Differential expression of thioredoxin binding protein-2/Txnip in human placenta: Possible involvement of hypoxia in its suppression during early pregnancy.

AIM: Thioredoxin binding protein-2 (TBP-2), which is identical to thioredoxin interacting protein (Txnip), controls cellular proliferation and differentiation. The aim of the present study was to compare TBP-2 protein and mRNA expression in human placenta during the three trimesters of pregnancy and to investigate the role of hypoxia in the change of these expressions in placental tissue. A secondary objective was to determine the gene expression of peroxisome proliferator-activated receptors (PPARs) in TBP-2 deficient placenta using TBP-2 gene disrupted mice (TBP-2-/- ). METHODS: Protein and mRNA expression of TBP-2 in human placenta from each trimester were analyzed by immunohistochemistry, Western blots, and by quantitative reverse-transcriptase-polymerase chain reaction. The effect of hypoxia on TBP-2 expression was tested using an explant culture of human placenta. In TBP-2-/- mouse placenta, we detected PPAR mRNA expression. RESULTS: TBP-2 was located in syncytiotrophoblasts and cytotrophoblasts, and also in the endothelium in human placenta. Its expression in the placenta was low in the first trimester, and increased in the second and third trimesters. Hypoxia decreased TBP-2 mRNA and protein expression in human placental explant culture. In TBP-2-/- mice, placental mRNA levels of PPARα and γ were significantly suppressed compared with those in wild-type mice. CONCLUSION: Hypoxia suppresses TBP-2 gene expression, which may ultimately alter placental development.

Thioredoxin binding protein-2 inhibits excessive fetal hypoglycemia during maternal starvation by suppressing insulin secretion in mice.

Glucose is a major fuel for fetal development. Fetal blood glucose level is mainly dependent on maternal blood glucose concentration, though it is also regulated by fetal insulin level. Thioredoxin binding protein-2 (TBP-2), which is identical to vitamin D3 up-regulated protein (VDUP1) and thioredoxin interacting protein (Txnip), was recently reported to be a key transcriptional factor controlling glucose metabolism. Here, we elucidated the functions of TBP-2 in maintaining blood glucose homeostasis during the fetal period. TBP-2(+/-) female mice were mated with TBP-2(+/-) male mice; beginning 16.5-d post coitum, pregnant mice were fed or fasted for 24 h. Under conditions of maternal starvation, the blood glucose levels of TBP-2(-/-) fetuses were significantly lower than those of TBP-2(+/+) fetuses, corresponding to the elevated plasma insulin levels of TBP-2(-/-) fetuses compared with those of TBP-2(+/+) fetuses. There was no difference between TBP-2(+/+) and TBP-2(-/-) fetuses in terms of their pancreatic beta-cell masses or the expression of placental glucose transporters under conditions of either maternal feeding or fasting. Thus, during maternal fasting, fetal TBP-2 suppresses excessive insulin secretion to maintain the fetus's glucose levels, implying that TBP-2 is a critical molecule in mediating fetal glucose homeostasis depending on nutrient availability.

Angiotensin II receptor blocker candesartan cilexetil, but not hydralazine hydrochloride, protects against mouse cardiac enlargement resulting from undernutrition in utero.

Epidemiologic studies have shown that malnutrition in utero is a risk factor for cardiovascular disease (CVD) in adulthood. Recently, we reported a mouse animal model of 30% maternal caloric reduction, in which adult offspring (undernourished [UN] offspring) showed a significant increase in cardiac remodeling-associated parameters, such as cardiac enlargement (CE) and coronary perivascular fibrosis (CPVF), as risk factors for CVD. To investigate the possible involvement of the angiotensin system, an angiotensin II receptor antagonist, candesartan cilexetil, or a nonspecific vasodilator, hydralazine hydrochloride, was administrated via a subcutaneously implanted miniosmotic pump to the UN offspring from 9 to 17 weeks after birth. Administration of candesartan cilexetil, but not hydralazine hydrochloride, significantly protected against CE. While administration of not only candesartan cilexetil but also hydralazine hydrochloride prevented an augmentation of CPVF. The angiotensin system seems to make a critical contribution to the developmental origins of cardiac enlargement.

