Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters.

BACKGROUND: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology. METHODS: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. RESULTS: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. CONCLUSION: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: a multicentre study.

BACKGROUND: Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. METHODS: Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables. FINDINGS: In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28-3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108-0.311, p<0.05), but not with the accumulated levels of PM2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202-0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186-0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures. INTERPRETATION: These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

Components of the Complete Blood Count as a Risk Predictor for Incident Hypertension in a Large Taiwanese Population Follow-up Study.

BACKGROUND: Previous studies investigating the relationship between hypertension (HT) and hematological parameters report inconsistent results, and most them included a small number of participants or only conducted a cross-sectional analysis of 1 or 2 hematological factors. Moreover, no large cohort follow-up studies have investigated this topic. The aim of this longitudinal study was to explore associations between components of the complete blood count (CBC) and incident HT using data from a large Taiwanese biobankMethods and Results: Hematological parameters including white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit (HCT), and platelet count were evaluated. We included 21,293 participants who did not have HT at baseline and followed them for a mean period of 3.9 years. During follow-up, 3,002 participants with new-onset HT (defined as incident HT) were identified. Univariable analysis revealed that high WBC count, high RBC count, high hemoglobin, high HCT, and low platelet count were associated with incident HT. Multivariable analysis after adjusting potential confounding factors found high WBC count (odds ratio [OR], 1.057; 95% confidence interval [CI], 1.028 to 1.087; P<0.001) and high HCT (OR, 1.023; 95% CI, 1.010 to 1.036; P<0.001) were still significantly associated with incident HT. CONCLUSIONS: High WBC count and high HCT were associated with incident HT.

Air pollution after acute bronchiolitis is a risk factor for preschool asthma: a nested case-control study.

BACKGROUND: Acute bronchiolitis and air pollution are both risk factor of pediatric asthma. This study aimed to assess subsequent exposure to air pollutants related to the inception of preschool asthma in infants with acute bronchiolitis. This study aimed to assess subsequent exposure to air pollutants related to the inception of preschool asthma in infants with acute bronchiolitis. METHODS: A nested case-control retrospective study was performed at the Kaohsiung Medical University Hospital systems between 2009 and 2019. The average concentration of PM10, PM2.5, SO2, NO, NO2, and NOX was collected for three, six, and twelve months after the first infected episode. Adjusted regression models were employed to evaluate the association between asthma and air pollution exposure after bronchiolitis. RESULTS: Two thousand six hundred thirty-seven children with acute bronchiolitis were included. Exposure to PM10, PM2.5, SO2, NO, NO2, and NOX in the three, six, and twelve months following an episode of bronchiolitis was found to significantly increase the risk of preschool asthma in infants with a history of bronchiolitis.(OR, 95%CI: PM10 = 1.517-1.559, 1.354-1.744; PM2.5 = 2.510-2.603, 2.148-3.061; SO2 = 1.970-2.040, 1.724-2.342; ; NO = 1.915-1.950, 1.647-2.272; NO2 = 1.915-1.950, 1.647-2.272; NOX = 1.752-1.970, 1.508-2.252) In a sensitive analysis of hospitalized infants, only PM10, PM2.5, SO2, and NO were found to have significant effects during all time periods. (OR, 95%CI: PM10 = 1.613-1.650, 1.240-2.140; PM2.5 = 2.208-2.286, 1.568-3.061; SO2 = 1.679-1.622, 1.197-2.292; NO = 1.525-1.557, 1.094-2.181) CONCLUSION: The presence of ambient PM10, PM2.5, SO2 and NO in the three, six, and twelve months following an episode of acute bronchiolitis has been linked to the development of preschool asthma in infants with a history of acute bronchiolitis.

Montelukast Increased IL-25, IL-33, and TSLP via Epigenetic Regulation in Airway Epithelial Cells.

