Dysregulation of Ceramide Metabolism Is Linked to Iron Deposition and Activation of Related Pathways in the Aorta of Atherosclerotic Miniature Pigs.

The miniature pig is a suitable animal model for investigating human cardiovascular diseases. Nevertheless, the alterations in lipid metabolism within atherosclerotic plaques of miniature pigs, along with the underlying mechanisms, remain to be comprehensively elucidated. In this study, we aim to examine the alterations in lipid composition and associated pathways in the abdominal aorta of atherosclerotic pigs induced by a high-fat, high-cholesterol, and high-fructose (HFCF) diet using lipidomics and RNA-Seq methods. The results showed that the content and composition of aortic lipid species, particularly ceramide, hexosyl ceramide, lysophosphatidylcholine, and triglyceride, were significantly altered in HFCF-fed pigs. Meanwhile, the genes governing sphingolipid metabolism, iron ion homeostasis, apoptosis, and the inflammatory response were significantly regulated by the HFCF diet. Furthermore, C16 ceramide could promote iron deposition in RAW264.7 cells, leading to increased intracellular reactive oxygen species (ROS) production, apoptosis, and activation of the toll-like receptor 4 (TLR4)/nuclear Factor-kappa B (NF-қB) inflammatory pathway, which could be mitigated by deferoxamine. Our study demonstrated that dysregulated ceramide metabolism could increase ROS production, apoptosis, and inflammatory pathway activation in macrophages by inducing iron overload, thus playing a vital role in the pathogenesis of atherosclerosis. This discovery could potentially provide a new target for pharmacological therapy of cardiovascular diseases such as atherosclerosis.

Atmospheric carbonyls in a heavy ozone pollution episode at a metropolis in Southwest China: Characteristics, health risk assessment, sources analysis.

Ambient carbonyls were continuously observed in the field during a heavy ozone pollution episode in Chengdu, China from August 4 to August 19, 2019, and the pollution characteristics, atmospheric photochemical reactivity, human health risk, and sources of carbonyls were analyzed. Fifteen carbonyls were quantified with average total mixing ratios of 20.38 ppbv Formaldehyde (9.86 ppbv), acetone (4.41 ppbv), and acetaldehyde (3.57 ppbv) were the three most abundant carbonyls. During the heavy ozone pollution episode, the concentration of carbonyls was found to be higher on pollution days than on the clean days, and relatively higher in the daytime, especially at noon on the pollution days. This was influenced by the intensity of photochemical reactions and precipitation. The "weekend effect" with the concentration of carbonyls was higher on the weekends than on the weekdays was pointed out. Formaldehyde, acetaldehyde and hexaldehyde were the dominant oxidative species during the observation. The carcinogenic and non-carcinogenic risk values of formaldehyde and acetaldehyde were higher on pollution days than on clean days, and these values were higher compared with those of other cities in China and abroad. Long-term exposure to these compounds should therefore be avoided. Diagnostic ratios and correlation analysis together with backward trajectory analysis showed that primary emission and secondary formation accounted 66%-76% and 24%-34% of carbonyls in Chengdu, respectively, with primary emission being the main sources of carbonyls, and carbonyls from the surrounding cities and emission from natural sources also had a significant contribution to the carbonyls in Chengdu.

Testosterone deficiency accelerates early stage atherosclerosis in miniature pigs fed a high-fat and high-cholesterol diet: urine 1H NMR metabolomics targeted analysis.

To gain insights into the role of testosterone in the development of atherosclerosis and its related metabolic pathways, we applied a proton nuclear magnetic resonance (1H NMR)-based metabolomics approach to investigate urine metabolic profiles in miniature pigs fed a high-fat and high-cholesterol (HFC) diet among intact male pigs (IM), castrated male pigs (CM) and castrated male pigs with testosterone replacement (CMT). Our results showed that testosterone deficiency significantly increased atherosclerotic lesion areas, intima-media thickness, as well as serum lipid levels in the CM pigs. Moreover, seventeen significantly changed metabolites were identified in both IM vs. CM and CMT vs. CM groups. Among these, seven were shared between the two comparative groups and were all significantly reduced in the urine of the CM group but rescued in the CMT group. In addition, the correlation analysis demonstrated that several metabolites, including niacinamide, myo-inositol, choline and 3-hydroxyisovalerate, were negatively correlated with atherosclerotic lesion areas. Our study demonstrated that testosterone deficiency accelerated early AS formation in HFC diet-fed pigs, which involved several metabolites predominantly related to lipid metabolism, inflammation, oxidative stress and endothelial disorders. Our results reveal potential pathways in the pathogenesis of atherosclerosis caused by testosterone deficiency and HFC diet.

