The effect of antifibrotic agents on acute respiratory failure in COVID-19 patients: a retrospective cohort study from TriNetX US collaborative networks.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on global health and economies, resulting in millions of infections and deaths. This retrospective cohort study aimed to investigate the effect of antifibrotic agents (nintedanib and pirfenidone) on 1-year mortality in COVID-19 patients with acute respiratory failure. METHODS: Data from 61 healthcare organizations in the TriNetX database were analyzed. Adult patients with COVID-19 and acute respiratory failure were included. Patients with a pre-existing diagnosis of idiopathic pulmonary fibrosis before their COVID-19 diagnosis were excluded. The study population was divided into an antifibrotic group and a control group. Propensity score matching was used to compare outcomes, and hazard ratios (HR) for 1-year mortality were calculated. RESULTS: The antifibrotic group exhibited a significantly lower 1-year mortality rate compared to the control group. The survival probability at the end of the study was 84.42% in the antifibrotic group and 69.87% in the control group. The Log-Rank test yielded a p-value of less than 0.001. The hazard ratio was 0.434 (95% CI: 0.264-0.712), indicating a significant reduction in 1-year mortality in the antifibrotic group. Subgroup analysis demonstrated significantly improved 1-year survival in patients receiving nintedanib treatment and during periods when the Wuhan strain was predominant. DISCUSSION: This study is the first to demonstrate a survival benefit of antifibrotic agents in COVID-19 patients with acute respiratory failure. Further research and clinical trials are needed to confirm the efficacy of these antifibrotic agents in the context of COVID-19 and acute respiratory failure.

The Effects of Biologics on Hematologic Malignancy Development in Patients with Ankylosing Spondylitis, Psoriasis, or Psoriatic Arthritis: A National Cohort Study.

Biologics are used for ankylosing spondylitis (AS), psoriasis, and psoriatic arthritis (PsA) treatment. The association between biologics and the development of hematologic malignancies is controversial, and data on patients with AS, psoriasis, and PsA are scarce. This retrospective cohort study used data from 2010 to 2020 from Taiwan's National Health Insurance Research Database (NHIRD). Patients with AS, psoriasis, and PsA were divided into a biologics and non biologics group after 1:10 propensity score matching. The hematologic malignancy incidences and the time-/dose-dependent effects on biologics were analyzed by Poisson regression to evaluate the incidence rate ratio (IRR). Of the 4157 biologics users and 38,399 non biologics users included in the study, 10 and 72 persons developed hematologic malignancies, respectively. Biologics only significantly increased the risk of hematologic malignancies in non-Hodgkin's lymphoma (IRR: 2.48, 95% confidence interval (CI): 1.28-4.80). Different treatment patterns, types of biologics prescribed, cumulative defined daily doses, comorbidities, and comedications did not significantly affect hematologic malignancy development. A significantly increased risk was observed when biologics had been prescribed for 1-2 years (IRR: 2.95, 95% CI: 1.14-7.67). Clinical professionals should be aware of a patients' risk of hematologic malignancies during the second year of biologic treatment.

Genome-Wide Association Studies for Albuminuria of Nondiabetic Taiwanese Population.

INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.

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.

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.

Reciprocal Relationships Between Problematic Social Media Use, Problematic Gaming, and Psychological Distress Among University Students: A 9-Month Longitudinal Study.

