Particulate matter, polycyclic aromatic hydrocarbons and metals, platelet parameters and blood pressure alteration: Multi-pollutants study among population.

Epidemiological findings have determined the linkage of fine particulate matter (PM2.5) and the morbidity of hypertension. However, the mode of action and specific contribution of PM2.5 component in the blood pressure elevation remain unclear. Platelets are critical for vascular homeostasis and thrombosis, which may be involved in the increase of blood pressure. Among 240 high-PM2.5 exposed, 318 low-PM2.5 exposed workers in a coking plant and 210 workers in the oxygen plant and cold-rolling mill enrolled in present study, both internal and external exposure characteristics were obtained, and we performed linear regression, adaptive elastic net regression, quantile g-computation and mediation analyses to analyze the relationship between urine metabolites of polycyclic aromatic hydrocarbons (PAHs) and metals fractions with platelets indices and blood pressure indicators. We found that PM2.5 exposure leads to increased systolic blood pressure (SBP) and pulse pressure (PP). Specifically, for every 10 µg/m3 increase in PM2.5, there was a 0.09 mmHg rise in PP. Additionally, one IQR increase in urinary 1-hydroxypyrene (1.06 µmol/mol creatinine) was associated with a 3.43 % elevation in PP. Similarly, an IQR increment of urine cobalt (2.31 µmol/mol creatinine) was associated with a separate 1.77 % and 4.71 % elevation of SBP and PP. Notably, platelet-to-lymphocyte ratio (PLR) played a mediating role in the elevation of SBP and PP induced by cobalt. Our multi-pollutants results showed that PAHs and cobalt were deleterious contributors to the elevated blood pressure. These findings deepen our understanding of the cardiovascular effects associated with PM2.5 constituents, highlighting the importance of increased vigilance in monitoring and controlling the harmful components in PM2.5.

Effect of botanical drugs in improving symptoms of hypertensive nephropathy: Analysis of real-world data, retrospective cohort, network, and experimental assessment.

Background/aim: Hypertensive nephropathy (HN) is a common complication of hypertension. Traditional Chinese medicine has long been used in the clinical treatment of Hypertensive nephropathy. However, botanical drug prescriptions have not been summarized. The purpose of this study is to develop a prescription for improving hypertensive nephropathy, explore the evidence related to clinical application of the prescription, and verify its molecular mechanism of action. Methods: In this study, based on the electronic medical record data on Hypertensive nephropathy, the core botanical drugs and patients' symptoms were mined using the hierarchical network extraction and fast unfolding algorithm, and the protein interaction network between botanical drugs and Hypertensive nephropathy was established. The K-nearest neighbors (KNN) model was used to analyze the clinical and biological characteristics of botanical drug compounds to determine the effective compounds. Hierarchical clustering was used to screen for effective botanical drugs. The clinical efficacy of botanical drugs was verified by a retrospective cohort. Animal experiments were performed at the target and pathway levels to analyze the mechanism. Results: A total of 14 botanical drugs and five symptom communities were obtained from real-world clinical data. In total, 76 effective compounds were obtained using the K-nearest neighbors model, and seven botanical drugs were identified as Gao Shen Formula by hierarchical clustering. Compared with the classical model, the Area under the curve (AUC) value of the K-nearest neighbors model was the best; retrospective cohort verification showed that Gao Shen Formula reduced serum creatinine levels and Chronic kidney disease (CKD) stage [OR = 2.561, 95% CI (1.025-6.406), p < 0.05]. With respect to target and pathway enrichment, Gao Shen Formula acts on inflammatory factors such as TNF-α, IL-1ß, and IL-6 and regulates the NF-κB signaling pathway and downstream glucose and lipid metabolic pathways. Conclusion: In the retrospective cohort, we observed that the clinical application of Gao Shen Formula alleviates the decrease in renal function in patients with hypertensive nephropathy. It is speculated that Gao Shen Formula acts by reducing inflammatory reactions, inhibiting renal damage caused by excessive activation of the renin-angiotensin-aldosterone system, and regulating energy metabolism.

