Mutual Associations of Exposure to Ambient Air Pollutants in the First 1000 Days of Life With Asthma/Wheezing in Children: Prospective Cohort Study in Guangzhou, China.

BACKGROUND: The first 1000 days of life, encompassing pregnancy and the first 2 years after birth, represent a critical period for human health development. Despite this significance, there has been limited research into the associations between mixed exposure to air pollutants during this period and the development of asthma/wheezing in children. Furthermore, the finer sensitivity window of exposure during this crucial developmental phase remains unclear. OBJECTIVE: This study aims to assess the relationships between prenatal and postnatal exposures to various ambient air pollutants (particulate matter 2.5 [PM2.5], carbon monoxide [CO], sulfur dioxide [SO2], nitrogen dioxide [NO2], and ozone [O3]) and the incidence of childhood asthma/wheezing. In addition, we aimed to pinpoint the potential sensitivity window during which air pollution exerts its effects. METHODS: We conducted a prospective birth cohort study wherein pregnant women were recruited during early pregnancy and followed up along with their children. Information regarding maternal and child characteristics was collected through questionnaires during each round of investigation. Diagnosis of asthma/wheezing was obtained from children's medical records. In addition, maternal and child exposures to air pollutants (PM2.5 CO, SO2, NO2, and O3) were evaluated using a spatiotemporal land use regression model. To estimate the mutual associations of exposure to mixed air pollutants with the risk of asthma/wheezing in children, we used the quantile g-computation model. RESULTS: In our study cohort of 3725 children, 392 (10.52%) were diagnosed with asthma/wheezing. After the follow-up period, the mean age of the children was 3.2 (SD 0.8) years, and a total of 14,982 person-years were successfully followed up for all study participants. We found that each quartile increase in exposure to mixed air pollutants (PM2.5, CO, SO2, NO2, and O3) during the second trimester of pregnancy was associated with an adjusted hazard ratio (HR) of 1.24 (95% CI 1.04-1.47). Notably, CO made the largest positive contribution (64.28%) to the mutual effect. After categorizing the exposure according to the embryonic respiratory development stages, we observed that each additional quartile of mixed exposure to air pollutants during the pseudoglandular and canalicular stages was associated with HRs of 1.24 (95% CI 1.03-1.51) and 1.23 (95% CI 1.01-1.51), respectively. Moreover, for the first year and first 2 years after birth, each quartile increment of exposure to mixed air pollutants was associated with HRs of 1.65 (95% CI 1.30-2.10) and 2.53 (95% CI 2.16-2.97), respectively. Notably, SO2 made the largest positive contribution in both phases, accounting for 50.30% and 74.70% of the association, respectively. CONCLUSIONS: Exposure to elevated levels of mixed air pollutants during the first 1000 days of life appears to elevate the risk of childhood asthma/wheezing. Specifically, the second trimester, especially during the pseudoglandular and canalicular stages, and the initial 2 years after birth emerge as crucial susceptibility windows. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-ROC-17013496; https://tinyurl.com/2ctufw8n.

Assisted reproductive technology induces different secondary sex ratio: parental and embryonic impacts.

BACKGROUND: Assisted reproduction technology (ART) has advanced significantly, raising concerns regarding its impact on the secondary sex ratio (SSR), which is the sex ratio at birth in offspring. This study aimed to explore factors affecting SSR in singletons, singletons from twin gestation, and twins from twin gestation within the context of ART. METHODS: A retrospective analysis was conducted on data from 8335 births involving 6,223 couples undergoing ART. Binary logistic regression assessed relationships between parental and embryonic factors and SSR in singletons and singletons from twin gestation. Multinomial logistic regression models were utilized to identify factors influencing SSR in twins from twin gestation. RESULTS: Secondary infertility (OR = 1.164, 95% CI: 1.009-1.342), advanced paternal age (OR = 1.261, 95% CI: 1.038-1.534), and blastocyst embryo transfer (OR = 1.339, 95% CI: 1.030-1.742) were associated with an increased SSR, while frozen embryo transfer (FET) showed a negative association with SSR (OR = 0.738, 95% CI: 0.597-0.912) in singletons. A longer duration of gonadotropin (Gn) usage reduced SSR in singletons (OR = 0.961, 95% CI: 0.932-0.990) and singletons from twin gestation (OR = 0.906, 95% CI: 0.838-0.980). In singletons from twin gestation, male-induced infertility (OR = 2.208, 95% CI: 1.120-4.348) and higher Gn dosage (OR = 1.250, 95% CI: 1.010-1.548) were significantly associated with an increased SSR. Women aged > 35 years and intracytoplasmic sperm injection (ICSI) were associated with lower SSR (OR = 0.539, 95% CI: 0.293-0.990 and OR = 0.331, 95% CI: 0.158-0.690, respectively). In twins from twin gestation, paternal age exceeded maternal age (OR = 0.682, 95% CI: 0.492-0.945) and higher Gn dosage (OR = 0.837, 95% CI: 0.715-0.980) were associated with a higher proportion of male twins. Cleavage stage transfer (OR = 1.754, 95% CI: 1.133-2.716) resulted in a higher percentage of boy-girl twins compared to blastocyst transfer. CONCLUSION: This study demonstrates the complex interplay of various factors in determining the SSR in ART, highlighting the importance of considering infertility type, paternal age, fertilization method, embryo transfer stage, and Gn use duration when assessing SSR. Nevertheless, further research with a large sample size is necessary to confirm and expand upon the findings of this study.