Isocaloric high-protein diet ameliorates systolic blood pressure increase and cardiac remodeling caused by maternal caloric restriction in adult mouse offspring.

Epidemiologic studies have shown that in utero malnutrition is a risk factor for adult cardiovascular disease (CVD). Recently, we reported a mouse animal model of 30% maternal caloric reduction, in which offspring showed a significant increase in systolic blood pressure (SBP) as well as in cardiac remodeling-associated morphological parameters such as cardiac enlargement and coronary perivascular fibrosis in adulthood. Using a similar animal model, we here demonstrated that an increased level of protein consumption during an undernourished pregnancy (high-protein diet; HPD) corrected for the development of CVD risk factors found in fetal undernourishment with less protein consumption (standard-protein diet; SPD). In contrast, maternal ad libitum feeding with HPD resulted in significantly elevated SBP and cardiac enlargement in offspring at 16 wks. Appropriate maternal protein ingestion might partly protect against the development of CVD risk factors in offspring.

Isocaloric high-protein diet as well as branched-chain amino acids supplemented diet partially alleviates adverse consequences of maternal undernutrition on fetal growth.

Maternal undernutrition causes fetal growth restriction. Protein is a vital dietary nutrient for fetal growth, and branched-chain amino acids (BCAA) are noted to have anabolic actions. In this study, we investigated the effects of maternal high-protein diet or BCAA-supplemented diet upon fetal growth under the condition of maternal calorie restriction. Pregnant mice were calorie-restricted (undernutrition: UN), using either a standard diet (S-UN group), high-protein diet (HP-UN group), or BCAA-supplemented diet (BCAA-UN group) to 70% of the control; dams fed ad libitum with a standard diet (S-NN group) from 10.5days post coitum (dpc) to 18.5dpc. The fetal weights of UN groups were significantly decreased compared to that of S-NN. However, the fetal weights of HP-UN and BCAA-UN were significantly higher by 5% and 4%, respectively, than those of S-UN, concomitant with augmentation of the gene and protein expressions of IGF-I and IGF-II in fetal liver. A high-protein diet as well as BCAA-supplemented diet partially improved fetal growth restriction caused by maternal calorie-restriction, suggesting a pivotal role of them in the amelioration of fetal growth restriction.

Neonatal exposure to leptin augments diet-induced obesity in leptin-deficient Ob/Ob mice.

OBJECTIVE: Epidemiological evidence has revealed that undernutrition in utero is closely associated with obesity and related detrimental metabolic sequelae in adulthood. Recently, using a wild-type (wt) mouse model in which offspring were exposed to intrauterine undernutrition (UN offspring), we reported that the premature leptin surge during neonatal growth promotes lifelong changes in energy regulating circuitry in the hypothalamus, thus playing an important role in the development of pronounced obesity on a high-fat diet (HFD) in adulthood. Here, we further evaluate the essential involvement of leptin in the developmental origins of obesity using leptin-deficient ob/ob mice. METHODS AND PROCEDURES: We assessed the progression of obesity on an HFD in adult leptin-deficient ob/ob male mice that were exposed to intrauterine undernutrition by maternal food restriction (ob/ob UN offspring) or to leptin treatment during the neonatal period; this treatment is comparable to the premature leptin surge observed in the wt-UN offspring. RESULTS: On an HFD, the body weight of the male ob/ob UN offspring paralleled that of the ob/ob offspring exposed to normal intrauterine nutrition (ob/ob NN offspring). In contrast, early exposure to leptin in the ob/ob NN offspring during early neonatal growth reproduced the development of pronounced obesity on an HFD in adulthood. DISCUSSION: The presence of leptin and associated energy regulation are indispensable in the acceleration of obesity on an HFD caused by undernutrition in utero. The premature leptin surge plays an essential role in the developmental origins of obesity as a programming signal during the early neonatal period.

The relationship between maternal plasma leptin levels and fetal growth restriction.

