Hepatoprotective effect of prenatal celecoxib in weaning preeclamptic rats: Role of HMGB1/MAPKs signaling.

Preeclampsia (PE) is often associated with multiple organ damage that remains noticeable postnatally. Here, we tested the hypotheses that antenatal therapy with nonsteroidal antiinflammatory drugs (NSAIDs) refashions liver damage induced by PE in weaning rats and that the high mobility group box 1 (HMGB1) signaling modulates this interaction. PE was induced by pharmacologic nitric oxide deprivation during the last week of gestation (Nω-nitro-L-arginine methyl ester, L-NAME, 50 mg/kg/day, oral gavage). Compared with control rats, weaning PE rats revealed substantial rises in serum transaminases together with histopathological signs of hepatic cytoplasmic changes, portal inflammation, and central vein dilation. While gestational NSAIDs reversed the elevated transaminases, they had no effects (celecoxib, naproxen) or even worsened (diclofenac) the structural damage. Molecularly, celecoxib was the most effective NSAID in (i) reversing PE-evoked upregulation of hepatic HMGB1 gene expression and concomitant increments and decrements in mitogen-activated protein kinases MAPKERK and MAPKp38 expression, respectively, and (ii) elevating and suppressing serum interleukin-10 and tumor necrosis factor-α, respectively. Alternatively, rises in serum interleukin-1ß and shifts in macrophage polarization towards an inflammatory phenotype caused by PE were comparably diminished by all NSAIDs. The data disclose an advantageous therapeutic potential for gestational celecoxib over diclofenac or naproxen in controlling hepatic dysfunction and HMGB1-interrelated inflammatory and oxidative sequels of PE.

Placenta-targeted Treatment Strategies for Preeclampsia and Fetal Growth Restriction: An Opportunity and Major Challenge.

The placenta plays a crucial role in maintaining normal pregnancy. The failure of spiral artery remodeling (SAR) is a key factor leading to placental ischemia and poor perfusion which is strongly associated with obstetric diseases, including preeclampsia (PE) and fetal growth restriction (FGR). Existing interventions for PE and FGR are limited and termination of pregnancy is inevitable when the maternal or fetus condition deteriorates. Considering the safety of the mother and fetus, treatments that may penetrate the placental barrier and harm the fetus are not accepted. Developing targeted treatment strategies for these conditions is urgent and necessary. With the proven efficacy of targeted therapy in treating conditions such as endometrial cancer and trophoblastic tumors, research on placental dysfunction continues to deepen. This article reviews the studies on placenta-targeted treatment and drug delivery strategies, summarizes the characteristics proposes corresponding improvement measures in targeted treatment, provides solutions for existing problems, and makes suggestions for future studies.

Ghrelin alleviates placental dysfunction by down-regulating NF-κB phosphorylation in LPS-induced rat model of preeclampsia.

In our previous study, we uncovered that ghrelin promotes angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro by activating the Jagged1/Notch2/VEGF pathway in preeclampsia (PE). However, the regulatory effects of ghrelin on placental dysfunction in PE are unclear. Therefore, we applied Normal pregnant Sprague-Dawley (SD) rats, treated with lipopolysaccharide (LPS), to establish a PE-like rat model. The hematoxylin-eosin (HE) staining method and immunohistochemistry (IHC) technology were used to detect morphological features of the placenta. IHC and Western blot were applied to examine Bax and Bcl-2 expression levels. The concentrations of serum soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PIGF) were assessed by enzyme-linked immunosorbent assay (ELISA) kit. In addition, the apoptosis rates of JEG-3 and HTR-8/SVneo trophoblast cells were determined by Annexin V-FITC/PI apoptosis detection kit. Cell migratory capacities were assessed by scratch-wound assay, and RNA-sequencing assay was used to determine the mechanism of ghrelin in regulating trophoblast apoptosis. It has been found that ghrelin significantly reduced blood pressure, urinary protein, and urine creatinine in rats with PE, at the meanwhile, ameliorated placental and fetal injuries. Second, ghrelin clearly inhibited placental Bax expression and circulating sFlt-1 as well as elevated placental Bcl-2 expression and circulating PIGF, restored apoptosis and invasion deficiency of trophoblast cells caused by LPS in vitro. Finally, transcriptomics indicated that nuclear factor kappa B (NF-κB) was the potential downstream pathway of ghrelin. Our findings illustrated that ghrelin supplementation significantly improved LPS-induced PE-like symptoms and adverse pregnancy outcomes in rats by alleviating placental apoptosis and promoting trophoblast migration.

