The discrepancy distribution of macrophage subsets in preeclampsia placenta with or without fetal growth restriction from a small cohort.

OBJECTIVES: To identify the effect of distribution characteristic of macrophages on placental function and angiogenesis in pregnancies with preeclampsia (PE) in presence of fetal growth restriction (FGR) or preeclampsia without FGR. MATERIAL AND METHODS: The study tested the hypothesis that there was association between distribution characteristic of macrophage subsets (marked by CD68, CD163, respectively) and placental capillary development, leading to placental dysfunction in PE pregnancies with FGR (n = 36). Changes in placental parameters related with efficiency and angiogenesis and macrophage phenotypes (CD68 and CD163) were evaluated by immunohistochemistry. Pearson correlation analysis was performed to analysis the association between macrophage phenotype and placental function as well the CD34 staining, respectively. Additionally, the localization of CD68 and CD163 was assessed by using immunoflurorescence staining. RESULTS: Pearson correlation analysis had shown the positive association between CD68 expression and microvessel formation and the reverse linear relationship between CD163 staining and placental sufficiency in PE + FGR placenta. The co-localization of CD163 and CD34 may pointed to the compensatory role of CD163 distribution involved in prompting neovascularization. CONCLUSIONS: The association between disturbed distribution of macrophages and placental efficiency and angiogenesis were only found in PE with FGR not in PE pregnancies without FGR, underlying the discrepancy role of macrophage subsets depending on the clinical phenotype of PE pregnancies.

The correlation between serum total bile acid and alanine aminotransferase of pregnant women and the disorders of neonatal hyperbilirubinemia-related amino acid metabolism.

BACKGROUND: To explore the association between liver metabolism-related indicators in maternal serum and neonatal hyperbilirubinemia (NHB), and further investigate the predictive value of these indicators in NHB-related amino acid metabolism disorders. METHODS: 51 NHB and 182 No-NHB newborns and their mothers who treated in the Fourth Hospital of Shijiazhuang from 2018 to 2022 were participated in the study. The differences in clinical data were compared by the Mann-Whitney U test and Chi-square test. Multivariate logistic regression was used to analyze the relationship between maternal serum indicators and the occurrence of NHB. The correlation analysis and risk factor assessment of maternal serum indicators with NHB-related amino acid metabolic disorders were performed using Spearman correlation analysis and multivariate logistic regression. RESULTS: Compared to the non NHB group, the NHB group had higher maternal serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, and total bile acid (TBA), while lower levels of serum albumin (ALB), total cholesterol (TC) and high-density lipoprotein (HDL). The levels of alanine (ALA), valine (VAL), ornithine (ORN), and proline (PRO) in the newborns were reduced in NHB group, while arginine (ARG) showed a tendency to be elevated. Multiple logistic regression analysis showed that maternal ALT, AST, ALT/AST, and TBA levels were all at higher risk with the development of NHB, whereas ALB, TC, and HDL levels were negatively associated with NHB development. Increasing maternal TBA level was associated with lower ALA (r=-0.167, p = 0.011), VAL (r=-0.214, p = 0.001), ORN (r=-0.196, p = 0.003), and PRO in the newborns (r=-0.131, p = 0.045). Maternal ALT level was negatively associated with ALA (r=-0.135, p = 0.039), VAL (r=-0.177, p = 0.007), ORN (r=-0.257, p < 0.001), while ALT/AST was positively correlated with ARG (r = 0.133, p = 0.013). After adjustment for confounding factors, maternal serum TBA and ALT were the independent risk factor for neonatal ORN metabolic disorders [(adjusted odds ratio (AOR) = 0.379, 95%CI = 0.188-0.762, p = 0.006), (AOR = 0.441, 95%CI = 0.211-0.922, p = 0.030)]. Maternal ALT level was an independent risk factor for neonatal VAL metabolic disorders (AOR = 0.454, 95%CI = 0.218-0.949, p = 0.036). CONCLUSIONS: The levels of high TBA, ALT, AST, and low HDL, TC of maternal were associated with the risk of NHB. Maternal TBA and ALT levels were independent risk factors for NHB-related amino acid disturbances which have value as predictive makers.

The association between maternal iron, zinc, copper levels in serum and pregnancy outcomes.