Leptin is a satiety hormone secreted from the adipose tissue and human placenta. We previously demonstrated that severe preeclampsia up-regulated leptin mRNA expression in the placenta and elevated maternal plasma leptin concentrations. Preeclampsia is frequently related to generation of small for gestational age (SGA) infant especially in cases with severe preeclampsia. However, it is still controversial whether the increase in maternal plasma leptin levels is associated with fetal growth restriction without complication of preeclampsia. Therefore, the aim of the present study was to explore the relationship between maternal plasma leptin levels and fetal growth in non-preeclamptic (n = 98) and preeclamptic (n = 40) women. In non-preeclamptic pregnant women, plasma leptin levels in SGA group (n = 11) were significantly higher than those in appropriate for gestational age (AGA) group (n = 87, P<0.05). In pregnant women with preeclampsia, likewise, plasma leptin levels in SGA group (n = 15) were significantly higher than those in AGA group (n = 25, P<0.05). In multiple linear regression analysis, maternal BMI, mean arterial blood pressure and Delta SD of neonatal body weight were significant factors for determining maternal plasma leptin levels in all population studied. Maternal BMI and Delta SD of neonatal body weight showed positive correlation with maternal plasma leptin levels when analysis was performed in non-preeclamptic subjects alone. In conclusion, maternal plasma leptin levels reflect, at least partly, deterioration in fetal growth.

Anatomic identification and functional outcomes of the nerve sparing Okabayashi radical hysterectomy.

OBJECTIVES: To clarify the anatomy necessary for the nerve sparing Okabayashi's radical hysterectomy, we meticulously separated the blood vessels and connective tissues to preserve the pelvic splanchnic nerve, the hypogastric nerve, and the bladder branch of the inferior hypogastric plexus under magnification (x2.5) during the Okabayashi radical hysterectomy. METHODS: Twenty-four patients (FIGO stage IB, n=22, and stage IIA, n=2) underwent meticulous nerve sparing radical hysterectomy during 2004 to 2006. Postoperative assessment of bladder function consisted of the time to (a) achieve a postvoid residual urine volume (PVR) less than 50 ml, (b) obtain a sensation of bladder fullness, and (c) obtain satisfaction of micturition. RESULTS: Isolation of the deep uterine vein could preserve one of the branches of the pelvic splanchnic nerve. The hypogastric nerve in the lateral rectal wall was isolated to the inferior hypogastric plexus. During the division of the posterior leaf of the vesicouterine ligament (VUL), isolation of the inferior vesical vein could reveal the bladder branch from the inferior hypogastric plexus. Only the uterine branch from the inferior hypogastric plexus was isolated and divided. Then, the T-shaped nerve plane consisting of the hypogastric nerve, the pelvic splanchnic nerve and the bladder branch from the inferior hypogastric plexus is preserved. Urinary functions: (a) 11 out of 24 patients had measured PVR of less than 50 ml by postoperative day (POD) 14 and all patients had achieved this by day 21 (mean POD: 14.64+/-2.04). (b) Twenty-two out of 24 patients reported a sensation of bladder fullness by POD 14 and all by POD 21 (mean POD: 11.25+/-1.78). (c) Seventeen out of 24 patients reported satisfaction of micturition by POD 14 and all by POD 21 (mean POD: 12.34+/-2.32). CONCLUSION: In order to accomplish the nerve sparing Okabayashi's radical hysterectomy, it is necessary to meticulously divide the posterior leaf of the vesicouterine ligament. By the separation of the inferior vesical vein in the posterior leaf of the vesicouterine ligament, the bladder branch from the inferior hypogastric plexus can be identified and preserved. All patients recovered their urinary function completely by POD 21.

Precise anatomy of the vesico-uterine ligament for radical hysterectomy.

OBJECTIVES: To clarify the anatomy of the vesico-uterine ligament (VUL), we meticulously separated the VUL under magnification (x2.5) during Okabayashi's radical hysterectomy. METHODS: Fifty-nine patients (TNM nomenclature: pTIb: 39, pT2a: 5, pT2b: 7, after trans-arterial anticancer-drug infusion treatment for the cervical cancer: 8) underwent this meticulous operation. Blood loss was recorded at two separate time points: during the separation of the VUL and after removal of the uterus. RESULTS: After complete separation of the uterine artery and superficial uterine vein from the ureter, we could identify the genuine connective tissue of the anterior leaf of the VUL in which we isolate and divide a distinct bundle of blood vessels: the cervicovesical vessels that cross over the ureter from the bladder to the cervix. The remaining tissues in the anterior leaf is only avascular connective tissue. The posterior leaf of the VUL is the tissue residing under the ureter connecting the posterior wall of the bladder and the lateral cervix/upper lateral vagina. In the connective tissues, we identified the middle and inferior vesical veins connecting with the deep uterine vein. The division of these veins could separate the urinary bladder with ureters completely from the lateral cervix and upper vagina. The mean blood loss during the separation of the VUL was 20+/-10 g (N=59) and after radical hysterectomy was 189+/-91.6 g (N=59). CONCLUSION: A precise network of blood vessels in the VUL is identified. The knowledge of this anatomy is important to perform radical hysterectomy.