Differential metabolic and hepatic transcriptome responses of two miniature pig breeds to high dietary cholesterol.

AIMS: Pigs are increasingly used as human metabolic disease models; however, there is insufficient research on breed-related genetic background differences. This study aimed to investigate the differential metabolic responses to high-fat and high-cholesterol (HFC) diet-induced non-alcoholic fatty liver disease (NAFLD) of two miniature pig breeds and explore the molecular mechanisms involved. MAIN METHODS: Male Wuzhishan (WZSP) and Tibetan pigs (TP) were randomly fed either a standard or an HFC diet for 24 weeks. Weight, serum lipids, bile acid, insulin resistance, liver function, liver histology, and hepatic lipid deposition were determined. RNA-Seq was used to detect the hepatic gene expression profiles. Western blot, immunohistochemistry, and qRT-PCR were used to detect the lipid and glucose metabolism-related gene expressions. KEY FINDINGS: The HFC diet caused obesity, hypertension, severe hypercholesterolemia, liver injury, increased hepatocellular steatosis and inflammation, and significantly increased serum insulin levels in both pig breeds. This diet led to higher serum and hepatic cholesterol level concentrations in WZSP and elevated fasting glucose levels in TP. Transcriptome analysis revealed that the genes controlling hepatic cholesterol metabolism and the inflammatory response were consistently regulated; lipid metabolism and insulin signaling related genes were uniquely regulated by the HFC diet in the WZSP and TP, respectively. SIGNIFICANCE: Our study demonstrated that the genetic background affects profoundly pigs' metabolic and hepatic responses to an HFC diet. These results deepened our understanding of the molecular mechanisms of HFC diet-induced NAFLD and provided a foundation for selecting the appropriate pig breeds for metabolic studies in the future.

Transcriptome profiling reveals multiple pathways responsible for the beneficial metabolic effects of Smilax glabra flavonoids in mouse 3T3-L1 adipocytes.

Smilax glabra Roxb. (SG) is a well-known traditional Chinese medicine that has been extensively used as both food and folk medicine in many countries. Although many beneficial health effects of SG and its primary components have been reported, their action on adipocyte function remains unknown. In the present study, we investigated the effects of the total flavonoids from Smilax glabra Roxb. (SGF) on lipid accumulation in mouse 3T3-L1 adipocytes and further elucidated its potential mechanism using RNA-Seq transcriptome technique. Our results showed that SGF exposure significantly decreased the lipid droplet size and the levels of cellular free fatty acids, while triglyceride accumulation was not affected by SGF. Transcriptome analysis revealed that SGF induced the expression of genes involved in triglyceride storage, fatty acid ß-oxidation and mitochondrial biogenesis. Furthermore, we also observed an increased cellular ATP level and mitochondrial mass after SGF exposure, indicating that SGF enhanced mitochondrial function. The other relevant transcriptional changes appeared to be involved in AMPK/PGC-1α signaling, inflammatory response, as well as PI3K/AKT and calcium signaling pathways, which might contribute to the beneficial metabolic effects of SGF on adipocyte function. The results of Western blotting confirmed that SGF could increase the phosphorylation of AMPK while decrease the phosphorylation of AKT in adipocytes. Altogether, our results provided novel information about the molecular mechanism responsible for the effects of SGF on fat storage in adipocytes and highlights the potential metabolic benefits of SGF on human obesity and its related chronic diseases.

Early morning home blood pressure control among treated patients with controlled office blood pressure.

Elevated morning blood pressure (BP) has a significantly increased risk of cardiovascular events, so morning BP is of substantial clinical importance for the management of hypertension. This study aimed to evaluate early morning BP control and its determines among treated patients with controlled office BP. From May to October 2018, 600 treated patients with office BP < 140/90 mm Hg were recruited from hypertension clinics. Morning BP was measured at home for 7 days. Morning home systolic blood pressure (SBP) increased by an average of 11.5 mm Hg and that morning home diastolic blood pressure (DBP) increased by an average of 5.6 mm Hg compared with office BP. Morning home SBP, DBP, and their moving average were more likely to be lower among patients with a office SBP < 120 mm Hg than among patients with a office SBP ranging from 120 to 129 mm Hg and from 130 to 139 mm Hg (P < .001). A total of 45% of patients had early morning BP < 135/85 mm Hg. The following factors were significantly correlated with morning BP control: male sex, age of <65 years, absence of habitual snoring, no drinking, adequate physical activity, no habit of high salt intake, office BP < 120/80 mm Hg, and combination of a calcium channel blocker (CCB) and angiotensin receptor blocker or angiotensin-converting enzyme inhibitor (ARB/ACEI). Less than half of patients with controlled office BP had controlled morning BP and that positive changes may be related to an office BP < 120/80 mm Hg, combination of a CCB and ACEI/ARB and a series of lifestyle adjustments.