Long-term exposure to ambient ozone and cardiovascular diseases: Evidence from two national cohort studies in China.

INTRODUCTION: The health effects of ambient ozone have been investigated in many previous studies. However, the effects of long-term exposure to ambient ozone on the incidence of cardiovascular disease (CVD) remain inconclusive. OBJECTIVES: To estimate the associations of long-term exposure to maximum daily 8-hours average ozone (MDA8 O3) with the incidence of total CVD, heart disease, hypertension, and stroke. METHODS: This was a prospective cohort study, and the data was obtained from the China Health and Retirement Longitudinal Survey (CHARLS) implemented during 2011-2018 and the China Family Panel Studies (CFPS) implemented during 2010-2018. We applied a Cox proportional hazards regression model to evaluate the associations of MDA8 O3 with total CVD, heart disease, hypertension, and stroke risks, and the corresponding population-attributable fractions (PAF) attributable to MDA8 O3 were also calculated. All analyses were conducted by R software. RESULTS: The mean MDA8 O3 concertation of all included participants in the CHARLS and CFPS were 51.03 part per billion (ppb) and 51.15 ppb, respectively. In the CHARLS including 18,177 participants, each 10 ppb increment in MDA8 O3 concentration was associated with a 31% increase [hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.22-1.42] in the risk of incident heart disease, and the corresponding population-attributable fractions (PAF) was 13.79% [10.12%-17.32%]. In the CFPS including 30,226 participants, each 10 ppb increment in MDA8 O3 concentration was associated with an increase in the risk of incident total CVD (1.07 [1.02-1.13]), and hypertension (1.10 [1.03-1.18]). The PAFs of total CVD, and hypertension attributable to MDA8 O3 were 3.53% [0.82%-6.16%], and 5.11% [1.73%-8.38%], respectively. Stratified analyses showed greater associations in males, urban areas, and Southern China. CONCLUSIONS: Long-term exposure to MDA8 O3 may increase the incidence of CVD. Therefore, the policies that control O3 and related precursors are persistently needed.

A two-center retrospective study: association of early caffeine administration and oxygen radical diseases in neonatology in Chinese preterm neonates.

Introduction: Since December 2012, the prophylactic use of caffeine to treat AOP in preterm infants has been approved in China. This study aimed to investigate the relationship between early caffeine treatment initiation and the incidence of oxygen radical diseases in neonatology (ORDIN) in Chinese preterm infants. Methods: A retrospective study was conducted at two hospitals in South China, involving 452 preterm infants with gestational ages less than 37 weeks. The infants were divided into early (227 cases, initiating within 48 h after birth) and late (225 cases, initiating over 48 h after birth) caffeine treatment group. Logistic regression analysis and Receiver Operating Characteristic (ROC) curves were used to evaluate the association between early caffeine treatment and the incidence of ORDIN. Results: The results showed that extremely preterm infants in early treatment group had a lower incidence of PIVH and ROP compared to those in the late treatment group (PIVH, 20.1% versus 47.8%, P = 0.02; ROP, 70.8% versus 89.9%, P = 0.025). Very preterm infants in the early treatment group had a lower incidence of BPD and PIVH compared to those in the late treatment group (BPD, 43.8% versus 63.1%, P = 0.002; PIVH, 9.0% versus 22.3%, P = 0.001). Moreover, VLBW infants who received early caffeine treatment exhibited a decreased incidence of BPD (55.9% versus 80.9%, P = 0.000), PIVH (11.8% versus 33.1%, P = 0.000), and ROP (69.9% versus 79.8%, P = 0.043) compared to those in the late treatment group. Infants in the early caffeine treatment showed a reduced likelihood of PIVH (adjusted odds ratio, 0.407; 95%CI, 0.188-0.846) but did not exhibit a significant association with other terms of ORDIN. ROC analysis revealed that early initiation of caffeine treatment was associated with lower risk of BPD, PIVH, and ROP in preterm infants. Discussion: In conclusion, this study demonstrates that early initiation of caffeine treatment is associated with a decreased incidence of PIVH in Chinese preterm infants. Further prospective investigations are necessary to verify and elucidate the precise effects of early caffeine treatment on complications in preterm Chinese infants.

