Modulation of NRF2/KEAP1 Signaling in Preeclampsia

Placentation is a key and tightly regulated process that ensures the normal development of the placenta and fetal growth. Preeclampsia (PE) is a hypertensive pregnancy-related disorder involving about 5–8% of all pregnancies and clinically characterized by de novo maternal hypertension and proteinuria. In addition, PE pregnancies are also characterized by increased oxidative stress and inflammation. The NRF2/KEAP1 signaling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. ROS activate NRF2, allowing its binding to the antioxidant response element (ARE) region present in the promoter of several antioxidant genes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase that neutralize ROS, protecting cells against oxidative stress damages. In this review, we analyze the current literature regarding the role of the NRF2/KEAP1 pathway in preeclamptic pregnancies, discussing the main cellular modulators of this pathway. Moreover, we also discuss the main natural and synthetic compounds that can regulate this pathway in in vivo and in vitro models

The HELLP syndrome: Clinical issues and management. A Review

<p>Abstract</p> <p>Background</p> <p>The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10–20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence.</p> <p>Methods</p> <p>Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases.</p> <p>Results and conclusion</p> <p>About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH (> 600 U/L), AST (≥ 70 U/L), and platelets < 100·10⁹/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment (≥ 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.</p

HTRA family proteins in pregnancy outcome

HTRA (High temperature requirement protease A) family proteins includes HTRA1 (L56 or PRSS11), HTRA2/Omi, HTRA3 (PRSP) and HTRA4. These are oligomeric serine proteases highly conserved from bacteria to humans and are involved in a variety of biological functions including the maintenance of normal cell physiology and pathogenicity such as cell growth, apoptosis, neurodegenerative disorders, inflammation diseases and cancer. These proteins are normally expressed in placental villi during all pregnancy but their expression is found to be altered in pathological pregnancies suggesting a possible role of those proteins in the development of human placenta. Moreover, some HTRA family proteins have also been found in maternal blood and were impaired in pathological pregnancy suggesting a possible role of some of these proteins as early markers of pregnancy outcome. The aim of this review is to summarize the data currently available on the role of HTRA family proteins in pregnancy focalizing their role in pregnancy complications such as Preeclampsia (PE), IntraUterine Growth Restriction (IUGR) and Spontaneus PreTerm Birth (SPTB)

Hop and artichoke extracts inhibit expression of extracellular matrix components in uterine leiomyoma cells

Objective: To screen 14 different plant extracts for their antifibrotic effect on human primary leiomyoma and healthy myometrial cells. Design: Preclinical study. Setting: University research laboratory. Patient(s): Human uterine leiomyoma and matched myometrial tissues were obtained from Caucasian premenopausal women with symptomatic uterine fibroids at the time of hysterectomy. Intervention(s): Primary human leiomyoma and myometrial cells were cultured in the absence or presence of the plant extracts. Main Outcome Measure(s): Quantification of the expression of extracellular matrix components, such as fibronectin 1 (FN1), collagen type I alpha 1 (COL1A1), and versican (VCAN), and the profibrotic growth factor activin A or inhibin beta A subunit (INHBA). Result(s): The cells were treated with the 14 extracts for 48 hours, and we measured FN1 messenger RNA (mRNA) expression. Of the 14 extracts, about (ABO) ABO-2 (hop) and ABO-9 (artichoke) significantly reduced FN1 expression in both the cell types. Next, we evaluated the effect of fractions of these 2 extracts on the mRNA expression of FN1 and other extracellular matrix components, such as COL1A1, VCAN, and INHBA, in leiomyoma and myometrial cells. We found that ABO-2 (hop) and ABO-9 (artichoke) as well as their fractions, ABO-AR-2016-015 (fraction of ABO-2) and ABO-AR-2014-168 (fraction of ABO-9), reduced the mRNA expression of FN1, COL1A1, VCAN, and INHBA in primary leiomyoma cells. In primary myometrial cells, the mRNA expression of FN1, COL1A1, VCAN, and INHBA was not greatly affected. Conclusion(s): These results suggest that the hop and artichoke extracts possess antifibrotic properties and support additional evaluation using in vivo models

Downregulation of argininosuccinate synthase 1 (ASS1) is associated with hypoxia in placental development

Argininosuccinate synthase (ASS1) is involved in nitric oxide production, which has a key role in placental development improving pregnancy outcomes. Syncytiotrophoblast and extravillous trophoblast differentiations are milestones of placental development and their impairment can cause pathologies, such as preeclampsia (PE) and fetal growth restriction (FGR). Immunohistochemistry and Western blotting were used to localize and quantify ASS1 in first trimester (8.2 +/- 1.8 weeks), third trimester (38.6 +/- 1.1 weeks), and PE (36.3 +/- 1.5 weeks) placentas. In addition, cell cultures were used to evaluate ASS1 expression under hypoxic conditions and the syncytialization process. Our data showed that ASS1 is localized in the villous cytotrophoblast of first trimester, third trimester, and PE placentas, while the villous cytotrophoblast adjacent to the extravillous trophoblast of cell columns as well as the extravillous trophoblast were negative for ASS1 in first trimester placentas. In addition, ASS1 was decreased in third trimester compared to the first trimester placentas (p = 0.003) and no differences were detected between third trimester and PE placentas. Moreover, ASS1 expression was decreased in hypoxic conditions and syncytialized cells compared to those not syncytialized. In conclusion, we suggest that the expression of ASS1 in villous cytotrophoblast is related to maintaining proliferative phenotype, while ASS1 absence may be involved in promoting the differentiation of villous cytotrophoblast in extravillous cytotrophoblast of cell columns in first trimester placentas