A risk score for carotid plaque as an assessment risk of cardiovascular risk among patients with hypertension.

This study aimed to describe the status of carotid plaques and develop a simple scoring system to predict the risk of carotid lesions in patients with hypertension. Basic testing for carotid plaques was carried out and used for risk score development (the training dataset, n = 2665) and validation (the test dataset, n = 1333). Independent predictors of carotid plaques from the multivariate model were assigned integer weights based on their coefficients and incorporated into a risk score. The discriminant ability of the score was tested by receiver operating characteristic analysis using the test dataset. A total of 1346 of 2665 patients were examined for carotid plaques, which were more frequent in men than in women, and increased with age. The final model included eight significant variables, and these variables were then used to develop a risk score for the prediction of carotid plaques. Receiver operating characteristic analysis demonstrated good discriminant power with a C-statistic of 0.732 (95% confidence interval: 0.713-0.751) and good calibration across quantiles of observed predicted risk (74.6%). We developed a simple risk score for the prediction of carotid plaques based on eight variables. The prediction model showed good discriminant power and calibration.

Control of cardiovascular disease risk factors among patients with type II diabetes in a primary-care setting in Beijing.

The aim of this study was to assess the control of blood glucose, blood pressure (BP), serum low-density lipoprotein cholesterol (LDL-c), and other cardiovascular disease risk factors among patients with type II diabetes in a primary-care setting in Beijing. We performed a cross-sectional, multi-center survey of 4056 patients with type II diabetes aged ≥40 years. In total, 22.6% were current smokers, 10.8% often drank alcohol, 29.0% were obese, and 67.4% participated in adequate levels of physical activity. About 70% of patients reported comorbid hypertension or dyslipidemia. Of these, 70.8% were being treated for diabetes and 79.3% for hypertension; 20.5% were receiving statins and 28.5% aspirin. The proportions of patients achieving their therapeutic target were 52.6% for fasting plasma glucose, 58.2% for BP, and 33.0% for LDL-c. Only 11.1% achieved all three goals. Among 1960 (48.3%) patients with a record of hemoglobin A1C, 27.8% achieved the hemoglobin A1C target (<6.5%). These data suggest that blood glucose and BP were more likely to be well controlled than LDL-c, the likelihood of control of multiple risk factors is low, and that the statin and aspirin use should be intensified in patients with a substantial risk of cardiovascular disease.

A preliminary analysis of the surface chemistry of atmospheric aerosol particles in a typical urban area of Beijing.

Atmospheric aerosol particle samples were collected using an Ambient Eight Stage (Non-Viable) Cascade Impactor Sampler in a typical urban area of Beijing from 27th Sep. to 5th Oct., 2009. The surface chemistry of these aerosol particles was analyzed using Static Time of Flight-Secondary Ion Mass Spectrometry (Static TOF-SIMS). The factors influencing surface compositions were evaluated in conjunction with the air pollution levels, meteorological factors, and air mass transport for the sampling period. The results show that a variety of organic ion groups and inorganic ions/ion groups were accumulated on the surfaces of aerosol particles in urban areas of Beijing; and hydrophobic organic compounds with short- or middle-chain alkyl as well as hydrophilic secondary inorganic compounds were observed. All these compounds have the potential to affect the atmospheric behavior of urban aerosol particles. PM1.1-2.1 and PM3.3-4.7 had similar elements on their surfaces, but some molecules and ionic groups demonstrated differences in Time of Flight-Secondary Ion Mass Spectrometry spectra. This suggests that the quantities of elements varied between PM1.1-2.1 and PM3.3-4.7. In particular, more intense research efforts into fluoride pollution are required, because the fluorides on aerosol surfaces have the potential to harm human health. The levels of air pollution had the most significant influence on the surface compositions of aerosol particles in our study. Hence, heavier air pollution was associated with more complex surface compositions on aerosol particles. In addition, wind, rainfall, and air masses from the south also greatly influenced the surface compositions of these urban aerosol particles.