Umbilical cord blood exosomes from very preterm infants with bronchopulmonary dysplasia aggravate lung injury in mice.

Bronchopulmonary dysplasia (BPD) is characterized by abnormal development of the blood vessels and alveoli in lungs, which largely occurs in premature infants. Exosomes (EXO) from very preterm infants (VPI) with BPD (BPD-EXO) impair angiogenic activities of human umbilical vein endothelial cells (HUVECs) via EXO-miRNAs cargo. This study aimed to determine whether and how BPD-EXO affect the development of BPD in a mouse model. We showed that treating BPD mice with BPD-EXO chronically and irreversibly aggravated lung injury. BPD-EXO up-regulated 139 and down-regulated 735 genes in the mouse lung tissue. These differentially expressed genes were enriched to the MAPK pathway (e.g., Fgf9 and Cacna2d3), which is critical to angiogenesis and vascular remodeling. BPD-EXO suppressed expression of Fgf9 and Cacna2d3 in HUVECs and inhibited migration, tube formation, and increased cell apoptosis in HUVECs. These data demonstrate that BPD-EXO aggravate lung injury in BPD mice and impair lung angiogenesis, plausibly leading to adverse outcomes of VPI with BPD. These data also suggest that BPD-EXO could serve as promising targets for predicting and treating BPD.

Umbilical cord blood-derived exosomes from healthy term pregnancies protect against hyperoxia-induced lung injury in mice.

Bronchopulmonary dysplasia (BPD) is a chronic, devastating disease primarily occurring in premature infants. To date, intervention strategies to prevent or treat BPD are limited. We aimed to determine the effects of umbilical cord blood-derived exosomes (UCB-EXOs) from healthy term pregnancies on hyperoxia-induced lung injury and to identify potential targets for BPD intervention. A mouse model of hyperoxia-induced lung injury was created by exposing neonatal mice to hyperoxia after birth until the 14th day post birth. Age-matched neonatal mice were exposed to normoxia as the control. Hyperoxia-induced lung injury mice were intraperitoneally injected with UCB-EXO or vehicle daily for 3 days, starting on day 4 post birth. Human umbilical vein endothelial cells (HUVECs) were insulted with hyperoxia to establish an in vitro model of BPD to investigate angiogenesis dysfunction. Our results showed that UCB-EXO alleviated lung injuries in hyperoxia-insulted mice by reducing histopathological grade and collagen contents in the lung tissues. UCB-EXO also promoted vascular growth and increased miR-185-5p levels in the lungs of hyperoxia-insulted mice. Additionally, we found that UCB-EXO elevated miR-185-5p levels in HUVECs. MiR-185-5p overexpression inhibited cell apoptosis, whereas promoted cell migration in HUVECs exposed to hyperoxia. The luciferase reporter assay results revealed that miR-185-5p directly targeted cyclin-dependent kinase 6 (CDK6), which was downregulated in the lungs of hyperoxia-insulted mice. Together, these data suggest that UCB-EXO from healthy term pregnancies protect against hyperoxia-induced lung injuries via promoting neonatal pulmonary angiogenesis partially by elevating miR-185-5p.

Effect of long-term exposure to PM2.5 on the risk of type 2 diabetes and arthritis in type 2 diabetes patients: Evidence from a national cohort in China.

