Preeclampsia Rats Research Articles

Polyunsaturated Fatty Acid Diet and Upregulation of Lipoxin A4 Reduce the Inflammatory Response of Preeclampsia.

The aim of this study was to investigate the effects and mechanisms of polyunsaturated fatty acids (PUFAs) and lipoxin A4 (LXA4) on preeclampsia (PE). The LXA4 level was significantly reduced in PE rats. The PUFA diet upregulated the expressions of lipoxygenase 12 (LOX12) and lipoxygenase 15 (LOX15) and downregulated those of cyclooxygenase-2, tumor necrosis factor-α (TNF-α), and endoglin. Lipopolysaccharides could inhibit cell growth and cause inflammatory response, while the presence of PUFAs inhibited the inflammatory response and promoted the expressions of LOX12, LOX15, and LXA4. Nordihydroguaiaretic acid (NDGA) regulated LXA4 expression and inflammation levels by affecting LOX. Inhibition of lipoxygenase 5 activity by NDGA upregulated the expressions of LOX12 and LOX15, while LXA4 reversed LXA4, nitric oxide downregulation, and TNF-α upregulation by NDGA. A decrease in LXA4 levels played an important role in the development and progression of PE.

Glycyrrhizin potentially suppresses the inflammatory response in preeclampsia rat model.

The expression of high-mobility group box 1 (HMGB1) in trophoblasts is elevated, which contributes to the development of preeclampsia. Thus, this study aimed to investigate the effect of glycyrrhizin, a natural HMGB1 inhibitor, on the development of preeclampsia. Preeclampsia was induced in pregnant Lewis rats through oral administration of L-NAME (50mg/kg/day) on gestational day (GD) 13-19. Glycyrrhizin (10, 30, or 60mg/kg/day) was given by oral gavage on GD 10-19. Systolic blood pressure (SBP), diastolic blood pressure (DBP), 24-hour proteinuria, live pup birth ratio, pup weight, pup body length, and placental weight were measured. Also, the expression levels of inflammatory factors (TNF-α, iNOS, IL-1, and IL-6), HMGB1, and TLR4 in the placenta or in the serum were analyzed by enzyme-linked immunosorbent assay, RT-PCR, and Western blot analysis. Glycyrrhizin significantly reduced the SBP, DBP, and 24-hour proteinuria on GD 16 and 20 in a dose-dependent manner and ameliorated the pregnancy outcomes in preeclampsia rats. The elevated inflammatory molecule levels were markedly decreased by glycyrrhizin not only in the serum but also in the placenta. Moreover, the upregulated HMGB1 and TLR4 expression levels were diminished by glycyrrhizin administration. This study shows that glycyrrhizin could alleviate preeclampsia and the preeclampsia-associated inflammatory reaction, and this effect could be attributed to HMGB1 inhibition.

Astragaloside IV alleviates lipopolysaccharide-induced preeclampsia-like phenotypes via suppressing the inflammatory responses.

Preeclampsia (PE) is a major cause of perinatal and maternal mortality and morbidity, which affects 2% to 8% of pregnancies in the world. The aberrant maternal inflammation and angiogenic imbalance have been demonstrated to contribute to the pathogenesis of PE. This research aimed to investigate the effect of Astragaloside IV (AsIV) in the treatment of PE and the underlying mechanisms. A rat PE-like model was established by tail vein injection of lipopolysaccharide (LPS) and different doses of AsIV (40 and 80 mg/kg) were treated at the same time. Systolic blood pressure, total urine protein and urine volume were observed. Serum and placenta inflammatory cytokines were measured by ELISA kit. The mRNA and protein expression of relative genes were analyzed by qRT-PCR and Western blotting. In PE-like rats, there were obvious increases in systolic blood pressure, total urine protein and urine volume, which were obviously alleviated by treatment with AsIV. Serum levels of interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), IL-6 and IL-18, as well as IL-4, IL-10, PIGF, VEGF and sFlt-1, were all reversed by treatment with AsIV. Meanwhile, AsIV treatment improved abnormal pregnancy outcomes, such as low litter size and low fetal weight. In addition, AsIV treatment downregulated the mRNA expression of inflammatory gene IL-1β and IL-6 in PE rats model, and AsIV treatment inhibited the activation of TLR-4, NF-κB, and sFlt-1 in the placenta of PE rats. Our findings indicated the first evidence that AsIV alleviated PE-like signs, and this improvement effect is possibly through inhibition of inflammation response via the TLR4/NF-κB signaling pathway.