AIMS: To investigate the associations of serum trace elements (iron, zinc, and copper) between women with different pregnancy outcomes. METHODS: About 774 pregnant women who came to The Fourth Hospital of Shijiazhuang for prenatal examination were investigated. The concentrations of trace elements in the serum of pregnant women in the third trimester were collected. Multivariate logistic regression was used to analyze the relationship between serum trace element levels and the different pregnancy outcomes. Multiple linear regression was used to analyze the relationship between serum trace elements levels and hypersensitive-C-reactive-protein. RESULTS: Results of the multiple logistic regression showed that zinc, copper and copper/zinc ratio were found to be associated with the risk of gestational diabetes mellitus, and zinc was a protective factor (p = 0.002) while copper and copper/zinc ratio as risk factors (p = 0.030 and p = 0.001, respectively) after adjusting for major confounders. It was found that iron and zinc were negatively associated with the risk of moderate or severe anemia (p = 0.022 and p = 0.001, respectively). In contrast, the copper/zinc ratio was positively related to the risk of moderate or severe anemia (p = 0.021). The adjusted relationships between copper and copper/zinc ratio with premature rupture of membranes were statistically significant (p = 0.007 and p = 0.037). Iron and zinc were negatively associated with the risk of chorioamnionitis, while copper and copper/zinc ratio were positively associated with the risk of chorioamnionitis (all p < 0.05). CONCLUSIONS: Serum iron, zinc and copper levels are closely related to pregnancy outcomes.

Correlation between high serum ferritin levels and adverse pregnancy outcomes in women with gestational diabetes mellitus.

Aims: To explore the association between higher serum ferritin (SF) levels in mid-pregnancy and adverse pregnancy outcomes in gestational diabetes mellitus (GDM) pregnancies, then develop a predictive cut-off value that might effectively predict the risk of adverse pregnancy outcomes in future clinical. Methods: The study involved 201 pregnant women with GDM. 201 gestational age and parity matched normoglycemic pregnant women were taken as control group. The differences in clinical data were compared by the Mann-Whitney U test and Chi-square tests. Multivariate logistic regression was used to determine the relationship between SF and GDM-relate adverse pregnancy outcomes. The predicted value of SF level was determined through receiver operating characteristic (ROC) curve analysis. Results: SF level was significantly higher in women with GDM [16.10 (27.30-9.50) (ng/mL) vs. 12.04 (18.11-7.06) (ng/mL), (p < 0.001)]. Meanwhile, higher levels of SF were also discovered in GDM women with preeclampsia and neonatal hypoglycemia and respiratory distress (all p < 0.05). In the adjusted model, a positive association was shown between SF and preeclampsia [adjusted odds ratio (AOR) = 1.032, 95%CI = 1.004-1.060, p = 0.024], neonatal hypoglycemia [adjusted odds ratio (AOR) = 1.047, 95%CI = 1.022-1.072, p < 0.001] and respiratory distress outcomes (AOR = 1.034, 95%CI = 1.011-1.058, p = 0.004) respectively. The area under ROC curve (AUC) for prediction of preeclampsia by SF combined with serum calcium, age, pre-pregnancy BMI and gestational weight gain (GWG) was 0.658 (95% CI = 50.8-80.8%, p = 0.028) with the cut-off value of 24.45 ng/mL, and the sensitivity and specificity were 58.8.0% and 64.3%, respectively. To predict neonatal hypoglycemia, the clinical point value of SF was 27.43 ng/mL with AUC was 0.800, sensitivity and specificity was 90.5% and 68.0% respectively. Predicting neonatal respiratory distress, the AUC value of the SF level was 0.730, with a cut-off value of 27.37 ng/mL and the sensitivity and specificity were 52.0% and 86.5%, respectively. Conclusions: Higher level of SF in mid-pregnancy was significantly associated with the risk of GDM and GDM-relate adverse pregnancy outcomes. Moreover, SF levels have moderate clinical value in predicting the adverse outcomes of maternal preeclampsia, neonatal hypoglycemia and respiratory distress.

The association between vitamin D levels in the second trimester of pregnancy and gestational diabetes mellitus.

BACKGROUND AND AIMS: 25-hydroxyvitamin D (25(OH)D) affects glucose metabolism by increasing insulin secretion and insulin receptor expression. However, whether 25(OH)D deficiency will increase the risk of gestational diabetes mellitus (GDM) has not been clearly reported. The purpose of this study is to assess the relationship between vitamin D levels in the second trimester of pregnancy and the risk of GDM. METHODS: According to the inclusion and exclusion criteria, 247 pregnant women came to the fourth hospital of Shijiazhuang (The affiliated obstetrics and gynecology hospital of Hebei Medical University) for obstetrics were investigated during the period of January 1, 2019 to December 31, 2020. The levels of 25(OH)D in the second trimester (16-20 weeks) and oral 75 g glucose tolerance test (OGTT) at 24-28 weeks of pregnancy were reviewed. The sociodemographic data were collected from questionnaire. Multivariate logistic regression was used to analyze the relationship between vitamin D levels and GDM. RESULTS: The incidence of GDM in the observation group (25(OH)D ≤ 26 ng/ml) was higher than that in the control group (25(OH)D > 26 ng/ml) (p = 0.039). Compared with control group, the observation group had significantly higher level of fasting plasma glucose (FPG) (4.7 [4.5-5.0] mmol/L vs. 4.6 [4.4-4.8] mmol/L, p = 0.012). In the whole study, the level of 25(OH)D was negatively correlated with FPG (r = - 0.164，p = 0.010). After adjusting for age, pre-pregnancy BMI, parity and adverse pregnancy history, compared with the observation group (25 (OH) D ≤ 26 ng/ml), the risk of developing GDM decreased by 50.9% in control group (25(OH)D > 26 ng/ml) (odds ratio [OR] = 0.491, 95% confidence interval [CI] = 0.243-0.989, p = 0.047). CONCLUSION: Adequate vitamin D levels during the second trimester of pregnancy may reduce the risk of GDM.

Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms.

Inflammation has recently emerged as an important contributor for cardiovascular disease development and participates pivotally in the development of neointimal hyperplasia and abdominal aortic aneurysms (AAA) formation. Kv7.4/KCNQ4, a K+ channel, is one of the important regulators of vascular function but its role in vascular inflammation is unexplored. Here, we showed that the expression of Kv7.4 channel was elevated in the neointima and AAA tissues from mice and humans. Genetic deletion or pharmacological inhibition of Kv7.4 channel in mice alleviated neointimal hyperplasia and AAA formation via downregulation of a set of vascular inflammation-related genes, matrix metalloproteinases (MMP) 2/9, and intercellular adhesion molecule (ICAM-1). Furthermore, genetic deletion or inhibition of Kv7.4 channel suppressed the activation of tumor necrosis factor receptor 1 (TNFR1)-nuclear factor (NF)-κB signaling pathway via blockade of interaction between TNFR1 and TNFR1-associated death domain protein (TRADD) in vascular smooth muscle cells (VSMCs). Knockdown of Kv7.4 in vivo identified VSMC-expressed Kv7.4 as a major factor in vascular inflammation. Collectively, our findings suggest that Kv7.4 channel aggravates vascular inflammatory response, which promotes the neointimal hyperplasia and AAA formation. Inhibition of Kv7.4 channel may be a novel therapeutic strategy for vascular inflammatory diseases.

Transcriptional Regulation of Voltage-Gated Sodium Channels Contributes to GM-CSF-Induced Pain.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the production of granulocyte and macrophage populations from the hematopoietic progenitor cells; it is one of the most common growth factors in the blood. GM-CSF is also involved in bone cancer pain development by regulating tumor-nerve interactions, remodeling of peripheral nerves, and sensitization of damage-sensing (nociceptive) nerves. However, the precise mechanism for GM-CSF-dependent pain is unclear. In this study, we found that GM-CSF is highly expressed in human malignant osteosarcoma. Female Sprague Dawley rats implanted with bone cancer cells develop mechanical and thermal hyperalgesia, but antagonizing GM-CSF in these animals significantly reduced such hypersensitivity. The voltage-gated Na+ channels Nav1.7, Nav1.8, and Nav1.9 were found to be selectively upregulated in rat DRG neurons treated with GM-CSF, which resulted in enhanced excitability. GM-CSF activated the Janus kinase 2 (Jak2)-signal transducer and activator of transcription protein 3 (Stat3) signaling pathway, which promoted the transcription of Nav1.7-1.9 in DRG neurons. Accordingly, targeted knocking down of either Nav1.7-1.9 or Jak2/Stat3 in DRG neurons in vivo alleviated the hyperalgesia in male Sprague Dawley rats. Our findings describe a novel bone cancer pain mechanism and provide a new insight into the physiological and pathological functions of GM-CSF.SIGNIFICANCE STATEMENT It has been reported that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a key role in bone cancer pain, yet the underlying mechanisms involved in the GM-CSF-mediated signaling pathway in nociceptors is not fully understood. Here, we showed that GM-CSF promotes bone cancer-associated pain by enhancing the excitability of DRG neurons via the Janus kinase 2 (Jak2)-signal transducer and activator of transcription protein 3 (Stat3)-mediated upregulation of expression of nociceptor-specific voltage-gated sodium channels. Our study provides a detailed understanding of the roles that sodium channels and the Jak2/Stat3 pathway play in the GM-CSF-mediated bone cancer pain; our data also highlight the therapeutic potential of targeting GM-CSF.

Suppression of KCNQ/M Potassium Channel in Dorsal Root Ganglia Neurons Contributes to the Development of Osteoarthritic Pain.

Osteoarthritic pain has a strong impact on patients' quality of life. Understanding the pathogenic mechanisms underlying osteoarthritic pain will likely lead to the development of more effective treatments. In the present study of osteoarthritic model rats, we observed a reduction of M-current density and a remarkable decrease in the levels of KCNQ2 and KCNQ3 proteins and mRNAs in dorsal root ganglia (DRG) neurons, which were associated with hyperalgesic behaviors. The activation of KCNQ/M channels with flupirtine significantly increased the mechanical threshold and prolonged the withdrawal latency of osteoarthritic model rats at 3-14 days after model induction, and all effects of flupirtine were blocked by KCNQ/M-channel antagonist, XE-991. Together, these results indicate that suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of osteoarthritic pain.