Background: The causal relationships between two specific types of problematic use in internet-related activities [i.e., problematic social media use (PSMU) and problematic gaming (PG)] and psychological distress remain controversial. The present study investigated the temporal relationships between PSMU, PG, and psychological distress (i.e., anxiety, depression) in university students. Methods: Hong Kong and Taiwan university students [N = 645; nmale = 266; mean = 20.95 years (SD = 5.63)] were recruited for a survey study, with follow-ups at 3, 6, and 9 months after baseline assessment. The Bergen Social Media Addiction Scale, Internet Gaming Disorder Scale-Short Form, and the Hospital Anxiety and Depression Scale were used to assess studied variables. Demographics including age, physical characteristics (i.e., height, weight, and body mass index), and cigarette use were compared between participants who completed all the follow-ups and those who dropped out. Random intercept cross-lagged models were constructed to understand the reciprocal relationships between PSMU, PG, and psychological distress. Results: No significant differences were found in age, physical characteristics, and cigarette use between participants who completed all the follow-ups and those who dropped out. Findings indicated that a high level of PSMU significantly increased the level of anxiety and a high level of anxiety significantly increased the level of PSMU. A high level of PSMU significantly increased the level of depression but the level of depression did not significantly affect the level of PSMU. A high level of PG significantly increased the level of anxiety, but the level of anxiety did not significantly affect the level of PG. A high level of depression significantly increased the level of PG, but the level of depression did not significantly affect the level of PG. Conclusion: The patterns of the causal relationship between PIU and psychological distress variables differ. A reciprocal relationship was only found between the level of PSMU and the level of anxiety. Moreover, the longitudinal design found no differences in the waves in terms of gaming by the participants.

Exploring the Interaction Effects of Gender Contentedness and Pubertal Timing on Adolescent Longitudinal Psychological and Behavioral Health Outcomes.

Background: Off-time pubertal timing (PT) and non-conforming gender identity have been reported to predict adverse health and well-being in adolescents. However, the joint effects of these two factors are less addressed. We aimed to investigate the main and interaction effects of gender identity, proxied by perceived gender contentedness (GC), and PT on longitudinal adolescent psychological and behavioral outcomes. Methods: Data (N = 1806, Mage = 13.3 ± 0.5 years) come from the Taiwan Youth Project, which prospectively followed a longitudinal cohort of Taiwanese junior high school students from 2000 (wave 1) to 2009 (wave 9). GC was self-reported at waves 1 and 9 in a binary response, and thus 4 GC trajectories were created. PT was defined using the Pubertal Developmental Scale, which mainly measured physical changes in puberty. Multiple linear regression analyses with gender stratification were applied to examine the effects of the GC trajectory and its interaction with PT on the outcomes. Results: A total of 1,562 subjects (86.5%) remained consistently satisfied with their gender, while the GC of 226 subjects (12.6%) changed at some point. Regression analyses found that males with gender dissatisfaction at wave 9 were likely to engage in delinquent behavior, and females in this group were more likely to have lower self-esteem, as compared to those with consistent GC. The interaction effect between the GC trajectory and PT appeared to be associated with smoking and drinking only at wave 1. Conclusions: These findings indicate that healthcare professionals should concentrate on gender non-conforming individuals at early adolescence, navigating them toward a healthy adulthood.

Change of Renal Gallium Uptake Correlated with Change of Inflammation Activity in Renal Pathology in Lupus Nephritis Patients.

BACKGROUND: Lupus nephritis (LN) often lead to end-stage renal disease in systemic lupus erythematosus patients. This study aimed to investigate the clinical application of renal gallium-67 scans for determining renal histological parameters in LN patients. METHODS: Between 2006 and 2018, 237 biopsy-proven and 35 repeat biopsies LN patients who underwent renal gallium scans before or after biopsy were included for analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. A delayed 48-h gallium scan was performed and interpreted by semiquantitative methods using left kidney/spine (K/S) ratio. The renal histological results were compared with gallium uptake. RESULTS: Out of 237 participants, 180 (76%) had proliferative LN. Baseline gallium left K/S ratio was significantly higher in class IV LN as compared to class III (median (interquartile range, IQR): 1.16 (1.0-1.3), 0.95 (0.9-1.1), respectively, p < 0.001). Furthermore, changes in gallium uptake between two biopsies were positively correlated with changes activity index (r = 0.357, p = 0.035), endocapillary hypercellularity (r = 0.385, p = 0.032), and neutrophils infiltration (r = 0.390, p = 0.030) in renal pathology. CONCLUSIONS: Renal gallium uptake is associated with active inflammation in LN. Changes in renal gallium uptake positively correlated with changes in activity index in renal pathology.

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.

Allergic rhinitis as a key factor for the development of gastroesophageal reflux disease in children.

