Dietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion.

Amino acid availability is monitored by animals to adapt to their nutritional environment. Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine cells (EECs) are believed to directly percept dietary amino acids and secrete regulatory peptides. However, the cellular machinery underlying amino acid-sensing by EECs and how EEC-derived hormones modulate feeding behavior remain elusive. Here, by developing tools to specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female EECs inhibits feeding, similar to human PYY. Mechanistically, dietary L-Glutamate acts through the metabotropic glutamate receptor mGluR to decelerate calcium oscillations in EECs, thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive EEC-derived NPF and relay an anorexigenic signal to the brain. Thus, our findings provide mechanistic insights into how EECs assess food quality and identify a conserved mode of action that explains how gut NPF/PYY modulates food intake.

How does green digital finance drive the low-carbon energy transition in China?

In the modern world, green digital financing is believed to be an efficient, resilient, and viable source of funding for crisis conditions and to solve the preceding issues in a timely manner. It is a modern tool of financing mainly introduced by the World Bank and the International Monetary Fund. Following the paths, most economies started considering it to solve their national economic issues. Thus, to fulfill the requirements of the modern world, current research aims to study the driving role of green digital financing on low-carbon energy transition in China. Using the generalized method of moments (GMM) model based on data collected from 2015 to 2020, this research made an effort to determine the empirical nexus between the green digital financing index and the low-carbon energy transition index and to recommend the possible policy implications to the policymakers and other practitioners. Results have shown that a 0.27% rise in green digital financing is observed in the Chinese economy from scratch, and it resulted from a 0.365% efficiency in the low-carbon energy transition in China. Accordingly, the study resulted that the role of green digital finance is clustering in the Chinese renewable energy industry, which impacts both the performance of the Chinese renewable energy industry and the economy. For more resilience, extended efficiency and viable energy transition study suggested the practical implications for the stakeholders to consider for practice. The novelty of the study is its motivation, findings, and solutions.

Lysine (K)-specific demethylase 5C regulates the incidence of severe preeclampsia by adjusting the expression of bone morphogenetic protein-7.

This study aimed to investigate the roles of the lysine (K)-specific demethylase 5C (KDM5C)-bone morphogenetic protein-7 (BMP-7) signaling pathway in the pathogenesis of severe preeclampsia (sPE). A total of 180 pregnant patients were enrolled in the study and classified into three groups: an early-onset sPE group (EOsPE) (n = 60), a late-onset sPE group (LOsPE) (n = 60), and a control group (normal pregnancy; n = 60). The messenger RNA (mRNA) and protein expression levels of bone morphogenetic protein receptor II (BMPRII), BMP-7, and KDM5C were detected in placenta samples from the two sPE groups, and their sites were evaluated using immunohistochemistry (IHC). The sPE groups showed an increased KDM5C mRNA expression, and the EOsPE group showed a decreased BMP-7 and BMPRII mRNA expression compared with the LOsPE group. However, contradictory results were discovered in terms of protein expression. Immunostaining of KDM5C, BMP-7, and BMPRII was observed in villous trophoblast and extravillous trophoblast cells. Compared with the control group, the staining intensity of KDM5C in the placental tissue trophoblast cell nucleus and vascular endothelial cells of the sPE groups was weaker, while that of BMP-7 and BMPRII was stronger, and the staining intensity was more subjective in the LOsPE group. Consistent findings were obtained by IHC and Western blot analysis. KDM5C nuclear-cytoplasmic translocation may regulate sPE through BMP-7 and its receptors. The KDM5C-BMP-7 signaling pathway may also lead to less invasion and increased apoptosis of the trophoblast cells, which is involved in the pathogenesis of sPE.

Neuron-derived neuropeptide Y fine-tunes the splenic immune responses.