Changes in intestinal flora in preeclampsia rats and effects of probiotics on their inflammation and blood pressure.

The aim of this study was to investigate the changes in intestinal flora in preeclampsia rats and the effects of probiotics on their inflammation and blood pressure. A total of 40 Specific Pathogen Free (SPF) Wistar rats were randomly selected in this study. Abdominal operation was performed to reduce uterine blood perfusion, so as to establish the model of preeclampsia in rats. All rats were randomly divided into two groups, namely, observation group (treated with probiotics, n=20) and control group (not treated with probiotics, n=20). Subsequently, the changes in serum endotoxin level during intervention, the 24-h urinary 99mTc-diethylene triamine pentaacetic acid (DTPA) excretion rate, and intestinal flora colonization ability after intervention were compared between the two groups. The distribution of intestinal flora after intervention was recorded in the two groups. Meanwhile, vascular endothelial function and blood pressure following intervention were compared between the two groups as well. In addition, the changing trend of inflammatory cytokines during intervention in the two groups, and the correlation of colonization ability of intestinal flora with changes in systolic blood pressure and high-sensitivity C-reactive protein (hs-CRP) level in patients were analyzed. At 3 days and 1 week after intervention, serum endotoxin level in the observation group was significantly lower than that in the control group at the same period (p<0.05). Following intervention, observation group exhibited remarkably higher excretion rate of 24-h urinary 99mTc-DTPA (p<0.05), stronger colonization ability of intestinal flora (p<0.05), higher levels of Bifidobacteria and Lactobacillus in intestinal flora (p<0.05), lower level of endothelin-1 (ET-1) (p<0.05) and higher level of nitric oxide (NO) (p<0.05) than the control group. In addition, the systolic blood pressure and diastolic blood pressure in the observation group were basically normal, which were both notably lower than those in the control group (p<0.05). At 3 days and 1 week after intervention, the levels of serum inflammatory cytokine hs-CRP in the observation group was markedly lower than that in the control group (p<0.05) at the same period. Furthermore, the colonization ability of intestinal flora was negatively associated with the changes in systolic blood pressure and hs-CRP level in patients (p<0.05). Treating preeclampsia rats with probiotics can effectively reduce the level of serum endotoxin, improve the body's capacity to eliminate metabolites and the colonization ability of intestinal flora, maintain the stability of intestinal flora, enhance vascular endothelial function, and reduce blood pressure and the body's inflammatory responses.

Improved placental vascular repair in a rat preeclampsia model by implantation of endothelial progenitor cells treated with platelet microparticles

ABSTRACT Objective: To detect the role of endothelial progenitor cells (EPCs) treated with platelet microparticles (PMPs) in preeclampsia. Methods: EPCs treated with/without PMPs were labeled and injected to PE rats. The differentiation of EPCs, the change of endothelial nitric oxide synthase (eNOS), blood pressure and proteinuria were measured. The blood pressure and proteinuria increased in each of PE groups, and were improved by EPCs which was strengthened by PMPs. Transplantation of EPCs increased placental angiogenesis. The trend of change of NO was the same as blood pressure. Conclusion: Transplantation of EPCs treated with PMPs improved blood pressure and proteinuria more effectively.

Exosomal microRNA-139-5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP-2 pathway via downregulation of protein tyrosine phosphatase.

AimExosomes present essential roles for intercellular interaction via extracellular pathways during systemic dysfunctions, including preeclampsia (PE). Here, we assessed the specific mechanism of mesenchymal stem cells (MSC)‐originated exosomes in PE.MethodsThe effects of exosomes on trophoblasts were studied by EdU, wound healing, Transwell and TUNEL assays. By microarray analysis, we found that exosomes enhanced the microRNA‐139‐5p (miR‐139‐5p) in trophoblasts, and confirmed the target gene of miR‐139‐5p by bioinformatics prediction and dual‐luciferase reporter gene assay. At the same time, ERK/MMP‐2 pathway‐related biomolecules were assessed through Western blot analysis. The pathway inhibitor was used for rescue experiments. Finally, the effect of exosomes on the pathology of PE rats was verified by in vivo experiments.ResultsThe exosomes originated from hucMSC fostered the trophoblast cell migration, invasion and proliferation and obstructed apoptosis. Moreover, miR‐139‐5p could be transmitted to trophoblasts through hucMSC‐secreted exosomes. miR‐139‐5p targeted protein tyrosine phosphatase (PTEN), which regulated the ERK/MMP‐2 pathway. Inhibition of the ERK/MMP‐2 pathway significantly reduced the promoting effect of exosomes on trophoblasts. Treatment with exosomes significantly lowered blood pressure values and reduced 24‐h proteinuria in PE rats.ConclusionhucMSC‐originated exosomes overexpressing miR‐139‐5p activated the ERK/MMP‐2 pathway via PTEN downregulation, thus accelerating trophoblast cell invasion and migration, and blocking apoptosis. These results demonstrated that hucMSC‐derived exosomes overexpressing miR‐139‐5p might be an innovative direction for therapeutic approaches against PE.