Eucommia granules activate Wnt/ß-catenin pathway, and improve oxidative stress, inflammation, and endothelial injury in preeclampsia rats.

PURPOSE: Pre-eclampsia (PE) is a pregnancy-related complication. Eucommia is effective in the treatment of hypertensive disorders in pregnancy, but the specific effects and possible mechanisms of Eucommia granules (EG) in PE remain unknown. The aim of this study was to investigate the effects and possible mechanisms of EG in PE rats. METHODS: Pregnant Sprague Dawley rats were divided into five groups (n = 6): the control group, the model group, the low-dose group, the medium-dose group, and the high-dose group of EG. The PE model was established by subcutaneous injection of levonitroarginine methyl ester. Saline was given to the blank and model groups, and the Eucommia granules were given by gavage to the remaining groups. Blood pressure and urinary protein were detected. The body length and weight of the pups and the weight of the placenta were recorded. Superoxide dismutase (SOD) activity and levels of malondialdehyde (MDA), placental growth factor (PIGF), and soluble vascular endothelial growth factor receptor-1 (sFIt-1) were measured in the placenta. Pathological changes were observed by hematoxylin-eosin staining. Wnt/ß-catenin pathway-related protein expression was detected using Western blot. RESULTS: Compared with the model group, the PE rats treated with EG had lower blood pressure and urinary protein. The length and weight of the pups and placental weight were increased. Inflammation and necrosis in the placental tissue was improved. SOD level increased, MDA content and sFIt-1/PIGF ratio decreased, and Wnt/ß-catenin pathway-related protein expression level increased. Moreover, the results of EG on PE rats increased with higher doses of EG. CONCLUSIONS: EG may activate the Wnt/ß-catenin pathway and inhibit oxidative stress, inflammation, and vascular endothelial injury in PE rats, thereby improving the perinatal prognosis of preeclamptic rats. EG may inhibit oxidative stress, inflammation, and vascular endothelial injury through activation of the Wnt/ß-catenin pathway in preeclampsia rats, thereby improving perinatal outcomes in PE rats.

Protective Effects of Aspirin Supplemented With Quercetin in L-NAME-Induced Preeclampsia-Like Rats.

Aspirin supplemented with quercetin was reported to enhance the therapeutic effects of aspirin in a rat model of preeclampsia. In this study, the underlying mechanisms were further explored. Preeclampsia was induced by L-NAME (50 mg/kg/day) via oral gavage from gestation day (GD)14 to GD19. Aspirin (1.5 mg/kg/day) administration was performed using aspirin mixed with rodent dough from GD0 to GD19. The administration of quercetin (2 mg/kg/day) was performed by intraperitoneal infusion from GD0 to GD19. Protein levels were evaluated using ELISA or Western blot, and microRNA (miRNA) level was evaluated by RT-PCR. Aspirin supplemented with quercetin ameliorated the increase of systolic blood pressure (SBP), proteinuria, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels, and improved the pregnancy outcomes in preeclampsia rats. Aspirin supplemented with quercetin inhibited miR-155 expression in preeclampsia rats. The decreased miR-155 level in placenta further increased the protein level of SOCS1 and inhibited the phosphorylation of p65. In this study, we demonstrated that aspirin supplemented with quercetin enhanced the effects of aspirin for the treatment of preeclampsia.

Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.

Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats.

