Mitigation of gestational diabetes-induced endothelial dysfunction through FGF21-NRF2 pathway activation involving L-Cystine.

Gestational diabetes mellitus (GDM) disrupts glucolipid metabolism, endangering maternal and fetal health. Despite limited research on its pathogenesis and treatments, we conducted a study using serum samples from GDM-diagnosed pregnant women. We performed metabolic sequencing to identify key small molecule metabolites and explored their molecular interactions with FGF21. We also investigated FGF21's impact on GDM using blood samples from affected women. Our analysis revealed a novel finding: elevated levels of L-Cystine in GDM patients. Furthermore, we observed a positive correlation between L-Cystine and FGF21 levels, and found that L-Cystine induces NRF2 expression via FGF21 for a period of 96 h. Under high glucose (HG) conditions, FGF21 upregulates NRF2 and downstream genes NQO1 and EPHX1 via AKT phosphorylation induced by activation of IRS1, enhancing endothelial function. Additionally, we confirmed that levels of FGF21, L-Cystine, and endothelial function at the third trimester were effectively enhanced through appropriate exercise and diet during pregnancy in GDM patients (GDM + ED). These findings suggest FGF21 as a potential therapeutic agent for GDM, particularly in protecting endothelial cells. Moreover, elevated L-Cystine via appropriate exercise and diet might be a potential strategy to enhance FGF21's efficacy.

OLFML3 suppresses trophoblast apoptosis via the PI3K/AKT pathway: A possible therapeutic target in preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a pregnancy complication that encompasses various pathogenic mechanisms. Shallow implantation of the placenta due to abnormal trophoblast behavior is considered an important mechanism underlying PE; however, its exact etiology remains unclear. METHODS: The expression of OLFML3 in the placenta and important clinical indicators were performed, followed by a correlation analysis. The effect of OLFML3 on the behavior of HTR-8/SVneo cells was examined, and the downstream molecular mechanisms of OLFML3 were investigated in HTR-8/SVneo cells. Additionally, a rat model of PE was generated by adenovirus injection via the tail vein to verify the role of OLFML3. RESULTS: OLFML3 is highly expressed in both syncytiotrophoblasts and cytotrophoblasts and deregulated in preeclamptic placentas. OLFML3 overexpression in HTR-8/SVneo cells promoted cell proliferation, migration, invasion, and impeded apoptosis, and triggered phosphorylation on ser473 of AKT. Conversely, OLFML3 knockdown exerted opposite effects. Furthermore, OLFML3 overexpression ameliorates CoCl2-induced apoptosis of HTR-8/SVneo cells. In a rat model, OLFML3 overexpression alleviates PE-associated maternal symptoms, leading to lower blood pressure, less severe proteinuria, improved fetal growth restriction, as well as upregulation of P-AKT and downregulation of Cleaved caspase3 and Bax. DISCUSSION: OLFML3 may alleviate PE development by inhibiting extravillous trophoblast cell apoptosis through the PI3K/AKT pathway. Our findings indicated that OLFML3 may provide a possible therapeutic target for PE.

Comparison of Chromosomal Microarray Analysis and Noninvasive Prenatal Testing in Pregnant Women with Fetal Ultrasonic Soft Markers.