BACKGROUND: Gastroesophageal reflux disease (GERD) may cause airway symptoms and some airway diseases exacerbate GERD symptoms. Asthma and allergic rhinitis (AR) have been identified as united airway disease because of their similar epidemiology and pathophysiology. Asthma has been considered a risk factor to develop GERD. However, the association between AR and GERD is not clear. We tried to investigate whether AR could increase the development of GERD. METHODS: Children diagnosed as AR without a prior history of GERD were conducted from the National Health Insurance Research Database between 2000 and 2005. After propensity score matching, we enrolled 36,588 children with AR and 36,588 non-AR children as the controls. Cox regression models were adopted to calculate the hazard ratio (HR) of GERD. RESULTS: AR children had a significantly increased risk of GERD than non-AR children (adjusted HR 1.91, 95% CI = 1.73-2.11, p < 0.001), especially in the age less than 6 years old (adjusted HR 2.68, 95% CI = 1.64-4.38, p < 0.001). The risk factor related to increased risk of GERD including age, gender, and chronic sinusitis. CONCLUSION: AR is a risk factor associated with the development of GERD in children.

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.

Azithromycin suppresses Th1- and Th2-related chemokines IP-10/MDC in human monocytic cell line.

BACKGROUND: Cytokines and chemokines play critical roles in the pathogenesis of asthma. Azithromycin, a macrolides, is frequently used in asthmatic children with lower respiratory tract infection and is reported having anti-inflammatory and immunomodulatory effects. However, the effects of azithromycin on the expression of TNF-α, Th1- and Th2-related chemokines, and neutrophil chemoattractant are unknown. We investigated the in vitro effects of azithromycin on the expression of TNF-α, Th1-related chemokine interferon-γ-inducible protein-10 (IP-10/CXCL10), Th2-related chemokine macrophage-derived chemokine (MDC/CCL22) and neutrophil chemoattractant growth-related oncogene-α (GRO-α/CXCL1) in THP-1 cells as a model for human monocytes. METHODS: THP-1 cells were pretreated with various concentrations of azithromycin before Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) stimulation. TNF-α, IP-10, MDC and GRO-α were measured by ELISA. Intracellular signaling was investigated by pathway inhibitors and Western blot. RESULT: Azithromycin suppressed MDC and IP-10 expression in LPS-stimulated THP-1 cells. However, azithromycin had no effect LPS-induced TNF-α and GRO-α expression. Western blotting revealed that azithromycin suppressed LPS-induced phosphorylation of mitogen-activated protein kinase (MAPK)-JNK and ERK expression, and also suppressed LPS-induced phosphorylation of nuclear factor (NF) κB-p65 expression. CONCLUSION: Azithromycin suppressed LPS-induced MDC expression via the MAPK-JNK and the NFκB-p65 pathway. Azithromycin also suppressed LPS-induced IP-10 via the MAPK-JNK/ERK and the NFκB-p65 pathway. Azithromycin may benefit asthmatic patients by suppressing chemokines expression.

The effects of acarbose on chemokine and cytokine production in human monocytic THP-1 cells.

BACKGROUND AND OBJECTIVES: Chronic inflammation induced by proinflammatory cytokines and chemokines is postulated to be involved in insulin resistance and ß-cell dysfunction in type 2 diabetes mellitus (T2DM). Acarbose, the α-glucosidase inhibitor, is an oral antidiabetic drug for T2DM. Acarbose suppresses inflammatory cytokine production in patients with T2DM, though the underlying mechanisms are unclear. In the present study, we aimed to investigate the anti-inflammatory effects and the exact mechanisms of acarbose in human monocytic THP-1 cells. METHODS: THP-1 cells were pretreated with acarbose and then stimulated with lipopolysaccharide (LPS). The levels of Th1-related chemokines, including interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), Th2-related chemokine macrophage-derived chemokine (MDC), and proinflammatory cytokine tumor necrosis factor-α (TNF-α), were determined by enzyme-linked immunosorbent assay. Intracellular signaling pathways were explored by Western blot analysis and using a chromatin immunoprecipitation assay. RESULTS: Acarbose suppressed the levels of IP-10, MCP-1, MDC, and TNF-α and downregulated phosphorylation of p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B-p65 (NF-κB-p65) in LPS-stimulated THP-1 cells. Acarbose suppressed LPS-induced acetylation of histones H3 (H3) and H4 in the IP-10 and MCP-1 promoter regions. These findings revealed the suppressive effects of acarbose on IP-10, MCP-1, MDC, and TNF-α production in THP-1 cells via, at least partially, the p38, JNK, ERK, and NF-κB-p65 pathways, as well as through epigenetic regulation via histone H3 and H4 acetylation. CONCLUSION: Our study points to the therapeutic anti-inflammatory potential of acarbose.