Undernutrition in utero augments systolic blood pressure and cardiac remodeling in adult mouse offspring: possible involvement of local cardiac angiotensin system in developmental origins of cardiovascular disease.

Evidence has emerged that undernutrition in utero is a risk factor for cardiovascular disorders in adulthood, along with genetic and environmental factors. Recently, the local expression of angiotensinogen and related bioactive substances has been demonstrated to play a pivotal role in cardiac remodeling, i.e. fibrosis and hypertrophy. The aim of the present study was to clarify the possible involvement of the local cardiac angiotensin system in fetal undernutrition-induced cardiovascular disorders. We developed a mouse model of undernutrition in utero by maternal food restriction, in which offspring (UN offspring) showed an increase in systolic blood pressure (8 wk of age, P < 0.05; and 16 wk, P < 0.01), perivascular fibrosis of the coronary artery (16 wk, P < 0.05) and cardiac cardiomegaly (16 wk, P < 0.01), and cardiomyocyte enlargement, concomitant with a significant augmentation of angiotensinogen (P < 0.05) and endothelin-1 (P < 0.01) mRNA expression and a tendency to increase in immunostaining for both angiotensin II and endothelin-1 in the left ventricles (16 wk). These findings suggest that fetal undernutrition activated the local cardiac angiotensin system-associated bioactive substances, which contributed, at least partly, to the development of cardiac remodeling in later life, in concert with the effects of increase in blood pressure.

Role of salvage cytoreductive surgery in the treatment of patients with recurrent ovarian cancer after platinum-based chemotherapy.

OBJECTIVES: The role of cytoreductive surgery, which is well established in the primary treatment for epithelial ovarian cancer, is controversial in recurrent disease. The aim of this study was to assess the clinical benefit of salvage surgical cytoreduction in patients with recurrent ovarian cancer after platinum-based chemotherapy. METHODS: We conducted a retrospective analysis of 46 patients with recurrent epithelial ovarian cancer treated at our department between 1988 and 2003. Twenty-three patients underwent salvage cytoreductive surgery (cytoreductive group), and the other 23 patients were treated without surgery (control group). RESULTS: Patients in cytoreductive group had a median survival of 41.7 months after recurrence, which was significantly longer than control group (18.8 months; P < 0.01). The duration of stay at home and the period oral intake was preserved were significantly longer in the cytoreductive group. In the cytoreductive group, survival was influenced by the residual disease after surgery (residual tumor diameter, <2 cm vs >2 cm; median survival, 50 months vs 35.2 months; P < 0.05). However, the number of recurrent sites (solitary vs multiple) and the lengths of treatment-free intervals after primary treatment (<6 months vs >6 months) showed no significant influence on survival. CONCLUSIONS: The application of cytoreductive surgery might improve the prognosis of patients with recurrent ovarian cancer if the tumor was resectable. Preserved prognoses of platinum-resistant disease with short treatment-free interval demonstrated in this study suggest that the concept of maximum cytoreduction might be introduced in the treatment of recurrent disease in the future.

[Obesity in offspring with maternal undernutrition during pregnancy].

Recent epidemiology demonstrates higher rate of obesity and metabolic syndrome in offspring with undernutrition in utero. IUGR babies with intrauterine undernutrition grow rapidly to catch up with normal growth course. Leptin is an adipocyte derived satiety factor that regulates food intake and energy expenditure. We demonstrated in mice model with maternal food restriction during pregnancy that premature leptin surge during neonatal catch up growth of the offspring lead them to impaired leptin sensitivity and obesity in adulthood.