Erythropoietin Mimetic Peptide (pHBSP) Corrects Endothelial Dysfunction in a Rat Model of Preeclampsia.

Preeclampsia is a severe disease of late pregnancy. Etiological factors and a pathogenetic pattern of events still require significant clarification, but it is now recognized that a large role is played by placentation disorders and emerging endothelial dysfunction. The administration of short-chain peptides mimicking the spatial structure of the B erythropoietin chain may become one of the directions of searching for new drugs for preeclampsia prevention and therapy. Simulation of ADMA-like preeclampsia in Wistar rats was performed by the administration of a non-selective NOS blocker L-NAME from the 14th to 20th day of pregnancy. The administration of the pHBSP at the doses of 10 µg/kg and 250 µg/kg corrected the established morphofunctional disorders. The greatest effect was observed at a dose of 250 µg/kg. There was a decrease in systolic and diastolic blood pressure by 31.2 and 32.8%, respectively (p < 0.0001), a decrease in the coefficient of endothelial dysfunction by 48.6% (p = 0.0006), placental microcirculation increased by 82.8% (p < 0.0001), the NOx concentration was increased by 42,6% (p = 0.0003), the greater omentum edema decreased by 11.7% (p = 0.0005) and proteinuria decreased by 76.1% (p < 0.0002). In addition, there was an improvement in the morphological pattern of the fetoplacental complex and the ratio of BAX to Bcl-2 expression which characterizes the apoptotic orientation of the cells.

Astragaloside IV ameliorates preeclampsia-induced oxidative stress through the Nrf2/HO-1 pathway in a rat model.

Preeclampsia (PE) can cause serious health problems for pregnant women and their infants. Astragaloside IV has been shown to exert cardioprotective, anti-inflammatory, and antioxidative effects on various disorders. We aimed to study the effects of Astragaloside IV on PE symptoms using an NG-nitro-l-arginine methyl ester (l-NAME)-induced rat model of PE. The pregnant rats' physiological features, including blood pressure, urine protein, serum soluble fms-like tyrosine kinase-1(sFlt-1)/placental growth factor (PlGF) ratio, and weight of placenta, as well as the weight, length, and survival of pups, were documented. The expression levels of target genes were analyzed by Western blot and qRT-PCR assays. The levels of target secreted proteins were determined by ELISA. We demonstrated that the administration of Astragaloside IV might exert a multitude of beneficial effects on attenuated PE symptoms in a rat model of PE. We further revealed that the effects of Astragaloside IV on PE rats were achieved, at least partially, through elimination of oxidative stress and stimulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Our study indicated that Astragaloside IV may serve as a promising candidate for the development of new therapeutic methods for patients with PE.

Abstract P212: Kidney Injury Caused By Preeclamptic Pregnancy Improves Postpartum In A Transgenic Rat Model

