Hydramethylnon induces mitochondria-mediated apoptosis in BEAS-2B human bronchial epithelial cells.

Typically used household chemicals comprise numerous compounds. Determining mixture toxicity, as observed when using household chemicals containing multiple substances, is of considerable importance from a regulatory perspective. Upon examining the toxic effects of household chemical mixtures, we observed that hydramethylnon combined with tetramethrin resulted in synergistic toxicity. To determine the unknown toxicity mechanism of hydramethylnon, which carries the risk of inhalation exposure when using household chemicals, we conducted a further investigation using BEAS-2B cells, a human bronchial epithelial cell line. Hydramethylnon-induced cytotoxicity was determined following 24 and 48 h of exposure using the water-soluble tetrazolium 1 and lactate dehydrogenase assays. To elucidate the toxicity mechanism, we utilized flow cytometry and measured the levels of apoptosis-related proteins and caspase activities. Given that hydramethylnon, as an insecticide, disrupts the mitochondrial electron transfer chain, we analyzed the relevant mechanisms, including mitochondrial superoxide levels as well as the mitochondrial membrane potential (MMP). Hydramethylnon dose-dependently induced BEAS-2B cell apoptosis via the intrinsic pathway. Furthermore, it significantly increased mitochondrial superoxide levels and disrupted the MMP. Pre-treatment with a caspase inhibitor (Z-DEVD-FMK) confirmed that hydramethylnon induced caspase-dependent apoptosis. Apoptosis, a key event in the toxicological process of chemicals, can lead to lung diseases, including fibrosis and cancer. The results of the present study suggest a mechanism of toxicity of hydramethrylnon, an organofluorine biocide whose toxicity has been little studied, to the lung epithelium. Considering the potential risks associated with inhalation exposure, these results highlight the need for careful management and regulation of hydramethylnon.

Association between phthalate exposure and risk of allergic rhinitis in children: A systematic review and meta-analysis.

Phthalates are ubiquitous in diverse environments and have been linked to a myriad of detrimental health outcomes. However, the association between phthalate exposure and allergic rhinitis (AR) remains unclear. To address this knowledge gap, we conducted a systematic review and meta-analysis to comprehensively evaluate the relationship between phthalate exposure and childhood AR risk. We searched the Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica Database, and PubMed to collect relevant studies and estimated pooled odds ratios (OR) and 95% confidence intervals (CI) for risk estimation. Ultimately, 18 articles, including seven cross-sectional, seven case-control, and four prospective cohort studies, were selected for our systematic review and meta-analysis. Our pooled data revealed a significant association between di-2-ethylhexyl phthalate (DEHP) exposure in children's urine and AR risk (OR = 1.188; 95% CI = 1.016-1.389). Additionally, prenatal exposure to combined phthalates and their metabolites in maternal urine was significantly associated with the risk of childhood AR (OR = 1.041; 95% CI = 1.003-1.081), although specific types of phthalates and their metabolites were not significant. Furthermore, we examined environmental phthalate exposure in household dust and found no significant association with AR risk (OR = 1.021; 95% CI = 0.980-1.065). Our findings underscore the potential hazardous effects of phthalates on childhood AR and offer valuable insights into its pathogenesis and prevention.

Efficacy of distance training program for cardiopulmonary resuscitation utilizing smartphone application and home delivery system.

AIM OF THE STUDY: Community cardiopulmonary resuscitation (CPR) education is important for laypersons. However, during the COVID-19 pandemic, with social distancing, conventional face-to-face CPR training was unavailable. We developed a distance learning CPR training course (HEROS-Remote) using a smartphone application that monitors real-time chest compression quality and a home delivery collection system for mannikins. This study aimed to evaluate the efficacy of the HEROS-Remote course by comparing chest compression quality with that of conventional CPR training. METHODS: We applied layperson CPR education with HEROS-Remote and conventional education in Seoul during the COVID-19 pandemic. Both groups underwent a 2-min post-training chest compression test, and we tested non-inferiority. Chest compression depth, rate, complete recoil, and composite chest compression score was measured. Trainees completed a satisfaction survey on CPR education and delivery. The primary outcome was the mean chest compression depth. RESULTS: A total of 180 trainees were enrolled, with 90 assigned to each training group. Chest compression depth of HEROS-Remote training showed non-inferiority to that of conventional training (67.4 vs. 67.8, p = 0.78), as well as composite chest compression score (92.7 vs. 95.5, p = 0.16). The proportions of adequate chest compression depth, chest compression rate, and chest compressions with complete chest recoil were similar in both training sessions. In the HEROS-Remote training, 90% of the trainees were satisfied with CPR training, and 96% were satisfied with the delivery and found it convenient. CONCLUSION: HEROS-Remote training was non-inferior to conventional CPR training in terms of chest compression quality. Distance learning CPR training using a smartphone application and mannikin delivery had high user satisfaction and was logistically feasible.

