.     

The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog

Objective

Cisplatin is a DNA-damaging antitumor agent that is highly effective in treating ovarian cancer. It activates the p53/p21 pathway for its cytotoxic mode of action, but it does not induce p21-dependent cell cycle arrest in G1. Therefore, we investigated this paradox, and used the model analog DAP as a positive control for p21-dependent G1-arrest.

Methods

Studies were conducted in p53-proficient ovarian A2780 tumor cells to examine Cdk activity, cell cycle distribution and DNA damage signaling after cisplatin or DAP in combination with the mitotic inhibitor nocodazole.

Results

Cisplatin consistently induced transient S-phase arrest by inhibiting Cdk2/cyclin A complex in S-phase at 12 h and then a durable G2/M-arrest by inhibiting Cdc2/cyclin B complex at 12-18 h. These inhibitions were associated with Chk1 and Chk2 activation and resultant increase in inhibitory tyrosine phosphorylation of Cdk2 and Cdc2. Cisplatin also potently inhibited G1-phase Cdk4/cyclin D1 and Cdk2/cyclin E activities at ~ 18 h. In agreement, exposure of cisplatin-treated A2780, HCT-116^p53−/− and HCT-116^p21−/− tumor cells to nocodazole revealed limited G1-arrest that was dependent on p53 and p21. In contrast, the durable G1-arrest by DAP, which failed to activate Chk1 and Chk2, was unaffected by nocodazole.

Conclusions

Cisplatin induced G1-arrest, but at an attenuated level. This was primarily due to orchestration of Cdk inhibition in S-phase first, then in G2, and finally in G1 that effectively blocked cells in G2 and prevented cells from progressing and arresting in G1. These studies demonstrate that cisplatin unequivocally activates G1-checkpoint response, but the fidelity of G1-arrest is compromised by Chk1/2 activation and checkpoint response in S- and G2/M-phase.