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 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-β 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.

With 16.15% of its total population aged 65 or above, Taiwan is already an aging society. Frailty is a natural consequence of aging, which may decrease physical strength and deteriorate physiological functioning. We examined the mediating effects of cognitive function, social support, activities of daily living (ADL), and depression in the relationship between age and frailty in older people living in the community. This cross-sectional study used a structured questionnaire to collect data from a convenience sample of 200 pre-frail to mildly frail older adults in southern Taiwan. Structural equation modeling was used for data analysis, with data collected from July to November 2020. ADL mediated the relationship between age and frailty, while cognitive function also mediated the relationship between age and frailty, indicating that ADL and cognitive function were significant determinants of frailty. The path from age to frailty was significant, indicating that age was a significant determinant of frailty. The standardized total effect of age affected frailty through the mediating roles of ADL and cognitive function. Age, depression, ADL, and cognitive function explained 59% of the variance in frailty among older adults. ADL and cognitive function are significant mediators of frailty among older adults.

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-β1 (TGF-β1), 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.

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.

Although school-based planned education has steadily been introduced, master-apprentice learning is still an indispensable part of medical education. All medical clinical teachers begin their careers as medical students, often without knowing exactly how they will learn to teach. Kilminster and Jolly identified three primary functions of clinical supervisors including clinical teaching, support and guidance, and work supervision. Therefore, we designed a study using questionnaires to assess the three factors of clinical educators for past supervised experiences, including 'being instructed,' 'being supported,' and 'being supervised,' based on Kilminster and Jolly's illustration in 2000, to see the relationship between the three factors mentioned above. The study started with a literature review to construct the essential items regarding past supervised experiences of physicians as clinical teachers. We invited 10 experts from fields including medical education and experienced clinical teachers to assess the content validity. One hundred physicians in teaching hospitals were sampled for the preliminary test. Another 364 physicians in teaching hospitals were sampled for the formal study of confirmatory factor analysis and pathway analysis. The" Past Supervised Experiences with Educational Roles Scale" showed satisfying reliability with all Cronbach's α values exceeding .80, and three factors from supervised experiences were identified, including 'being supported,' 'being instructed,' and 'being supervised.' In our model, the 'being supported' experience could positively affect 'being supervised' with significance, directly and indirectly, by being instructed. Our study developed a validated instrument that allows investigation of the formation of better-supervised experiences from current physicians. Our findings inspired us to focus more on supportive coaching in teaching and supervising medical trainees. Our study indicated that faculty development for skills of supporting students is crucial to effective clinical teaching and supervision.