Mechanism of Beraprost Effects on Pulmonary Hypertension: Contribution of Cross-Binding to PGE2 Receptor 4 and Modulation of O2 Sensitive Voltage-Gated K+ Channels

Background: The purpose of this study is to elucidate mechanism(s) by which the orally active PGI2 analog, Beraprost (BPS), ameliorates pulmonary hypertension (PH). Prostaglandins are an important treatment for PH. Mechanisms of their action are not fully elucidated in relation to receptor subtype and effects on O2 sensitive Kv channels.Methods: Distal (3rd order and beyond) pulmonary arteries from chronically hypoxic rats and from humans with established PH were studied. Measurements included pulmonary haemodynamics and histology, vascular reactivity, prostanoid receptor expression and activity of the O2 sensitive Kv channels.Results: Prostacyclin receptor (IP), prostaglandin receptor E3 (EP3) and prostaglandin receptor E4 (EP4) are the main pulmonary artery receptor subtypes in both rat and human pulmonary arteries. Circulating levels of PGI2 and PGE2 were reduced in PH. PH was also associated with reduced receptor expression of IP but not of EP4. The effects on IP expression were overcome with BPS. Dilatory responses in PH to BPS were reduced in the presence of EP4 blockade. Expression and activity of oxygen sensitive Kv channels were reduced in pulmonary artery smooth muscle cell from rats with PH and humans with PAH and were also overcome by administration of BPS. Effects of BPS on oxygen sensitive Kv channels were reduced in the presence of EP4 blockade implicating the EP4 receptor, as well as the IP receptor, in mediating BPS effects.Conclusion: Reduced expression of pulmonary IP receptors and reduced activity of O2 sensitive Kv channels are found in PH in both humans and rats. The orally active prostacyclin analogue, BPS, is able to reverse these changes, partly through binding to the EP4 receptor

Non-invasive imaging techniques for early diagnosis of bilateral cardiac dysfunction in pulmonary hypertension: current crests, future peaks

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease that eventually leads to heart failure (HF) and subsequent fatality if left untreated. Right ventricular (RV) function has proven prognostic values in patients with a variety of heart diseases including PAH. PAH is predominantly a right heart disease; however, given the nature of the continuous circulatory system and the presence of shared septum and pericardial constraints, the interdependence of the right and left ventricles is a factor that requires consideration. Accurate and timely assessment of ventricular function is very important in the management of patients with PAH for disease outcomes and prognosis. Non-invasive modalities such as cardiac magnetic resonance (CMR) and echocardiography (two-dimensional and three-dimensional), and nuclear medicine, positron emission tomography (PET) play a crucial role in the assessment of ventricular function and disease prognosis. Each modality has its own strengths and limitations, hence this review article sheds light on (i) ventricular dysfunction in patients with PAH and RV–LV interdependence in such patients, (ii) the strengths and limitations of all available modalities and parameters for the early assessment of ventricular function, as well as their prognostic value, and (iii) lastly, the challenges faced and the potential future advancement in these modalities for accurate and early diagnosis of ventricular function in PAH

MicroRNA-483 amelioration of experimental pulmonary hypertension.

Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with more severe disease. RNA-seq and bioinformatics analyses showed that miR-483 targets several PAH-related genes, including transforming growth factor-β (TGF-β), TGF-β receptor 2 (TGFBR2), β-catenin, connective tissue growth factor (CTGF), interleukin-1β (IL-1β), and endothelin-1 (ET-1). Overexpression of miR-483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF-β, TGFBR2, β-catenin, CTGF, IL-1β, and ET-1. In contrast, inhibition of miR-483 increased these genes in ECs. Rats with EC-specific miR-483 overexpression exhibited ameliorated pulmonary hypertension (PH) and reduced right ventricular hypertrophy on challenge with monocrotaline (MCT) or Sugen + hypoxia. A reversal effect was observed in rats that received MCT with inhaled lentivirus overexpressing miR-483. These results indicate that PAH is associated with a reduced level of miR-483 and that miR-483 might reduce experimental PH by inhibition of multiple adverse responses

Nitrogen Balance Index Prediction of Winter Wheat by Canopy Hyperspectral Transformation and Machine Learning