BACKGROUND: It remains unclear whether type 2 diabetes and the complication of arthritis are causally related to the PM2.5 pollutant. Therefore, we aimed to investigate the associations of long-term PM2.5 exposure with type 2 diabetes and with arthritis in type 2 diabetes patients. MATERIALS AND METHODS: This study used data from the China Health and Retirement Longitudinal Survey (CHARLS) implemented during 2011-2018. The associations were analyzed by Cox proportional hazards regression models, and the population-attributable fraction (PAF) was calculated to assess the burden of type 2 diabetes and arthritis-attributable to PM2.5. RESULTS: A total of 21,075 participants were finally included, with 19,121 analyzed for PM2.5 and type 2 diabetes risk and 12,427 analyzed for PM2.5 and arthritis risk, of which 1,382 with newly-diagnosed type 2 diabetes and 1,328 with arthritis during the follow-up. Overall, each 10 µg/m3 increment in PM2.5 concentration was significantly associated with an increase in the risk of type 2 diabetes (HR = 1.26, 95 %CI1.22 to 1.31), and the PAF of type 2 diabetes attributable to PM2.5 was 13.54 %. In type 2 diabetes patients, each 10 µg/m3 increment in PM2.5 exposure was associated with an increase in arthritis (HR = 1.42, 95 %CI: 1.28 to 1.57), and the association was significantly greater than that (H = 1.23, 95 %CI: 1.19 to 1.28) in adults without type 2 diabetes. The PAFs of arthritis-attributable to PM2.5 in participants with and without type 2 diabetes were 18.54 % and 10.69 %, respectively. CONCLUSION: Long-term exposure to PM2.5 may increase the risk of type 2 diabetes and make type 2 diabetes patients susceptible to arthritis.

High value valorization of lignin as environmental benign antimicrobial.

Lignin is a natural aromatic polymer of p-hydroxyphenylpropanoids with various biological activities. Noticeably, plants have made use of lignin as biocides to defend themselves from pathogen microbial invasions. Thus, the use of isolated lignin as environmentally benign antimicrobial is believed to be a promising high value approach for lignin valorization. On the other hand, as green and sustainable product of plant photosynthesis, lignin should be beneficial to reduce the carbon footprint of antimicrobial industry. There have been many reports that make use of lignin to prepare antimicrobials for different applications. However, lignin is highly heterogeneous polymers different in their monomers, linkages, molecular weight, and functional groups. The structure and property relationship, and the mechanism of action of lignin as antimicrobial remains ambiguous. To show light on these issues, we reviewed the publications on lignin chemistry, antimicrobial activity of lignin models and isolated lignin and associated mechanism of actions, approaches in synthesis of lignin with improved antimicrobial activity, and the applications of lignin as antimicrobial in different fields. Hopefully, this review will help and inspire researchers in the preparation of lignin antimicrobial for their applications.

Case Report: Neonatal genital prolapse in a pair of premature Twins.

Neonatal genital prolapse is a rare situation. This report presents a unique case involving a pair of premature female twins who both developed vaginal wall prolapse without any neurological deficits. Multiple factors such as selective intrauterine growth restriction, feeding intolerance, extrauterine growth retardation, and elevated intra-abdominal pressure after birth may have contributed to the development of this phenomenon. Notably, the severity of prolapse was more pronounced in the twin with lower birth weight and smaller for gestational age. After a five-month follow-up period, the twins' prolapsed vaginal wall fully retracted due to a combination of conservative treatment and enhanced nutritional support.

Sox9-expressing cells promote regeneration after radiation-induced lung injury via the PI3K/AKT pathway.

BACKGROUND: Radiation-induced lung injury (RILI) is considered one of the most common complications of thoracic radiation. Recent studies have focused on stem cell properties to obtain ideal therapeutic effects, and Sox9 has been reported to be involved in stem cell induction and differentiation. However, whether Sox9-expressing cells play a role in radiation repair and regeneration remains unknown. METHODS: We successfully obtained Sox9CreER, RosatdTomato and RosaDTA mice and identified Sox9-expressing cells through lineage tracing. Then, we evaluated the effects of the ablation of Sox9-expressing cells in vivo. Furthermore, we investigated the underlying mechanism of Sox9-expressing cells during lung regeneration via an online single-cell RNA-seq dataset. RESULTS: In our study, we demonstrated that Sox9-expressing cells promote the regeneration of lung tissues and that ablation of Sox9-expressing cells leads to severe phenotypes after radiation damage. In addition, analysis of an online scRNA-Seq dataset revealed that the PI3K/AKT pathway is enriched in Sox9-expressing cells during lung epithelium regeneration. Finally, the AKT inhibitor perifosine suppressed the regenerative effects of Sox9-expressing cells and the AKT pathway agonist promotes proliferation and differentiation. CONCLUSIONS: Taken together, the findings of our study suggest that Sox9-expressing cells may serve as a therapeutic target in lung tissue after RILI.