The nervous and immune systems are closely entwined to maintain the immune balance in health and disease. Here, we showed that LPS can activate suprarenal and celiac ganglia (SrG-CG) neurons and upregulate NPY expression in rats. Single-cell sequencing analysis revealed that knockdown of the NPY gene in SrG-CG altered the proliferation and activation of splenic lymphocytes. In a neuron and splenocyte coculture system and in vivo experiments, neuronal NPY in SrG-CG attenuated the splenic immune response. Notably, we demonstrated that neuronal NPF in Drosophila exerted a conservative immunomodulatory effect. Moreover, numerous SNPs in NPY and its receptors were significantly associated with human autoimmune diseases, which was further supported by the autoimmune disease patients and mouse model experiments. Together, we demonstrated that NPY is an ancient language for nervous-immune system crosstalk and might be utilized to alleviate inflammatory storms during infection and to modulate immune balance in autoimmune diseases.

Intravital imaging strategy FlyVAB reveals the dependence of Drosophila enteroblast differentiation on the local physiology.

Aging or injury in Drosophila intestine promotes intestinal stem cell (ISC) proliferation and enteroblast (EB) differentiation. However, the manner the local physiology couples with dynamic EB differentiation assessed by traditional lineage tracing method is still vague. Therefore, we developed a 3D-printed platform "FlyVAB" for intravital imaging strategy that enables the visualization of the Drosophila posterior midgut at a single cell level across the ventral abdomen cuticle. Using ISCs in young and healthy midgut and enteroendocrine cells in age-associated hyperplastic midgut as reference coordinates, we traced ISC-EB-enterocyte lineages with Notch signaling reporter for multiple days. Our results reveal a "differentiation-poised" EB status correlated with slow ISC divisions and a "differentiation-activated" EB status correlated with ISC hyperplasia and rapid EB to enterocyte differentiation. Our FlyVAB imaging strategy opens the door to long-time intravital imaging of intestinal epithelium.

Identification of Key Genes and Long Noncoding RNA-Associated Competing Endogenous RNA (ceRNA) Networks in Early-Onset Preeclampsia.

BACKGROUND: Preeclampsia (PE) is a pregnancy-specific hypertension syndrome and is one of the leading causes of maternal and perinatal morbidity and mortality. Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in many diseases, including preeclampsia. The present study is aimed at identifying the key genes and lncRNA-associated competing endogenous RNA (ceRNA) networks in early-onset preeclampsia (EOPE). METHODS: We investigated expression profiles of differentially expressed lncRNAs (DElncRNAs) and genes (DEGs) in placental tissues of EOPE and healthy controls with Human LncRNA Array v4. The potential functions of DEGs and DElncRNAs were predicted using the clusterProfiler package. The lncRNA-mRNA coexpression network was constructed via Pearson's correlation coefficient. The protein-protein interaction (PPI) network of DEGs was constructed, and the hub genes were obtained using the STRING database and Cytoscape. The ceRNA networks were constructed based on miRWalk and LncBase v2. qRT-PCR was performed to confirm the expression of lncRNA MIR193BHG, PROX1-AS1, and GATA3-AS1. ROC curves were performed to assess the clinical value of lncRNA MIR193BHG, PROX1-AS1, and GATA3-AS1 in the diagnosis of EOPE. RESULTS: We found 6 hub genes (SPP1, CCR2, KIT, ENG, ACKR1, and FLT1) altered in placental tissues of EOPE and constructed a ceRNA network, including 21 lncRNAs, 3 mRNAs, and 69 miRNAs. The expression of lncRNA MIR193BHG and GATA3-AS1 were elevated and showed good clinical values for diagnosing EOPE. CONCLUSION: This study provides novel insights into the lncRNA-related ceRNA network in EOPE and identified two lncRNAs as potential prognostic biomarkers in EOPE.

HIF­1α affects trophoblastic apoptosis involved in the onset of preeclampsia by regulating FOXO3a under hypoxic conditions.

