This study aimed to investigate the therapeutic effect of Leonuri Herba aqueous decoction on primary dysmenorrhea(PD) and explore the underlying mechanism in conjunction with untargeted metabolomics. Forty adult female rats were randomly divi-ded into a normal group, a model control group, ibuprofen(0.12 g·kg~(-1)) group, and high-and low-dose Leonuri Herba aqueous decoction(5 and 2.5 g·kg~(-1)) groups, with eight rats in each group. The PD rat model was prepared using intramuscular injection of estradiol benzoate combined with intraperitoneal injection of pitocin. Drugs were administered by gavage from the 4th day of modeling for 7 d. After the last administration, pitocin was injected intraperitoneally, and the writhing latency and writhing times within 30 min were recorded. The uterine and ovarian coefficients were determined. Estradiol(E_2), progesterone(Prog), oxytocin(OT), cyclooxyge-nase 2(COX-2), prostaglandin E_2(PGE_2), prostaglandin F_(2α)(PGF_(2α)), and Ca~(2+) levels in uterine tissues were measured by ELISA and biochemical kits. Morphological changes in uterine and ovarian tissues were observed by hematoxylin-eosin(HE) staining. The protein expression of oxytocin receptor(OTR), prostaglandin E_2 receptor 3(EP3), and estrogen receptor alpha(ERα) in uterine tissues was detected by immunohistochemistry. The mRNA expression of OTR, PGE_2 receptors 1-4(EP1, EP2, EP3, and EP4), and PGF_(2α) receptor(FP) in uterine tissues was detected by quantitative real-time PCR. Untargeted metabolomics analysis was performed by ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(LC-QTOF-MS) technology to screen potential biomarkers and enrich metabolic pathways. The results showed that Leonuri Herba was able to significantly reduce the writhing times in PD rats(P<0.05 or P<0.01), significantly reduce the uterine and ovarian coefficients(P<0.01), and improve their histomorphology. After treatment with Leonuri Herba, PGE_2 content was significantly increased(P<0.05), COX-2, PGF_(2α) and Ca~(2+) content, and PGF_(2α)/PGE_2 was significantly decreased(P<0.05 or P<0.01), and OT content was decreased, while E_2 and Prog content tended to further increase in uterine tissues of PD rats. Correspondingly, OTR and EP3 protein expression was significantly downregulated(P<0.05 or P<0.01) and ERα protein expression was upregulated(P<0.05) in uterine tissues. The mRNA expression of FP and EP4 in uterine tissues was significantly downregulated(P<0.01), and the mRNA expression of EP1, EP3, and OTR showed a decreasing trend. The untargeted metabolomics results showed that 10 differential metabolites were restored in the plasma of PD rats after Leonuri Herba treatment. The results indicate that Leonuri Herba is effective in the prevention and treatment of PD, and the underlying mechanism may be attributed to the regulation of PGs synthesis and corresponding receptor binding.
Humans ; Rats ; Female ; Animals ; Estrogen Receptor alpha ; Oxytocin ; Dysmenorrhea/metabolism* ; Cyclooxygenase 2 ; Dinoprostone ; RNA, Messenger/metabolism* ; Dinoprost