Spontaneous regression of congenital cystic adenomatoid malformation of the lung: longitudinal examinations by magnetic resonance imaging.

We report a case of large cystic adenomatoid malformation of the lung (CCAM), which occupied almost the entire left lung with a prominent mediastinal shift at 24 weeks of gestation. The volume of the lesion, determined by magnetic resonance imaging (MRI), was 27.0 cm3. Subsequent MRI and ultrasound examinations revealed a spontaneous resolution of the lesion at 32 and 36 weeks of gestation without a mediastinal shift, when the lesion volume was 12.8 cm3 and 5.6 cm3, respectively. At 37 weeks of gestation, a mature male baby weighing 2638 g with an Apgar score of 7 was delivered by elective cesarean section. A lobectomy of the left upper lobe of the lung was carried out at 3 days of age, due to an enlargement of the CCAM after birth.

Cyclic mechanical stretch augments hyaluronan production in cultured human uterine cervical fibroblast cells.

Hyaluronan (HA) a glycosaminoglycan with high affinity for water molecules stimulates local inflammatory reactions. Parturition causes a dramatic increase in the amount of HA fragments in the uterine cervix, thereby contributing to a rapid softening as well as opening of the cervical canal, i.e. cervical ripening. The aim of this study was to investigate the possible involvement of cyclic distension caused by labour in the augmentation of HA production during cervical ripening. Immunohistochemistry and/or RT-PCR detected hyaluronan synthase (HAS)1, 2 and 3 in samples of human cervical tissue obtained from pregnant women. Labour-like cyclic mechanical stretch for 24, 36 and 48 h significantly enhanced the secretion of HA, from cultured human uterine cervical fibroblast (CxF) cells, 128.7, 151.4 and 173.2%, respectively, concomitant with a significant augmentation of HAS1 (36, 48 h), HAS2 (24, 36 and 48 h) and HAS3 (48 h) mRNA expression. Cyclic mechanical stretch for 12, 36 and 48 h increased molecular size of the HA secreted from CxF cells. In conclusion, cyclic mechanical stretch of the uterine cervix caused by the presenting part of the fetus in labour may contribute to the increase in the secretion of HA during the process of cervical ripening.

Role of premature leptin surge in obesity resulting from intrauterine undernutrition.

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to "developmental origins of health and disease."

Simultaneous increases of leptin and gonadotropin-releasing hormone following exogenous estrogen administration in women with normally menstrual cycle.

The aim of this study was to investigate whether administration of exogenous estrogen affects the changes of leptin and GnRH levels in women with normal menstrual cycle. A total of 18 women received a bolus intravenous injection of 20 mg conjugated estrogen (premarin group) at 0800 during the fifth day of menstrual cycle, while another 18 women were administered 20 mL of normal saline as the control group. Fasting blood samples were collected at 0, 4, 8, 24, 28, 32, 48, 56, 72 and 96 hours after injection for analyses of leptin, GnRH, estrone (E(1)), estradiol (E(2)), LH and FSH. Both the mean plasma levels of E(1) and E(2) were significantly increased from 4 hours and significantly sustained elevated levels up to 72 hours after injection of premarin. Simultaneous significant increases of leptin and GnRH levels were observed at 28, 32 and 48 hours after injection, while the controls remained constant. The mean LH and FSH levels were initially suppressed and then significantly increased at 56 and 72 hours after premarin administration. Leptin appears to be involved in the regulation of positive feedback mechanism of estrogen by conveyance of metabolic signal to affect the release of GnRH in hypothalamus, while its participation in the modulation of negative feedback remains unknown.

17beta-estradiol up-regulates prostacyclin production in cultured human uterine myometrial cells via augmentation of both cyclooxygenase-1 and prostacyclin synthase expression.