Preeclamptic pregnancies involve mild renal injuries. However, there has been evidence that women with a history of preeclampsia (PE) have an increased risk to develop kidney disease in association to high blood pressure later in life. This study aims to characterize renal injury during pregnancy and postpartum in an established transgenic rat model for PE. Female Sprague-Dawley rats transgenic for the human angiotensinogen gene develop a PE phenotype in pregnancy, including cardiac remodeling, when mated with male rats harboring the human renin gene. Postpartum, blood pressure restores but cardiac remodeling persists. We hypothesize that PE during pregnancy mediates kidney injuries but does not fully restore after ending of the high blood pressure (postpartum). The renal alterations were analyzed by histological staining, gene expression and urine analysis. PE rats have elevated mean arterial blood pressure during pregnancy (PE d19 148.4 ± 20.7 mmHg) compared to normotensive values in control animals (WT d19 105.3 ± 4.6 mmHg). During PE increased expression of kidney injury marker 1 ( Kim-1/18S : PE d21 4.14 ± 3.26; WT d21 0.08 ± 0.02), neutrophil gelatinase associated lipocalin 2 ( Ngal/18S : PE d21 1.64 ± 0.83; WT d21 0.59 ± 0.28) and connective-tissue growth factor ( Ctgf/18S: PE d21 1.51 ± 0.46; WT d21 0.92 ± 0.32) were detected. Kidneys of PE rats showed mild glomerular (PAS-positive glomerular area PE d21 86.2 ± 4.4%; WT d21 79.1 ± 3.2%) and tubular changes during PE pregnancy resulting in albuminuria (albumin/creatinine ratio PE d19 2193.8 ± 1878.2; WT d19 290.4 ± 252.0). However, 4 weeks after pregnancy (approx. 2 years in humans) most of the PE related renal damages were absent including albuminuria and elevated expression of biomarkers ( Kim-1/18S : PE d50 0.09 ± 0.05; WT d50 0.23 ± 0.13; Ctgf/18S : PE d50 0.78 ± 0.25; WT d50 0.8 ± 0.25; Ngal/18S : PE d50 0.37 ± 0.17; WT 50 0.47 ± 0.11). Only mild enlargement of glomerular tuft area (PE d50 7523.8 ± 418.7 μm 2 ; WT d50 7058.4 ± 198.8 μm 2 ) was detected. Overall, the glomerular and tubular injuries are present during pregnancy in this transgenic PE rat. Most restore postpartum, speculating long-term kidney failure observed in humans is associated to hypertension and additional cardiovascular events.

Ligustrazine-induced microRNA-16-5p inhibition alleviates preeclampsia through IGF-2.

Preeclampsia (PE), a serious complication of pregnancy, is associated with abnormal trophoblast cell differentiation and autophagy. Herein, we investigated the molecular mechanism underlying the function of ligustrazine (2,3,5,6-tetramethylpyrazine, TMP), a constituent of the traditional Chinese plant medicine Ligusticum wallichii, in PE. Lipopolysaccharide (LPS) was applied to induce a PE rat model, followed by tail vein injection of TMP or lentiviral vector overexpressing microRNA-16-5p (miR-16-5p). Human trophoblast cell line JEG3 was cultured in vitro to construct a PE cell model, followed by t he treatment with different concentrations of TMP, miR-16-5p mimic/inhibitor, or shRNA (shRNA) against insulin growth factor-2 (IGF-2) (sh-IGF-2). Formation of autophagosomes and autophagy-related proteins were then examined. Cell counting kit-8 (CCK-8) and Transwell assays were applied to measure trophoblast cell viability and migration. The binding affinity between miR-16-5p and IGF-2 was verified by dual luciferase report assay. After TMP treatment, autophagosome formation was reduced in trophoblast cells of placental tissue of PE rats, along with downregulation of autophagy-related proteins Light Chain 3 (LC3)-II/LC3-I, Beclin1 (BECN1), and SQSTM1. Moreover, TMP repressed JEG3 cell autophagy, promoted viability and migration concentration-responsively. MiR-16-5p was upregulated in PE, and TMP inhibited miR-16-5p expression. Besides, miR-16-5p downregulated IGF-2 expression to promote cell autophagy and inhibit the viability and migration of JEG3 cells. Further, in vivo experiments validated that TMP impeded PE progression in rats by regulating the miR-16-5p/IGF-2 axis. In summary, TMP inhibits trophoblast cell autophagy and promotes its viability and migration in PE rat model through regulating the miR-16-5p/IGF-2 axis.

Effect of preeclampsia and preeclampsia severity on insulin, HOMA-IR, and betatrophin levels in non-diabetic pregnant women