Preeclampsia (PE) is characterized by maternal hypertension, fetal growth restriction (FGR), and increased inflammation and populations of cytotoxic NK cells (cNKs) and inflammatory T-Helper 17 cells (TH17s). Both cytotoxic NK cells and TH17 cells are heavily influenced via IL-1ß signaling. Caspase 1 activity leads to the release of the inflammatory cytokine IL-1ß, which is increased in women with PE. Therefore, we tested the hypothesis that the inhibition of Caspase 1 with VX-765 in rats with reduced uterine perfusion pressure (RUPP) will attenuate PE pathophysiology. On gestation day (GD) 14, timed pregnant Sprague-Dawley rats underwent the RUPP or Sham procedure and were separated into groups that received either vehicle or VX-765 (50 mg/kg/day i.p.). On GD19, MAP was measured via carotid catheter and blood and tissues were collected. Bio-Plex and flow cytometry analysis were performed on placental tissues. Placental IL-1ß was increased in the RUPP rats vs. the Sham rats and treatment with VX-765 reduced IL-1ß in the RUPP rats. Caspase 1 inhibition reduced placental cNKs and TH17s in RUPP rats compared to vehicle-treated RUPP rats. Increased MAP was observed in RUPP rats compared with Sham rats and was reduced in RUPP + VX-765 rats. Placental reactive oxygen species (ROS) were elevated in RUPP rats compared to Sham rats. VX-765 administration reduced ROS in treated RUPP rats. Caspase 1 inhibition increased the number of live pups, yet had no effect on fetal weight or placental efficiency in the treated groups. In conclusion, Caspase 1 inhibition reduces placental IL-1ß, inflammatory TH17 and cNK populations, and reduces MAP in RUPP rats. These data suggest that Caspase 1 is a key contributor to PE pathophysiology. This warrants further investigation of Caspase 1 as a potential therapeutic target to improve maternal outcomes in PE.

An Examination of the Effect of Aspirin and Salicylic Acid on Soluble Fms-like Tyrosine Kinase-1 Release from Human Placental Trophoblasts.

Low-dose aspirin (LDA) is efficacious in preventing preeclampsia, but its mechanism of action is unclear. Conflicting evidence suggests that it may inhibit placental trophoblast release of soluble fms-like tyrosine kinase-1 (sFlt1), a key mediator of preeclampsia. We examined whether, and at what concentrations, aspirin and its principal metabolite, salicylic acid, modulate sFlt1 release and/or expression in trophoblasts. Human trophoblast lines BeWo and HTR-8/SVneo were cultured; BeWo cells were also treated with 1% oxygen vs. normoxia to mimic hypoxia in preeclamptic placentas. Cells were treated with aspirin or salicylic acid vs. vehicle for 24 h at concentrations relevant to LDA and at higher concentrations. Protein concentrations (ELISA) and mRNA expression (RT-PCR) of sFlt1 were determined. Under normoxia, LDA-relevant concentrations of aspirin (10-50 µmol/L) or salicylic acid (20-100 µmol/L) had no significant effect on sFlt1 protein release or mRNA expression in BeWo cells. However, inhibition was observed at higher concentrations (1 mmol/L for aspirin and ≥200 µmol/L for salicylic acid). Hypoxia enhanced sFlt1 protein release and mRNA expression in BeWo cells, but these responses were not significantly affected by either aspirin or salicylic acid at LDA concentrations. Similarly, neither drug altered sFlt1 protein secretion or mRNA expression in normoxic HTR-8/SVneo cells at LDA concentrations. We suggest that direct modulation of trophoblast release or expression of sFlt1 is unlikely to be a mechanism underlying the clinical efficacy of LDA in preeclampsia.

Suppression of circular RNA serum and glucocorticoid-induced kinase 1 elevates antioxidant molecules and angiogenesis in trophoblast cells to attenuate preeclampsia via microRNA-508-3p to target and restrain PUM homolog 1.