Nitrogen balance index (NBI) is an important indicator for scientific diagnostic and quantitative research on crop growth status. The quick and accurate assessment of NBI is necessary for farmers to make timely N management decisions. The objective of the study was to estimate winter wheat NBI based on canopy hyperspectral features between 400–1350 nm combined with machine learning (ML) methods in the individual and whole growth stages. In this study, 3 years of winter wheat plot experiments were conducted. Ground-level canopy hyperspectral reflectance and corresponding plant NBI values were measured during the jointing, booting, flowering and filling stages. Continuous removal spectra (CRS) and logarithmic transformation spectra (LOGS) were derived from the original canopy spectra. Sensitive bands and vegetation indices (VIs) highly correlated with NBI under different spectral transformations were selected as hyperspectral features to construct the NBI estimation models combined with ML algorithms. The study indicated that the spectral transformation significantly improved the correlation between the sensitive bands, VIs and the NBI. The correlation coefficient of the sensitive band in CRS in the booting stage increased by 27.87%, reaching −0.78. The leaf chlorophyll index (LCI) in LOGS had the highest correlation with NBI in the filling stage, reaching a correlation coefficient of −0.96. The NBI prediction accuracies based on the sensitive band combined with VIs were generally better than those based on the univariate hyperspectral feature, and the prediction accuracy of each growth stage was better than that of the whole growth stage. The random forest regression (RFR) method performed better than the support vector regression (SVR) and partial least squares regression (PLS) methods. The NBI estimation model based on the LOGS-RFR method in the filling stage could explain 95% of the NBI variability with relative prediction deviation (RPD) being 3.69. These results will provide a scientific basis for better nitrogen nutrition monitoring, diagnosis, and later for field management of winter wheat

miR-223 Inhibits Lipid Deposition and Inflammation by Suppressing Toll-Like Receptor 4 Signaling in Macrophages

Atherosclerosis and its complications rank as the leading cause of death with the hallmarks of lipid deposition and inflammatory response. MicroRNAs (miRNAs) have recently garnered increasing interests in cardiovascular disease. In this study, we investigated the function of miR-223 and the underlying mechanism in atherosclerosis. In the atherosclerotic ApoE−/− mice models, an obvious increase of miR-223 was observed in aortic atherosclerotic lesions. In lipopolysaccharide (LPS) activated macrophages, its expression was decreased. The miR-223 overexpression significantly attenuated macrophage foam cell formation, lipid accumulation and pro-inflammatory cytokine production, which were reversed by anti-miR-223 inhibitor transfection. Mechanism assay corroborated that miR-223 negatively regulated the activation of the toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) pathway. Pretreatment with a specific inhibitor of NF-κB (pyrrolidinedithiocarbamate, PDTC) strikingly abrogated miR-223 silence-induced lipid deposition and inflammatory cytokine production. Furthermore, PI3K/AKT was activated by miR-223 up-regulation. Pretreatment with PI3K/AKT inhibitor LY294002 strikingly ameliorated the inhibitory effects of miR-223 on the activation of TLR4 and p65, concomitant with the increase in lipid deposition and inflammatory cytokine production. Together, these data indicate that miR-223 up-regulation might abrogate the development of atherosclerosis by blocking TLR4 signaling through activation of the PI3K/AKT pathway, and provides a promising therapeutic avenue for the treatment of atherosclerosis

The relationship between maternal anxiety and cortisol during pregnancy and birth weight of chinese neonates

Abstract Background To determine the relationship between maternal anxiety and cortisol values and birth weight at various stages of pregnancy. Methods Two hundred sixteen pregnant Chinese women were assessed for anxiety and depression and had measurement of morning fasting serum cortisol. Women were assessed either in the first (71), second (72) or third (73) trimester. Birth weights of all children were recorded. Results There were significant negative correlations between anxiety level and birth weight of − 0.507 (p  0.5 for all). Maternal cortisol was significantly inversely related to birth weight in trimester 1 (r = − 0.322) and with borderline significance in trimester 2 (r = − 0.229). Anxiety score and maternal cortisol were significantly correlated in each trimester (r = 0.551, 0.650, 0.537). When both anxiety score and maternal cortisol were simultaneously included in multiple regression analyses only anxiety score remained significant. Conclusion Whilst both maternal anxiety score and maternal cortisol are inversely related to birth weight the associations with anxiety score were more robust perhaps indicating the importance of mechanisms other than, or in addition to, maternal cortisol in mediating the effects of anxiety. The findings indicate the importance of measures to reduce maternal anxiety, particularly of a severe degree, at all stages of pregnancy. Trial registration The study was approved by the Ethics Committee of the 1st Affiliated Hospital of Xi’an Jiaotong University