The effect of NSAIDs exposure on breast cancer risk in female patients with autoimmune diseases.

Both breast cancer and autoimmune diseases (ADs) are predominant in women. NSAIDs are common medications for AD. Evidence on the association between NSAIDs use and breast cancer risk is controversial. We investigated the association between NSAIDs exposure and breast cancer risk in female patients with AD. AD patients older than 18 years of age were enrolled from Taiwan Longitudinal Health Insurance Database 2005. The NSAID users were defined as AD patients who had ever taken NSAIDs for at least 3 months between 2000 and 2009. All individuals were followed from the date of first diagnosis of AD to the end of 2013 to evaluate the risk of breast cancer. We estimated the adjusted hazard ratio (HR) using Cox proportional hazard regression after adjusting for age, comorbidities and medications. A total of 12 331 NSAID users and 12 331 non-NSAID users were included in this study after 1: 1 individual matching. The NSAID users were less likely to develop breast cancer than the non-NSAID users (adjusted HR: 0.37; 95% confidence interval: 0.27-0.50; P < 0.001), even if they used NSAIDs with low cumulative defined daily doses (adjusted HR: 0.42; 95% confidence interval: 0.34-0.53; P < 0.001). The incidence of new-onset breast cancer in NSAID users was significantly decreased in users taking selective cyclooxygenase 2 inhibitors, diclofenac, ibuprofen and piroxicam. Lower cumulative hazard rates were found in the AD patients who used NSAIDs (P < 0.001). NSAID exposure is associated with a decreased risk of breast cancer in female AD patients.

Effects of childhood adversity and resilience on Taiwanese youth health behaviors.

BACKGROUND: Adverse childhood experiences (ACEs) can leave negative impacts on one's health behaviors or social functioning later in life. Resilient characteristics have been shown to mitigate effects against risk behaviors in developing adolescents. However, clinical and research attention has rarely been given to jointly consider the effects of ACEs and resilient characteristics on health behaviors in Taiwanese youth. METHOD: A total of 200 individuals aged 15-22 years were recruited from primary care settings, communities, and schools. Participants completed questionnaires assessing their ACEs, resilient characteristics, and health behaviors. Univariate analysis was firstly used to describe the correlates of ACEs and resilient characteristics. Further multivariate logistic regression analysis was used to examine the association of both factors with health behaviors. RESULTS: More than half (61.5%) of those surveyed had been exposed to at least one category of ACE. Verbal (37%) and physical (21%) abuses were the most common types of ACEs. The counts in the ACE categories were associated with being involved in physical fights (odds ratio 1.28 [confidence interval 1.01-1.63]), property damage (1.29 [1.03-1.61]), running away from home (1.30 [1.05-1.60]), bullying victimization (1.37 [1.16-1.61]), and sleep problems/tiredness (1.25 [1.03-1.52]). Meanwhile, resilience scores were associated with decreased odds of infrequent seatbelt use (0.47 [0.23-0.97]), low fruit and vegetable intake (0.42 [0.21-0.86]) unsatisfied body image (0.46 [0.22-0.97]), and sleep problems/tiredness (0.37 [0.18-0.79]). CONCLUSIONS: ACEs and resilience characteristics play a significant role in shaping youth health behaviors. Further research should be undertaken to identify ways to build resilience against health risks in youth with prior ACE exposure.

M2 macrophage subset decrement is an indicator of bleeding tendency in pediatric dengue disease.

