Bioflavonoid luteolin prevents sFlt-1 release via HIF-1α inhibition in cultured human placenta

Preeclampsia (PE) is a serious hypertensive complication of pregnancy and is a leading cause of maternal death and major contributor to maternal and perinatal morbidity, including establishment of long-term complications. The continued prevalence of PE stresses the need for identification of novel treatments which can target prohypertensive factors implicated in the disease pathophysiology, such as soluble fms-like tyrosine kinase 1 (sFlt-1). We set out to identify novel compounds to reduce placental sFlt-1 and determine whether this occurs via hypoxia-inducible factor (HIF)-1α inhibition. We utilized a commercially available library of natural compounds to assess their ability to reduce sFlt-1 release from primary human placental cytotrophoblast cells (CTBs). Human placental explants from normotensive (NT) and preeclamptic (PE) pregnancies were treated with varying concentrations of luteolin. Protein and mRNA expression of sFlt-1 and upstream mediators were evaluated using ELISA, western blot, and real-time PCR. Of the natural compounds examined, luteolin showed the most potent inhibition of sFlt-1 release, with >95% reduction compared to vehicle-treated. Luteolin significantly inhibited sFlt-1 in cultured placental explants compared to vehicle-treated in a dose- and time-dependent manner. Additionally, significant decreases in HIF-1α expression were observed in luteolin-treated explants, suggesting a mechanism for sFlt-1 downregulation. The ability of luteolin to inhibit HIF-1α may be mediated through the Akt pathway, as inhibitors to Akt and its upstream regulator phosphatidylinositol-3 kinase (PI3K) resulted in significant HIF-1α reduction. Luteolin reduces anti-angiogenic sFlt-1 through inhibition of HIF-1α, making it a novel candidate for the treatment of PE

Is short-term-variation of fetal-heart-rate a better predictor of fetal acidaemia in labour? A feasibility study

Background Continuous intrapartum fetal monitoring is challenging and its clinical benefits are debated. The project evaluated whether short-term-variation (STV) and other computerised fetal heart rate (FHR) parameters (baseline FHR, long-term-variation, accelerations and decelerations) predicted acidaemia at birth. The aims of the study were to assess the changes in FHR pattern during labour and determine the feasibility of undertaking a definitive trial by reporting the practicalities of using the monitoring device, participant recruitment, data collection and staff training. Methods 200 high-risk women carrying a term singleton, non-anomalous fetus, requiring continuous FHR monitoring in labour were consented to participate from the Jessop Wing maternity unit, Sheffield, UK. The trans-abdominal fetal ECG monitor was placed as per clinical protocol. During the monitoring session, clinicians were blinded to the computerised FHR parameters. We analysed the last hour of the FHR and its ability to predict umbilical arterial blood pH <7.20 using receiver operator characteristics (ROC) curves. Results Of 200 women, 137 cases were excluded as either the monitor did not work from the onset of labour (n = 30), clinical staff did not return or used the monitor on another patient (n = 37), umbilical cord blood not obtained (n = 25), FHR data not recorded within an hour of birth (n = 34) and other reasons (n = 11). In 63 cases included in the final analysis, the computer-derived FHR parameters did not show significant correlation with umbilical artery cord pH <7.20. Labour was associated with a significant increase in short and long term variation of FHR and number of deceleration (P<0.001). However, baseline FHR decreased significantly before delivery (P<0.001). Conclusions The project encountered a number of challenges, with learning points crucial to informing the design of a large study to evaluate the potential place of intrapartum computerised FHR parameters, using abdominal fetal ECG monitor before its clinical utility and more widespread adoption can be ascertained

Impact of dietary patterns, individual and workplace characteristics on blood pressure status among civil servants in Bida and Wushishi communities of Niger State, Nigeria

The global burden estimate of hypertension is alarming and results in several million deaths annually. A high incidence of sudden deaths from cardiovascular diseases in the civil workforce in Nigeria is often reported. However, the associations between Dietary Patterns (DPs), individual, and workplace characteristics of hypertension among this workforce have not been fully explored. This study aimed to identify DP in the Bida and Wushishi Communities of Niger State and establish its relationship with hypertension along with other individual and workplace characteristics. Factor analysis was used to establish DP, Chi-square test to identify their relationships with hypertension, and logistic regression to determine the predictor risk factors. The prevalence of hypertension was 43.7%; mean weight, height, and body fat were: 72.8±15 kg, 166±8.9 mm and 30.4%, respectively. Three DPs: “Efficient Diet,” “Local diet,” and “Energy Boost Diet” were identified. The factor loading scores for these factors were divided into quintiles Q1–Q5; none of them had a significant effect on hypertension status. Conversely, increase in age, the Ministry, Department, and Agency (MDA) of employment, frequency of eating in restaurants, and obesity were identified as significant risk factors. After adjusting for confounders (age, body mass index, MDA, and eating habits), a high score (Q5) in “efficient diet pattern” was significantly related to a lower likelihood of hypertension than a low score (Q1). The prevalence of hypertension among the participants was relatively very high. An increase in age and working in educational sector were risk factors associated with hypertension. Therefore, it is recommended that civil servants engage in frequent exercise and undergo regular medical checkups, especially as they get older. These findings highlight the need for large-scale assessment of the impact of variables considered in this study on hypertension, among the civil workforce across Niger state and Nigeria

Immune Mechanisms Linking Obesity and Preeclampsia

Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-α, IL-6 and IL-17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies

Suicidal behavior risks during adolescent pregnancy in a low-resource setting: A qualitative study