Fibrinogen on extracellular vesicles derived from polyhexamethylene guanidine phosphate-exposed mice induces inflammatory effects via integrin ß.

Polyhexamethylene guanidine phosphate (PHMG-p), used as a humidifier disinfectant, causes interstitial lung disease, obliterative bronchiolitis, and lung fibrosis; however, little is known about its effect on intercellular interactions. Extracellular vesicles (EVs), which carry diverse compounds including proteins, RNA, and DNA to mediate cell-to-cell communication through their paracrine effects, have been highlighted as novel factors in lung fibrogenesis. This study aimed to identify the effect of proteins on small EVs (sEVs) from bronchoalveolar lavage fluid (BALF) of the recipient cells after PHMG-p exposure. A week after intratracheal administration of PHMG-p, sEVs were isolated from BALF of tissue showing overexpressed inflammatory and fibrosis markers. To investigate the role of sEVs in inflammation, naïve macrophages were cultured with sEVs, which induced their activation. To identify sEV proteins that are associated with these responses, proteomics analysis was performed. In the gene ontology analysis, coagulation, fibrinolysis, and hemostasis were associated with the upregulated proteins in sEVs. The highest increase was observed in fibrinogen levels, which was also related to those gene ontologies. We validated role of exosomal fibrinogen in inflammation using recombinant fibrinogen and an inhibitor of the integrin, which is the binding receptor for fibrinogen. Overall, we elucidated that increased fibrinogen levels in the early sEVs-PHMG activated inflammatory response during early fibrosis. These results suggest that sEVs from the BALF of PHMG-p-exposed mice could aggravate fibrogenesis by activating naïve macrophages via various proteins in the sEVs, Furthermore, this finding will be broadening the spectrum of communicating mediators.

The Impact of the COVID-19 Outbreak on Emergency Medical Service: An Analysis of Patient Transportations and Time Intervals.

BACKGROUND: This study aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) outbreak on the Emergency Medical Service (EMS) system in South Korea. The study focused on the differences in EMS time intervals following the COVID-19 outbreak, particularly for patients with fever. METHODS: A retrospective analysis of EMS patient transportation data from 2017 to 2022 was conducted using the national EMS database. RESULTS: Starting from the year 2020, coinciding with the COVID-19 outbreak, all EMS time intervals experienced an increase. For the years 2017 to 2022, the mean response time interval values were 8.6, 8.6, 8.6, 10.2, 12.8, and 11.4 minutes, and the mean scene time interval values were 7.1, 7.2, 7.4, 9.0, 9.8, and 10.9 minutes. The mean transport time interval (TTI) values were 12.1, 12.3, 12.4, 14.2, 16.9, and 16.2 minutes, and the mean turnaround time interval values were 27.6, 27.9, 28.7, 35.2, 42.0, and 43.1 minutes. Fever (≥ 37.5°C) patients experienced more pronounced prolongations in EMS time intervals compared to non-fever patients and had a higher probability of being non-transported. The mean differences in TTI between fever and non-fever patients were 0.8, 0.8, 0.8, 4.3, 4.8, and 3.2 minutes, respectively, from 2017 to 2022. Furthermore, the odds ratios for fever patients being transported to the emergency department were 2.7, 2.9, 2.8, 1.1, 0.8, and 0.7, respectively, from 2017 to 2022. CONCLUSION: The study findings highlight the significant impact of the COVID-19 outbreak on the EMS system and emphasize the importance of ongoing monitoring to evaluate the burden on the EMS system.

Polystyrene microplastic particles induce autophagic cell death in BEAS-2B human bronchial epithelial cells.

