Gestational Hypoxia Impaired Endothelial Nitric Oxide Synthesis Via miR-155-5p/NADPH Oxidase/Reactive Oxygen Species Axis in Male Offspring Vessels.

BACKGROUND: Nitric oxide (NO) is the most important vasodilator secreted by vascular endothelial cells, and its abnormal synthesis is involved in the development of cardiovascular disease. The prenatal period is a critical time for development and largely determines lifelong vascular health in offspring. Given the high incidence and severity of gestational hypoxia in mid-late pregnancy, it is urgent to further explore whether it affects the long-term synthesis of NO in offspring vascular endothelial cells. METHODS AND RESULTS: Pregnant Sprague-Dawley rats were housed in a normoxic or hypoxic (10.5% O2) chamber from gestation days 10 to 20. The thoracic aortas of fetal and adult male offspring were isolated for experiments. Gestational hypoxia significantly reduces the NO-dependent vasodilation mediated by acetylcholine in both the fetal and adult offspring thoracic aorta rings. Meanwhile, acetylcholine-induced NO synthesis is impaired in vascular endothelial cells from hypoxic offspring thoracic aortas. We demonstrate that gestational hypoxic offspring exhibit a reduced endothelial NO synthesis capacity, primarily due to increased expression of NADPH oxidase 2 and enhanced reactive oxygen species. Additionally, gestational hypoxic offspring show elevated levels of miR-155-5p in vascular endothelial cells, which is associated with increased expression of NADPH oxidase 2 and reactive oxygen species generation, as well as impaired NO synthesis. CONCLUSIONS: The present study is the first to demonstrate that gestational hypoxia impairs endothelial NO synthesis via the miR-155-5p/NADPH oxidase 2/reactive oxygen species axis in offspring vessels. These novel findings indicate that the detrimental effects of gestational hypoxia on fetal vascular function can persist into adulthood, providing new insights into the development of vascular diseases.

Tracing the geographical origin of endangered fungus Ophiocordyceps sinensis, especially from Nagqu, using UPLC-Q-TOF-MS.

Ophiocordyceps sinensis (OS), known as "soft gold", played an important role in local economic development. OS from different producing areas was difficult to be discriminated by the appearance. Nagqu OS, a distinguished and safeguarded geographical indication product, commands a premium price in market. The real claim of OS geographical origins is urgently required. Here, 81 OS samples were collected from Tibetan Plateau in China to explore markers for tracing origins. OS from Xigazê can be distinguished by dark color of head of caterpillar. Then 57 samples, a fully representative training-sample set, were used to set up OPLS-DA models by nontargeted metabolomics from UPLC-QTOF-MS. Certain markers were successfully identified and validation using 21 blind test samples confirmed that the markers can trace the geographical origin of OS, especially Nagqu samples. It was affirmed that UPLC-QTOF-MS-based untargeted metabolomics coupled with OPLS-DA was a reliable strategy to trace the geographical origins of OS.

Calcium signals and potential therapy targets in ovarian cancer (Review).

Ovarian cancer (OC) is a deadly disease. The poor prognosis and high lethality of OC are attributed to its high degrees of aggressiveness, resistance to chemotherapy and recurrence rates. Calcium ion (Ca2+) signaling has received attention in recent years, as it appears to form an essential part of various aspects of cancer pathophysiology and is a potential therapeutic target for OC treatment. Disruption of normal Ca2+ signaling pathways can induce changes in cell cycle progression, apoptosis, proliferation and migration and invasion, leading to the development of the malignant phenotype of tumors. In the present review, the main roles of ion channel/receptor/pump­triggered Ca2+ signaling pathways located at the plasma membrane and organelle Ca2+ transport in OC are summarized. In addition, the potential of Ca2+ signaling as a novel target for the development of effective treatment strategies for OC was discussed. Furthering the understanding into the role of Ca2+ signaling in OC is expected to facilitated the identification of novel therapeutic targets and improved clinical outcomes for patients.

Prenatal dexamethasone exposure impaired vascular reactivity in adult male offspring cerebral arteries.