Analyzing the pathogenesis of systemic lupus erythematosus complicated by atherosclerosis using transcriptome data.

Background: Accumulating evidence supports the predisposition of systemic lupus erythematosus (SLE) to atherosclerosis (AS). However, the common pathogenesis of these two diseases remains unclear. This study aimed to explore the mechanisms of SLE complicated by AS. Methods: Gene expression profiles of SLE (GSE50772) and AS (GSE100927) were downloaded from the Gene Expression Omnibus. We analyzed differentially expressed genes (DEGs) of SLE and AS and performed enrichment analyses separately. After analyzing the common DEGs (CDEGs), we performed functional enrichment analysis, protein-protein interaction (PPI) network analysis, and hub genes (HGs) identification of CDEGs. Then, we performed a co-expression analysis of HGs and verified their expression and diagnostic value. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells (IICs). Finally, we verified the reliability of the screening pathway. Results: We obtained 530 DEGs from the GSE50772 dataset and 448 DEGs from the GSE100927 dataset. The results of the enrichment analysis showed that there were many similar immune- and inflammation-related processes between the two diseases. We analyzed 26 CDEGs (two downregulated genes and 24 upregulated genes) and enrichment analysis highlighted the important role of the IL-17 signaling pathway. We identified five HGs (CCR1, CD163, IL1RN, MMP9, and SIGLEC1) using the CytoHubba plugin and HGs validation showed that the five HGs screened were reliable. Co-expression networks showed that five HGs can affect mononuclear cell migration. Immune cell infiltration analysis indicated monocytes in SLE and M0 macrophages in AS accounted for a high proportion of all IICs, and the difference in infiltration was obvious. We also found a significant positive correlation between CCR1, CD163, IL1RN, and MMP9 and monocytes in SLE, and a significant positive correlation between CCR1, IL1RN, MMP9, and SIGLEC1 and M0 macrophages in AS. Pathway validation also demonstrated that the IL-17 signaling pathway was a key pathway for the differentiation of monocytes into macrophages. Conclusions: The five HGs may promote the differentiation of monocytes into macrophages by influencing the IL-17 signaling pathway, leading to SLE complicated by AS. Our study provides insights into the mechanisms of SLE complicated by AS.

Predicting Coupled Herbs for the Treatment of Hypertension Complicated with Coronary Heart Disease in Real-World Data Based on a Complex Network and Machine Learning.

Hypertension and coronary heart disease are the most common cardiovascular diseases, and traditional Chinese medicine is applied as an auxiliary treatment for common cardiovascular diseases. This study is based on 3 years of electronic medical record data from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine. A complex network and machine learning algorithm were used to establish a screening model of coupled herbs for the treatment of hypertension complicated with coronary heart disease. A total of 5688 electronic medical records were collected to establish the prescription network and symptom database. The hierarchical network extraction algorithm was used to obtain core herbs. Biological features of herbs were collected from public databases. At the same time, five supervised machine learning models were established based on the biological features of the coupled herbs. Finally, the K-nearest neighbor model was established as a screening model with an AUROC of 91.0%. Seventy coupled herbs for adjuvant treatment of hypertension complicated with coronary heart disease were obtained. It was found that the coupled herbs achieved the purpose of adjuvant therapy mainly by interfering with cytokines and regulating inflammatory and metabolic pathways. These results show that this model can integrate the molecular biological characteristics of herbs, preliminarily screen combinations of herbs, and provide ideas for explaining the value in clinical applications.

Summarizing the Effective Herbs for the Treatment of Hypertensive Nephropathy by Complex Network and Machine Learning.