Mesenchymal stem cells from different sources show distinct therapeutic effects in hyperoxia-induced bronchopulmonary dysplasia in rats.

Mesenchymal stem cells (MSCs) have been shown as an effective medicinal means to treat bronchopulmonary dysplasia (BPD). The widely used MSCs were from Wharton's jelly of umbilical cord (UC-MSCs) and bone marrow (BM-MSCs). Amniotic fluid MSCs (AF-MSCs) may be produced before an individual is born to treat foetal diseases by autoplastic transplantation. We evaluated intratracheal (IT) MSCs as an approach to treat an hyperoxia-induced BPD animal model and compared the therapeutic effects between AF-, UC- and BM-MSCs. A BPD animal model was generated by exposing newborn rats to 95% O2 . The continued stress lasted 21 days, and the treatment of IT MSCs was conducted for 4 days. The therapeutic effects were analysed, including lung histology, level of inflammatory cytokines, cell death ratio and state of angiogenesis, by sacrificing the experimental animal at day 21. The lasting hyperoxia stress induced BPD similar to the biological phenotype. The treatment of IT MSCs was safe without deaths and normal organ histopathology. Specifically, the treatment was effective by inhibiting the alveolar dilatation, reducing inflammatory cytokines, inducing angiogenesis and lowering the cell death ratio. AF-MSCs had better therapeutic effects compared with UC-MSCs in relieving the pulmonary alveoli histological changes and promoting neovascularization, and UC-MSCs had the best immunosuppressive effect in plasma and lung lysis compared with AF-MSCs and BM-MSCs. This study demonstrated the therapeutic effects of AF-, UC- and BM-MSCs in BPD model. Superior treatment effect was provided by antenatal MSCs compared to BM-MSC in a statistical comparison.

Umbilical Cord Blood-Derived Exosomes From Very Preterm Infants With Bronchopulmonary Dysplasia Impaired Endothelial Angiogenesis: Roles of Exosomal MicroRNAs.

Premature infants have a high risk of bronchopulmonary dysplasia (BPD), which is characterized by abnormal development of alveoli and pulmonary vessels. Exosomes and exosomal miRNAs (EXO-miRNAs) from bronchoalveolar lavage fluid are involved in the development of BPD and might serve as predictive biomarkers for BPD. However, the roles of exosomes and EXO-miRNAs from umbilical cord blood of BPD infants in regulating angiogenesis are yet to be elucidated. In this study, we showed that umbilical cord blood-derived exosomes from BPD infants impaired angiogenesis in vitro. Next-generation sequencing of EXO-miRNAs from preterm infants without (NBPD group) or with BPD (BPD group) uncovered a total of 418 differentially expressed (DE) EXO-miRNAs. These DE EXO-miRNAs were primarily enriched in cellular function-associated pathways including the PI3K/Akt and angiogenesis-related signaling pathways. Among those EXO-miRNAs which are associated with PI3K/Akt and angiogenesis-related signaling pathways, BPD reduced the expression of hsa-miR-103a-3p and hsa-miR-185-5p exhibiting the most significant reduction (14.3% and 23.1% of NBPD group, respectively); BPD increased hsa-miR-200a-3p expression by 2.64 folds of the NBPD group. Furthermore, overexpression of hsa-miR-103a-3p and hsa-miR-185-5p in normal human umbilical vein endothelial cells (HUVECs) significantly enhanced endothelial cell proliferation, tube formation, and cell migration, whereas overexpressing hsa-miR-200a-3p inhibited these cellular responses. This study demonstrates that exosomes derived from umbilical cord blood of BPD infants impair angiogenesis, possibly via DE EXO-miRNAs, which might contribute to the development of BPD.