BACKGROUND: Cerebrovascular disease is one of the leading causes of death worldwide. Middle cerebral artery (MCA) is the largest and most complex of cerebral arteries. The prenatal period is a critical time for development, which largely determines lifelong health. Clinically, glucocorticoids (GCs) administration to accelerate preterm fetal lung maturation has become standard practice. Prenatal GCs administration increases cardiovascular risks in offspring, but little is known regarding the side effects on offspring MCA function. OBJECTIVE: We investigated the alterations of MCA reactivity following prenatal GCs administration in postnatal offspring. METHOD AND RESULTS: Pregnant Sprague-Dawley rats received synthetic GCs (dexamethasone, DEX) during the last week of pregnancy, and we examined vascular reactivity, cellular electrophysiology, and gene promoter epigenetic modifications in the male offspring MCA. Our results showed that prenatal DEX exposure increased the sensitivity of offspring MCA to Angiotensin II, which was resulted from the increased Cav1.2 (L-type Ca2+ channels subunit alpha1 C). Mechanistically, prenatal DEX exposure resulted in a transcriptionally active chromatin structure at the Cav1.2 gene promoter by altering histone modifications. This activation led to increased expression of vascular Cav1.2 gene, ultimately resulting in increased MCA contractility in offspring. CONCLUSION: The present study is the first to demonstrate that the adverse effects of prenatal GCs administration on cerebrovascular tone persist into adulthood, providing new insights into developmental origins of cerebrovascular disease.

Recent Developments on the Roles of Calcium Signals and Potential Therapy Targets in Cervical Cancer.

Intracellular calcium (Ca2+) concentration ([Ca2+]i) is implicated in proliferation, invasion, and metastasis in cancerous tissues. A variety of oncologic therapies and some candidate drugs induce their antitumor effects (in part or in whole) through the modulation of [Ca2+]i. Cervical cancer is one of most common cancers among women worldwide. Recently, major research advances relating to the Ca2+ signals in cervical cancer are emerging. In this review, we comprehensively describe the current progress concerning the roles of Ca2+ signals in the occurrence, development, and prognosis of cervical cancer. It will enhance our understanding of the causative mechanism of Ca2+ signals in cervical cancer and thus provide new sights for identifying potential therapeutic targets for drug discovery.

Research progress of placental vascular pathophysiological changes in pregnancy-induced hypertension and gestational diabetes mellitus.

The placenta is a vital organ for fetal development, providing the fetus with nutrients, oxygen, and other important factors. Placenta is rich in blood vessels. Abnormal placental vascular function and blood circulation may lead to insufficient blood supply to the fetus in the uterus, leading to serious consequences such as pregnancy complications, fetal distress and even stillbirth. Pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM) are common complications of pregnancy. Recent studies report that pregnancy complications are often accompanied by changes in placental vascular structure and function. What are the physiological characteristics of human placental blood vessels? What are the pathological changes in the state of PIH and GDM? What are the relationships between these pathological changes and the occurrence of these pregnancy complications? Answers to these questions not only increase the understanding of placental vascular characteristics, but also provide important information for revealing the pathological mechanism of PIH and GDM. This article will summarize the research on the pathological changes of placental blood vessels in PIH and GDM, hoping to further unravel the physiological and pathological characteristics of placental blood vessels in the state of PIH and GDM, provide information for guiding clinical treatment for PIH and GDM.

Research Progress of DNA Methylation in Endometrial Cancer.

Endometrial cancer (EC)) is one of the most common malignant tumors of the female genital system, with an increasing incidence and mortality, worldwide. Although the therapeutic strategy of EC is still complicated and challenging, further understanding of carcinogenesis from a gene perspective would allow an effort to improve therapeutic precision in this complex malignancy. DNA methylation is the most widely studied epigenetic alteration in human tumors. Aberrant DNA methylation events, resulting in altered gene expression, are features of many tumor types. In this review, we provide an update on evidence about the roles of aberrant DNA methylation within some classical tumor suppressor genes and oncogenes in endometrial carcinogenesis, and report on recent advances in the understanding of the contribution of aberrant DNA methylation to EC, as well as opportunities and challenges of DNA methylation in EC management and prevention.