OBJECTIVE: To investigate the effect of Heliotropium indicum L. (H. indicum L.) on uterine involution and its underlying mechanisms in both in vivo and in vitro study. METHODS: For in vivo studies, postpartum rats were randomly divided into 2 groups (n=24 for each): control group and treated group which were orally and daily administered with ethanolic extract of H. indicum L. (250 mg/kg body weight) until day 5 of postpartum. Uteri were collected for analysis of weight, cross-sectional area, collagen cross-sectional area, and collagen content on postpartum day 1, 3, and 5 (n=8 for each) from both groups. Blood samples were collected for hepatotoxicity and 17β-estradiol (E₂) measurement. For in vitro studies, the extract effects on uterine contraction at half maximum effective concentration of 2.50 mg/mL were studied in organ bath system for at least 20 min. RESULTS: Uterine parameters were significantly decreased after treated with extract of H. indicum L. (P<0.05). H. indicum L. extract significantly accelerated the reduction of those parameters and significantly decreased E₂ (P<0.05). The extract facilitated uterine involution with no hepatotoxicity. H. indicum L. extract significantly stimulated uterine contraction (P<0.05) and synergized with oxytocin, prostaglandin and its precursor, linoleic acid. By investigating the different sequencing of the extract with the additional stimulants (added before or after), the two showed antagonistic effects, but still showed potentiated force when compared with control (without the stimulants). CONCLUSIONS The underlying mechanisms by which H. indicum L. facilitated uterine involution might be due to reducing E₂ which induces collagenase activity, leading to decreases in uterine weight and size and stimulating uterine contraction. Our study provides new findings for future drug development for facilitating uterine involution with H. indicum L.
Pregnancy ; Female ; Rats ; Animals ; Heliotropium ; Uterus ; Plant Extracts/pharmacology* ; Oxytocin ; Collagen/pharmacology*

OBJECTIVE: To observe the effects of electroacupuncture (EA) on NLRP3 inflammasome and its downstream protein gastermin D (GSDMD) in rats with primary dysmenorrhea (PDM), and to explore the potential mechanism of EA on the treatment of PDM. METHODS: Forty healthy female SD rats without pregnancy were randomly divided into a control group, a model group, an EA group and an ibuprofen group, 10 rats in each group. PDM model was prepared by injection of estradiol benzoate and oxytocin. Except the control group, the rats in each group were subcutaneously injected with estradiol benzoate for 10 days, and oxytocin was injected on the 11th day. The rats in the EA group were intervened with EA (dense wave, frequency of 50 Hz) at "Guanyuan" (CV 4) and "Sanyinjiao" (SP 6) at the same time of modeling, once a day, 20 min each time, for 10 consecutive days. The rats in the ibuprofen group were treated with 0.8 mL of ibuprofen by gavage (concentration of ibuprofen solution was 1.25 mg/mL) for 10 consecutive days. After modeling, the writhing reaction was observed. After intervention, the HE staining method was used to observe the histological morphology of uterus and evaluate the pathological damage score of uterus; ELISA method was used to detect the serum levels of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α); Western blot method was used to detect the protein expression of NLRP3, apoptosis related spot like protein (ASC), caspase-1, GSDMD, GSDMD-N and inflammatory factors (interleukin [IL]-1β, IL-18) in uterine tissue. RESULTS: In the model group, a large number of vacuolar degeneration and death of endometrial epithelial cells, spiral arterioles congestion in lamina propria and neutrophil infiltration were observed. In the EA group, there was a small amount of vacuolar degeneration and death of endometrial epithelial cells, a small amount of spiral arterioles congestion in the lamina propria, and a small amount of neutrophils infiltration. In the ibuprofen group, there was very small number of degeneration and death of endometrial epithelial cells, and no obvious arterial congestion was found in lamina propria, and neutrophil infiltration was occasionally seen. Compared with the control group, in the model group the number of writhing was increased (P<0.01), the writhing reaction score and serum level of PGF2α and PGF2α/PGE2 value were increased (P<0.01), the level of PGE2 was decreased (P<0.01). Compared with the model group, in the EA group and the ibuprofen group the number of writhing were decreased (P<0.05), the latency of writhing was prolonged (P<0.01), the writhing reaction scores and serum levels of PGF2α and PGF2α/PGE2 values were decreased (P<0.05, P<0.01), the levels of PGE2 were increased (P<0.01). Compared with the control group, the protein expression of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18 in the uterine tissues of rats was increased in the model group (P<0.01). Compared with the model group, the protein expression of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18 in the uterine tissues of rats was decreased in the EA group and the ibuprofen group (P<0.01, P<0.05). There was no significant difference between the EA group and the ibuprofen group in the above indexes (P>0.05). CONCLUSION EA could alleviate pain and uterine tissue injury in rats with PDM. The mechanism may be related to the inhibition of the activation of NLRP3 inflammasome in rat uterine tissues, thereby inhibiting pyroptosis and its inflammatory factors release.
Animals ; Female ; Pregnancy ; Rats ; Caspases ; Dinoprost ; Dinoprostone ; Dysmenorrhea ; Electroacupuncture ; Ibuprofen ; Inflammasomes ; Interleukin-18 ; NLR Family, Pyrin Domain-Containing 3 Protein ; Oxytocin ; Phosphate-Binding Proteins ; Pyroptosis ; Rats, Sprague-Dawley ; Uterus

