Yuedan Wang

Association Between Changes in Air Pollution Levels During the Beijing Olympics and Biomarkers of Inflammation and Thrombosis in Healthy Young Adults

CONTEXTnAir pollution is a risk factor for cardiovascular diseases (CVD), but the underlying biological mechanisms are not well understood.nnnOBJECTIVEnTo determine whether markers related to CVD pathophysiological pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution.nnnDESIGN, SETTING, AND PARTICIPANTSnUsing a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics, we measured pollutants daily and the outcomes listed below in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). We used linear mixed-effects models to estimate the improvement in outcome levels during the Olympics and the anticipated reversal of outcome levels after pollution controls ended to determine whether changes in outcome levels were associated with changes in pollutant concentrations.nnnMAIN OUTCOME MEASURESnC-reactive protein (CRP), fibrinogen, von Willebrand factor, soluble CD40 ligand (sCD40L), soluble P-selectin (sCD62P) concentrations; white blood cell count (WBC); heart rate; and blood pressure.nnnRESULTSnConcentrations of particulate and gaseous pollutants decreased substantially (-13% to -60%) from the pre-Olympic period to the during-Olympic period. Using 2-sided tests conducted at the .003 level, we observed statistically significant improvements in sCD62P levels by -34.0% (95% CI, -38.4% to -29.2%; P < .001) from a pre-Olympic mean of 6.29 ng/mL to a during-Olympic mean of 4.16 ng/mL and von Willebrand factor by -13.1% (95% CI, -18.6% to -7.5%; P < .001) from 106.4% to 92.6%. After adjustments for multiple comparisons, changes in the other outcomes were not statistically significant. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. The fraction of above-detection-limit values for CRP (percentage ≥ 0.3 mg/L) was reduced from 55% in the pre-Olympic period to 46% in the during-Olympic period and reduced further to 36% in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Willebrand factor, heart rate, sCD62P, and sCD40L concentrations.nnnCONCLUSIONSnChanges in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of inflammation and thrombosis and measures of cardiovascular physiology in healthy young persons. These findings are of uncertain clinical significance.

Inflammatory and Oxidative Stress Responses of Healthy Young Adults to Changes in Air Quality during the Beijing Olympics

RATIONALEnUnprecedented pollution control actions during the Beijing Olympics provided a quasi-experimental opportunity to examine biologic responses to drastic changes in air pollution levels.nnnOBJECTIVESnTo determine whether changes in levels of biomarkers reflecting pulmonary inflammation and pulmonary and systemic oxidative stress were associated with changes in air pollution levels in healthy young adults.nnnMETHODSnWe measured fractional exhaled nitric oxide, a number of exhaled breath condensate markers (H(+), nitrite, nitrate, and 8-isoprostane), and urinary 8-hydroxy-2-deoxyguanosine in 125 participants twice in each of the pre- (high pollution), during- (low pollution), and post-Olympic (high pollution) periods. We measured concentrations of air pollutants near where the participants lived and worked. We used mixed-effects models to estimate changes in biomarker levels across the three periods and to examine whether changes in biomarker levels were associated with changes in pollutant concentrations, adjusting for meteorologic parameters.nnnMEASUREMENTS AND MAIN RESULTSnFrom the pre- to the during-Olympic period, we observed significant and often large decreases (ranging from -4.5% to -72.5%) in levels of all the biomarkers. From the during-Olympic to the post-Olympic period, we observed significant and larger increases (48-360%) in levels of these same biomarkers. Moreover, increased pollutant concentrations were consistently associated with statistically significant increases in biomarker levels.nnnCONCLUSIONSnThese findings support the important role of oxidative stress and that of pulmonary inflammation in mediating air pollution health effects. The findings demonstrate the utility of novel and noninvasive biomarkers in the general population consisting largely of healthy individuals.

Comparisons of ultrafine and fine particles in their associations with biomarkers reflecting physiological pathways.

Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics compared to before and after the Olympics, we conducted the current study to compare ultrafine particles (UFPs) and fine particles (PM2.5) in their associations with biomarkers reflecting multiple pathophysiological pathways linking exposure and cardiorespiratory events. Number concentrations of particles (13.0–764.7 nm) and mass concentrations of PM2.5 were measured at two locations within 9 km from the residence and workplace of 125 participating Beijing residents. Each participant was measured 6 times for biomarkers of autonomic function (heart rate, systolic and diastolic blood pressures), hemostasis (von Willebrand factor, soluble CD40 ligand, and P-selectin), pulmonary inflammation and oxidative stress (exhaled nitric oxide and exhaled breath condensate pH, malondialdehyde, and nitrite), and systemic inflammation and oxidative stress (urinary malondialdehyde and 8-hydroxy-2′-deoxyguanosine, plasma fibrinogen, and white blood cells). Linear mixed models were used to estimate associations of biomarkers with UFPs and PM2.5 measured 1–7 days prior to biomarker measurements (lags). We found that the correlation coefficient for UFPs at two locations (∼9 km apart) was 0.45, and at the same location, the correlation coefficient for PM2.5 vs UFPs was −0.18. Changes in biomarker levels associated with increases in UFPs and PM2.5 were comparable in magnitude. However, associations of certain biomarkers with UFPs had different lag patterns compared to those with PM2.5, suggesting that the ultrafine size fraction (≤100 nm) and the fine size fraction (∼100 nm to 2.5 μm) of PM2.5 are likely to affect PM-induced pathophysiological pathways independently.

Malondialdehyde in exhaled breath condensate and urine as a biomarker of air pollution induced oxidative stress

Underlying mechanisms by which air pollutants adversely affect human health remain poorly understood. Oxidative stress has been considered as a potential mechanism that may promote lipid peroxidation by reactive oxygen species, leading to the formation of malondialdehyde (MDA) that is excreted in biofluids (e.g., urine and exhaled breath condensate (EBC)). A panel study was conducted to examine whether concentrations of MDA in EBC and urine were associated, respectively, with changes in air pollution levels brought by the Beijing Olympic air pollution control measures. EBC and urine samples from 125 healthy adults were collected twice in each of the pre-, during-, and post-Olympic periods. Period-specific means of MDA and changes in MDA levels associated with increases in 24-h average pollutant concentrations were estimated using linear mixed-effects models. From the pre- to the during-Olympic period, when concentrations of most pollutants decreased, EBC MDA and urinary MDA significantly decreased by 24% (P<0.0001) and 28% (P=0.0002), respectively. From the during-Olympic to the post-Olympic period, when concentrations of most pollutants increased, EBC MDA and urinary MDA increased by 28% (P=0.094) and 55% (P=0.046), respectively. Furthermore, the largest increases in EBC MDA associated with one interquartile range (IQR) increases in all pollutants but ozone ranged from 10% (95% CI: 2%, 18%) to 19% (95% CI: 14%, 25%). The largest increases in urinary MDA associated with IQR increases in pollutant concentration ranged from 9% (95%: 0.3%, 19%) to 15% (95% CI: 3%, 28%). These findings support the utility of EBC MDA as a biomarker of oxidative stress in the respiratory tract and urinary MDA as a biomarker of systemic oxidative stress in relation to air pollution exposure in healthy young adults. Both EBC and urine samples can be collected noninvasively in the general population.

Measurement of inflammation and oxidative stress following drastic changes in air pollution during the Beijing Olympics: a panel study approach

Ambient air pollution has been linked to cardiovascular and respiratory morbidity and mortality in epidemiology studies. Frequently, oxidative and nitrosative stress are hypothesized to mediate these pollution effects, however precise mechanisms remain unclear. This paper describes the methodology for a major panel study to examine air pollution effects on these and other mechanistic pathways. The study took place during the drastic air pollution changes accompanying the 2008 Olympics in Beijing, China. After a general description of air pollution health effects, we provide a discussion of panel studies and describe the unique features of this study that make it likely to provide compelling results. This study should lead to a clearer and more precise definition of the role of oxidative and nitrosative stress, as well as other mechanisms, in determining acute morbidity and mortality from air pollution exposure.