Background: Suicide is one of the most common causes of death among female adolescents. A greater risk is seen among adolescent mothers who become pregnant outside marriage and consider suicide as the solution to unresolved problems. We aimed to investigate the factors associated with suicidal behavior among adolescent pregnant mothers in Kenya. Methods: A total of 27 Focus Group Discussions (FGDs) and 8 Key Informant Interviews (KIIs) were conducted in a rural setting (Makueni County) in Kenya. The study participants consisted of formal health care workers and informal health care providers (traditional birth attendants and community health workers), adolescent and adult pregnant and post-natal (up to six weeks post-delivery) women including first-time adolescent mothers, and caregivers (husbands and/or mothers-in-law of pregnant women) and local key opinion leaders. The qualitative data was analyzed using Qualitative Solution for Research (QSR) NVivo version 10. Results: Five themes associated with suicidal behavior risk among adolescent mothers emerged from this study. These included: (i) poverty, (ii) intimate partner violence (IPV), (iii) family rejection, (iv) social isolation and stigma from the community, and (v) chronic physical illnesses. Low economic status was associated with hopelessness and suicidal ideation. IPV was related to drug abuse (especially alcohol) by the male partner, predisposing the adolescent mothers to suicidal ideation. Rejection by parents and isolation by peers at school; and diagnosis of a chronic illness such as HIV/AIDS were other contributing factors to suicidal behavior in adolescent mothers. Conclusion: Improved social relations, economic and health circumstances of adolescent mothers can lead to reduction of suicidal behaviour. Therefore, concerted efforts by stakeholders including family members, community leaders, health care workers and policy makers should explore ways of addressing IPV, economic empowerment and access to youth friendly health care centers for chronic physical illnesses. Prevention strategies should include monitoring for suicidal behavior risks during pregnancy in both community and health care settings. Additionally, utilizing lay workers in conducting dialogue discussions and early screening could address some of the risk factors and reduce pregnancy- related suicide mortality in LMICs

Antihypertensive therapy increases tetrahydrobiopterin levels and NO/cGMP signaling in small arteries of angiotensin II-infused hypertensive rats

We previously reported that small mesenteric arteries from hypertensive rats have increased NOS-derived H2O2 and reduced NO/cGMP signaling. We hypothesized that antihypertensive therapy lowers blood pressure through a tetrahydrobiopterin (BH4)-dependent mechanism restoring NO/cGMP signaling and endothelial NOS (NOS3; eNOS) phosphorylation in small arteries. To test this hypothesis, small mesenteric arteries from normotensive rats (NORM), angiotensin II-infused rats (ANG), ANG rats with triple therapy (reserperine, hydrochlorothiazide, and hydralazine), or ANG rats with oral BH4 therapy were studied. Both triple therapy and oral BH4 therapy attenuated the rise in systolic blood pressure in ANG rats and restored NO/cGMP signaling in small arteries similarly. Triple therapy significantly increased vascular BH4 levels and BH4-to-BH2 ratio similar to ANG rats with BH4 supplementation. Furthermore, triple therapy (but not oral BH4 therapy) significantly increased GTP cyclohydrolase I (GTPCH I) activity in small arteries without a change in expression. NOS3 phosphorylation at Ser1177 was reduced in small arteries from ANG compared with NORM, while NOS3 phosphorylation at Ser633 and Thr495 were similar in ANG and NORM. NOS3 phosphorylation at Ser1177 was restored with triple therapy or oral BH4 in ANG rats. In conclusion, antihypertensive therapy regulates NO/cGMP signaling in small arteries through increasing BH4 levels and NOS3 phosphorylation at Ser1177

Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells

Preeclampsia is a pregnancy-specific disorder of maternal hypertension and reduced renal hemodynamics linked to reduced endothelial function. Placental ischemia is thought to be the culprit of this disease, as it causes the release of factors like tumor necrosis factor (TNF)-α that induce vascular endothelin-1 (ET-1) production. Interestingly, placental ischemia-induced hypertension in rats [reduced uterine perfusion pressure (RUPP) model] is abolished by ETA receptor blockade, suggesting a critical role for ET-1. Although it has been found that systemic induction of heme oxygenase (HO)-1 is associated with reduced ET-1 production and attenuated hypertension, it is unclear whether HO-1 directly modulates the increased ET-1 response to placental factors. We tested the hypothesis that HO-1 or its metabolites inhibit ET-1 production in human glomerular endothelial cells induced by serum of RUPP rats or TNF-α. Serum (5%) from RUPP hypertensive (mean arterial blood pressure 119 ± 9 mmHg) vs. normotensive pregnant (NP, 101 ± 6 mmHg, P &lt; 0.001) rats increased ET-1 production (RUPP 168.8 ± 18.1 pg/ml, NP 80.3 ± 22.7 pg/ml, P &lt; 0.001, n = 12/group). HO-1 induction [25 µM cobalt photoporphyrin (CoPP)] abolished RUPP serum-induced ET-1 production (1.6 ± 0.8 pg/ml, P &lt; 0.001), whereas bilirubin (10 µM) significantly attenuated ET-1 release (125.3 ± 5.2 pg/ml, P = 0.005). Furthermore, TNF-α-induced ET-1 production (TNF-α 31.0 ± 8.4 vs. untreated 7.5 ± 0.4 pg/ml, P &lt; 0.001) was reduced by CoPP (1.5 ± 0.8 pg/ml, P &lt; 0.001) and bilirubin (10.5 ± 4.3 pg/ml, P &lt; 0.001). These results suggest that circulating factors released during placental ischemia target the maternal glomerular endothelium to increase ET-1, and that pharmacological induction of HO-1 or bilirubin could be a treatment strategy to block this prohypertensive pathway in preeclampsia. </jats:p