Hypertensive nephropathy is a common complication of hypertension. Traditional Chinese medicine has been used in the clinical treatment of hypertensive nephropathy for a long time, but the commonly used prescriptions have not been summarized, and the basic therapeutic approaches have not been discussed. Based on data from 3 years of electronic medical records of traditional Chinese medicine used at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine, a complex network and machine learning algorithm was used to explore the prescribed herbs of traditional Chinese medicine in the treatment of hypertensive nephropathy (HN). In this study, complex network algorithms were used to describe traditional Chinese medicine prescriptions for HN treatment. The Apriori algorithm was used to analyze the compatibility of these treatments with modern medicine. Data on the targets and regulatory genes related to hypertensive nephropathy and the herbs that affect their expression were obtained from public databases, and then, the signaling pathways enriched with these genes were identified on the basis of their participation in biological processes. A clustering algorithm was used to analyze the therapeutic pathways at multiple levels. A total of 1499 prescriptions of traditional Chinese medicines used for the treatment of hypertensive renal damage were identified. Fourteen herbs used to treat hypertensive nephropathy act through different biological pathways: huangqi, danshen, dangshen, fuling, baizhu, danggui, chenpi, banxia, gancao, qumai, cheqianzi, ezhu, qianshi, and niuxi. We found the formulae of these herbs and observed that they could downregulate the expression of inflammatory cytokines such as TNF, IL1B, and IL6 and the NF-κB and MAPK signaling pathways to reduce the renal inflammatory damage caused by excessive activation of RAAS. In addition, these herbs could facilitate the deceleration in the decline of renal function and relieve the symptoms of hypertensive nephropathy. In this study, the traditional Chinese medicine approach for treating hypertensive renal damage is summarized and effective treatment prescriptions were identified and analyzed. Data mining technology provided a feasible method for the collation and extraction of traditional Chinese medicine prescription data and provided an objective and reliable tool for use in determining the TCM treatments of hypertensive nephropathy.

Independent effect of main components in particulate matter on DNA methylation and DNA methyltransferase: A molecular epidemiology study.

BACKGROUND: There is a paucity of mechanistic information on the DNA methylation and particulate matter (PM) exposure. This study aimed to investigate the association of PM and its component with DNA methylation, and the roles of DNA methyltransferase (DNMTs). METHODS: There were 240 high-exposed, 318 low-exposed and 210 non-exposed participants in this study. Individual concentrations of PM, polycyclic aromatic hydrocarbons (PAHs) and metals were identified by the monitoring data in their workplaces. Urinary 1-OHP and metals were determined as exposure markers. The global DNA methylation (% 5mC) and the mRNA expression of DNMT1, DNMT3A and DNMT3B were measured. We used mediation analysis to evaluate the role of DNMTs expression on DNA methylation alteration induced by PAHs and metals components. RESULTS: The decreasing trend of % 5mC was associated with increment of PM exposure in all subjects. We found that one IQR increase in total PAHs (3.82 µg/m3) and urinary 1-OHP (1.06 µmol/mol creatinine) were associated with a separate 6.08% and 7.26% decrease in % 5mC (P = 0.009, P < 0.001), and one IQR increase in urinary Ni (27.75 µmol/mol creatinine) was associated with a 3.29% decrease in % 5mC (P = 0.03). The interaction of urinary 1-OHP with Ni on global DNA methylation (%5mC) was not found (P interaction = 0.89). PM exposure was significantly associated with decreased mRNA level of DNMT3B, but the mediated effect of the PAHs and Ni levels on % 5mC through the DNMT3B pathway was not observed. CONCLUSIONS: We found the decrement of global DNA methylation and DNMT3B expression with elevated PM levels in population. The independent mode of action on DNA hypomethylation was found from PAHs and metal components. Global DNA hypomethylation might be a potential biomarker for evaluation of adverse health effects in response to PM exposure.