Weighted gene coexpression network reveals downregulation of genes in bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a serious lung disease observed in premature infants, known to cause considerable morbidity and mortality. Its prognosis is influenced by a complex network of genetic interactions. In this study, we determined the potential key factors in the pathogenesis of this condition. METHODS: We constructed scale-free gene coexpression network using weighted gene coexpression network analysis. The analysis was carried out on the GSE8586 dataset, which contains the expression profiles of umbilical cord tissue homogenates from 20 neonates with BPD and 34 unaffected controls. RESULTS: Our analysis identified one significantly downregulated coexpression module related to the BPD phenotype. It was significantly enriched in genes related to human T-cell leukemia virus infection and the mitogen-activated protein kinase pathway. In this module, the expression of the following four hub genes in infants with BPD was significantly decreased: Fos proto-oncogene (FOS), BTG antiproliferation factor 2 (BTG2), Jun proto-oncogene (JUN), and early growth response protein 1 (EGR1). The downregulation of these hub genes was verified in clinical samples derived from blood and umbilical cord tissue. CONCLUSION: The decreased expression of FOS, BTG2, JUN, and EGR1 is associated with BPD and, therefore, could be used as biomarkers to diagnose early BPD.

[A clinical analysis of neurobehavioral development within one year after birth in preterm infants with bronchopulmonary dysplasia].

OBJECTIVE: To study the effect of bronchopulmonary dysplasia (BPD) on neurobehavioral development within one year after birth in preterm infants. METHODS: A retrospective analysis was performed for the preterm infants with a gestational age of <34 weeks who were born from September 2017 to December 2019 and completed the follow-up assessments of neurobehavioral development at the corrected gestational ages of 40 weeks and 3, 6, and 12 months. According to their diagnosis, they were divided into a BPD group with 23 infants and a non-BPD group with 27 infants. The outcome of neurobehavioral development was compared between the two groups at different time points. RESULTS: There was no significant difference in the neonatal behavioral neurological assessment score between the BPD and non-BPD groups at the corrected gestational age of 40 weeks (P>0.05). Based on the Gesell Developmental Scale, compared with the non-BPD group, the BPD group had significantly lower global developmental quotient (DQ) and DQs of fine motor, adaptive behavior, and personal-social behavior at the corrected gestational ages of 3, 6, and 12 months (P<0.05). For both groups, the DQ of language at the corrected gestational age of 6 months was significantly higher than that at the corrected gestational age of 12 months (P<0.017), the DQ of personal-social behavior at the corrected gestational age of 6 months was significantly higher than that at the corrected gestational age of 3 months (P<0.017), and the DQ of adaptive behavior at the corrected gestational age of 12 months was significantly higher than that at the corrected gestational ages of 3 and 6 months (P<0.017). Based on the BSID-II scale, there were no significant differences in mental development index and psychomotor development index at each time point between the two groups (P>0.05). The mental development index at the corrected gestational age of 3 months was significantly higher than that at the corrected gestational ages of 6 and 12 months in both groups (P<0.001). CONCLUSIONS: Preterm infants with BPD have delayed neurodevelopment within one year after birth compared with those without BPD, which should be taken seriously in clinical practice.

Long Noncoding RNA HOXA-AS3 Integrates NF-κB Signaling To Regulate Endothelium Inflammation.

The long noncoding RNA HOXA-AS3 has recently been reported to act as a critical regulator in inflammation-linked lung adenocarcinoma. However, the roles of HOXA-AS3 in endothelium inflammation and related vascular disorders remain poorly defined. In the current study, we identified HOXA-AS3 to be a critical activator to promote NF-κB-mediated endothelium inflammation. HOXA-AS3, a chromatin-associated regulator which colocalizes with NF-κB at specific gene promoters, was found to interact with NF-κB and positively regulate its activity through control of the expression of the NF-κB inhibitor protein IκBα and the acetylation status at the K310 site of p65. More importantly, clinicopathological analysis showed that HOXA-AS3 expression has a significant positive correlation with atherosclerosis. Thus, we conclude that HOXA-AS3 may serve as a crucial biomarker for the clinical diagnosis of atherosclerosis, as well as a promising therapeutic target for the treatment of multiple inflammatory vascular diseases. In addition, this study suggests the functional importance of HOXA-AS3 in the regulation of inflammatory disorders.

Sexual Dimorphisms of Preeclampsia-Dysregulated Transcriptomic Profiles and Cell Function in Fetal Endothelial Cells.