BackgroundThe aim of the study was to evaluate the effect of preeclampsia and its severity on insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), and betatrophin levels in non-diabetic pregnant women. MethodsOur study comprised 102 pregnant women who were divided into the following three groups: (1) control, (2) severe preeclampsia, and (3) mild preeclampsia. The women were screened with the single-stage 75-g oral glucose tolerance test (OGTT), and the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria were used for diagnosis. Those women with type 2 diabetes (T2D) mellitus or gestational diabetes mellitus (GDM) were excluded from the study. ResultsMaternal demographic characteristics were similar among the groups. Fasting plasma glucose and postprandial 2-h plasma glucose levels were significantly increased in the severe-preeclampsia group compared to that in the other groups. Fasting insulin levels were 14.3 ± 8.7uU/mL in the severe-preeclampsia group, 19.1 ± 6.0uU/mL in the mild-preeclampsia group, and 20.5 ± 12.5uU/mL in the control group and significantly lower in the severe-preeclampsia group than in the mild-preeclampsia and control groups. The serum betatrophin level was 7.8 ± 2.6 ng/mL in the severe-preeclampsia group, 6.1 ± 1.8 ng/mL in the mild-preeclampsia group, and 5.8 ± 1.3 ng/mL in the control group and significantly increased in the severe-preeclampsia group compared to other groups. HOMA-IR was similar among the groups. Maternal serum insulin levels were negatively (r = −0,255; P = 0.010) and serum betatrophin levels were positively (r = 0.368; P ≤ 0.001) correlated with preeclampsia severity. ConclusionOur results indicated that severe preeclampsia effect maternal serum glucose, insulin and betatrophin levels. Histhopatholical and immunohistochemical demostrations on pancreatic cells in new preeclampsia rat models will expand the information on the current situation.

Implication of nuclear factor-erythroid 2-like 2/heme oxygenase 1 pathway in the protective effects of coenzyme Q10 against preeclampsia-like in a rat model.

Preeclampsia has ranked as one of the leading causes of both maternal and prenatal morbidity and mortality around the world. The hypotensive effect of coenzyme Q10 has been widely reported in preeclampsia rat model. However, the detailed mechanism remains unclear. L-NAME was utilized to establish the preeclampsia rat model. Biomarker assessments were performed to identify the levels of vascular factors including soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF), the circulating cytokines including interleukin 6, tumor necrosis factor α and interleukin 1β, and oxidative stress factors including malondialdehyde, H2 O2 , glutathione, superoxide dismutase, glutathione peroxidase, and Catalase. QRT-PCR was used to demonstrate the levels of cytokines in placenta tissues, and Western blot was performed to estimate the nuclear factor-erythroid 2-like 2 (Nrf2) and heme oxygenase 1 (HO-1) protein levels. Coenzyme Q10 treatment decreased the blood pressure in rat model with preeclampsia by regulating the circulating levels of sFlt-1 and PlGF. Coenzyme Q10 attenuated serum and placental inflammation and oxidative stress in L-NAME-induced preeclampsia rats. Coenzyme Q10 activated the placental Nrf2/HO-1 pathway in L-NAME-induced preeclampsia rats. Coenzyme Q10 attenuated placental inflammatory and oxidative stress, thereby protecting the rats against preeclampsia by activating the Nrf2/HO-1 pathway.

Neurotoxicity in pre-eclampsia involves oxidative injury, exacerbated cholinergic activity and impaired proteolytic and purinergic activities in cortex and cerebellum.

Women with a history of pre-eclampsia (PE) tend to have a higher risk of developing cardiovascular and neurological diseases later in life. Imbalance in oxidative markers and purinergic enzymes have been implicated in the pathogenesis of neurological disease. This study investigated the effect of PE on oxidative imbalance, purinergic enzyme inhibitory activity, acetylcholinesterase and chymotrypsin activities in the brain of PE rat model at post-partum/post-natal day (PP/PND) 60. Pregnant rats divided into early-onset and late-onset groups were administered with Nω-nitro-l-arginine methyl through drinking water at gestational days 8-17. Rats were allowed free access to water throughout the pregnancy and allowed to deliver on their own. The mother and the pups were euthanized at PP and PND 60, respectively, the cortex and the cerebellum excised, homogenized and stored for analyses of the enzymes. Results showed an increase in nitric oxide and malondialdehyde with a concomitant decrease in reduced glutathione and superoxide dismutase, an indication of oxidative damage. Also, there was an increase in acetylcholinesterase activity with a decrease in chymotrypsin, adenylpyrophosphatase and ecto-nucleoside triphosphate diphosphohydrolase activities in both the cortex and the cerebellum of the mother and the pups at PND 60. These results indicate the involvement of oxidative stress, increased cholinergic activity and depleted proteolytic and purinergic activities in PE-induced neurotoxicity.