Antenatal Dexamethasone Exposure Impairs Vascular Contractile Functions via Upregulating IP3 Receptor 1 and Cav1.2 in Adult Male Offspring.

BACKGROUND: Administration of antenatal glucocorticoids remains common practice for treating preterm delivery. Antenatal glucocorticoid exposure increased the risk of developing vascular diseases in later life, but the precise mechanisms remain unclear. This study aimed to explore the effects and mechanisms of antenatal exposure to clinically relevant doses of dexamethasone (synthetic glucocorticoids) on vascular functions in adult male offspring. METHODS: Pregnant Sprague-Dawley rats received dexamethasone or vehicle during the last week of pregnancy. Male offspring were killed at gestational day 21 (Fetus) or postnatal day 120 (adult offspring). Mesenteric arteries were collected for vascular function, electrophysiology, target gene expression, and promotor methylation studies. RESULTS: Antenatal dexamethasone exposure increased phenylephrine-mediated vascular contractility in offspring, which was resulted by the activated inositol 1,4,5-trisphosphate (IP3) receptor and L-type Ca2+ channels. Specifically, increases of IP3R1 (IP3 receptor 1) and Cav1.2 (L-type Ca2+ channels subunit alpha1 C) were responsible for an activated IP3-Ca2+ pathway in the vasculature, and eventually predisposed the antenatal dexamethasone offspring to vascular hypercontractility. In addition, IP3R1 and Cav1.2 was upregulated through transcriptional mechanism; the overall changes in promotor histone modifications were consistent with the corresponding changes in transcriptional levels of the 2 genes, suggesting that antenatal dexamethasone exposure activated the transcription of IP3R1 and Cav1.2 via altering promotor histone modifications. CONCLUSIONS: Taken together, this study demonstrated that antenatal dexamethasone exposure resulted in vascular adverse outcomes in male offspring that is linked to the increases of IP3R1 and Cav1.2 mediated by epigenetic modifications in the vasculature.

Unveiling the Role of DNA Methylation in Vascular CACNA1C Tissue-Specific Expression.

Objective: Calcium voltage-gated channel subunit alpha1 C (CACNA1C) plays a critical role in many vascular physiological and pathological processes. Determining its tissue-specific expression pattern and clarifying the underlying molecular mechanisms are necessary and meaningful. Methods: We selected several representative vessels from normal male Sprague-Dawley rats. Vessel tissue or primary vascular smooth muscle cells were isolated for vascular function, electrophysiology, gene expression and promoter methylation studies. Results: We found CACNA1C had tissue-specific expressions in vessels. The specific manifestations were as follows: CACNA1C expression was highest in thoracic aorta, second lowest in middle cerebral and pulmonary artery, and lowest in mesenteric artery. Excitingly, an opposing trend was observed between CACNA1C expression and its promoter methylation. Conclusions: This study was the first report to indicate that DNA methylation could be involved in regulating CACNA1C tissue-specific expressions and vasoconstriction function in vascular system. This study not only provided more information for further understanding the physiological characteristics of vascular CACNA1C expressions, also strengthened the idea that DNA methylation plays important roles in regulating vascular smooth muscle cells function and the consequent occurrence of vascular diseases.

Effects of prenatal hypoxia on placental glucocorticoid barrier: Mechanistic insight from experiments in rats.

Prenatal hypoxia is the most common stress in mid-late gestation that usually arise from maternal, placental and/or fetal factors. As a multifunctional organ enabling optimal fetal growth, placenta must adapt to diverse environmental stressors. Excessive glucocorticoids exposure is known to have adverse effects on fetal growth. The fetus is shielded by a placental glucocorticoid barrier by 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2). However, the effects and underlying mechanisms of intrauterine hypoxia on placental glucocorticoid barrier are largely unknown. This study was the first to determine the effects and its mechanisms. Pregnant rats were exposed to hypoxia (10.5% O2) from gestational day (GD)10-20. At GD20, expression of 11-ßHSD2 were determined in placenta, and corticosterone levels were measured in maternal and fetal plasma. Prenatal hypoxia disrupted the placental glucocorticoid barrier by suppressing 11-ßHSD2 expression. Meanwhile, the decreased 11-ßHSD2 was correlated with an increased DNA methylation within its gene promoter. Together, these results indicated that prenatal hypoxia impair placental glucocorticoid barrier, was strongly associated with reprogrammed 11-ßHSD2 expression via a DNA methylation-mediated epigenetic mechanism.