BACKGROUND/PURPOSE: Dengue disease is widespread in tropical and sub-tropical regions. Severe dengue infection is characterized by plasma leakage, fluid accumulation, severe bleeding, or vital organ impairment. Bleeding is a critical complication of dengue disease. However, the biomarkers of dengue disease are still unknown. Macrophages have a distinct polarization phenotype related to M1/M2 classification. Macrophage polarization toward the pro-inflammatory M1 phenotype is considered critical for efficient antiviral immune responses, whereas the anti-inflammatory M2 phenotype is considered essential for tissue remodeling. We investigated macrophage polarization patterns in the peripheral blood of pediatric patients with dengue disease. METHODS: Medical records and laboratory data were collected from 23 pediatric healthy controls and 100 dengue disease samples from 50 dengue patients. Macrophage polarization-related surface markers were assessed using flow cytometry. RESULTS: The percentage of macrophages in the peripheral blood was higher in dengue patients than in the healthy controls. The percentages of M2a and M2c macrophage subsets were higher and the percentage of M1 macrophage subset was lower in dengue patients than in healthy controls. However, the percentages of M1, M2a and M2b macrophage subsets in dengue patients with bleeding tendency were lower than that without bleeding tendency. The percentages of M2a, M2b, and M2c macrophage subsets were positively correlated with platelet counts. CONCLUSION: Decreased the percentages of M2 macrophage subsets in pediatric dengue patients are associated with bleeding tendency and lower platelet counts.

Altered monocyte differentiation and macrophage polarization patterns in patients with breast cancer.

BACKGROUND: Macrophage heterogeneity is the main feature of the tumour microenvironment. Breast cancer is one of the most life-threatening cancers. However, macrophage polarization patterns in different tumour stages and the importance of its relationship to human epidermal growth factor receptor 2 (HER2) in breast cancer remains highly unclear. The present study investigated the patterns of monocyte differentiation and macrophage polarization in breast cancer. METHODS: Patients with breast cancer (n = 48) and healthy controls (n = 39) were prospectively recruited. The percentages and subsets of circulating macrophage-like cells were analysed by flow cytometry, and the polarization patterns of these cells in the peripheral blood of patients with breast cancer were compared with those of healthy controls. In addition, macrophage polarization patterns in different stages and HER2 status in breast cancer were investigated. RESULTS: The percentages of circulating macrophages, which are defined as PM-2 K+ cells in the peripheral blood, were significantly higher in patients with breast cancer than in healthy controls. The percentages of M1-like macrophages were significantly lower, but those of M2-like macrophages were significantly higher in patients with breast cancer than in healthy controls. The percentage of M2c-like macrophages was significantly higher in advanced (stages II and III) breast cancer. However, the patterns of macrophage polarization were not associated with HER2 status in breast cancer. CONCLUSIONS: Aberrant macrophage polarization was observed in breast cancer and was correlated with breast cancer stage. These quantitative data may provide new molecular biomarkers and potential therapeutic targets in breast cancer.

Suppressive effects of metformin on T-helper 1-related chemokines expression in the human monocytic leukemia cell line THP-1.

PURPOSE OF THE STUDY: Type 1 and type 2 diabetes mellitus (DM) are chronic T-cell-mediated inflammatory diseases. Metformin is a widely used drug for type 2 DM that reduces the need for insulin in type 1 DM. However, whether metformin has an anti-inflammatory effect for treating DM is unknown. We investigated the anti-inflammatory mechanism of metformin in the human monocytic leukemia cell line THP-1. MATERIALS AND METHODS: The human monocytic leukemia cell line THP-1 was pretreated with metformin and stimulated with lipopolysaccharide (LPS). The production of T-helper (Th)-1-related chemokines including interferon-γ-induced protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), Th2-related chemokine macrophage-derived chemokine, and the proinflammatory chemokine tumor necrosis factor-α was measured using enzyme-linked immunosorbent assay. Intracellular signaling pathways were investigated using Western blot analysis and chromatin immunoprecipitation assay. RESULTS: Metformin suppressed LPS-induced IP-10 and MCP-1 production as well as LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B (NF-κB). Moreover, metformin suppressed LPS-induced acetylation of histones H3 and H4 at the IP-10 promoter. CONCLUSIONS: Metformin suppressed the production of Th1-related chemokines IP-10 and MCP-1 in THP-1 cells. Suppressive effects of metformin on IP-10 production might be attributed at least partially to the JNK, p38, ERK, and NF-κB pathways as well as to epigenetic regulation through the acetylation of histones H3 and H4. These results indicated the therapeutic anti-inflammatory potential of metformin.