Preeclampsia (PE) is a pregnancy-specific syndrome that has severe implications on perinatal mortality and morbidity. Excessive apoptosis of trophoblasts induced by hypoxia may be associated with the development of PE, but the exact pathogenesis is unknown. Forkhead box O transcription factor 3a (FOXO3a) is activated under hypoxic conditions. Furthermore, hypoxia­inducible factor­1α (HIF­1α) is sensitive to variations in partial oxygen pressure. Thus, the aims of the present study were to investigate the expression levels of HIF­1α and FOXO3a in placental samples of early onset severe PE, and their effect on trophoblastic apoptosis under hypoxic conditions. Cobalt chloride was used to establish the hypoxic model. The present study examined the expression levels of HIF­1α and FOXO3a in the placental tissues and HTR8/SVneo cells under hypoxic conditions. It was found that HIF­1α and FOXO3a were highly expressed in placental tissues of patients with PE and in HTR8/SVneo cells under hypoxic conditions. Furthermore, knockdown of FOXO3a using a specific small interfering RNA (siRNA) decreased apoptosis in HTR8/SVneo cells. Moreover, it was found that after knockdown of HIF­1α using siRNA, FOXO3a expression and the apoptotic rate were reduced in HTR8/SVneo cells. Therefore, the present results indicated that the elevated expression of HIF­1α increased trophoblastic apoptosis by regulating FOXO3a, which may be involved in the pathogenesis of PE.

Resveratrol induces SIRT1-Dependent autophagy to prevent H2O2-Induced oxidative stress and apoptosis in HTR8/SVneo cells.

INTRODUCTION: Pre-eclampsia (PE) is a serious complication of pregnancy, and the likely pathogenic basis of early onset PE are placental dysfunction and increased oxidative stress. Resveratrol (RES) is a potent antioxidant which has shown beneficial effects in many diseases. The aim of this study was to investigate the protective effects of RES against oxidative stress-induced damage in trophoblasts, and elucidate the potential mechanisms. METHODS: We established an in vitro model of oxidative stress by exposing the human first-trimester extravillous trophoblast cell line HTR8/SVneo to H2O2. The level of oxidative stress was reflected by ROS, MDA and SOD. The viability of cells was determined by the MTS assay. Apoptosis was detected using Annexin V-FITC staining and flow cytometry. Levels of SIRT1(sirtuin 1) and autophagy-related proteins (LC3, Beclin-1, p62) were detected by western blot. Autophagosomes were observed by transmission electron microscopy (TEM). RESULTS: Pre-treatment with RES significantly ameliorated H2O2-induced cytotoxicity, morphological damage, oxidative stress and apoptosis. Mechanistically, RES restored the levels of SIRT1 and autophagy-related proteins including LC3-II, Beclin-1 and p62 that were dysregulated by H2O2. Blocking autophagy by 3-methyladenine (3-MA) completely abolished the protective effects of RES, as did knocking down SIRT1. CONCLUSION: RES may protect human trophoblasts against H2O2-induced oxidative stress by activating SIRT1-dependent autophagy, and therefore has therapeutic potential in PE.

Clinical features of vitamin D deficiency in children: A retrospective analysis.

Vitamin D is very important for children's health. Previous studies have shown that vitamin D deficiency leads to a series of diseases in adults. However, pediatricians are mostly aware of rickets caused by vitamin D deficiency in children and poorly aware of other symptoms. This study aimed to retrospectively analyze the different clinical features of vitamin D deficiency to enhance identification by pediatricians, thus minimizing misdiagnosis. In this study, we retrospectively analyzed the clinical features of vitamin D deficiency in 268 children aged 0-14 years from June 2016 to May 2018 in the Third Affiliated Hospital of Zhengzhou University. Serum 25-hydroxy vitamin D [25(OH)D] levels were determined using the chemiluminescence method. Of the 268 cases, 101 cases showed movement disorder (37.7%) and 167 nervous system abnormalities (62.3%). Among all cases, 6 were misdiagnosed as febrile seizures (2.23%), 5 as epilepsy (1.86%), 2 as Tourette syndrome (0.74%), and 2 as developmental retardation (0.74%). There were significant differences in patients with clinical characteristics of movement disorder and nervous system abnormalities partly between Pre-and post-vitamin D treatment. This analysis revealed that vitamin D deficiency occurs not only in children but also in adolescents, with diverse clinical features. Therefore, pediatricians should pay more attention to clinical different signs and symptoms, and future studies should be conducted to confirm the mechanisms of these processes.