Antenatal Diagnosis and Management of Fetal Intestinal Volvulus: Case Series and Literature Review

Fetal intestinal volvulus is a rare condition that can lead to hemorrhage, bowel necrosis, and urgent surgical treatment after birth. Thus, prompt diagnosis and treatment are essential to avoiding fetal or neonatal demise. Prenatal ultrasound is a keystone tool in the diagnostic course. However, sonographic findings tend to be non-specific, with limited understanding of the pathophysiology behind their atypical presentation. With a literature review and a case series, we aim to optimize the antenatal diagnosis and management of this rare but life-threatening condition. Six cases from our institution were retrospectively analyzed over 12 years. A literature review was conducted until December 2022. A total of 300 articles matched the keyword "Fetal volvulus", and 52 studies were eligible for the review. Our 6 cases are added to the 107 cases reported in the literature of fetal intestinal volvulus with antenatal ultrasound assessment and without associated gastroschisis or omphalocele. Several prenatal symptoms and ultrasound markers, even if not specific, were more frequently reported. Different experiences of management were described regarding follow-up, the timing of delivery, the mode of delivery, and surgery outcomes. This paper highlights the importance of suspecting and assessing fetal volvulus at routine ultrasound scans, describing the most frequent antenatal presentations and management in order to improve fetal and neonatal outcomes

Quercetin and indole-3-carbinol inhibit extracellular matrix expression in human primary uterine leiomyoma cells

Research question: What is the effect of quercetin and indole-3-carbinol (I3C) on extracellular matrix expression, cell migration and proliferation in human myometrial and uterine leiomyoma cells. Design: Myometrial and leiomyoma cells were treated with quercetin or I3C at different concentrations (10 µg/ml; 50 µg/ml; 100 µg/ml; and 250 µg/ml) for 48 h to measure mRNA and protein expressions of extracellular matrix (collagen 1A1, fibronectin and versican), as well as cell migration and the proliferation rate. Results: Quercetin decreased mRNA levels of collagen 1A1 in myometrial (P < 0.0001) and leiomyoma cells (P < 0.0001). Quercetin reduced mRNA and protein levels of fibronectin in myometrial cells (P < 0.05) and fibronectin protein in leiomyoma cells (P < 0.05). I3C reduced collagen 1A1 mRNA levels in myometrial (P < 0.05) and leiomyoma cells at higher dose (P < 0.05). The protein levels of fibronectin were also reduced in both myometrial and leiomyoma cells with highest dose of I3C (P < 0.05), although mRNA levels were not affected in leiomyoma cells. Neither quercetin nor I3C treatment altered versican mRNA levels in both cell types. A significant reduction of the migration of both myometrial and leiomyoma cells in response to quercetin was observed (P < 0.05) and I3C (P < 0.05 for myometrial and P < 0.01 for leiomyoma cells) treatment. Both quercetin and I3C significantly reduced myometrial cell proliferation (P < 0.05). Conclusions: The in-vitro anti-fibrotic, anti-migratory and anti-proliferative effects of quercetin and I3C form the scientific basis for developing new therapeutic, preventive agents, or both, for uterine leiomyomas

Uterine Leiomyoma: Available Medical Treatments and New Possible Therapeutic Options

Uterine leiomyomas (fibroids or myomas) are benign tumors of the uterus and are clinically apparent in up to 25% of reproductive-age women. Heavy or abnormal uterine bleeding, pelvic pain or pressure, infertility, and recurrent pregnancy loss are generally associated with leiomyoma. Although surgical and radiological therapies are frequently used for the management of this tumor, medical therapies are considered the first-line treatment of leiomyoma. Evidence Acquisition and Synthesis: A review was conducted of electronic and print data comprising both original and review articles on pathophysiology and medical treatments of uterine leiomyoma retrieved from the PubMed or Google Scholar database up to June 2012. These resources were integrated with the authors' knowledge of the field. Conclusion: To date, several pathogenetic factors such as genetic factors, epigenetic factors, estrogens, progesterone, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in leiomyoma development and growth. On the basis of current hypotheses, several medical therapies have been investigated. GnRH agonist has been approved by US Food and Drug Administration for reducing fibroid volume and related symptoms. In addition, the FDA also approved an intrauterine device, levonorgestrel-releasing intrauterine system (Mirena), for additional use to treat heavy menstrual bleeding in intrauterine device users only. Currently, mifepristone, asoprisnil, ulipristal acetate, and epigallocatechin gallate have been shown to be effective for fibroid regression and symptomatic improvement which are all in clinical trial. In addition, some synthetic and natural compounds as well asgrowth factor inhibitors arenow under laboratory investigation, and they could serve as future therapeutic options