Polycyclic aromatic hydrocarbons exposure and hematotoxicity in occupational population: A two-year follow-up study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational pollutants. To date, the effect and mechanism by which PAHs exposure impaired hematopoietic system remains unclear. METHODS: We examined the capability of PAHs to disrupt hematopoiesis in a study of 639 male participants in China by measuring complete blood counts (CBC) in 2013 and 2014. Gas chromatography-mass spectrometry (GC/MS) method was used to measure airborne levels of PAHs and benzene. We measured 1-hydroxypyrene (1-OHP), S-phenylmercapturic acid (SPMA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urinary by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method. RESULTS: We found decreased dose-response of white blood cells, eosinophils, monocytes and lymphocytes with increased PAHs exposure in two consecutive years. We did not find association between benzene with CBC in our study. After stratification analysis by smoking status, the findings were highly consistent. White blood cells, monocytes and red blood cell counts were decreased in high urinary 8-OHdG group. CONCLUSIONS: Our study showed that PAHs could impair the hematopoietic system independently, and oxidative stress might play an important role in potential hematotoxicity.

Declining Pulmonary Function in Populations with Long-term Exposure to Polycyclic Aromatic Hydrocarbons-Enriched PM2.5.

This study assesses the effects of long-term exposure to ambient air pollutants on inflammatory response and lung function. We selected 390 male coke oven workers with exposure to polycyclic aromatic hydrocarbons (PAHs) and fine particulate matter (PM2.5) and 115 control workers. The average duration in the exposed group was 9.10 years. The total amount of PAHs was more enriched in PM2.5 which collected from the coke oven workshops compared with the control areas. Correspondingly, the internal PAHs exposure indicated by urinary 1-hydroxypyrene (1-OHP) in the exposure group increased 25.7-fold compared to that of the control group. Moreover, the increasing level of urinary 1-OHP was associated with the decrease of forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC). In non-current smokers of exposure group, inverse correlation of 1-OHP with FEV1/FVC was also found. Particularly, an exposure duration-dependent decline in FEV1/FVC and mean forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%) indicated that small airways were functionally obstructed. Furthermore, the increasing serum high-sensitivity C-reactive protein (hs-CRP) was correlated with the decline in pulmonary function in all subjects. These findings provide a clue that long-term exposure to PAHs-enriched PM2.5 impairs pulmonary function in occupational population.

Reduced serum club cell protein as a pulmonary damage marker for chronic fine particulate matter exposure in Chinese population.

BACKGROUND: Exposure to fine particulate matter (PM2.5) pollution is associated with increased morbidity and mortality from respiratory diseases. However, few population-based studies have been conducted to assess the alterations in circulating pulmonary proteins due to long-term PM2.5 exposure. METHODS: We designed a two-stage study. In the first stage (training set), we assessed the associations between PM2.5 exposure and levels of pulmonary damage markers (CC16, SP-A and SP-D) and lung function in a coke oven emission (COE) cohort with 558 coke plant workers and 210 controls. In the second stage (validation set), significant initial findings were validated by an independent diesel engine exhaust (DEE) cohort with 50 DEE exposed workers and 50 controls. RESULTS: Serum CC16 levels decreased in a dose response manner in association with both external and internal PM2.5 exposures in the two cohorts. In the training set, serum CC16 levels decreased with increasing duration of occupational PM2.5 exposure history. An interquartile range (IQR) (122.0µg/m3) increase in PM2.5 was associated with a 5.76% decrease in serum CC16 levels, whereas an IQR (1.06µmol/mol creatinine) increase in urinary 1-hydroxypyrene (1-OHP) concentration was associated with a 5.36% decrease in serum CC16 levels in the COE cohort. In the validation set, the concentration of serum CC16 in the PM2.5 exposed group was 22.42% lower than that of the controls and an IQR (1.24µmol/mol creatinine) increase in urinary 1-OHP concentration was associated with a 12.24% decrease in serum CC16 levels in the DEE cohort. CONCLUSIONS: Serum CC16 levels may be a sensitive marker for pulmonary damage in populations with high PM2.5 exposure.

Cardiac Dysregulation and Myocardial Injury in a 6-Hydroxydopamine-Induced Rat Model of Sympathetic Denervation.