AIM: Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension and proteinuria. Recently, multiple circular RNAs (circRNAs) were considered latent clinical diagnostic markers or therapeutic targets. This study was to explore the impact of circRNA serum and glucocorticoid-induced kinase 1 (SGK1) on PE via influencing the microRNA (miR)-508-3p/PUM homolog 1 (PUM1) axis. METHODS: Placental tissues of 34 pregnant women with PE and 34 normal pregnant women were collected to measure circRNA SGK1 (circSGK1), miR-508-3p, and PUM1. Human placental trophoblasts HTR-8/SVneo were transfected with plasmids, thereafter to observe proliferation, migration, invasion, and apoptosis, analyze antioxidant molecules Troxerutin (TXN), Glutamate-cysteine ligase catalytic subunit (GCLC), NAD (P) H-quinone oxidoreductase 1 (NQO1), and determine angiogenesis. After the construction of the PE rat model, antioxidant molecules TXN, GCLC, and NQO1, vascular-associated factor vascular endothelial growth factor A (VEGF-A), and histopathological conditions were tested. Examination of the binding of circSGK1 and miR-508-3p with PUM1 was performed. RESULTS: Our data showed that circSGK1 expression was elevated in the placenta of patients with PE. Silenced circSGK1 or elevated miR-508-3p promoted the growth and antioxidant molecules and angiogenesis in trophoblast cells; CircSGK1 combined with miR-508-3p, and miR-508-3p targeted PUM1. CONCLUSIONS: In summary, suppression of circSGK1 augments antioxidant molecules and angiogenesis in trophoblast cells to attenuate PE via miR-508-3p to target PUM1.

The Effect of the cAMP Signaling Pathway on HTR8/SV-Neo Cell Line Proliferation, Invasion, and Migration After Treatment with Forskolin.

Pre-eclampsia (PE) is thought to be related to placental dysfunction, particularly poor extravillous trophoblast (EVT) invasion and migration abilities. However, the pathogenic mechanism is not fully understood. This article describes the impact of the cyclic adenosine monophosphate(cAMP) signaling pathway on EVT behavior, focusing on EVT proliferation, invasion, and migration. Here, we used the HTR8/SV-neo cell line to study human EVT function in vitro. HTR8/SV-neo cells were treated with different concentrations of forskolin (cAMP pathway-specific agonist) to alter intracellular cAMP levels, and dimethyl sulfoxide (DMSO) was used as the control. First, a cAMP assay was performed to measure the cAMP concentration in HTR8/SV-neo cells treated with different forskolin concentrations, and cell proliferation was assessed by constructing cell growth curves and assessing colony formation. Cell invasion and migration were observed by Transwell experiments, and intracellular epithelial-mesenchymal transition (EMT) marker expression was evaluated by quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB). According to our research, the intracellular cAMP levels in HTR8/SV-neo cells were increased in a dose-dependent manner, and HTR8/SV-neo cell proliferation, invasion and migration were significantly enhanced. The expression of EMT and angiogenesis markers was upregulated. Additionally, with the increase in intracellular cAMP levels, the phosphorylation of intracellular mitogen-activated protein kinase (MAPK) signaling pathway components was significantly increased. These results suggested that the cAMP signaling pathway promoted the phosphorylation of MAPK signaling components, thus enhancing EVT functions, including proliferation, invasion, and migration, and to a certain extent, providing a novel direction for the treatment of PE patients.

Pregnancies in women with antineutrophil cytoplasmatic antibody associated vasculitis.

PURPOSE OF REVIEW: Antineutrophil cytoplasmatic antibody associated vasculitis (AAV) usually manifests after age fifty, thus making it very rare during reproductive age. Although rare, AAV, particularly eosinophilic granulomatosis with polyangiitis, can manifest at a younger age. AAV can also appear for the first time during pregnancy. RECENT FINDINGS: Data from pregnant patients with AAV mostly derive from case reports or retrospective studies, with an absolute number of <100 published cases. Therefore, numbers of results of pregnancy outcome vary widely. SUMMARY: As with other chronic autoimmune diseases, patients and infants seem to be at a higher risk for preterm delivery, intrauterine growth retardation and preeclampsia. Possible treatment for AAV in pregnancy depends upon gestational age and include glucocorticosteroids, azathioprine, intravenous immunoglobulins, and in severe cases rituximab and even cyclophosphamide. Plasma exchange might be an option in selected patients. Aside from cyclophosphamide these medications can also be used during breastfeeding. Acetylsalicylic-acid 100-150 mg/day reduces the risk of preeclampsia, also in this population. Patients should be counseled prior to conception and medication that is suitable for pregnancy should be established early on. During pregnancy, we recommend close monitoring of disease activity, blood pressure and ideally to co-consult with a gynecologist in an interdisciplinary approach.