Objective: This study aimed to assess the utility of chromosomal microarray analysis (CMA) and noninvasive prenatal testing (NIPT) in detecting clinically significant chromosomal abnormalities among fetuses presenting ultrasonic soft markers (USMs). Methods: A retrospective observational study, spanning from January 1, 2019, to September 30, 2022, enrolled 539 singleton pregnant women with fetal USMs at our center. Of these, 418 cases (77.6%) underwent NIPT, while 121 cases (22.4%) opted for invasive prenatal diagnosis post-appropriate genetic counseling. Cases with high-risk NIPT results proceeded to invasive prenatal diagnosis, where conventional karyotyping and CMA were concurrently performed. Further stratification was done based on the number of USMs, classifying cases into single-USM and multiple-USM groups. Results: Of the 24 cases (4.5%) exhibiting abnormal findings, 17 presented numerical chromosomal abnormalities, 2 featured clinically significant copy number variations (CNVs), 3 showed variants of unknown significance (VOUS), 1 displayed LOH, and 1 exhibited chromosome nine inversion. Notably, 18 cases (75%) theoretically detectable by karyotyping (eg, sizes above 10Mb) and 16 cases (66.7%) detectable by NIPT for five common aneuploidies were identified. Six submicroscopic findings (25%) were exclusively detectable by CMA. The predominant clinically relevant aberrations were observed in the thickened nuchal-translucency (TNT) group (9/35, 25.7%), followed by the multiple soft markers group (3/32, 9.3%). In the NIPT group, the false positive rate was 1.22%, and the false negative rate was 0%. Conclusion: The prevalence of chromosome aneuploidy exceeded that of submicroscopic chromosomal imbalance in pregnant women with fetal USMs. NIPT demonstrated efficacy, particularly for soft markers like echogenic intracardiac focus. However, for those with TNT and multiple soft markers, invasive prenatal diagnosis, including CMA testing, is recommended as the primary investigative approach.

Clinical Biochemical Indicators and Intestinal Microbiota Testing Reveal the Influence of Reproductive Age Extending from the Mother to the Offspring.

Age is an important factor that determines the physiological functions of the human body, but the changes in maternal physiology, biochemistry, and intestinal flora related to reproductive age and their impact on offspring are not clear. Here, we tested and analyzed the clinical physiological and biochemical indicators and/or intestinal flora, matching the data of 252 parturients and their newborns. We found that 4 clinical indicators, including the white blood cell count and the absolute value of monocytes, were significantly related to the reproductive age (P < 0.05). The composition of the intestinal flora also varied with age, and the intestinal flora of advanced-age women (≥35 years old) was different from that of middle-aged women (>25 and <35 years old). We also found that changes in maternal clinical physiological and biochemical indicators related to reproductive age could reflect changes in the abundance of bacteria, such as Peptococcus and Vibrio, and changes in the intestinal flora spread to offspring. These results provide new evidence to explain the increased adverse pregnancy outcomes of mothers of inappropriate age, describe the increased health risks of newborns, help us examine the importance of age-appropriate birth from a broader perspective, and contribute to the discovery of mother-child bonds for a better understanding of healthy reproduction. IMPORTANCE In this study, we demonstrated that physiological indicators and the gut microbiome fluctuate drastically among parturients of different reproductive ages and that there is a significant correlation between the two changes. Mothers of different ages had different gut microbes, and the gut microbiota varied as the childbearing age became too high. Changes in the gut microbiome with maternal reproductive age affected the offspring, and the influence of reproductive age on the intestinal flora had a synergistic effect between mother and child that was revealed for the first time. The maternal childbearing age might affect the colonization of the offspring's initial flora. The results provide new evidence to explain the increased adverse pregnancy outcomes of mothers of inappropriate age, describe the increased health risks of newborns, and contribute to the discovery of mother-child bonds for a better understanding of healthy reproduction.

Integrating Choline and Specific Intestinal Microbiota to Classify Type 2 Diabetes in Adults: A Machine Learning Based Metagenomics Study.