Antenatal dexamethasone retarded fetal long bones growth and development by down-regulating of insulin-like growth factor 1 signaling in fetal rats.

OBJECTIVE: Dexamethasone (DEX), a synthetic glucocorticoid, has been widely used as a medication for premature delivery. However, the side effects of antenatal DEX treatment on fetal bone development, as well as the underlying mechanisms still remain to be elucidated. Here, we aimed to explore the effects and the related mechanisms of antenatal DEX exposure during late pregnancy on fetal bone growth and development. METHODS: Pregnant Sprague-Dawley rats were randomly divided into DEX group and vehicle group from gestational day 14 (GD14). Pregnant rats in DEX group were intraperitoneally injected once with DEX (200 µg/kg body weight) on GD14, 16, 18, and 20. The vehicle group rats were administered the same amount of normal saline at the same time. Pregnant rats were anesthetized at GD21 to harvest fetal femurs for analysis. RESULTS: Antenatal DEX treatment delayed fetal skeletal growth via inhibiting extracellular matrix (ECM) synthesis and downregulating insulin-like growth factor 1 (IGF1) signaling. Several components of IGF1 signaling pathway, including IGF1 receptor, insulin receptor substrate, as well as serine-threonine protein kinase, were down-regulated in fetal growth plate chondrocytes following DEX treatment. CONCLUSION: This study indicated that antenatal DEX treatment-retarded fetal skeletal growth was associated with the down-regulation of IGF1 signaling in growth plate chondrocytes, providing important information about the impact of antenatal DEX application four courses on premature infant.

Correlation of amniotic fluid index and placental aquaporin 1 levels in terms of preeclampsia.

INTRODUCTION: Aquaporin 1 (AQP1) plays an important role in regulation of maternal-fetal fluid exchange and amniotic fluid volume. This present study aimed to determine the relationship between amniotic fluid index and placental AQP1 levels in terms of preeclampsia, and to reveal possible pathophysiological changes of AQP1 expression under preeclamptic conditions. METHODS: Placental tissues and medical records information were obtained from 389 preeclamptic and 447 uncomplicated pregnancies. Placental AQP1 levels were analyzed by molecular biological methods, DNA methylation within gene promotor was determined by targeted bisulfite sequencing assay. RESULTS: Here, we found that preeclamptic pregnancy had a greater frequency of oligohydramnios, and higher placental AQP1 levels. There was a significantly inverse correlation between amniotic fluid index and placental AQP1 levels in preeclampsia cases. Additionally, the increased AQP1 was correlated with a decreased DNA methylation within its gene promoter. DISCUSSION: Overall, this was the first description that a greater frequency of oligohydramnios in preeclampsia was strongly associated with reprogrammed AQP1 expression via a DNA methylation-mediated epigenetic mechanism. This study suggested AQP1 might play an important role in regulating maternal-fetal fluid balance under preeclamptic conditions, providing new information for further understanding the pathophysiological mechanism of oligohydramnios in preeclampsia.

Antenatal Hypoxia Affects Pulmonary Artery Contractile Functions via Downregulating L-type Ca2+ Channels Subunit Alpha1 C in Adult Male Offspring.