Luteolin prevents TNF-α-induced NF-κB activation and ROS production in cultured human placental explants and endothelial cells.

INTRODUCTION: Preeclampsia (PE) is a serious hypertensive pregnancy disorder and a leading cause of maternal and perinatal morbidity and mortality. Despite the prevalence and complications, there are no approved therapeutics to relieve PE symptoms. Inflammation, oxidative stress, and angiogenic imbalance have been shown to contribute to the PE pathophysiology, though there is a lack of understanding in how best to target these pathways in PE. We recently demonstrated that the bioflavonoid luteolin is a potent inhibitor of the anti-angiogenic and pro-hypertensive soluble fms-like tyrosine kinase 1 (sFlt-1), and here we aimed to determine if luteolin was also capable of reducing inflammation and oxidative stress pathways. METHODS: Tumor necrosis factor (TNF)-α, which is upregulated in PE, was utilized to stimulate these pathways in human placental explants and endothelial cells. Endothelin-1 (ET-1) and interleukin (IL)-6 in the media from explants and cells were measured via ELISA, and NF-κB localization and reactive oxygen species were detected via fluorescence microscopy. RESULTS: Pretreatment with luteolin demonstrated significant reductions in NF-κB activation, reactive oxygen species, superoxide, and IL-6 and ET-1 expression in endothelial cells. We also saw a significant reduction in phosphorylation of NF-κB in human placental explants. DISCUSSION: These data demonstrate that luteolin inhibits pathways implicated in the development of PE and should be explored further for its potential as a PE therapeutic.

Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials.

OBJECTIVE: Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and preterm delivery. Women with polycystic ovary syndrome (PCOS) are prone to these adverse pregnancy outcomes. However, the contribution of PROK1 to the development of pregnancy complications and the effect of metformin and hyperandrogenism on s-PROK1 in PCOS have not been studied previously. DESIGN: This work is a post hoc analysis of two prospective, randomised, placebo-controlled trials. SETTING: Pregnant women with PCOS were included from 11 study centres in Norway. PARTICIPANTS: From 313 women, 264 participated in the present study after exclusions due to dropouts or insufficient serum samples. INTERVENTION: Women with PCOS were randomly administered with metformin or placebo, from first trimester to delivery. PRIMARY AND SECONDARY OUTCOME MEASURES: s-PROK1 was analysed using ELISA at gestational week 19 and related to pregnancy complications, fasting insulin levels, homoeostatic model assessment for insulin resistance (HOMA-IR), testosterone, or androstenedione levels, metformin use, PCOS phenotype and hyperandrogenism. RESULTS: Maternal s-PROK1 in the second trimester did not predict pregnancy-induced hypertension, pre-eclampsia or late miscarriage/preterm delivery in women with PCOS. However, s-PROK1 was lower in women who used metformin before inclusion, both in those randomised to metformin and to placebo, compared with those who did not. s-PROK1 was also lower in those who used metformin both at conception and during pregnancy compared with those who used metformin from inclusion or did not use metformin at all. s-PROK1 was lower in hyperandrogenic compared with normo-androgenic women with PCOS. CONCLUSIONS: Maternal s-PROK1 in the second trimester did not predict pregnancy complications in PCOS. Those who used metformin at conception and/or during pregnancy had lower s-PROK1. PCOS women with hyperandrogenism exhibited lower s-PROK1 compared with normo-adrogenic phenotypes. TRIAL REGISTRATION NUMBER: NCT03259919 and NCT00159536.