Effects of Thymus schimperi and Moringa stenopetala Leaf Extracts on Lipid Peroxidation and Total Antioxidant Status in Pre-eclampsia Rat Models

Background: Hypertensive disorders of pregnancy (HDP) are common pregnancy complications, with a cumulative incidence of 7%. Pre-eclampsia (PE) is the most common clinical type of HDP and one of the five top leading causes of maternal mortality worldwide. There is imbalance between lipid peroxides and antioxidant system in PE. Established PE is associated with increased concentrations of oxidative stress markers including lipid peroxidation products, and a reduction in antioxidant concentrations.&#x0D; Methods: A case control experimental method was employed on Wistar rats with induced pre-eclampsia using nitric oxide-nitro-L-arginine methyl ester (L-NAME). Lipid peroxide content was estimated according to the method of Ohkawa et al. 1979. Total antioxidant capacity was assayed using colorimetric azinobis 2, 2′3-ethyl-benzothiazoline-6-sulfonate (ABTS) radical cathion decolorization assay.&#x0D; Results: Lipid peroxides of untreated PE rat models were significantly (p&lt;0.01) higher (0.57±0.08 nmol of malondyaldehide (MDA) per gram tissue weight) compared to normal pregnant controls (0.11±0.03 nmol). PE rat models that received aqueous leaf extracts of Thymus schimperi (ALETS) had (0.09±0.01, 0.07±0.002 and 0.02±0.002 nmol) (p&lt;0.05) while, those PE rat models that received aqueous leaf extracts of Moringa stenopetala (ALEMS) had (0.36±0.08, 0.20±0.003 and 0.13±0.02 nmol) (p&lt;0.05) with daily doses of 250 mg/kg, 500 mg/kg and 1000 mg/kg respectively. On the other hand, untreated PE rat models had significantly (p&lt;0.01) lower levels of serum total anti-oxidants (24.5±0.9 μg/ml of ascorbic acid equivalent) compared to normal pregnant controls (28.1±0.4 μg/ml). ALETS or ALEMS treated PE rat models had significantly (p&lt;0.01) higher levels of serum total anti-oxidants in a dose dependent manner compared to untreated PE controls; (27.6±0.3, 29.5±0.3, 31.2±0.4 μg/ml and 29.2±0.3, 29.7±0.3, 30.6±0.4 μg/ml) with daily doses of 250 mg/kg, 500 mg/kg and 1000 mg/kg respectively. ALETS treated PE rat models had significantly (p&lt;0.05) reduced total lipid peroxides compared to ALEMS treated counterparts.&#x0D; Conclusion: ALETS and ALEMS might have significant therapeutic effects against PE syndrome through reducing lipid peroxides and increasing total anti-oxidants.

Glucocorticoid Exposure Induces Preeclampsia via DampeningLipoxin A4, an Endogenous Anti-Inflammatory and Proresolving Mediator.

The pathogenesis of preeclampsia (PE) involves several pathophysiological processes that may be affected by glucocorticoid (GC). We confirmed previously that GC exposure could result in PE, while PE is linked to a deficiency of lipoxin A4 (LXA4), an endogenous dual anti-inflammatory and proresolving mediator. The present study was to investigate whether GC exposure induces PE via dampening LXA4. In the study, cortisol levels of PE women were higher than those of normal pregnancies, LXA4 levels were downregulated in both PE patients and GC-mediated PE rats, and leukotriene B4 (LTB4) levels were upregulated in both PE patients and GC- mediated PE rats. Moreover, cortisol levels were negatively correlated to LXA4 levels, while positively correlated to LTB4 levels in PE patients. Mechanically, GC downregulated LXA4 via disturbing its biosynthetic enzymes, including ALOX15, ALOX5B and ALOX5, especially activating ALOX5, the key enzyme for class switching between LXA4 and LTB4. Importantly, replenishing LXA4 could ameliorate PE-related symptoms and placental oxidative stress in PE rat model induced by GC. Moreover, LXA4 could inhibit GC-mediated ALOX5 activation and LTB4 increase, and also suppress 11β-HSD2 expression and corticosterone upregulation. The protective actions of LXA4 might be explained by its roles in antagonizing the adverse effects of GC on trophoblast development. Together, our findings indicate that GC exposure could contribute to PE through dampening LXA4, and GC/LXA4 axis may represent a common pathway through which PE occurs.

Magnesium sulfate prophylaxis attenuates the postpartum effects of preeclampsia by promoting M2 macrophage polarization.