Emerging evidence is examining the precise role of intestinal microbiota in the pathogenesis of type 2 diabetes. The aim of this study was to investigate the association of intestinal microbiota and microbiota-generated metabolites with glucose metabolism systematically in a large cross-sectional study in China. 1160 subjects were divided into three groups based on their glucose level: normal glucose group (n=504), prediabetes group (n=394), and diabetes group (n=262). Plasma concentrations of TMAO, choline, betaine, and carnitine were measured. Intestinal microbiota was measured in a subgroup of 161 controls, 144 prediabetes and 56 diabetes by using metagenomics sequencing. We identified that plasma choline [Per SD of log-transformed change: odds ratio 1.36 (95 confidence interval 1.16, 1.58)] was positively, while betaine [0.77 (0.66, 0.89)] was negatively associated with diabetes, independently of TMAO. Individuals with diabetes could be accurately distinguished from controls by integrating data on choline, and certain microbiota species, as well as traditional risk factors (AUC=0.971). KOs associated with the carbohydrate metabolism pathway were enhanced in individuals with high choline level. The functional shift in the carbohydrate metabolism pathway in high choline group was driven by species Ruminococcus lactaris, Coprococcus catus and Prevotella copri. We demonstrated the potential ability for classifying diabetic population by choline and specific species, and provided a novel insight of choline metabolism linking the microbiota to impaired glucose metabolism and diabetes.

Maternal, umbilical arterial metabolic levels and placental Nrf2/CBR1 expression in pregnancies with and without 25-hydroxyvitamin D deficiency.

BACKGROUND: The aim of this case-control study was to document maternal, umbilical arterial metabolic levels and correlations in pregnancies with and without 25-hydroxyvitamin D [25(OH)D] deficiency, while, also investigating the expression of nuclear factor erythroid 2 related factor 2 (Nrf2) and carbonyl reductase 1 (CBR1) in the placenta. METHODS: One hundred participants, 50 deficient for 25(OH)D and 50 normal, were recruited from among hospitalized single-term pregnant women who had elected for cesarean section. Umbilical arterial and placental samples were collected during cesarean section. Metabolic levels were assessed for the 25(OH)D deficiency and control groups' maternal, umbilical arterial samples. Nrf2 and CBR1 expression levels were investigated in the placentas of 12 pregnant women with 25(OH)D deficiency and 12 controls. RESULTS: Compared with the control participants, the 25(OH)D deficient women had significantly higher triglyceride (TG) levels (3.80 ± 2.11 vs. 2.93 ± 1.16 mmol/L, 3.64 ± 1.84 vs. 2.81 ± 1.16 mmol/L, p < .01, .001); lower high density lipoprotein cholesterol (HDL-C) levels (1.54 ± 0.32 vs. 1.82 ± 0.63 mmol/L, 1.41 ± 0.72 vs. 2.44 ± 1.68 mmol/L, p < .001, .01) in both material blood and the umbilical artery. In addition, Nrf2 and CBR1 expression levels were lower in the maternal 25(OH)D deficient placenta. CONCLUSION: 25(OH)D deficient pregnant women have higher TG levels and lower HDL-C levels in both material blood and the umbilical artery. TG level is negatively correlated with 25(OH)D in both the maternal serum and infant umbilical artery. 25(OH)D deficiency also lowers placental expression of Nrf2 and CBR1.Supplemental data for this article is available online at here.

The oral microbiome of pregnant women facilitates gestational diabetes discrimination.

The oral microbiota plays an important role in the development of various diseases, whereas its association with gestational diabetes mellitus (GDM) remains largely unclear. The aim of this study is to identify biomarkers from the oral microbiota of GDM patients by analyzing the microbiome of the saliva and dental plaque samples of 111 pregnant women. We find that the microbiota of both types of oral samples in GDM patients exhibits differences and significantly varies from that of patients with periodontitis or dental caries. Using bacterial biomarkers from the oral microbiota, GDM classification models based on support vector machine and random forest algorithms are constructed. The area under curve (AUC) value of the classification model constructed by combination of Lautropia and Neisseria in dental plaque and Streptococcus in saliva reaches 0.83, and the value achieves a maximum value of 0.89 by adding clinical features. These findings suggest that certain bacteria in either saliva or dental plaque can effectively distinguish women with GDM from healthy pregnant women, which provides evidence of oral microbiome as an informative source for developing noninvasive biomarkers of GDM.

The relationship between maternal vitamin D deficiency and glycolipid metabolism and adverse pregnancy outcome.