BACKGROUND: Cardiac sympathetic denervation is found in various cardiac pathologies; however, its relationship with myocardial injury has not been thoroughly investigated. METHODS: Twenty-four rats were assigned to the normal control group (NC), sympathectomy control group (SC), and a sympathectomy plus mecobalamin group (SM). Sympathectomy was induced by injection of 6-OHDA, after which, the destruction and distribution of sympathetic and vagal nerve in the left ventricle (LV) myocardial tissue were determined by immunofluorescence and ELISA. Heart rate variability (HRV), ECG and echocardiography, and assays for myocardial enzymes in serum before and after sympathectomy were examined. Morphologic changes in the LV by HE staining and transmission electron microscope were used to estimate levels of myocardial injury and concentrations of inflammatory cytokines were used to reflect the inflammatory reaction. RESULTS: Injection of 6-OHDA decreased NE (933.1 ± 179 ng/L for SC vs. 3418.1± 443.6 ng/L for NC, P < 0.01) and increased NGF (479.4± 56.5 ng/mL for SC vs. 315.85 ± 28.6 ng/mL for NC, P < 0.01) concentrations. TH expression was reduced, while ChAT expression showed no change. Sympathectomy caused decreased HRV and abnormal ECG and echocardiography results, and histopathologic examinations showed myocardial injury and increased collagen deposition as well as inflammatory cell infiltration in the cardiac tissue of rats in the SC and SM groups. However, all pathologic changes in the SM group were less severe compared to those in the SC group. CONCLUSIONS: Chemical sympathectomy with administration of 6-OHDA caused dysregulation of the cardiac autonomic nervous system and myocardial injuries. Mecobalamin alleviated inflammatory and myocardial damage by protecting myocardial sympathetic nerves.

Investigating the role of acute mental stress on endothelial dysfunction: a systematic review and meta-analysis.

Chronic stress is a known risk factor for both endothelial dysfunction and cardiovascular disease (CVD), but less is known of how acute mental stress affects the vasculature. In this systematic review and meta-analysis, we analyzed the impact of acute mental stress on flow-mediated dilation (FMD), an indicator of endothelial function. We searched the Medline, Cochrane, EMBASE, and ISI Web of Knowledge databases through May 2014, to identify publications in English-language journals. The primary outcome was the change in FMD from baseline to the time of measurement. We also assessed the risk of bias and the heterogeneity of included studies. Our search identified eight prospective studies, which displayed significant heterogeneity. Four studies measured FMD while the subject was performing the task; six measured FMD after the task had been completed. The total number of participants was 164. The pooled results indicate that FMD did not change significantly while the task was being performed (pooled difference in means: -0.853; 95 % confidence interval (CI), -3.926/2.220; P = 0.586); however, FMD measured after the task was completed was significantly less than baseline (pooled difference in means: -2.450; 95 %CI, -3.925/-0.975; P = 0.001). In conclusions, our findings provide evidence that an acute stressful experience has a delayed, negative impact on the function of the endothelium. Repeated exposure to short-term stress may lead to permanent injury of the vasculature. Therefore, assessment of patients' exposure to both repeated acute mental stress and chronic stress may be useful in determining their risk of developing CVD.

Effect of anger on endothelial-derived vasoactive factors in spontaneously hypertensive rats.

AIMS: We tested whether anger affects the balance between endothelium-derived vasodilators and vasoconstrictors in spontaneously hypertensive rats (SHRs). METHODS: Five endothelium-produced vasoactive factors (nitric oxide, prostacyclin, urotensin, endothelin and thromboxane B2) were measured in an established SHR behavioural model of anger, in "non-angry" SHR rats, and in control Wistar-Kyoto rats. RESULTS: All angry SHR rats showed the typical angry behaviour and angry SHR rats had significantly higher blood pressure and heart rate than control rats. Angry rats had significantly lower levels of two vasodilators, nitric oxide and prostacyclin, and significantly higher levels of two vasoconstrictors, endothelin and thromboxane B2 than either non-angry SHR or control rats. Levels of a third vasoconstrictor, urotensin, were significantly lower in angry SHR than in non-angry SHR or control rats. CONCLUSIONS: Our results suggest that anger causes an imbalance of endothelium-produced vasodilating and vasoconstricting substances. This may have implications for the development and/or progression of hypertension.