Effects of montelukast on M2-related cytokine and chemokine in M2 macrophages.

BACKGROUND/PURPOSE: Asthma is a chronic airway inflammatory disease mediated by T-helper (Th)2 cells. Montelukast (trade name Singulair) is a cysteinyl leukotriene receptor antagonist used for asthma treatment. Mirroring Th1-Th2 polarization, two distinct states of macrophages have been recognized: the classically activated (M1) macrophages and the alternatively activated (M2) macrophages. M2 polarization is known to be a response to the Th2 cytokines; however, the effects of montelukast on M2 macrophages have not been well characterized. The aim of the present study was to investigate the effects of montelukast on the expression of cytokines and chemokines in M2-like macrophages, and to explore possible intracellular signaling pathways. METHODS: The human monocytic leukemia cell line THP-1 and human monocytes from healthy donors were cultured with interleukin-4 for M2 polarization, and then the cells were pretreated with or without montelukast before lipopolysaccharide (LPS) stimulation. Supernatants were collected to determine interleukin-10, I-309/CCL1, and MDC/CCL22 levels by enzyme-linked immunosorbent assay. Intracellular signaling was investigated using nuclear factor (NF)-κB inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, and western blot analysis. RESULTS: LPS-induced interleukin-10 and I-309/CCL1 expression was significantly suppressed by montelukast in THP-1-derived and human monocyte-derived M2 macrophages after LPS stimulation. MDC/CCL22 expression was only significantly suppressed by montelukast in THP-1-derived M2 macrophages after 48 hours of incubation. In western blot analysis, montelukast was able to suppress LPS-induced MAPK-phospho-p38 and NF-κB-phospho-p65 expression. CONCLUSION: Montelukast suppressed LPS-induced M2-related cytokines and chemokines in alternatively activated macrophages, and the effects might be mediated through the MAPK-p38 and NF-κB-p65 pathways.

Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification.

The treatment of rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-α) inhibitors could lead to adverse effects. Therefore, the identification of downstream therapeutic targets is important. Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is related to RA disease activity, and epigenetic modifications are hypothesized to regulate gene expression in RA pathogenesis. We studied the effects of two TNF-α inhibitors, etanercept and adalimumab, on CCL2 expression and the potentially associated intracellular mechanisms, including epigenetic regulation. Etanercept and adalimumab decreased CCL2 production in THP-1 cells and human primary monocytes, as detected using enzyme-linked immunosorbent assays, and these changes in the CCL2 levels were independent of the TNF-α levels. Etanercept and adalimumab suppressed mitogen-activated protein kinase (MAPK) phospho-p38, phospho-JNK, phospho-ERK and nuclear factor-κB (NF-κB) phospho-p65, as demonstrated using western blot analyses. The investigation of epigenetic modifications using chromatin immunoprecipitation revealed that etanercept and adalimumab down-regulated acetylation of histone (H)3 and H4 in the CCL2 promoter region by decreasing the recruitment of the NF-κB associated acetyltransferases p300, CBP and PCAF. Etanercept and adalimumab also down-regulated trimethylation of H3K4, H3K27, H3K36 and H3K79 in the CCL2 promoter region by decreasing the expression of the related methyltransferases WDR5 and Smyd2. We demonstrated that TNF-α inhibitors exert immunomodulatory effects on CCL2 expression in human monocytes via MAPKs, NF-κB and epigenetic modifications. These findings broaden the mechanistic knowledge related to TNF-α inhibitors and provide novel therapeutic targets for RA.