Preeclampsia impairs fetoplacental vascular function and increases risks of adult-onset cardiovascular disorders in children born to preeclamptic mothers, implicating that preeclampsia programs fetal vasculature in utero. However, the underlying mechanisms remain elusive. We hypothesize that preeclampsia alters fetal endothelial gene expression and disturbs cytokines- and growth factors-induced endothelial responses. RNA sequencing analysis was performed on unpassaged human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic pregnancies. Functional assays for endothelial monolayer integrity, proliferation, and migration were conducted on passage 1 HUVECs from normotensive and preeclamptic pregnancies. Compared with normotensive cells, 926 and 172 genes were dysregulated in unpassaged female and male HUVECs from preeclamptic pregnancies, respectively. Many of these preeclampsia-dysregulated genes are associated with cardiovascular diseases (eg, heart failure) and endothelial function (eg, cell migration, calcium signaling, and endothelial nitric oxide synthase signaling). TNF (tumor necrosis factor)-α-, TGF (transforming growth factor)-ß1-, FGF (fibroblast growth factor)-2-, and VEGFA (vascular endothelial growth factor A)-regulated gene networks were differentially disrupted in unpassaged female and male HUVECs from preeclamptic pregnancies. Moreover, preeclampsia decreased endothelial monolayer integrity in responses to TNF-α in both female and male HUVECs. Preeclampsia decreased TGF-ß1-strengthened monolayer integrity in female HUVECs, whereas it enhanced FGF-2-strengthened monolayer integrity in male HUVECs. Preeclampsia promoted TNF-α-, TGF-ß1-, and VEGFA-induced cell proliferation in female, but not in male HUVECs. Preeclampsia inhibited TNF-α-induced cell migration in female HUVECs, but had an opposite effect on male HUVECs. In conclusion, preeclampsia differentially dysregulates cardiovascular diseases- and endothelial function-associated genes/pathways in female and male fetal endothelial cells in association with the sexual dimorphisms of preeclampsia-dysregulated fetal endothelial function.

G Protein α Subunit 14 Mediates Fibroblast Growth Factor 2-Induced Cellular Responses in Human Endothelial Cells.

During pregnancy, a tremendous increase in fetoplacental angiogenesis is associated with elevated blood flow. Aberrant fetoplacental vascular function may lead to pregnancy complications including pre-eclampsia. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) are crucial regulators of fetoplacental endothelial function. G protein α subunit 14 (GNA14), a member of Gαq/11 subfamily is involved in mediating hypertensive diseases and tumor vascularization. However, little is known about roles of GNA14 in mediating the FGF2- and VEGFA-induced fetoplacental endothelial function. Using human umbilical vein endothelial cells (HUVECs) cultured under physiological chronic low oxygen (3% O2 ) as a cell model, we show that transfecting cells with adenovirus carrying GNA14 complementary DNA (cDNA; Ad-GNA14) increases (p < 0.05) protein expression of GNA14. GNA14 overexpression blocks (p < 0.05) FGF2-stimulated endothelial migration, whereas it enhances (p < 0.05) endothelial monolayer integrity (maximum increase of ~35% over the control at 24 hr) in response to FGF2. In contrast, GNA14 overexpression does not significantly alter VEGFA-stimulated cell migration, VEGFA-weakened cell monolayer integrity, and intracellular Ca++ mobilization in response to adenosine triphosphate (ATP), FGF2, and VEGFA. GNA14 overexpression does not alter either FGF2- or VEGFA-induced phosphorylation of ERK1/2. However, GNA14 overexpression time-dependently elevates (p < 0.05) phosphorylation of phospholipase C-ß3 (PLCß3) at S1105 in response to FGF2, but not VEGFA. These data suggest that GNA14 distinctively mediates fetoplacental endothelial cell migration and permeability in response to FGF2 and VEGFA, possibly in part by altering activation of PLCß3 under physiological chronic low oxygen.

GNA11 differentially mediates fibroblast growth factor 2- and vascular endothelial growth factor A-induced cellular responses in human fetoplacental endothelial cells.