An LC-MS/MS method for the simultaneous quantitation of sulfasalazine and sulfapyridine in human placenta.

Sulfasalazine has been identified as a candidate molecule to be investigated as an intervention to treat preterm pre-eclampsia during pregnancy. However, placental exposure of sulfasalazine and its systemically absorbed metabolite, sulfapyridine, is unknown. A robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously quantitate these analytes in human placenta with an application to a pilot clinical trial. The placental tissue was homogenised using a water:methanol (1:1, v/v) mixture, followed by sample extraction using both protein precipitation and solid phase extraction. Sulfasalazine-d4 and sulfapyridine-d4 were used as internal standards. An Agilent Poroshell EC-C18 (3.0 ×100 mm, 2.7 µm) column was used for chromatographic separation, with gradient elution employed at a flow rate of 0.450 mL/min over a total run time of seven minutes. The mobile phases consisted of water with 0.1% formic acid (mobile phase A) and acetonitrile:methanol (90:10, v/v) with 0.1% formic acid (mobile phase B). A Shimadzu-8040 mass spectrometer was operated in multiple reaction monitoring (MRM) mode using positive electrospray ionisation (ESI). For both analytes, the assay was validated over the range 30-30,000 ng/mL, or 150-150,000 ng/g. During inter-day validations (n = 18), the average accuracies of quality controls ranged from 101.6% to 112.7% with corresponding precisions of 4.4-6.7% for sulfasalazine, and from 97.4% to 108.4%, with corresponding precisions of 3.7-10.0% for sulfapyridine. No significant matrix effects were observed, and the method proved to be sensitive and specific for both analytes. This study presents the first validated analytical method for quantifying sulfasalazine and sulfapyridine in human placenta as part of a pilot clinical trial to generate preliminary data on its pharmacokinetics and efficacy as in intervention for preterm pre-eclampsia.

Pathophysiology of Preeclampsia and L-Arginine/L-Citrulline Supplementation as a Potential Strategy to Improve Birth Outcomes.

In preeclampsia, the shallow invasion of cytotrophoblast cells to uterine spiral arteries, leading to a reduction in placental blood flow, is associated with an imbalance of proangiogenic/antiangiogenic factors to impaired nitric oxide (NO) production. Proangiogenic factors, such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), require NO to induce angiogenesis through antioxidant regulation mechanisms. At the same time, there are increases in antiangiogenic factors in preeclampsia, such as soluble fms-like tyrosine kinase type 1 receptor (sFIt1) and toll-like receptor 9 (TLR9), which are mechanism derivates in the reduction of NO bioavailability and oxidative stress in placenta.Different strategies have been proposed to prevent or alleviate the detrimental effects of preeclampsia. However, the only intervention to avoid the severe consequences of the disease is the interruption of pregnancy. In this scenario, different approaches have been analysed to treat preeclamptic pregnant women safely. The supplementation with amino acids is one of them, especially those associated with NO synthesis. In this review, we discuss emerging concepts in the pathogenesis of preeclampsia to highlight L-arginine and L-citrulline supplementation as potential strategies to improve birth outcomes. Clinical and experimental data concerning L-arginine and L-citrulline supplementation have shown benefits in improving NO availability in the placenta and uterine-placental circulation, prolonging pregnancy in patients with gestational hypertension and decreasing maternal blood pressure.

The role played by oral antioxidant therapies in preventing and treating preeclampsia: An updated meta-analysis.