OBJECTIVE: Maternal vitamin D deficiency is associated with glucose and lipid metabolism in the mother and offspring. Meanwhile, it can also lead to adverse pregnancy outcomes. The aim of this case-control study was to document maternal, umbilical arterial glucose and lipid metabolic levels and correlations in pregnancies with or without vitamin D deficiency, while also investigating adverse pregnancy outcomes. DESIGN/PARTICIPANTS/MEASUREMENTS: A total of 425 pregnant women who received antenatal care and delivered at Wenzhou People's Hospital were enrolled. According to their serum 25-hydroxyvitamin D [25(OH)D] level, the pregnant women were divided into the vitamin D deficiency group [25(OH)D < 20 ng/mL, 185 participants] and the control group [25(OH)D ≥ 20 ng/mL, 240 participants]. Maternal blood samples were collected at 24-28 weeks of gestation and delivery for 75-g oral glucose tolerance test (OGTT), and measurements of glucose and lipid metabolite levels and 25(OH)D levels. Umbilical arterial samples were collected during delivery (33.57-41.43 gestational weeks). RESULTS: Compared with control participants, vitamin D deficiency women had significantly higher concentrations of fasting blood-glucose (P < .01), 1-h OGTT plasma glucose (P < .01), 2-h OGTT plasma glucose (P < .01), insulin (P < .01), HOMA-IR (P < .01), LDL (P < .01) and triglycerides (P = .02) and lower concentrations of HOMA-S (P < .01). Compared with the control group, vitamin D deficiency women had higher concentrations of triglycerides (P < .01) and lower concentrations of HDL-C (P < .01) and HOMA-ß (P = .01) in infant umbilical arterial blood. Pearson's correlation analysis demonstrated that the maternal 25(OH)D level was negatively correlated with maternal plasma glucose, insulin, LDL-C, cholesterol, triglyceride and HOMA-IR (r = -.38, -.27, -.2, -.11, -.11, -.33 and .11; P < .01, <.01, <.01, <.05, <.05 and <.01, respectively), while there was a positive correlation between maternal serum 25(OH)D and HOMA-S (r = .11, P < .05). The triglyceride level in the umbilical artery was negatively correlated with maternal serum 25(OH)D concentration (r = -.286, P < .01), while the HDL-C and HOMA-ß in umbilical artery were positively related (r = .154, .103, P < .01). Compared with the control group, the incidences of pre-eclampsia [4.8% (9/185) vs 1.25% (3/240), P = .03], gestational diabetes mellitus [19.45% (36/185) vs 12.08% (29/240), P = .04] and premature rupture of membranes [15.68% (29/185) vs 5.42% (13/240), P < .01] were higher in the vitamin D deficiency group. CONCLUSION: Vitamin D deficiency during pregnancy is associated with maternal glucose and lipid metabolism and pregnancy outcomes. Therefore, it is worth recommending to maintain vitamin D status at an optimal level in pregnant women to prevent metabolic disorders and pregnancy complications.

Maternal 25-Hydroxyvitamin D Deficiency Promoted Metabolic Syndrome and Downregulated Nrf2/CBR1 Pathway in Offspring.

Metabolic syndrome is a disorder of energy use and storage, which is characterized by central obesity, dyslipidemia, and raised blood pressure and blood sugar levels. Maternal 25-hydroxyvitamin D deficiency is known to cause metabolic changes, chronic disease, and increased adiposity in adulthood. However, the underlying mechanism of induced metabolic syndrome (MetS) in the offspring in vitamin D deficient pregnant mothers remains unclear. We identified that maternal 25-hydroxyvitamin D deficiency enhances oxidative stress, which leads to the development of MetS in the mother and her offspring. Further, immunohistochemical, Western blotting, and qRT-PCR analyses revealed that maternal 25-hydroxyvitamin D deficiency inhibited the activation of the Nrf2/carbonyl reductase 1 (CBR1) pathway in maternal placenta, liver, and pancreas, as well as the offspring's liver and pancreas. Further analyses uncovered that application of 25-hydroxyvitamin D activated the Nrf2/CBR1 pathway, relieving the oxidative stress in BRL cells, suggesting that 25-hydroxyvitamin D regulates oxidative stress in offspring and induces the activation of the Nrf2/CBR1 pathway. Taken together, our study finds that maternal 25-hydroxyvitamin D deficiency is likely to result in offspring's MetS probably via abnormal nutrition transformation across placenta. Depression of the Nrf2/CBR1 pathway in both mothers and their offspring is one of the causes of oxidative stress leading to MetS. This study suggests that 25-hydroxyvitamin D treatment may relieve the offspring's MetS.