Interactions among insulin resistance, inflammation factors, obesity-related gene polymorphisms, environmental risk factors, and diet in the development of gestational diabetes mellitus.

PURPOSE: The aim of this study was to investigate the correlations and interactions between the polymorphisms of insulin resistance-related genes (ADIPOQ rs2241766), inflammation factors (TNF-α rs1800629, IL-6 rs1800795), obesity-related genes (GNB3 rs5443, ADRB rs1042714), and risk factors for gestational diabetes mellitus (GDM) such as diet structure in the development of GDM. MATERIALS AND METHODS: This research was conducted among women who visited the third-affiliate hospital of Zhengzhou University for pregnancy checkups from 1 June 2014 to 30 December 2014. Based on the results of a 75-g glucose tolerance test (OGTT), 140 pregnant women with GDM were randomly selected as a part of the GDM group and140 healthy, pregnant women as part of the control group. Relevant clinical and laboratory data for the child and the mother including her pregnancy outcomes and the delivery mode were collected for the epidemiological survey. RESULTS: The results showed that risk factors for GDM are advanced age, the hepatitis B virus, family history of diabetes, high body mass index before pregnancy, and weight gain of ≥10 kg before 24-week gestation. We found that diet structures were severely unbalanced. The polymorphisms rs2241766 and rs5443 were found to potentially be associated with GDM; moreover, a positive interaction was demonstrated between rs2241766 and age, and a negative interaction was demonstrated with weight gain of ≥10 kg before 24-week gestation. CONCLUSION: Our findings demonstrate that both environmental risk factors and genetic background contribute to the development of GDM.

Increased TLR4 and TREM-1 expression on monocytes and neutrophils in preterm birth: further evidence of a proinflammatory state.

Objective: Increased inflammation is considered as a risk factor and a promoter of preterm birth (PTB). Monocytes and neutrophils are the main sources of cytokines in the early inflammatory phase. So far, very few studies have indicated CD14/TLR4 and TREM-1 on the monocytes and neutrophils as important targets in PTB. Materials and methods: TLR4 and TREM-1 on CD14+ maternal and cord blood monocytes and neutrophils were detected using flow cytometry in 48 normal term women, 48 PTB with chorioamnionitis (CCA) women, and 40 PTB without CCA women. In the fetal membranes, mRNA and protein levels of the CD14/TLR4-TREM-1 signaling pathway, CD14, TLR4, NF-κBp65, and TREM-1 were analyzed by qRT-PCR and western blot. ELISA was further used to detect TLR4 and TREM-1 levels in maternal and cord serums. Results: Compared with the normal term and PTB without CCA women, we found that (1) TLR4 and TREM-1 levels on CD14+ maternal and cord blood monocytes and neutrophils in the PTB with CCA group were elevated (p < .001); (2) the protein and mRNA expressions of CA14, TLR4, NF-κBp65, and TREM-1 of the PTB with CCA group were upregulated (p < .001); (3) Maternal and cord serum concentrations of TLR4 and TREM-1 in the PTB with CCA group were greater (p < .001). Conclusions: The high levels of TLR4 and TREM-1 surface expression were observed on CD14+ maternal and cord blood monocyte and neutrophils, confirming their proinflammatory profiles in PTB with CCA. TLR4 and TREM-1 on monocyte and neutrophils might have a role in infection-related PTB.

Long noncoding RNA DQ786243 interacts with miR-506 and promotes progression of ovarian cancer through targeting cAMP responsive element binding protein 1.

Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in several cancers and associated with the proliferation of cancer cells. The objective of this study was to investigate the role and the underlying mechanisms of DQ786243 in ovarian cancer. In the current study, DQ786243 was specifically upregulated in ovarian cancer tissues and cell lines. Knockdown of DQ786243 inhibited the ability of cell migration, invasion, proliferation, colony formation and wound healing, whereas promoted cell apoptosis and induced G0/G1 cell cycle arresting. By using online tools and mechanistic analysis, we demonstrated that DQ786243 could directly bind to microRNA-506 (miR-506) and downregulate its expression. Moreover, DQ786243 reversed the inhibitory effect of miR-506 on the growth of ovarian cancer cells, which might be involved in the derepression of cAMP responsive element binding protein 1 (CREB1) expression. Further investigation into the mechanisms showed that knockdown of DQ786243 inhibited the epithelial to mesenchymal transition (EMT) process in ovarian cancer cells. Finally, xenograft experiments further confirmed that knockdown of DQ786243 notably suppressed the proliferation and EMT process in vivo. Taken together, our study showed for the first time that DQ786243 interacted with miR-506 and promoted progression of ovarian cancer via targeting CREB1 in ovarian cancer. The results might help to probe the feasibility of lncRNA-directed therapy for this deadly disease.

[Effects of Environmental Factors on the Synergy of Functional Bacteria in Completely Autotrophic Granular Sludge].

To obtain experimental evidences for optimizing a completely autotrophic nitrogen removal process based on granules, the effects of dissolved oxygen (DO) concentration, temperature (t), initial ammonium (NH4+-N) concentration, and solution pH conditions on the synergy between the aerobic and anaerobic ammonium-oxidizing bacteria (AOB and AMX) were investigated using a single factor batch experiment, while the analysis of the microbial community structure within them was conducted using MiSeq high-throughput pyrosequencing. Results revealed that AOB (genus Nitrosomonas) and AMX (genus Candidatus Kuenenia) dominated in the granules, representing relative abundances of 32.9% and 9.8%, respectively. For the granules, the highest specific nitrogen removal rate of q(TN)=(17.7±1.0) mg·(g·h)-1 was obtained at a DO concentration of 2 mg·L-1, while the initial NH4+-N concentration was set at 100 mg·L-1. And a lower DO level resulted in partial nitritation became the rate-limiting step of process, otherwise, it would be the ANAMMOX reaction instead. According to the free energy of the reactions, the activity of AMX was more sensitive to low temperature than that of AOB. When the reaction temperature was lower than 30℃, nitrite accumulation could be observed in bulk liquid, with the significant decrease of q(TN) for the granules. Under the same oxygen supply conditions, an initial NH4+-N concentration lower than 100 mg·L-1 could inhibit the activity of AMX partly. However, with an initial NH4+-N concentration over 150 mg·L-1, either oxygen-limiting or high free ammonia concentration could lead to the dramatic decrease of q(TN). In addition, the effective synergy of the two types of ammonium oxidizers in granules was always achieved at solution pH in the range of 7.0-8.5.

Structure-Guided Combinatorial Engineering Facilitates Affinity and Specificity Optimization of Anti-CD81 Antibodies.

Hepatitis C viral infection is the major cause of chronic hepatitis that affects as many as 71 million people worldwide. Rather than target the rapidly shifting viruses and their numerous serotypes, four independent antibodies were made to target the host antigen CD81 and were shown to block hepatitis C viral entry. The single-chain variable fragment of each antibody was crystallized in complex with the CD81 large extracellular loop in order to guide affinity maturation of two distinct antibodies by phage display. Affinity maturation of antibodies using phage display has proven to be critical to therapeutic antibody development and typically involves modification of the paratope for increased affinity, improved specificity, enhanced stability or a combination of these traits. One antibody was engineered for increased affinity for human CD81 large extracellular loop that equated to increased efficacy, while the second antibody was engineered for cross-reactivity with cynomolgus CD81 to facilitate animal model testing. The use of structures to guide affinity maturation library design demonstrates the utility of combining structural analysis with phage display technologies.