Comparison of inflammation, arterial stiffness and traditional cardiovascular risk factors between rheumatoid arthritis and inflammatory bowel disease

BACKGROUND: Inflammation plays an important role in the pathogenesis of atherosclerosis. The link between rheumatoid arthritis (RA) and an increased risk of cardiovascular disease and mortality is well established; however, the association between inflammatory bowel disease (IBD) and cardiovascular risk is controversial. Arterial stiffness is both a marker and risk factor for atherosclerosis. Here we aimed to 1) compare circulating markers of inflammation and endothelial dysfunction, traditional cardiovascular risk factors, and arterial stiffness between RA and IBD to help to understand their different associations with cardiovascular disease; 2) assess the impacts of circulating markers of inflammation and endothelial dysfunction, and traditional risk factors on arterial stiffness. METHODS: Patients with RA (n = 43) and IBD (n = 42), and control subjects (n = 73) were recruited. Plasma inflammatory markers and von Willebrand factor (vWF) were measured by Multiplex assays or ELISA. Arterial stiffness was determined by brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) was measured. Framingham Risk Score (FRS) was calculated, and other traditional risk factors were also documented. RESULTS: Plasma levels of several inflammatory markers and vWF were significantly but comparably elevated in RA and IBD compared with controls, except for a higher level of C-reactive protein (CRP) in RA than IBD. Compared to controls, FRS, body mass index, waist circumference, and triglycerides were increased in RA, but not in IBD. baPWV did not significantly differ among 3 groups, while ABI was modestly but significantly lower in IBD than controls. Circulating markers (macrophage migration inhibitory factor, tumour necrosis factor-α, CRP, and vWF) were significantly associated with baPWV. However, traditional risk factors (age, systolic blood pressure, body mass index, diabetes and triglycerides) were the parameters associated with baPWV in multiple regression analyses (overall r = 0.866, p < 0.001). CONCLUSIONS: RA has a higher level of CRP and more pronounced traditional cardiovascular risk factors than IBD, which may contribute to the difference in their associations with cardiovascular disease and mortality. Traditional risk factors, rather than inflammation markers, are major predictors of arterial stiffness even in subjects with inflammatory disorders. Our results point to the importance of modifying traditional risk factors in patients with inflammatory disorders

Aged black tea alleviates constipation in mice by modulating intestinal neurotransmitters and decreasing AQP3 and AQP9 expression

Background: Black tea is fully fermented tea with abundant functional components that benefit the gastrointestinal tract. But whether black tea extract relieves constipation is unknown. Therefore, we used loperamide to induce constipation in mice to assess the therapeutical effect of extracts from aged black tea with different storage times. Design: Sixty-three C57BL/6J male mice were randomly divided into Control group (Con), Model group (Mod), Positive group (Pos), aged 6 years group (15Y), aged 4 years group (17Y), aged 2 years group (19Y), and unaged group (21Y). Mice were given loperamide (20 mg/kg, twice a day) to induce constipation for 10 days, and black tea extracts (500 mg/kg) were intragastrically given for 7 days while continuing modeling. Results: The results showed that black tea extracts relieved constipation symptoms by improving defecation weight, fecal water content, and gastrointestinal transit rate. Black tea extracts can also protect colon tissue, regulate serum neurotransmitters, increase the levels of excitatory neurotransmitters motilin (MTL) and substance P (SP), and decrease the levels of inhibitory neurotransmitters vasoactive intestinal peptide (VIP) and nitric oxide (NO). Immunohistochemistry (IHC) showed that black tea extracts were able to reduce AQP3 and AQP9 expression in the colon of constipated mice. In addition, Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showed that black tea extracts could decrease AQP3 and AQP9 mRNA expression. The relief effect of aged black tea (15Y) with the longest storage was better than that of other years, which may be due to the role of active ingredients such as thearubigins (TRs), soluble sugar, tea polysaccharide (TPS), gallic acid (GA), and catechin gallate (CG) in aged black tea. Conclusions: Based on these results, we believe that regular consumption of black tea is effective in relieving constipation, and that black tea is more effective in relieving constipation as the storage time increases