AIMS: Performing an up-to-date meta-analysis of oral antioxidant therapies and determining whether they are effective in preventing and/or treating preeclampsia (PE). DATA SYNTHESIS: Search was performed in PubMed, CENTRAL, LILACS, Web of Science, and ScienceDirect databases. The risk of bias was assessed based on using Cochrane Collaboration's tool. A funnel plot was created, and Egger's and Peter's test was carried out to assess publication bias in the primary outcome of prevention studies. The overall quality of the evidence was assessed based on using the Grading of Recommendations Assessment, Developing and Evaluation (GRADE) tool; a formal protocol was published in the PROSPERO database (registration number CRD42022348992). In total, 32 studies were taken into consideration for analysis purposes; 22 studies focused on investigating preeclampsia prevention methods, whereas 10 focused on its treatment. Significant results associated with the incidence of preeclampsia were observed in prevention studies comprising 11,198 subjects and 1106 events in the control groups, as well as 11,156 subjects and 1048 events in the intervention groups (relative risk [RR]: 0.86, 95% confidence interval [CI]: [0.75, 0.99], P = 0.03; I2 = 44%, P = 0.02). With respect to outcomes associated with treatment studies, only intrauterine growth restriction has shown significant effects. Egger's and Peter's test has evidenced publication bias. Six outcomes in prevention studies were classified as having low quality and two as having moderate quality, whereas all three outcomes assessed in treatment studies were classified as having moderate quality. CONCLUSIONS: Antioxidant therapy has shown beneficial effects on preeclampsia prevention; moreover, the positive impact of this therapy on intrauterine growth restriction was observed during the disease treatment.

Effect of 17-Hydroxyprogesterone Caproate on Interleukin-6 and Tumor necrosis factor-alpha in expectantly managed early-onset preeclampsia.

The study aimed to evaluate the effect of 17 hydroxy progesterone (17-OHPC) on interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in expectantly managed early-onset preeclampsia (PE). A randomized open-label controlled study included women who were diagnosed as early-onset PE if they assigned to expectant management according to the American College of Obstetricians and Gynecologists (ACOG) 2013 criteria for diagnosis of severity of PE. Patients were randomized into Group A (40 patients) received 17-OHPC 250 mg intra-muscular at admission and every 7 days thereafter and Group B (40 patients) was given the usual conservative measures of early-onset PE as a control group. Blood samples were obtained from all participants for measurements of TNF-α and IL-6 levels at admission and repeated at termination of pregnancy. The primary outcome was the mean difference between TNF-α and IL-6 levels before and after treatment in both groups. TNF-α and IL-6 levels at admission were not different between the two groups. However, there was a significant difference concerning these inflammatory biomarkers within the same group at admission and at termination (p < 0.001), with significant decline of IL-6 and TNF-α level in the 17-OHPC treated group and significant rise of IL-6 and TNF-α in the control group. There was a strong positive correlation between systolic blood pressure (SBP) at admission and TNF-α level (r= 0.867, p=0.017), and moderately positive significant correlation between diastolic blood pressure (DBP) at admission and TNF-α (r=0.610, p < 0.001). There was a mild positive significant correlation between IL-6 levels and SBP (r= 0.231, p=0.039), and DBP (r= 0.203, p= 0.041) at admission. In conclusion, 17-OHPC has no effect in improving maternal or neonatal outcomes in conservatively managed early onset PE, although it alters the inflammatory markers levels (IL-6 and TNF-α) that could improve the pathogenesis of PE.

Patients' understanding of long-term cardiovascular risks and associated health-seeking behaviours after pre-eclampsia.

OBJECTIVE: The lifelong risks of cardiovascular disease following hypertensive disorders of pregnancy are well described. Awareness of these risks and associated health-seeking behaviours among affected individuals remains unclear. We aimed to assess participants' knowledge of their cardiovascular disease risk and relevant health-seeking behaviours following a pregnancy affected by preeclampsia or gestational hypertension. METHODS: We undertook a single-site, cross-sectional cohort study. The target population included individuals who birthed at a large tertiary referral centre in Melbourne, Australia, between 2016 and 2020, and were diagnosed with gestational hypertension or pre-eclampsia. Participants completed a survey assessing pregnancy details, medical comorbidities, knowledge of future risks and health-seeking behaviours post-pregnancy. RESULTS: 1526 individuals met inclusion criteria and 438 (28.6%) completed the survey. Of these, 62.6% (n=237) were unaware of their increased risk of cardiovascular disease following a hypertensive disorder of pregnancy. Participants who reported awareness of their increased risk were more likely to have annual blood pressure monitoring (54.6% vs 38.1%, p<0.01), and at least one assessment of blood cholesterol (p<0.01), blood glucose (p=0.03) and renal function (p=0.01). Participants who were aware were more likely to be taking antihypertensive medication (24.5% vs 6.6%, p<0.01) since pregnancy, compared with those who were unaware. There were no differences between groups in diet, exercise or smoking habits. CONCLUSION: Among our study cohort, risk awareness was associated with increased health-seeking behaviours. Participants who were aware of their increased risk of cardiovascular disease were more likely to have regular cardiovascular risk factor assessments. They were also more likely to be taking antihypertensive medication.