Preeclampsia is a complex disorder that is characterized by new onset hypertension and proteinuria at or after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and fetal morbidity and mortality. MgSO4 is commonly used to treat severe preeclampsia, but its mechanism of action is poorly understood, and investigations into the effects of MgSO4 during the postpartum period are lacking. In this study, timed-pregnant Sprague-Dawley rats received low-dose lipopolysaccharide (LPS) on gestational day 14 to induce preeclampsia. Maternal and fetal outcomes and the macrophage profile 1 week after delivery were explored. On postpartum day (PD) 7, the maternal systolic blood pressure and urinary protein level were significantly increased, the number of M1 macrophages was increased and the number of M2 macrophages was decreased in the maternal kidney and brain; the median duration of gestation, the number of live fetuses, and the fetal weight/placenta weight ratio were significantly decreased; and the percentage of growth-restricted pups and fetal mortality were significantly increased in preeclampsia rats compared to normal pregnant control rats. Prophylactic MgSO4 decreased blood pressure at PD7, improved pregnancy outcomes, and promoted the polarization of M2 macrophages in the kidney and of M2 microglia in the brain of preeclampsia rats. These findings confirm that the pathophysiology of preeclampsia involves the dysregulation of the inflammatory response and the activation of M1 macrophages in several target organs during pregnancy. MgSO4 prophylaxis attenuates the postpartum effects of preeclampsia by promoting M2 macrophage polarization in the maternal kidney and brain.

Extra Virgin Olive Oil Modulates Vasodilator Enzyme Level by Repairing Angiogenesis Function in Rat Model of Preeclampsia

Objective: This study aimed to determine the effect of Extra Virgin Olive Oil (EVOO) on vasodilator enzyme by repairing angiogenic function in rat model of preeclampsia. Materials and methods: This research consisted of five groups; negative control (normal pregnant rats) group, positive control (preeclampsia rat model) group, preeclampsia rat model groups given EVOO in 3 different doses (0.5 ml/day, 1 ml/day, and 2 ml/day, respectively). Blood pressure measurements were carried out on day 12, 15, and 19 of pregnancy. After the rats were sacrificed, the placentas were collected to determine endothelial Nitric Oxide Synthase (eNOS) level of maternal plasma to determine soluble Fms-like Tyrosine Kinase 1 (sFlt-1) and Vascular Endothelial Growth Factor (VEGF) level. Results: There were significant higher sFlt-1 level (p < 0.001), lower VEGF level (p = 0.009), and lower eNOS level (p = 0.034) between negative and positive control groups. After EVOO administration, sFlt-1 level was lower in dose 1 and 2 groups but higher in dose 3 group in accordance with VEGF and eNOS levels that were increasing both in dose 1 and dose 2 groups but decreasing in dose 3. There were significant differences between positive control and dose 1 (p = 0.015) and dose 2 (p = 0.001) in sFlt-1 level. None of all dose groups were statistically different with positive control group in VEGF level (dose 1 p = 0.601; dose 2 p = 0.297; dose 3 p = 0.805). eNOS levels of all dose groups were statistically different from that of the positive control group (dose 1 p = 0.014; dose 2 p = 0.001; dose 3 p = 0.024). Conclusion: Administration of EVOO modulates eNOS as vasodilator enzyme by repairing the angiogenic function indicated by decreased sFlt-1 level and increased VEGF in rat model of preeclampsia.

Protective Effects of Thymus schimperi and Moringa stenopetala Leaf Extracts on Arterial Blood Pressure and Urine Protein Level in Pre-eclampsia Rat Models

Background: Pre-eclampsia (PE) is a common hypertensive disorder during pregnancy and one of the leading causes of perinatal mortality and morbidity. There is no curative modern drug to treat PE. Therefore, researches done on traditional medications have paramount importance in discovering therapeutic and /or protective agents from plant materials. In Ethiopia, there are claims that some indigenous medicinal plants such as Thymus and Moringa can have potential protective functions against PE. The aim of this study was to prove the claims.&#x0D; Methods: Experiments were performed to investigate the effects of aqueous leaf extracts of Thymus schimperi (ALETS) and Moringa stenopetala (ALEMS) on PE rat models induced by nitro-L-arginine methyl ester (L-NAME); a nitric oxide synthase inhibitor. A non-invasive tail cuff blood pressure recorder (Model 179 Amplifier, IITC INC, Life Science Instruments, Woodland Hills, California) was used to determine the arterial blood pressure from rat tail. Urine analysis to determine protein levels was performed using a dipstick, semi-qualitative method as per manufacturer’s instructions (CYBO DFI Korea).&#x0D; Results: ALETS treated PE rat models showed significantly reduced mean arterial blood pressure (MAP) in mmHg; 108±3 (P&lt;0.05), 105±1 (P&lt;0.01) and 99±2 (P&lt;0.01); also the same pattern of results were seen in ALEMS treated PE groups with MAP of 106±1 (P&lt;0.05), 103±1 (P&lt;0.05) and 101±1 (P&lt;0.05) at daily doses of 250 mg/kg, 500 mg/kg and 1000 mg/kg, respectively, compared to untreated case group that had 123±3.7 mmHg at gestation day (GD) 19 . Untreated PE rat models showed significant proteinuria (2000±20 mg/L) throughout the gestation period; while PE rat models treated with either ALETS or ALEMS had significantly reduced (p&lt;0.05) proteinuria in dose dependent pattern (150±15 mg/L) at a dose of 1 gm/kg for each plant extract at GD 19.&#x0D; Conclusion: Aqueous leaf extracts of either Thymus schimperi or Moringa stenopetala might reduce and control arterial pressure in PE rat models in a dose dependent manner. The extracts also could reduce level of proteinuria in the same pattern. Further investigation should, however, be carried out to confirm their uses in prevention and/or treatment of pregnancy-induced hypertension among human cases.