The epithelium-derived cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are important mediators that initiate innate type 2 immune responses in asthma. Leukotriene receptor antagonists (LTRAs) are commonly used to prevent asthma exacerbations. However, the effects of LTRAs on epithelium-derived cytokines expression in airway epithelial cells are unclear. This study aimed to investigate the effects of LTRAs on the expression of epithelium-derived cytokines in human airway epithelial cells and to explore possible underlying intracellular processes, including epigenetic regulation. A549 or HBE cells in air-liquid interface conditions were pretreated with different concentrations of LTRAs. The expression of epithelium-derived cytokines and intracellular signaling were investigated by real-time PCR, enzyme-linked immunosorbent assay, and Western blot. In addition, epigenetic regulation was investigated using chromatin immunoprecipitation analysis. The expression of IL-25, IL-33, and TSLP was increased under LTRAs treatment and suppressed by inhaled corticosteroid cotreatment. Montelukast-induced IL-25, IL-33, and TSLP expression were mediated by the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways and regulated by histone H3 acetylation and H3K36 and H3K79 trimethylation. LTRAs alone might increase inflammation and exacerbate asthma by inducing the production of IL-25, IL-33, and TSLP; therefore, LTRA monotherapy may not be an appropriate therapeutic option for asthma.

Comparative Gut Microbiome Differences between High and Low Aortic Arch Calcification Score in Patients with Chronic Diseases.

Gut dysbiosis can induce chronic inflammation and contribute to atherosclerosis and vascular calcification. The aortic arch calcification (AoAC) score is a simple, noninvasive, and semiquantitative assessment tool to evaluate vascular calcification on chest radiographs. Few studies have discussed the relationship between gut microbiota and AoAC. Therefore, this study aimed to compare the microbiota composition between patients with chronic diseases and high or low AoAC scores. A total of 186 patients (118 males and 68 females) with chronic diseases, including diabetes mellitus (80.6%), hypertension (75.3%), and chronic kidney disease (48.9%), were enrolled. Gut microbiota in fecal samples were analyzed by sequencing of the 16S rRNA gene, and differences in microbial function were examined. The patients were divided into three groups according to AoAC score, including 103 patients in the low AoAC group (AoAC ≤ 3), 40 patients in the medium AoAC group (3 < AoAC ≤ 6), and 43 patients in the high AoAC group (AoAC > 6). Compared to the low AoAC group, the high AoAC group had a significantly lower microbial species diversity (Chao1 index and Shannon index) and increased microbial dysbiosis index. Beta diversity showed that the microbial community composition was significantly different among the three groups (p = 0.041, weighted UniFrac PCoA). A distinct microbial community structure was found in the patients with a low AoAC, with an increased abundance at the genus level of Agathobacter, Eubacterium coprostanoligenes group, Ruminococcaceae UCG-002, Barnesiella, Butyricimonas, Oscillibacter, Ruminococcaceae DTU089, and Oxalobacter. In addition, there was an increased relative abundance of class Bacilli in the high AoAC group. Our findings support the association between gut dysbiosis and the severity of AoAC in patients with chronic diseases.

Risk of cognitive impairment from exposure to incense smoke.

Incense is aromatic biotic material that releases fragrant smoke when burned. We aim to investigate the cognition risks from incense smoke. We obtained data from Taiwan Biobank in community. Cognition function was assessed by mini-mental state examination (MMSE). There were 978 participants in our study, including incense exposure (N = 131) and without incense exposure (N = 847). MMSE scores and registration sub-scores were lowered in incense exposure group than the other group. Incense exposure is one of the independent risk factors for cognitive decline in MMSE and registration sub-scores after adjusting confounding factors We concluded the risk of cognitive impairment, with predominant in registration in healthy individuals with incense exposure in community.

Suppressive Effects of 4-(Phenylsulfanyl) Butan-2-One on CCL-1 Production via Histone Acetylation in Monocytes.