Resveratrol inhibits multiple organ injury in preeclampsia rat model.

OBJECTIVE:  To investigate the effects of resveratrol on multiple organ injury and energy metabolism and its possible mechanism in preeclampsia model. METHODS:  A total of 45 clean-grade female adults Sprague Dawley (SD) rats (weight 270-320 g) were randomly divided into three groups: a control group, preeclampsia group (PE), and Preeclampsia with resveratrol treatment group (RE). Preeclampsia was induced in rats by administering 200 mg/kg/day L-NAME. Expression levels of TNF-α and IL-6 in the lungs and kidney tissues were analysed by ELISA, while the activity of superoxide dismutase (SOD) and malondialdehyde (MDA) was determined by biochemical assays. The levels of lactic acid and pyruvate were detected using biochemical assays, while the epinephrine level in the kidney and heart tissues was determined by the ELISA method. Reverse transcription polymerase chain reaction and the western blotting were used to detect the expression of pyruvate dehydrogenase kinase 4 (PDK4) in the myocardial tissues. RESULTS:  We found that resveratrol treatment inhibited the levels of IL-6, TNF-α, and MDA in the lungs and kidney tissues, while the SOD activity was increased. Treatment with resveratrol reduced the levels of lactic acid, pyruvate, and epinephrine in the kidney and heart tissues. Furthermore, resveratrol treatment significantly increases the expression of PDK4 myocardial tissues in RE group compared to PE group. CONCLUSION:  Resveratrol may inhibit the release of tissue inflammatory factors, regulate the body's energy metabolism, and ultimately protect tissue damage caused during Preeclampsia.

Sulfasalazine for the treatment of preeclampsia in a nitric oxide synthase antagonist mouse model.

INTRODUCTION: Development of a therapeutic that targets the pathophysiological elements of preeclampsia would be a major advance for obstetrics, with potential to save the lives of countless mothers and babies. We recently identified anti-inflammatory drug sulfasalazine as a prospective candidate therapeutic for treatment of preeclampsia. In primary human cells and tissues in vitro, sulfasalazine potently decreased secretion of anti-angiogenic sFlt-1 and sENG, increased production of pro-angiogenic PlGF, mitigated endothelial dysfunction, and promoted whole vessel vasodilation. METHODS: Using nitric oxide synthase antagonist Nω-Nitro-l-arginine methyl ester hydrochloride, a preeclampsia-like phenotype was induced in pregnant mice, including high blood pressure, fetal growth restriction, and elevated circulating sFlt-1. Mice were treated with sulfasalazine or vehicle from gestational day (D)13.5, with blood pressure measurements across gestation, fetal measurements at D17.5, and wire myograph assessment of vasoactivity. RESULTS: Sulfasalazine had a modest effect on blood pressure, decreasing diastolic and mean blood pressure on D13.5, but not later in gestation, or systolic blood pressure. Sulfasalazine was not able to rescue fetal growth, in male or female fetuses. There was a suggestion of improved vasoactivity with sulfasalazine, but further clarification is required. DISCUSSION: In this mouse model of preeclampsia, sulfasalazine did not sustain reductions in blood pressure nor affect fetal parameters of size and weight, both desirable attributes of a viable preeclampsia therapeutic. While these data suggest sulfasalazine might improve vasoactivity, murine toxicity considerations limited the dose range of sulfasalazine that could be tested in the current study.