MiR-30 inhibits proliferation of trophoblasts in preeclampsia rats partially related to MAPK/ERK pathway.

Effect of micro ribonucleic acid (miR)-30 on the proliferation of trophoblasts in preeclampsia (PE) rats through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway was studied. The miR-30 mimic was transfected into the trophoblast HTR8/SVNEO cell lines. The effects of expression level of miR-30 on the proliferation and hypoxia-induced apoptosis of HTR8/SVNEO cells were detected via methyl thiazolyl tetrazolium (MTT) assay and Annexin V/propidium iodide staining, respectively, using the flow cytometer. A total of 30 pregnant Sprague-Dawley rats were randomly divided into control group (CTL group, n=10), PE rat group (PE group, n=10) and PE + miR-30 Mimic group (PE+agomiR-30 group, n=10) using a random number table. The protein expression levels of phosphorylated ERK (p-ERK)1/2, ERK1/2, proliferating cell nuclear antigen (PCNA) and tubulin were determined using western blot analysis, and the mRNA expression level of ERK1/2 was detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression level of PCNA in tissues was detected via immunohistochemistry. The results of MTT assay showed that the proliferation of HTR8/SVNEO cells significantly declined in hypoxic environment, while miR-30 promoted the proliferation of HTR8/SVNEO cells and alleviated the hypoxia-induced inhibition on cell proliferation. It was found that the trophoblast apoptosis rate was increased in hypoxia group compared with that in CTL group, while it was significantly decreased in miR-30 Mimic group compared with that in hypoxia group. PE group had obviously decreased p-ERK and PCNA expression levels as well as p-ERK/ERK ratio in placental tissues compared with CTL group, while PE+agomiR-30 group had an obviously increased expression level of PCNA as well as p-ERK/ERK ratio in placental tissues compared with PE group. MiR-30 activates the MAPK/ERK signaling pathway and increases the expression level of PCNA through raising the p-ERK level and p-ERK/ERK ratio, thereby inhibiting cell apoptosis and promoting cell proliferation.

Melatonin attenuates hypertension and oxidative stress in a rat model of L-NAME-induced gestational hypertension.

Preeclampsia is a life-threatening multiorgan systemic disease with manifestations including gestational hypertension, oxidative stress, and vascular dysfunction. We aimed to evaluate the therapeutic effects of melatonin on an L-NAME (NLG-nitro-l-arginine methyl ester)-induced rat preeclampsia model. During gestation, L-NAME was added to drinking water at 50 mg/kg/day from gestation day (GD) 8. Rats received the combination of L-NAME with melatonin (10 mg/kg/day), or aspirin (1.5 mg/kg/day), and rats that received only L-NAME or no treatments were used as controls. Aspirin was mixed with rodent chow and melatonin was administered intraperitoneally. Blood pressure and urine protein content were monitored every 3 days. On GD19, blood samples were collected for biochemical analysis. Compared to untreated L-NAME rats, melatonin led to markedly lowered blood pressure and urine protein content, and recovery in the fetus alive ratio, fetal weight, and the fetal weight/placental weight ratio. Compared to untreated L-NAME rats, plasma antioxidant capacity and plasma malondialdehyde were increased and decreased by melatonin, respectively, in L-NAME rats. Melatonin treatment also reduced sFlt-1, increased PlGF, and decreased the sFlt-1/PlGF ratio. In the placenta, melatonin also reduced sFlt-1 levels and increased Nrf2, PlGF, and HO-1 levels. We have demonstrated in a rat model of preeclampsia that melatonin exerts significant protective effects through lowering blood pressure and reducing oxidative stress.