Mutational spectrum of the phenylalanine hydroxylase gene in patients with phenylketonuria in the central region of China.

Phenylketonuria (PKU, OMIM 261600) caused by phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disease that is characterized by abnormalities of phenylalanine metabolism. In this study, a total of 77 patients, originating from the central region of China and who were diagnosed with PAH deficiency at the third affiliated hospital of Zhengzhou University, were enrolled in this study. The 13 exons and 12 flanking introns of the PAH gene were analyzed by Sanger sequencing and next generation sequencing. The sequencing data were aligned to the hg19, PAHvdb and HGMD databases to characterize the genotypes of PKU patients, and genotype-phenotype correlations and BH4 responsiveness predictions were performed using BIOPKUdb. In total, 149 alleles were characterized among the 154 PKU alleles. These mutations were located in exons 2-13, and intron 12 of the PAH gene, with a relative frequency of ≥5%, for EX6-96A>G, p.R241C, p.R243Q, p.V399V and p.R53H. Additionally, a novel variant, p.D84G, was identified. The genotype correlated with clinical symptoms in 33.3-100% of the cases, depending on the disease severity, and BH4 responsiveness predictions show that only five patients with MHP-PKU and one patient with Mild-PKU were predicted to be BH4 responsive. In conclusion, we have characterized the mutational spectrum of PAH in the central region of China and have identified a novel mutation. The hotspot mutation information might be useful for screening, diagnosis and treatment of PKU.

Differentiation in Nitrogen-Converting Activity and Microbial Community Structure between Granular Size Fractions in a Continuous Autotrophic Nitrogen Removal Reactor.

The differentiations in nitrogen-converting activity and microbial community structure between granular size fractions in a continuous completely autotrophic nitrogen removal over nitrite (CANON) reactor, having a superior specific nitrogen removal rate of 0.24 g/(g VSS·d), were investigated by batch tests and high-throughput pyrosequencing analysis, respectively. Results revealed that a high dissolved oxygen concentration (>1.8 mg/l) could result in efficient nitrite accumulation with small granules (0.2-0.6 mm in diameter), because aerobic ammonium-oxidizing bacteria (genus Nitrosomonas) predominated therein. Meanwhile, intermediate size granules (1.4-2.0 mm in diameter) showed the highest nitrogen removal activity of 40.4 mg/(g VSS·h) under sufficient oxygen supply, corresponding to the relative abundance ratio of aerobic to anaerobic ammonium-oxidizing bacteria (genus Candidatus Kuenenia) of 5.7. Additionally, a dual substrate competition for oxygen and nitrite would be considered as the main mechanism for repression of nitrite-oxidizing bacteria, and the few Nitrospira spp. did not remarkably affect the overall performance of the reactor. Because all the granular size fractions could accomplish the CANON process independently under oxygen limiting conditions, maintaining a diversity of granular size would facilitate the stability of the suspended growth CANON system.

[Start-up of a High Performance Nitrosation Reactor Through Continuous Growth of Aerobic Granular Sludge].

In order to examine the continuous growth capacity of the nitrosation granular sludge (NGS), the sludge was inoculated to start up the columnar sequencing batch reactor (SBR). During 130 d, the concentration of mixed liquor suspended solids (MLSS) in SBR increased from 0.1 g·L-1 to 11.8 g·L-1, corresponding to the nitrite-nitrogen accumulation rate of 0.4-4.9 kg·(m3·d)-1, promoted by a higher ammonia-nitrogen loading rate (NLR) from 0.74 kg·(m3·d)-1 to 6.66 kg·(m3·d)-1in the influent. Because of the obvious increase in small granules (size<200 µm), the mean average diameter of NGS decreased significantly at NLR<4.44 kg·(m3·d)-1. At higher NLR values, the growth of the mean average diameter of NGS could be fitted well using a modified logistic model. The specific growth rate of the k value was 0.0229 d-1. In addition, the combined inhibition of nitrite oxidizing bacteria (NOB) was expected at relatively high concentrations of both free ammonia (FA) and free nitrite acid (FNA); thus, the nitrite accumulation ratio (NAR) in the effluent was always higher than 80%. These results provide a feasible approach to start up a high-performance NGS reactor at the industrial-scale.