Background Antenatal intrauterine fetal hypoxia is a common pregnancy complication that has profound adverse effects on an individual's vascular health later in life. Pulmonary arteries are sensitive to hypoxia, but adverse effects of antenatal hypoxia on pulmonary vasoreactivities in the offspring remain unknown. This study aimed to determine the effects and related mechanisms of antenatal hypoxia on pulmonary artery functions in adult male offspring. Methods and Results Pregnant Sprague-Dawley rats were housed in a normoxic or hypoxic (10.5% O2) chamber from gestation days 10 to 20. Male offspring were euthanized at 16 weeks old (adult offspring). Pulmonary arteries were collected for vascular function, electrophysiology, target gene expression, and promoter methylation studies. In pulmonary artery rings, contractions to serotonin hydrochloride, angiotensin II, or phenylephrine were reduced in the antenatal hypoxic offspring, which resulted from inactivated L-type Ca2+ channels. In pulmonary artery smooth muscle cells, the basal whole-cell Ca2+ currents, as well as vasoconstrictor-induced Ca2+ transients were significantly reduced in antenatal hypoxic offspring. In addition, increased promoter methylations within L-type Ca2+ channel subunit alpha1 C were compatible with its reduced expressions. Conclusions This study indicated that antenatal hypoxia programmed long-lasting vascular hypocontractility in the male offspring that is linked to decreases of L-type Ca2+ channel subunit alpha1 C in the pulmonary arteries. Antenatal hypoxia resulted in pulmonary artery adverse outcomes in postnatal offspring, was strongly associated with reprogrammed L-type Ca2+ channel subunit alpha1 C expression via a DNA methylation-mediated epigenetic mechanism, advancing understanding toward the effect of antenatal hypoxia in early life on long-term vascular health.

DNA Methylation-Reprogrammed Ang II (Angiotensin II) Type 1 Receptor-Early Growth Response Gene 1-Protein Kinase C ε Axis Underlies Vascular Hypercontractility in Antenatal Hypoxic Offspring.

As the most common clinical stress during mid and late pregnancy, antenatal hypoxia has profound adverse effects on individual's vascular health later in life, but the underlying mechanisms are still not understood. The purpose of this study was to reveal the mechanisms of the acquired vascular dysfunction in offspring imposed by antenatal hypoxia. Pregnant rats were housed in a normoxic or hypoxic (10.5% oxygen) chamber from gestation day 10 to 21. Male offspring were euthanized at gestational day 21 (fetus) or postnatal 16 weeks old (adult offspring). Mesenteric arteries were collected for examining Ang II (angiotensin II)-mediated vascular contractility, gene expression, and promoter methylation. Antenatal hypoxia increased vascular sensitivity to Ang II, which was resulted by an upregulated AT1R (angiotensin II type 1 receptor). The increased AT1R was correlated with a hypomethylation-mediated activated transcription of Agtr1a (alpha subtype of AT1R). In addition, we presented evidences that there was an AT1R-Egr1 (early growth response gene 1)-PKCε (ε isoform of protein kinase C) axis in vasculature; AT1R could modulate PKCε expression via upregulating Egr1; Egr1 mediated transcription activation of PKCε via Egr1 binding sites in PKCε gene promoter. Overall, antenatal hypoxia activated AT1R-Egr1-PKCε axis in vasculature, eventually predisposed offspring to vascular hypercontractility. This is the first description that antenatal hypoxia resulted in vascular adverse outcomes in postnatal offspring, was strongly associated with reprogrammed gene expression via a DNA methylation-mediated epigenetic mechanism, advancing understanding toward the influence of adverse antenatal factors in early life on long-term vascular health.

Measurement and Visualization of Tight Rock Exposed to CO2 Using NMR Relaxometry and MRI.

Understanding mechanisms of oil mobilization of tight matrix during CO2 injection is crucial for CO2 enhanced oil recovery (EOR) and sequestration engineering design. In this study exposure behavior between CO2 and tight rock of the Ordos Basin has been studied experimentally by using nuclear magnetic resonance transverse relaxation time (NMR T2) spectrum and magnetic resonance imaging (MRI) under the reservoir pressure and temperature. Quantitative analysis of recovery at the pore scale and visualization of oil mobilization are achieved. Effects of CO2 injection, exposure times and pressure on recovery performance have been investigated. The experimental results indicate that oil in all pores can be gradually mobilized to the surface of rock by CO2 injection. Oil mobilization in tight rock is time-consuming while oil on the surface of tight rock can be mobilized easily. CO2 injection can effectively mobilize oil in all pores of tight rock, especially big size pores. This understanding of process of matrix exposed to CO2 could support the CO2 EOR in tight reservoirs.