The 4-(phenylsulfanyl) butan-2-one (4-PSB-2), a marine-derived compound from soft coral, was proven to have multiple biological activities including neuroprotection and potent anti-inflammatory effects. CC chemokine ligand (CCL)-1 belongs to T helper (Th)2-related chemokines that are involved in the recruitment of Th2 inflammatory cells. Histone acetylation has been recognized as a critical mechanism underlying the regulated cytokine and chemokine production. Our study tried to investigate the anti-inflammatory effect of 4-PSB-2 on CCL-1 production in human monocytes and explore possible underlying intracellular processes, including epigenetic regulation. To confirm our hypothesis, human monocyte THP-1 cell line and primary CD14+ cells were pretreated with various concentrations of 4-PSB-2 and then were stimulated with lipopolysaccharide (LPS). The CCL-1 concentration was measured by enzyme-linked immunosorbent assays, and the intracellular signaling pathways and epigenetic regulation of 4-PSB-2 were investigated by using Western blotting and chromatin immunoprecipitation analysis. In this study, we found that 4-PSB-2 had a suppressive effect on LPS-induced CCL-1 production. Moreover, this suppressive effect of 4-PSB-2 was mediated via intracellular signaling such as the mitogen-activated protein kinase and nuclear factor-κB pathways. In addition, 4-PSB-2 could suppress CCL-1 production by epigenetic regulation through downregulating histone H3 and H4 acetylation. In short, our study demonstrated that 4-PSB-2 may have a potential role in the treatment of allergic inflammation.

Impact of the synergistic effect of pneumonia and air pollutants on newly diagnosed pulmonary tuberculosis in southern Taiwan.

BACKGROUND: An increased incidence of pulmonary tuberculosis (PTB) among patients with pulmonary diseases exposed to air pollution has been reported. OBJECTIVE: To comprehensively investigate the association between pneumonia (PN) and air pollution with PTB through a large-scale follow-up study. METHODS: We conducted a retrospective study using data from the Kaohsiung Medical University Hospital Research Database and the Taiwan Air Quality Monitoring Database. We included adult patients with PN, PTB and other comorbidities according to ICD-9 codes. Control subjects without PN were matched by age, sex and ten comorbidities to each PN patient at a ratio of 4:1. RESULTS: A total of 82,590 subjects were included. The PTB incidence rate was significantly higher in the PN group (2,391/100,000) than in the control group (1,388/100,000). The crude hazard ratio (HR) of PN-associated PTB incidence decreased with time, and the overall 7 years the HR (95% confidence interval; CI) was 1.74 (1.55-1.96). The overall adjusted HR and 95% CI of PN-related PTB in the multivariate Cox regression analysis was 3.38 (2.98-3.84). In addition, there was a cumulative lag effect of all air pollutants within 30 days of exposure. The peak adjusted HRs for PTB were noted on the 3rd, 8th, 12th and 12th days of PM2.5, O3, SO2 and NO exposure, respectively. The overall peak HRs (95% CI) of PM2.5, O3, SO2 and NO were 1.145 (1.139-1.152), 1.153 (1.145-1.161), 1.909 (1.839-1.982) and 1.312 (1.259-1.367), respectively, and there was a synergistic effect with pneumonia on the risk of PTB. CONCLUSIONS: A strong association was found between past episodes of PN and the future risk of PTB. In addition, air pollutants including PM2.5, SO2, O3 and NO, together with previous episodes of PN, had both long-term and short-term impact on the incidence of PTB.

Associations and Interactions between Heavy Metals with White Blood Cell and Eosinophil Count.