A case report of Turner syndrome associated with fetal nuchal cystic hygroma and bilateral syndactyly of the hands and feet.

BACKGROUND: Turner syndrome (45,X), accounts for 1-2% of conceptions which typically miscarry early in the first trimester. Cases detected prenatally often present with cystic hygroma, which is an ultrasound marker for aneuploidy generally, but Turner syndrome particularly. In this study, we report a second trimester intrauterine fetal demise (IUFD), complicated by a marked cystic hygroma and bilateral syndactyly of the fingers and toes. CASE PRESENTATION: A 25-year-old woman presented for her first prenatal visit at 22-week gestation with IUFD. Color Doppler ultrasound revealed a septated nuchal lymphatic hygroma and hydrops fetalis, characterized by edema of the whole body, substantial pleural effusion and abdominal fluid. Pregnancy was further complicated by oligohydramnios. Following labor induction, a stillborn female baby was delivered at 22 weeks gestation. Autopsy confirmed the presence of huge nuchal cystic hygroma (10 cm × 10 cm × 6 cm) and generalized edema. Bilateral, partial syndactyly involving digits 2-5 of the fingers and toes were also observed. Chromosomal analysis revealed a 45,X karyotype. CONCLUSIONS: We investigated an unusual case of severe septated nuchal cystic hygroma associated with bilateral syndactyly of the fingers and toes in a stillborn infant with Turner syndrome. Although cystic hygroma has been frequently reported in 45,X the severity is marked in this case. In addition, syndactyly is not a typical complication of Turner syndrome. This case emphasizes the importance of early ultrasound in pregnancy.

Correlation of CXCR4/CXCR7 signaling pathway with pre-eclampsia.

The possible role of C-X-C chemokine receptor type 4 (CXCR4)/CXCR7 signaling pathway in pre-eclampsia (PE) was investigated to study the expression of CXCR4/CXCR7 in serum of PE patients and its correlation and relationship with PE. Twenty patients with mild PE and 40 cases with severe PE enrolled into the PE group and 60 cases of the normal pregnancy group during the same period were selected as the objects of study. The changes in expression of serum CXCR4 messenger ribonucleic acid (mRNA) and CXCR7 mRNA were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and CXCR4/CXCR7 protein concentration in serum was determined by enzyme-linked immunosorbent assay (ELISA). The pregnancy termination time of gravid was earlier in the severe PE group than that in the normal pregnancy group (P<0.05); the mean arterial pressure (MAP), systolic pressure, diastolic pressure were higher in patients with mild and severe PE than those in the normal pregnancy group (P<0.05). The results of RT-qPCR showed that the mRNA expression of serum CXCR4 and CXCR7 in PE patients were distinctly higher than those in the normal pregnancy group (P<0.05). The expression level of CXCR4 mRNA was positively correlated with that of CXCR7 mRNA (r=0.567, P=0.02). The results of ELISA displayed that the content of CXCR4/CXCR7 in serum of patients with PE was remarkably higher than that in the normal pregnancy group (P<0.05); the expression of serum CXCR4/CXCR7 in patients with severe PE was higher than in those with mild PE (P<0.05). The expression level of serum CXCR4 protein was positively correlated with that of CXCR7 protein (r=0.563, P=0.01). The expression level of CXCR4/CXCR7 may be closely related to the formation of PE.