Brain/metabolism* ; Oxytocin ; Light

OBJECTIVE: To investigate the perinatal outcome and risk factors of precipitate labor in term primipara. METHODS: A total of 6951 full-term singleton primiparas with cephalic vaginal delivery in Women's Hospital, Zhejiang University School of Medicine from January 2020 to December 2020 were enrolled, among whom 381 cases of precipitate labor were classified as the precipitate labor group and 762 cases of normal labor were randomly selected as the control group. The perinatal outcomes of the two groups were compared, and the risk factors of precipitate labor were analyzed by multivariate logistic regression. RESULTS: The incidence of precipitate labor in full-term, singleton pregnancy and cephalic primiparas was 5.48% (381/6951). The durations of the first and second stages of labor in the precipitate labor group were significantly shorter than that in the control group ( P<0.01); while there was no significant difference in the duration of the third stage of labor between the two groups ( P>0.05). Compared with the control group, the incidence of soft birth canal laceration in the precipitate labor group was increased ( P<0.01). However, there was no significant difference in postpartum hemorrhage and neonatal related perinatal outcomes between the two groups (all P>0.05). Multivariate logistic regression analysis showed that maternal height ( OR=1.038, 95% CI: 1.010-1.067, P<0.01), gestational age at delivery ( OR=0.716, 95% CI: 0.618-0.829, P<0.01), late miscarriage ( OR=1.986, 95% CI: 1.065-3.702, P<0.05), membrane rupture before labor ( OR=1.802, 95% CI: 1.350-2.406, P<0.01), labor induction by transcervical balloon ( OR=3.230, 95% CI: 2.027-5.147, P<0.01), labor induction by propess ( OR=2.332, 95% CI: 1.632-3.334, P<0.01) and labor induction by oxytocin ( OR=0.291, 95% CI: 0.219-0.386, P<0.01) were independently associated with precipitate labor. CONCLUSIONS The incidence of precipitate labor in full-term, singleton pregnancy was not low. Precipitate labor could lead to a significant increase in perineal laceration. Maternal height, history of late miscarriage, membrane rupture before labor and labor induction by transcervical balloon, labor induction by propess are risk factors, while labor induction by oxytocin and late gestational time of delivery are protective factors for precipitate labor in term primipara.
Infant, Newborn ; Pregnancy ; Female ; Humans ; Oxytocin ; Abortion, Spontaneous ; Lacerations/etiology* ; Labor, Induced/adverse effects* ; Risk Factors ; Retrospective Studies