OBJECTIVE: To investigate whether 17beta-estradiol elevates prostacyclin (PGI(2)) production in human myometrial cells in the middle of gestation. METHODS: The concentration of 6-keto-PGF(1alpha), a stable metabolite of PGI(2), in the culture medium was assessed using enzyme-linked immunosorbent assay (ELISA). Western blot analysis and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) using TaqMan (Applied Biosystems, Foster City, CA) technology were performed to evaluate the expression of cytosolic phopholipase A(2) (cPLA(2)), cyclooxygenase-1 (COX-1), COX-2, and prostacyclin synthase (PGIS) in cultured human myometrial cells prepared from second trimester pregnant women (n = 3) after stimulation with 17beta-estradiol. RESULTS: Treatment with 17beta-estradiol (4-400 nM) dose-dependently elevated PGI(2) secretion from cultured human myometrial cells. Western blot analysis detected cPLA(2) and COX-1 and PGIS protein expression in the cultured human myometrial cells; however, COX-2 protein expression was below the detection sensitivity. Stimulation with 40-nM 17beta-estradiol significantly up-regulated protein and mRNA expression of both COX-1 and PGIS. CONCLUSION: 17beta-Estradiol from placenta may contribute to the augmentation of PGI(2) production in the human myometrium in the middle of gestation via up-regulation of both COX-1 and PGIS expression.

Cyclic mechanical stretch augments both interleukin-8 and monocyte chemotactic protein-3 production in the cultured human uterine cervical fibroblast cells.

Intensive local leukocyte infiltration in the uterine cervix is a characteristic feature in the process of cervical ripening. The infiltrated leukocytes include neutrophils, macrophages and monocytes, which are believed to play important roles in cervical ripening by secreting elastase, matrix metalloproteinase and interleukin-1 (IL-1). Interleukin-8 (IL-8) and monocyte chemotactic protein-3 (MCP-3) belong to the CXC and CC chemokine families, and mediate the chemotaxis of neutrophils and monocytes/macrophages respectively. The aim of the present study was to investigate the possible involvement of IL-8 and MCP-3 in leukocyte chemotaxis in cervical ripening. Immunohistochemistry and RT-PCR detected both IL-8 and MCP-3 expression in human pregnant uterine cervices. Labour-like cyclic mechanical stretch for 48 h significantly elevated both IL-8 (555%) and MCP-3 (360%) secretion from cultured human uterine cervical fibroblast (CxF) cells (P<0.05 for both). Cyclic mechanical stretch for 24, 36 and 48 h significantly increased both IL-8 and MCP-3 mRNA expression in CxF cells (P<0.05 for all). The stretch-induced augmentation of both IL-8 and MCP-3 expression was significantly suppressed by an activator protein-1 (AP-1) inhibitor, curcumin. These data suggest that cyclic mechanical stretch of the uterine cervix by the presenting part of the fetus during labour may augment both IL-8 and MCP-3 production in the uterine cervix via AP-1 activation.

Significant increase in maternal plasma leptin concentration in induced delivery: a possible contribution of pro-inflammatory cytokines to placental leptin secretion.

Maternal plasma leptin concentration is significantly increased during pregnancy. However, its roles in pregnancy, especially in labor, have not been fully clarified. We measured plasma leptin concentrations in pregnant women during the course of induced labor, just after spontaneous vaginal delivery and Cesarean section at term. We also studied the regulation of leptin secretion from term placental tissue and BeWo cells, a trophoblastic cell-line. Plasma leptin concentrations increased significantly during labor (58.9 +/- 9.2 ng/ml) compared to those before labor induction (37.5 +/- 5.8 ng/ml, P<0.05), then decreased 3-6 days postpartum (14 +/- 3 ng/ml, n = 6, P<0.0001) to the levels of normal nonpregnant women. Leptin concentrations within an hour and 24 hours after spontaneous vaginal delivery were significantly higher than those after Cesarean section (P<0.05 for both comparisons). Similarly, leptin mRNA expression in placental tissues obtained after spontaneous vaginal delivery was significantly greater than that in those obtained after Cesarean section without labor (P<0.05). IL-1alpha and TNF-alpha treatment significantly stimulated leptin secretion and leptin mRNA expression in explant culture of human term placental tissue and in BeWo cells as compared with those in vehicle controls (P<0.05, for all comparisons). By contrast, oxytocin and prostaglandin F(2alpha) treatment had no effects on leptin secretion from explant culture of human term placental tissue or from BeWo cells. These data indicate that pro-inflammatory cytokines might stimulate placental leptin secretion, thus finally contributing to the increase in plasma leptin concentration during labor.