KEY POINTS: Fetoplacental vascular growth is critical to fetal growth. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) are two major regulators of fetoplacental vascular growth. G protein α subunit 11 (GNA11) transmits signals from many external stimuli to the cellular interior and may mediate endothelial function. It is not known whether GNA11 mediates FGF2- and VEGFA-induced endothelial cell responses under physiological chronic low O2 . In the present study, we show that knockdown of GNA11 significantly decreases FGF2- and VEGFA-induced fetoplacental endothelial cell migration but not proliferation and permeability. Such decreases in endothelial migration are associated with increased phosphorylation of phospholipase C-ß3. The results of the present study suggest differential roles of GNA11 with respect to mediating FGF2- and VEGFA-induced fetoplacental endothelial function. ABSTRACT: During pregnancy, fetoplacental angiogenesis is dramatically increased in association with rapidly elevated blood flow. Any disruption of fetoplacental angiogenesis may lead to pregnancy complications such as intrauterine growth restriction. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) are crucial regulators of fetoplacental angiogenesis. G protein α subunits q (GNAq) and 11 (GNA11) are two members of the Gαq/11 subfamily involved in mediating vascular growth and basal blood pressure. However, little is known about the roles of GNA11 alone with respect to mediating the FGF2- and VEGFA-induced fetoplacental endothelial function. Using a cell model of human umbilical cord vein endothelial cells cultured under physiological chronic low O2 (3% O2 ), we showed that GNA11 small interfering RNA (siRNA) dramatically inhibited (P < 0.05) FGF2- and VEGFA-stimulated fetoplacental endothelial migration (by ∼36% and ∼50%, respectively) but not proliferation and permeability. GNA11 siRNA also elevated (P < 0.05) FGF2- and VEGFA-induced phosphorylation of phospholipase C-ß3 (PLCß3) at S537 in a time-dependent fashion but not mitogen-activated protein kinase 3/1 (ERK1/2) and v-akt murine thymoma viral oncogene homologue 1 (AKT1). These data suggest that GNA11 mediates FGF2- and VEGFA-stimulated fetoplacental endothelial cell migration partially via altering the activation of PLCß3.

Different concentrations of docosahexanoic acid supplement during lactation result in different outcomes in preterm Sprague-Dawley rats.

PROPOSE: In this study, we evaluated the effects of different concentrations of docosahexanoic acid (DHA) supplement on preterm Sprague-Dawley rat pups, and in parallel, measured the phosphorylation activity of the mTOR pathway in the hippocampal CA1 area. METHODS: Preterm Sprague-Dawley rat pups were randomly assigned to experimental groups which included; a sufficient DHA group (100 mg/kg/day); an enriched DHA group (300 mg/kg/day); an excess DHA group (800 mg/kg/day); and a deficient DHA group (normal saline gavage 0.1 ml/10 g). Body weight (g) was measured at days 1/7/14/21/28/42, respectively. Spatial learning and memory were also tested using the Morris water maze at week 6 (day 42). Finally, activation of the mTOR signaling pathway in hippocampal CA1 area were evaluated by western blotting. RESULTS: Postnatal sufficient/enriched docosahexanoic acid supplement ameliorated body weight restriction, spatial learning and memory restriction, and decreased phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. Furthermore, excess docosahexanoic acid supplement impeded weight gain and spatial learning and memory, perturbed serum unsaturated fatty acid, and downregulated phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. CONCLUSION: Postnatal sufficient/enriched DHA supplement ameliorated growth and spatial learning and memory impairment and upregulated the mTOR pathway in preterm pups, although excessive DHA supplement did not have any beneficial effects.

Effect of parental physiological conditions and assisted reproductive technologies on the pregnancy and birth outcomes in infertile patients.

Assisted reproductive technologies (ART) are widely used to treat infertility. Emerging evidence suggested that ART was associated with perinatal or neonatal problems, however, little is known about the ART related risk factors. Here using 21136 ART cases, we determined the impacts of parental physiological conditions in the ART mediated pregnancy outcomes. In addition, we further evaluated the effects of three different ART methods (frozen-thawed embryo transfer [FET], in vitro fertilization [IVF] and intracytoplasmic sperm injection [ICSI]) in the pregnancy and birth outcomes in ART mediated pregnancy. Our data revealed that older parental age increases the risks of abortion, preterm birth and low body weight birth. Higher maternal BMI (Body mass index) level correlates with higher abortion rate. Moreover, pregnancy with multiple fetuses has severer adverse outcomes compared to singleton pregnancy. Among the three ART methods, ICSI is associated with lower ratios of ectopic pregnancy, abortion and deformity compared to FET and IVF. Our study revealed new clinical insights into the ART related risk factors and suggested that both the parental physiological conditions and ART methods should be evaluated to develop better ART mediated infertility treatments.