Background: A prolonged interval from prelabor rupture of membranes to delivery is associated with an increase in the incidence of maternal and neonatal morbidities and mortality. Various agents have been tested to improve the cervical Bishop score to expedite the delivery of the fetus and lessen the maternal and neonatal complications. Objective: To compare two protocols for labor induction in pregnant women with prelabor rupture of membranes (PROM). Population: Subjects were recruited from the University of Santo Tomas Hospital (Private Division and Clinical Division). Pregnant women with a live, term, singleton fetus, cephalic presentation, a reactive Non stress test, who presented with PROM and a Bishop score of ?5, with no previous Cesarean section, or other uterine surgery. Methodology: This is a two-arm superiority, open label, randomized controlled trial. Pregnant women with a live, term, singleton fetus, cephalic presentation, a reactive Non stress test, who presented with PROM and a Bishop score of ?5, and with no previous Cesarean section or other uterine surgery were randomly assigned to receive either intravenous (IV) oxytocin infusion or intracervical dinoprostone 0.5 mg gel followed 6 hours later by IV oxytocin infusion. Results: Vaginal delivery within 24 hours of labor induction increased significantly with intracervical dinoprostone gel followed by IV oxytocin infusion (87% versus 61%; RR: 1.43; 95% CI: 0.99 – 2.06; P<0.044). Comparable result was observed for nulliparous women included in the study population. The time interval from labor induction to active phase was significantly shorter in the dinoprostone-oxytocin group than in the oxytocin alone group (2.4 ± 2.1 versus 6.3 ± 1.4 hours; p<0.001). The time interval from labor induction to delivery was also significantly shorter in the dinoprostoneoxytocin group (6.3 ± 1.5 versus 10.4 ± 1.4 hours; p<0.000). Cesarean delivery rates were statistically similar in the dinoprostone-oxytocin and oxytocin alone groups (17% versus 40%; p=0.102). The neonatal outcomes were comparable in both groups, except for birth weight. Conclusion Intracervical dinoprostone 0.5 mg gel followed 6 hours later by an oxytocin infusion in term women presenting with PROM and an unfavorable cervix (Bishop Score of 5 or less) was associated with a higher rate of vaginal delivery within 24 hours, shorter time interval from labor induction to active phase of labor, and shorter time interval from labor induction to delivery, and no difference in maternal and neonatal complications was observed compared with oxytocin infusion alone.
Dinoprostone ; Oxytocin ; Labor ; Induced

Background: Acupressure may stimulate oxytocin release from the pituitary gland, which in turn regulates uterine contractions to improve the progress of labor; hence, studies have shown that acupressure on the Spleen 6 (SP6) point may be a complementary strategy for augmenting labor and/or shortening the first stage of labor without causing adverse effects to the mother or the newborn. Objective: To compare contractions produced by acupuncture technique from the contractions produced by conventional method using oxytocin in terms of: intensity, duration and interval of the uterine contractions and to determine if acupuncture technique at Sanyinjiao (spleen 6) and Hegu (Large Intestine 4) can be used as alternative method in establishing uterine contractions in Contraction Stress Test (CST) as a means of fetal surveillance. Methodology: This is a Randomized Controlled Trial done in University of Santo Tomas Hospital. This included 54 term pregnant patients who met the inclusion criteria and were randomized into two groups: 27 patients in Acupuncture group and 27 patients in Oxytocin group (control group). All recruited patients were hooked to electronic fetal monitor to obtain baseline strips for 20 minutes. Acupuncture needles were applied bilaterally at Sanyinjiao (spleen 6) and Hegu (Large Intestine 4) for 20 minutes to the study subjects. Results: Subjects who received acupuncture had greater intensity (p=0.551) and significant longer duration (p=0.001) of uterine contractions than the oxytocin group. However, there was significant shorter interval of uterine contractions after oxytocin treatment (p=0.013) than acupuncture. Furthermore, subjects who were in the acupuncture group obtained initial uterine contractions and achieved desirable uterine contractions faster than oxytocin. Conclusion Application of acupuncture in Spleen 6 (Sanyinjiao SP6) and Large Intestine 4 (Hegu LI4) can initiate and induce uterine contractions faster. Acupuncture technique when compared to the conventional method using oxytocin, produces stronger and longer contractions. Furthermore, there is shorter mean time to achieve initial and adequate contractions thru acupuncture technique. Contractions also disappear in a much shorter time in acupuncture technique than in oxytocin group hence ideal for outpatient setting.
Pregnancy ; Female ; Uterine Contraction ; Oxytocin ; Acupuncture Therapy