Role of Berberine in the Treatment of Methicillin-Resistant Staphylococcus aureus Infections

Berberine is an isoquinoline alkaloid widely used in the treatment of microbial infections. Recent studies have shown that berberine can enhance the inhibitory efficacy of antibiotics against clinical multi-drug resistant isolates of methicillin-resistant Staphylococcus aureus (MRSA). However, the underlying mechanisms are poorly understood. Here, we demonstrated that sub-minimum inhibitory concentrations (MICs) of berberine exhibited no bactericidal activity against MRSA, but affected MRSA biofilm development in a dose dependent manner within the concentration ranging from 1 to 64u2009μg/mL. Further study indicated that berberine inhibited MRSA amyloid fibrils formation, which consist of phenol-soluble modulins (PSMs). Molecular dynamics simulation revealed that berberine could bind with the phenyl ring of Phe19 in PSMα2 through hydrophobic interaction. Collectively, berberine can inhibit MRSA biofilm formation via affecting PSMs’ aggregation into amyloid fibrils, and thereby enhance bactericidal activity of antibiotics. These findings will provide new insights into the multiple pharmacological properties of berberine in the treatment of microbial-generated amyloid involved diseases.

The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: pu200a=u200a0.0629, from lag 3 to lag 6: pu200a=u200a0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.

Berberine: A Medicinal Compound for the Treatment of Bacterial Infections

Berberine is an isoquinoline alkaloid mainly extracted from Rhizoma Coptidis, which is an efficient therapeutic agent to combat bacterial infections. However, bioactive assay manifested that berberine exhibited poor effect on antibacterial properties. In the present paper, we reviewed the multiple activities of berberine, including inhibition of biofilm formation, anti-inflammation effect, and clinical trials, which indicate the possible mechanism of berberine in the treatment of bacterial infections.

TFDP3 Regulates Epithelial-Mesenchymal Transition in Breast Cancer.

Breast cancer remains a lethal disease to women due to lymph node metastasis, the tumor microenvironment, secondary resistance and other unknown factors. Several important transcription factors involved in this disease, such as PTEN, p53 and beta-catenin, have been identified and researched in-depth as candidates for targeted therapy in breast cancer. TFDP3 is a new, promising candidate for transcriptional regulation in breast cancer, although it was first identified in hepatocellular carcinoma. Here, we demonstrate that TFDP3 is expressed in a variety of malignancies, normal testis tissue and breast cancer cell lines and thus provide evidence that TFDP3 is a cancer-testis antigen. We illustrate that overexpression or silencing TFDP3 interferes with epithelial-mesenchymal transition but does not influence cell proliferation, indicating that the TFDP3 protein acts as a transcription factor during epithelial-mesenchymal transition. These data highlight that TFDP3 is expressed in breast cancer, that it is a member of the cancer-testis antigen family and that it functions as a regulator in epithelial-mesenchymal transition.

Staphylococcus aureus Phenol-Soluble Modulins α1–α3 Act as Novel Toll-Like Receptor (TLR) 4 Antagonists to Inhibit HMGB1/TLR4/NF-κB Signaling Pathway

Phenol-soluble modulins (PSMs) have recently emerged as key virulence determinants, particularly in highly aggressive Staphylococcus aureus isolates. These peptides contribute to the pathogenesis of S. aureus infections, participating in multiple inflammatory responses. Here, we report a new role for S. aureus PSMs in high mobility group box-1 protein (HMGB1) induced inflammation by modulating toll-like receptor (TLR) 4 pathway. Direct ligation of TLR4 with S. aureus PSMα1–α3 and PSMβ1–β2 was identified by surface plasmon resonance. Remarkably, the binding affinity of TLR4 with HMGB1 was attenuated by PSMα1–α3. Further study revealed that PSMα1–α3 directly inhibited HMGB1-induced NF-κB activation and proinflammatory cytokines production in vitro using HEK-Blue hTLR4 cells and THP-1 cells. To analyze the molecular interactions between PSMs and TLR4, blast similarity search was performed and identified that PSMα1 and PSMβ2 were ideal templates for homology modeling. The three-dimensional structures of PSMα2, PSMα4, PSMβ1, and δ-toxin were successfully generated with MODELLER, and further refined using CHARMm. PSMs docking into TLR4 were done using ZDOCK, indicating that PSMα1–α3 compete with HMGB1 for interacting with the surrounding residues (336–477) of TLR4 domain. Our study reveals that S. aureus PSMα1–α3 can act as novel TLR4 antagonists, which account at least in part for the staphylococcal immune evasion. Modulation of this process will lead to new therapeutic strategies against S. aureus infections.