The accumulation of heavy metals in the body has been associated with an elevated immune response. The aim of this study was to investigate the associations among heavy metals and white blood cell (WBC) and eosinophil count in the general population in southern Taiwan. We also explored the interactions and synergetic effects of heavy metals on WBC and eosinophil count. We conducted a health survey in the general population living in southern Taiwan between June 2016 and September 2018. Seven heavy metals were measured: blood lead (Pb), and urine cadmium (Cd), copper (Cu), nickel, arsenic (As), chromium and manganese (Mn). A total of 2,447 participants were enrolled. In multivariable analysis, high concentrations of Pb (log per 1 mg/L; coefficient ß, 0.332; p = 0.005) and Cu (log per 1 µg/dL; coefficient ß, 0.476; p < 0.001) were significantly associated with a high WBC count. In addition, high concentrations of Pb (log per 1 mg/L; coefficient ß, 0.732; p < 0.001), As (log per 1 µg/L; coefficient ß, 0.133; p = 0.015), Cu (log per 1 µg/dL; coefficient ß, 0.181; p = 0.018), and Cd (log per 1 µg/L; coefficient ß, 0.139; p = 0.002) were significantly associated with a high eosinophil count. Further, the effect of interactions between Pb and As (coefficient ß, 0.721; p = 0.029) and Mn and Cu (coefficient ß, 0.482; p = 0.018) on WBC count, and As and Cu (unstandardized coefficient ß, 0.558; p = 0.002) on eosinophil count were statistically significant. In conclusion, the heavy metals Pb, As, Cu, and Cd were associated with WBC and eosinophil count. In addition, synergistic effects of heavy metal poisoning on the association with WBC and eosinophil count were also observed.

Association between secondhand smoke and peripheral arterial disease: a meta-analysis of cross-sectional studies.

PURPOSE: The association between secondhand smoke (SHS) and peripheral arterial disease (PAD) was inconsistent and the studies were relatively scarce, hence, we conducted a meta-analysis of the association between SHS and PAD. MATERIALS AND METHODS: We systematically searched three electronic databases (PubMed, EMBASE, and Web of Science), and calculated the pooled prevalence risk ratio (RR) and estimated standard error by random effect model from the meta-analysis. Furthermore, we performed a subgroup meta-analysis according to the location of SHS exposure. RESULTS: We initially identified 502 articles from the electronic database, and 6 articles, cross-sectional data from 4 cross-sectional studies and 2 prospective cohort studies, were included in the meta-analysis. Among these six articles, two studies showed a significant correlation between SHS exposure and PAD, whereas no study showed a negative correlation between SHS exposure and PAD. In the meta-analysis, pooled prevalence showed a significant association between SHS exposure and PAD (RR = 1.23; 95% confidence interval [CI] 1.08-1.41; z = 3.02, p = 0.003). In the subgroup analysis based on location of SHS exposure, the prevalence RR of PAD at home was 1.30 (95% CI 1.14-1.49, Z-3.99, p < 0.0001). The prevalence RR in the subgroup of SHS exposure at work was not significant (RR = 0.89; 95% CI 0.55-1.44; z = 0.48, p = 0.63). CONCLUSION: Exposure to SHS was significantly and positively associated with PAD. Moreover, we found a significant association between exposure to SHS and PAD at home, but the association was not significant at work.

Role of Macrophages in Air Pollution Exposure Related Asthma.

Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction, bronchial hyper-responsiveness, and airway inflammation. The chronic inflammation of the airway is mediated by many cell types, cytokines, chemokines, and inflammatory mediators. Research suggests that exposure to air pollution has a negative impact on asthma outcomes in adult and pediatric populations. Air pollution is one of the greatest environmental risks to health, and it impacts the lungs' innate and adaptive defense systems. A major pollutant in the air is particulate matter (PM), a complex component composed of elemental carbon and heavy metals. According to the WHO, 99% of people live in air pollution where air quality levels are lower than the WHO air quality guidelines. This suggests that the effect of air pollution exposure on asthma is a crucial health issue worldwide. Macrophages are essential in recognizing and processing any inhaled foreign material, such as PM. Alveolar macrophages are one of the predominant cell types that process and remove inhaled PM by secreting proinflammatory mediators from the lung. This review focuses on macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants in asthma.

Arsenic Induces M2 Macrophage Polarization and Shifts M1/M2 Cytokine Production via Mitophagy.