Efficient transmembrane anion transport mediated by a bis(imidazolyl)-functionalized bis(choloyl) conjugate.

A bis(imidazolyl)-functionalized bis(choloyl) conjugate was synthesized and assessed for its transmembrane anionophoric activity by means of chloride ion selective electrode technique and pyranine assays. The results indicate that under the assay conditions, this conjugate was capable of mediating the symport of proton and anions, presumably via a channel mechanism. In addition, this compound was found to exhibit much higher anionophoric activity than the analogue without imidazolyl groups, revealing the significant role of the imidazolyl groups in the anion transport process.

2,6-Bis(benzimidazol-2-yl)pyridine as a potent transmembrane anion transporter.

2,6-Bis(benzimidazol-2-yl)pyridine was shown to exhibit potent anionophoric activity via a process of both Cl(-)/NO3(-) antiport and H(+)/Cl(-) symport. This is in sharp contrast to the finding that its corresponding N-methylated analog exhibited negligible activity and reveals the importance of the imidazolyl-NH fragments in the anion-transport process.

Gender-specific associations of sleep duration with uncontrolled blood pressure in middle-aged patients.

OBJECTIVE: The present study was designed to evaluate the associations between sleep duration and uncontrolled blood pressure in a hospital-based sample of middle-aged adults. METHODS: Between March 2012 and December 2012, a cross-sectional survey was conducted among the hypertensive outpatients of Anzhen Hospital and a community hospital in Beijing, China. Eligible participants were adults aged 35-55 years with an established diagnosis of hypertension and had been on standard antihypertensive drug treatment for at least 6 months. An interviewer-led questionnaire was used to collect the participants' demographic, lifestyle and dietary information, as well as medical histories. Usual sleep durations were categorized as <7 h, 7-8 h and >8 h per night. Logistic regression models were used to assess gender-specific associations between sleep duration and uncontrolled hypertension, with adjustment for age, gender, family history, diabetes, smoking, alcohol consumption and physical activity. RESULTS: A total of 3038 participants were finally investigated. Among them, 1569 (51.6%) patients had their blood pressure uncontrolled. In men, no significant association was found between sleep duration categories and uncontrolled hypertension. In women, compared with those sleeping <7 h, longer sleepers tended to have a lower risk of uncontrolled hypertension for sleeping 7-8 hours (odds ratio [OR] 0.537, 95% confidence interval [CI], 0.370-0.780) and sleeping >8 h (OR 0.316, 95% CI, 0.202-0.494), respectively. CONCLUSION: Modest associations between short sleep duration and uncontrolled hypertension were seen in middle-aged women but not in men in the hypertensive population.

Does lipophilicity affect the effectiveness of a transmembrane anion transporter? Insight from squaramido-functionalized bis(choloyl) conjugates.

Six squaramido-functionalized bis(choloyl) conjugates were synthesized and fully characterized on the basis of NMR ((1)H and (13)C) and ESI MS (LR and HR) data. Their transmembrane anionophoric activity was investigated in detail by means of chloride ion selective electrode technique and pyranine assay. The data indicate that this set of compounds is capable of promoting the transmembrane transport of anions presumably via proton/anion symport and anion exchange processes, and that lipophilicity in terms of clog P from 3.90 to 8.32 affects the apparent ion transport rate in a concentration-dependent fashion. Detailed kinetic analysis on the data obtained from both the chloride efflux and pH discharge experiments reveals that there may exist an optimum clog P range for the intrinsic ion transport rate. However, lipophilicity exhibits little effect on the effectiveness of this set of compounds in terms of either k2/Kdiss or EC50 values.

Survivin gene functions and relationships between expression and prognosis in patients with nasopharyngeal carcinoma.