BACKGROUND: Nicardipine, a calcium channel blocker, is used to treat hypertension in pregnancy or preterm labor. The current study was conducted to investigate the relaxant effects of nicardipine on the isolated uterine smooth muscle of the pregnant rat.METHODS: We obtained uterine smooth muscle strips from pregnant female SD rats. After uterine contraction with oxytocin 10 mU/ml, we added nicardipine (10⁻¹² to 10⁻⁸ M) accumulatively every 20 min. We recorded active tension and frequency of contraction, and calculated EC₅ (effective concentration of 5% reduction), EC₂₅, EC₅₀, EC₇₅, and EC₉₅ of active tension and frequency of contraction using a probit model.RESULTS: Nicardipine (10⁻¹² to 10⁻⁸ M) decreased active tension and frequency of contraction in a concentration-dependent manner. The EC₅₀ and EC₉₅ of nicardipine in the inhibition of active tension of the uterine smooth muscle were 2.41 × 10⁻¹⁰ M and 3.06 × 10⁻⁷ M, respectively. The EC₅₀ and EC₉₅ of nicardipine in the inhibition of frequency of contraction of the uterine smooth muscle were 9.04 × 10⁻¹¹ and 4.18 × 10⁻⁷ M, respectively.CONCLUSIONS: Nicardipine relaxed and decreased the frequency of contraction of the uterine smooth muscle in a concentration-dependent pattern. It might be possible to adjust the clinical dosage of nicardipine in the obstetric field based on our results, but further clinical studies are needed to confirm them.
Animals ; Calcium Channels ; Female ; Humans ; Hypertension ; Muscle, Smooth ; Nicardipine ; Obstetric Labor, Premature ; Oxytocin ; Pregnancy ; Rats ; Relaxation ; Uterine Contraction ; Uterus

One of the core symptoms in anxiety disorders is dysregulated fear response. It is crucial for psychologists and neuroscientists to understand how fear responses are enhanced and inhibited. Although oxytocin (OXT) was initially conceived as a prosocial molecule and mammalian neuropeptide that enhances cooperation and trust, later studies showed that it produces modulatory influence on fear responses. Therefore, OXT is now regarded as a promising pharmacological agent to boost treatment response in anxiety disorders. However, the effect of OXT on fear responses have been somewhat complex, and there are some contradictions among animal experiments and human studies. In this article, we summarize recent studies that employed animal models, brain region-specific manipulations and preclinical studies to explore the role of OXT in the acquisition and processing of fear response. We also discuss the methodological differences among these studies and review the potential factors that may contribute to the complicated effect of OXT on fear response. This review will help to promote the potential clinical application of OXT.
Animals ; Brain ; drug effects ; Fear ; drug effects ; Humans ; Oxytocics ; pharmacology ; Oxytocin ; pharmacology

PURPOSE: The purpose of this study is to clarify the relevance of breastfeeding and its preventive effect on maternal hypertension as well as to evaluate the theoretical mechanism behind of it through systematic evaluation of existing articles. METHODS: For systematic evaluation of literatures in recent 5 years, 5 most suitable articles were selected with the key words, (breastfeeding or breastfeed or lactation) AND (hypertension or high blood pressure or hypertensive disorders) from PubMed, EMBASE, and Cochran Library, and carefully reviewed by 2 researchers. RESULTS: Breastfeeding women have less frequently developed hypertension in their later life. Depending on the duration of breastfeeding, compared to nonbreastfeeding women, breastfeeding women's odds ratio for developing hypertension are 0.87 (95% confidence interval [CI], 0.76–0.99), 0.83 (95% CI, 0.68–1.00), and 0.79 (95% CI, 0.65–0.97) each for 0–6 months, 6–12 months, and greater than 12 months of breastfeeding. As the number of breastfeeding children increases, the incidence of maternal hypertension decreases. In addition, both partial and exclusive breastfeeding lower the risk of developing maternal hypertension. Though the mechanism of prophylactic effect of breastfeeding on hypertension is not conclusive, reset hypothesis, oxytocin release, the increase of ghrelin and protein peptide YY, as well as epigenetic programming are considered to be relevant to the etiology of the condition. CONCLUSION: Breastfeeding prevents maternal hypertension later in life. Studies show dose-response relationship of breastfeeding as the duration matters. In addition, both partial and exclusive breastfeeding have preventive effect on maternal hypertension. Numerous mechanisms are continuously being reported and further studies are needed for clarification.
Breast Feeding ; Child ; Epigenomics ; Female ; Ghrelin ; Humans ; Hypertension ; Incidence ; Odds Ratio ; Oxytocin ; Peptide YY