Arsenic is an environmental factor associated with epithelial-mesenchymal transition (EMT). Since macrophages play a crucial role in regulating EMT, we studied the effects of arsenic on macrophage polarization. We first determined the arsenic concentrations to be used by cell viability assays in conjunction with previous studies. In our results, arsenic treatment increased the alternatively activated (M2) macrophage markers, including arginase 1 (ARG-1) gene expression, chemokine (C-C motif) ligand 16 (CCL16), transforming growth factor-ß1 (TGF-ß1), and the cluster of differentiation 206 (CD206) surface marker. Arsenic-treated macrophages promoted A549 lung epithelial cell invasion and migration in a cell co-culture model and a 3D gel cell co-culture model, confirming that arsenic treatment promoted EMT in lung epithelial cells. We confirmed that arsenic induced autophagy/mitophagy by microtubule-associated protein 1 light-chain 3-II (LC3 II) and phosphor-Parkin (p-Parkin) protein markers. The autophagy inhibitor chloroquine (CQ) recovered the expression of the inducible nitric oxide synthase (iNOS) gene in arsenic-treated M1 macrophages, which represents a confirmation that arsenic indeed induced the repolarization of classically activated (M1) macrophage to M2 macrophages through the autophagy/mitophagy pathway. Next, we verified that arsenic increased M2 cell markers in mouse blood and lungs. This study suggests that mitophagy is involved in the arsenic-induced M1 macrophage switch to an M2-like phenotype.

Salivary cytokine - A non-invasive predictor for bronchopulmonary dysplasia in premature neonates.

BACKGROUND: To find a less invasive method of cytokine detection for premature neonates, we conducted this cohort study to investigate the salivary cytokines and to analyze their correlations with bronchopulmonary dysplasia (BPD). METHODS: Premature neonates younger than 34 weeks of gestational age without maternal or neonatal infection were recruited. Salivary samples were collected on their first (D1) and seventh (D7) days of life. The cytokine levels were detected by MILLPLEX® MAP Human multiplex assay. One-way analysis of variance, the Kruskal-Wallis test, Pearson's chi-square test, and logistic regression were used to analyze the data. RESULTS: Totally 125 neonates were enrolled and separated into four groups: control, mild, moderate, and severe BPD group. The salivary levels of D1 interleukin (IL)-6, IL-8, IL-10, IL-17, interferon (IFN)-γ, and D7 IL-6 (p = 0.001, 0.001, 0.000, 0.043, 0.037 and 0.001, respectively) were significantly higher in the BPD groups than in the control group. After adjusting for the gestational age, acid-base equivalent, and absolute neutrophil count, comparing to the control group, the levels of D7 IL-17 became significantly lower in all three BPD groups (p = 0.032, 0.030, and 0.030, respectively) and that of D7 IFN-α2 became significantly lower in the severe BPD group (p = 0.037). CONCLUSION: Early-life salivary cytokine levels were correlated with the development of BPD in premature neonates. This study provides a novel method to predict BPD early and non-invasively.

Associations of dermal diethyl phthalate level with changes in lung function test value mediated by absolute eosinophil count: A panel study of adults in southern Taiwan.

Phthalate concentrations in indoor and outdoor dust are associated with respiratory disease. Both immunoglobulin E (IgE) and eosinophil count are associated with airway inflammation from exposure to environmental allergens. Dermal phthalate level can be used as a matrix for assessing personal exposure through direct absorption from the air, particle deposition, or contact with contaminated products. However, the association between dermal phthalate level and changes in lung function test values, as mediated by immunological response, remains unclear. In total, 237 adults in southern Taiwan were recruited. Spirometry measurements (in L) of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were taken on visits 1 (2016-2018) and 2 (2019). Dermal phthalate level, absolute eosinophil count, and IgE level were recorded on visit 1. Mean changes in FVC and FEV1 decrease pear year, as determined through pairwise comparisons, were significant (diffFVCper year: -0.46, 95% CI: -0.51, -0.41; p < 0.001; diffFEV1per year: -0.37, 95% confidence interval [CI]: -0.41, -0.34; p < 0.001). For FEV1 decrease, log-unit increases in dermal diethyl phthalate (DEP) were positively associated with diffFEV1per year (ß = 0.096; 95% CI: 0.042, 0.150; p = 0.001) and negatively associated with absolute eosinophil count (ß= -0.201; 95% CI: -0.380, -0.023; p= 0.027). Log-unit increases in absolute eosinophil count were negatively associated with diffFEV1per year (ß= -0.109; 95% CI: -0.150, -0.068; p < 0.001). Absolute eosinophil count mediated 19.70% of the association between dermal DEP level and diffFEV1per year. For FVC decrease, log-unit increases in dermal DEP were positively associated with diffFVCper year (ß = 0.095; 95% CI: 0.035, 0.155; p = 0.002) and negatively associated with absolute eosinophil count (ß = -0.243; 95% CI: -0.427, -0.060; p = 0.010). Log-unit increases in absolute eosinophil count were negatively associated with diffFVCper year (ß= -0.122; 95% CI: -0.168, -0.076; p < 0.001). Absolute eosinophil count mediated 29.98% of the association between dermal DEP level and diffFVCper year. The results suggest that dermal DEP level is positively associated with changes in lung function test values and is mediated by absolute eosinophil count.