This study aimed to investigate the relationship between prognosis and protein and mRNA expression of an apoptotic inhibitor gene, survivin, in patients with nasopharyngeal carcinoma. Furthermore, functions of the survivin gene in the CNE2 nasopharyngeal carcinoma cell line were assessed. Immunohistochemistry and in situ hybridization were used in detecting the survivin protein and mRNA in 44 nasopharyngeal carcinoma specimens, and 30 chronic nasopharyngitis samples as controls. Survivin gene expression in CNE2 cell line was suppressed with an shRNA (short hairpin RNA). The positive ratios of expression for survivin protein and mRNA in nasopharyngeal carcinoma were 79.5% and 75.0% respectively, obviously higher than in the control group (p<0.01), and there is very good consistency between the two methods. The mean survival time of patients with higher survivin protein or mRNA expression was shorter than in patients with lower levelsv(p<0.01). Proliferation of the CNE2 cell line was distinctly inhibited by the shRNA . The results indicate that overexpression of the survivin gene plays an important role in onset and development of nasopharyngeal carcinoma, and it may be helpful for prognostic appraisal.

Synthesis and transmembrane anion/cation symport activity of a rigid bis(choloyl) conjugate functionalized with guanidino groups.

A rigid bis(choloyl) conjugate functionalized with guanidino groups was synthesized and fully characterized on the basis of NMR ((1)H and (13)C) and ESI MS (LR and HR) data. Its transmembrane ionophoric activity across egg-yolk l-α-phosphatidylcholine-based liposomal membranes was investigated by means of chloride ion selective electrode technique and pH discharge assay. The data indicate that under the assay conditions, this conjugate was capable of promoting the transport of anions, presumably via a cation/anion symport process. A Hill analysis reveals that two molecules of this compound are assembled into the transport-active species.

Synthesis and potent ionophoric activity of a squaramide-linked bis(choloyl) conjugate.

A squaramide-linked bis(choloyl) conjugate was synthesized and fully characterized on the basis of NMR ((1)H and (13)C) and ESI MS (LR and HR) data. Fluorescence and chloride ion selective electrode assays indicate that this compound exhibits potent ionophoric activity across egg-yolk L-α-phosphatidylcholine-based liposomal membranes, presumably via an anion-modulating anion-cation co-transport/symport process. A Hill analysis reveals that three molecules of this compound are assembled into the transport-active species.

Synthesis and anionophoric activities of dimeric polyamine-sterol conjugates: the impact of rigid vs. flexible linkers.

Two dimeric spermine-choloyl conjugates were synthesized and found to be capable of promoting the transport of anions across egg-yolk L-α-phosphatidylcholine-based liposomal membranes, via an anion-exchange mechanism and with moderate selectivity with respect to monoanionic ions. A Hill analysis indicated that these two conjugates exhibited similar aggregation behaviors. However, the conjugate bearing a rigid p-bis(aminomethyl)benzene moiety functioned more efficiently than the analogue having a flexible putrescine linker.

Synthesis and ionophoric activities of functionalized bis(choloyl) conjugates with a rigid core.

Three bis(choloyl) conjugates bearing a rigid p-phenylenediamine/p-bis(aminomethyl)benzene linker and amino/acetamido groups were synthesized, and fully characterized on the basis of (1)H NMR, ESI-MS and HRMS. Their ionophoric activities were investigated by means of pH discharge assay. The results indicate that these conjugates exhibit potent ionophoric activities across egg-yolk l-α-phosphatidylcholine (EYPC)-based liposomal membranes, via a cation/proton antiport mechanism. They show moderate ion selectivity among alkali metal ions. Of the three conjugates, the ones having amino groups transport alkali metal ions in the order of Na(+)>Li(+)>K(+)≈Rb(+)≈Cs(+), whereas the one having acetamido groups functions in the order of Li(+)>Na(+)>K(+)≈Rb(+)≈Cs(+).

A Density Functional Study of [2+3] versus [2+2] Addition of Ethylene to Chromium-Oxygen Bonds in Chromyl Chloride.

Density functional theory (DFT) calculations have been carried out on the [2+2] and [2+3] addition of ethylene to Cr=O bonds in CrO(2)Cl(2). The [2+3] addition was found to be more favorable with an electronic reaction enthalpy of -9.6 kcal/mol and an activation barrier of 15.8 kcal/mol. The corresponding values for the [2+2] addition were 15.4 and 27.9 kcal/mol, respectively. It was concluded that epoxides formed in the reaction between CrO(2)Cl(2) and olefins are unlikely to originate from a [2+2] addition path to a Cr=O bond as previously suggested. The two addition reactions were analyzed by the intrinsic reaction coordinate method, and comparisons were made to a previous study of [2+2] and [2+3] addition by ethylene to OsO(4). Qualitative considerations were used to rationalize why the addition of ethylene to metal-oxygen bonds in tetrahedral d(0) oxo complexes seems more prone to proceed by a [2+3] mechanism.