HMGB1-RAGE signaling pathway in severe preeclampsia.

INTRODUCTION: Placental dysfunction and increased inflammation are believed to underlie the pathogenesis of severe preeclampsia (PE). High-mobility group box 1 (HMGB1), a recently identified inflammatory cytokine, has been known to contribute to the development of inflammatory responses in PE. This study intends to elucidate the mechanisms of HMGB1-RAGE signaling pathway in the pathogenesis of PE. METHODS: The mRNA levels of relative gene of HMGB1 pathway, HMGB1, RAGE and NF-κB p65, were analyzed by real-time PCR in placentas collected from 61 normotensive pregnant women and 64 women with severe PE. Additionally, levels of HMGB1 and RAGE protein were detected in frozen placental specimens by western blot, and the locations of them were evaluated in the well-characterized tissue microarray by immunohistochemistry. ELISA was further used to detect HMGB1 level in maternal serum. RESULTS: Compared with matched control placentas, the mRNA levels of HMGB1, RAGE and NF-κB p65 were increased in severe preeclamptic placentas. In severe preeclamptic placentas, HMGB1 and RAGE immunoreactivity were increased in the cytoplasm of trophoblast cells. Western blot was employed to further confirm that RAGE protein level was elevated significantly in severe PE group. In addition, there was an increased level of HMGB1 in the maternal serum of severe PE group. DISCUSSION: HMGB1 nuclear-cytoplasmic translocation may induce the binding of HMGB1 to its receptors, consequently, intrigue NF-κB activity in severe PE. HMGB1-RAGE signaling pathway may be involved in the pathogenesis of PE.

Decreased expression and activation of Stat3 in severe preeclampsia.

Severe preeclampsia (PE) is a major cause of maternal mortality and morbidity worldwide. Signal transducer and activator of transcription 3 (Stat3) signal pathway can modulate various fundamental cellular processes. However, whether Stat3 plays a role in the pathogenesis of severe PE is unknown. Therefore, in this study, the expression levels of Stat3 pathway-related genes and proteins, Stat3, pStat3, IL-6, Mcl-1L, Bcl-xL, survivin, MMP-2, and MMP-9, were evaluated by immunohistochemistry (IHC), Western blot analysis and real-time PCR in the severe preeclamptic placentas. Our results showed that Stat3 and pStat3 immunoreactivity were localized in both extravillous cytotrophoblast cells and villous trophoblast cells in the placentas. As compared with normotensive pregnancies, significantly decreased expressions of Stat3 and pStat3 proteins were observed in extravillous cytotrophoblast cells, villous trophoblast cells and entire placentas in patients with severe PE. The expression levels of Stat3, IL-6, survivin and MMP-2 mRNA were significantly decreased in severe preeclamptic placentas, while Mcl-1L, Bcl-xL and MMP-9 mRNA levels were unchanged. IHC results further confirmed that there was a significant decrease of IL-6, survivin and MMP-2 proteins expression in the severe preeclamptic placentas compared with the normal specimens. These findings suggested that decreased expression and activation of the Stat3 may be caused by decreased expression of a Stat3 upstream gene, such as IL-6. Decreased Stat3 expression and activation may play an important role in the pathogenesis of PE through regulation of the transcription of the Stat3 targeted genes survivin and MMP-2 to modulate apoptosis and invasion of placental trophoblastic cells.