IL-25 Induced ROS-Mediated M2 Macrophage Polarization via AMPK-Associated Mitophagy.

Interleukin (IL)-25 is a cytokine released by airway epithelial cells responding to pathogens. Excessive production of reactive oxygen species (ROS) leads to airway inflammation and remodeling in asthma. Mitochondria are the major source of ROS. After stress, defective mitochondria often undergo selective degradation, known as mitophagy. In this study, we examined the effects of IL-25 on ROS production and mitophagy and investigated the underlying mechanisms. The human monocyte cell line was pretreated with IL-25 at different time points. ROS production was measured by flow cytometry. The involvement of mitochondrial activity in the effects of IL-25 on ROS production and subsequent mitophagy was evaluated by enzyme-linked immunosorbent assay, Western blotting, and confocal microscopy. IL-25 stimulation alone induced ROS production and was suppressed by N-acetylcysteine, vitamin C, antimycin A, and MitoTEMPO. The activity of mitochondrial complex I and complex II/III and the levels of p-AMPK and the mitophagy-related proteins were increased by IL-25 stimulation. The CCL-22 secretion was increased by IL-25 stimulation and suppressed by mitophagy inhibitor treatment and PINK1 knockdown. The Th2-like cytokine IL-25 can induce ROS production, increase mitochondrial respiratory chain complex activity, subsequently activate AMPK, and induce mitophagy to stimulate M2 macrophage polarization in monocytes.

Acrylamide Induces Mitophagy and Alters Macrophage Phenotype via Reactive Oxygen Species Generation.

Acrylamide is a readily exposed toxic organic compound due to its formation in many carbohydrate rich foods that are cooked at high temperatures. Excessive production of reactive oxygen species (ROS), which is an important factor for mitophagy, has been reported to lead to airway inflammation, hyper-responsiveness, and remodeling. Epigenetic regulation is an important modification affecting gene transcription. In this study, the effects of acrylamide on ROS productions and mitophagy were investigated. The human monocytic cell line THP-1 was treated with acrylamide, and ROS productions were investigated by flow cytometry. The mitochondrial and epigenetic involvement was evaluated by quantitative real-time PCR. Histone modifications were examined by chromatin immunoprecipitation assays. Mitophagy was detected by Western blotting and confocal laser microscopy. Acrylamide promoted mitochondria-specific ROS generation in macrophages. The gene expression of mitochondrial respiratory chain complex II SDHA was increased under acrylamide treatment. Acrylamide induced histone H3K4 and H3K36 tri-methylation in an SDHA promoter and increased mitophagy-related PINK1 expression, which promoted a M2-like phenotypic switch with increase TGF-ß and CCL2 levels in THP-1 cells. In conclusion, acrylamide induced ROS production through histone tri-methylation in an SDHA promoter and further increased the expression of mitophagy-related PINK-1, which was associated with a macrophage M2 polarization shift.

M2b macrophage subset decrement as an indicator of cognitive function in Alzheimer's disease.

AIM: Alzheimer's disease (AD) is a chronic neurodegenerative disease. Various inflammatory processes account for the pathology of AD, and macrophages in particular have a distinct polarization phenotype related to M1/M2 classification. We aimed to investigate macrophage polarization patterns as an indicator of cognitive function in AD. METHODS: We recruited 54 non-demented individuals as control and 105 AD patients as experimental groups respectively. Percentages of macrophage (PM2K+ CD14+ and PM2K+ CD14- ) and macrophage polarization subsets (M1, M2a, M2b, and M2c) were assessed using flow cytometry. All AD patients were classified by dementia severity using clinical Dementia Rating scale (CDR) as CDR 0.5, 1 and ≧2. AD patients had cognitive function evaluation using Mini-Mental State Examination (MMSE) and Cognitive Assessment Screening Instrument (CASI). We compared the macrophage polarization patterns between control and patient groups. Cognitive function was evaluated in association with macrophage polarization patterns in AD patients. RESULTS: The percentages of PM2K+ CD14+ and PM2K+ CD14- macrophages were higher in AD patients than in controls. M2b macrophage subset decrement and M1 macrophage subset increment of PM2K+ CD14+ and PM2K+ CD14- macrophages were observed in AD patients compared with controls. Although percentages of macrophage subsets were not consistent with CDR staging, PM2K+ CD14+ M2b macrophage subset decrement was correlated with worse cognitive functioning by MMSE and CASI in AD patients. CONCLUSION: M2b macrophage subset decrement and M1 macrophage subset increment were noted in AD patients, while PM2K+ CD14+ M2b macrophage subset decrement indicated worse cognitive function in such patients.

Allergen-specific immunotherapy enhances CD8+ CD25+ CD137+ regulatory T cells and decreases nasal nitric oxide.

BACKGROUND: 4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8+ Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8+  CD25+  CD137+ Treg suppressive function to decrease nasal nitric oxide (nNO) levels. METHODS: Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8+  CD25+ T cells and suppressive function of CD8+  CD25+  CD137+ Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8+  CD25+  CD137+ T cells was analyzed by Western blotting. RESULTS: Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8+ T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8+  CD25+  CD137+ population in PBMCs. Pam3CSK4-stimulated CD8+  CD25+  CD137+ Tregs induced IL-10 and TGF-ß and suppressed CD4+  CD25- T-cell proliferation mainly by cell contact inhibition. CD8+  CD25+  CD137+ Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8+  CD25+ T cells decreased Pam3CSK4-activated Foxp3 expression. CONCLUSION: Der p IT expanded CD8+  CD25+  CD137+ Tregs and decreased nNO levels. Induced CD137 expression on CD8+  CD25+ Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.

A Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Oral Administration of a Heat-Treated Lactobacillus paracasei  Supplement in Infants with Atopic Dermatitis Receiving Topical Corticosteroid Therapy.

BACKGROUND/AIMS: Atopic dermatitis (AD) is a common disease in infancy, for which topical steroids are the first-line therapy but have side effects. Innovative approaches are needed to reduce the burden of AD and corticosteroid usage in infants. METHODS: The once-daily consumption of heat-treated probiotic Lactobacillus paracasei GM-080 or placebo for 16 weeks as supplementary approach to topical treatment with fluticasone propionate cream was compared in AD infants aged 4-30 months. Outcomes were SCORAD and its subscores, TEWL, Infants' Dermatitis Quality of Life Index (IDQOL), corticoid "sparing effect," CCL17/TARC, and IgE status. RESULTS: SCORAD, objective SCORAD, itching, and IDQOL decreased significantly (p < 0.001) over the treatment period in both treatment groups. Slight decreases (ns) were noted in TEWL in lesional and unaffected skin and CCL17 levels. There were no differences between the treatment groups. Total IgE increased over the treatment period in both groups, with significantly higher increase in the heat-treated probiotic group (p = 0.038). There was no evidence of a corticoid "sparing effect" by the probiotic. CONCLUSIONS: In this design, the probiotic L. paracasei was not beneficial as a complementary approach to topical corticosteroids in infants with AD. However, slight beneficial effects may have been masked by the moderate potency corticoid.