The detection of high levels of microplastics in indoor and outdoor air has increased concerns regarding its toxic effects on the respiratory system. They are not easily degradable and can be deposited deep in the lungs. Although several studies have reported inhalation toxicities of microplastics, they are still controversial due to a lack of evidence. Herein, we evaluated the inhalation toxicities of three differently charged polystyrene microplastics (PS-MPs), the most abundant microplastics in the air. Cytotoxicity and ROS generation were evaluated using WST-1 and DCF-DA assays, respectively. To evaluate the toxic effects on the lung, inflammatory responses were analyzed after repeated exposure to the PS-MPs through intratracheal instillation. To explore the mechanism of toxicity, autophagy and ER stress-associated proteins were analyzed. Only the positively charged PS-MPs (NH2 -PS-MPs) showed cytotoxicity and increased ROS generation in BEAS-2B cells. Similarly, only NH2 -PS-MPs significantly increased the expression and secretion of the pro-inflammatory cytokine IL-ß in the animal experiments. The expression of ER stress proteins indicated that NH2 -PS-MPs increased ER stress via PERK-EIF2α and ATF4-CHOP pathways. Moreover, accumulation of NH2 -PS-MPs in lysosomes and deformity of the nucleus were observed in BEAS-2B cells with autophagy induction. Taken together, our results demonstrated that NH2 -PS-MPs induced autophagic cell death in bronchial epithelial cells, leading to inflammatory responses in the lungs. These results suggest that repeated inhalation of microplastics can result in inflammatory responses in the lung through cellular damage of lung epithelial cells, and that inhalation microplastics should be monitored to reduce inhalation health risks.

Reprogrammed lung epithelial cells by decrease of miR-451a in extracellular vesicles contribute to aggravation of pulmonary fibrosis.

Extracellular vesicles (EVs) play novel roles in homeostasis through cell-to-cell communication in human airways via transferring miRNAs. However, the contribution of EV miRNAs to pulmonary phenotypic homeostasis is not clearly understood. Hence, the aim of this study was to elucidate the functional role of miRNAs obtained from epithelium-derived EVs in lung fibrogenesis. Pulmonary fibrosis was induced by exposure of polyhexamethylene guanidine phosphate (PHMG-p)-instilled mice. In histopathological changes, a clear phenotypic change was observed in bronchial epithelium. For figuring out the role of EVs derived from conditioned media of untreated cells (EV-Con) and PHMG-p-treated BEAS-2B (EV-PHMG), significant increase in EVs released from PHMG-p-treated BEAS-2B was detected. Functional analysis with targets of differentially expressed miRNAs in EVs was annotated to epithelial-mesenchymal transition (EMT). Especially, the most abundant miRNA, miR-451a, was downregulated in EV of PHMG-p-treated BEAS-2B cells. We found that odd-skipped related 1 (OSR1) was a putative target for miR-451a, which had been known as a transcription factor of several fibrosis-associated genes. Transfer of decreased miR-451a via EV-PHMG upregulated OSR1 and induced EMT compared to Con-EV-treated cells. In pulmonary fibrosis mice, miR-451a levels were significantly reduced in EV derived from bronchoalveolar lavage fluid and OSR1 expression was increased in lung tissues of mice with PHMG-p exposure. MiR-451a-transfected EVs markedly alleviated fibrogenesis in the PHMG-p-exposed lungs. Low level of miR-451a in EVs modulated EMT and fibrogenesis in recipient cells by increasing OSR1 levels in vitro and in vivo. Our results suggest that transferring EV miR-451a induces anti-fibrotic autocrine effect by downregulating its target, OSR1 maintaining pulmonary homeostasis disrupted by PHMG-p exposure, which can be a potential therapeutic target.

Anti-fibrotic effects of brevilin A in hepatic fibrosis via inhibiting the STAT3 signaling pathway.

Hepatic fibrosis is a chronic liver disease characterized by the accumulation of extracellular matrix (ECM). Activation of hepatic stellate cells (HSCs) after repetitive liver damage is a key event in hepatic fibrogenesis. As part of ongoing research projects to identify pharmacologically effective natural products, the phytochemical investigation of a MeOH extract of Centipeda minima led to the isolation of a sesquiterpene lactone, brevilin A, which was explored to elucidate potential anti-fibrotic effects by reversing HSC activation. First, we observed that transforming growth factor (TGF)-ß1 treatment significantly increased the expression levels of HSC activation marker, α-smooth muscle actin (α-SMA), and ECM protein such as collagen and fibronectin. Then, we demonstrated that brevilin A reversed the TGF-ß1-induced increase in protein and mRNA expression levels of α-SMA and collagen. To investigate the underlying molecular mechanism of brevilin A, we evaluated the effects of brevilin A on the STAT3 signaling pathway. STAT3 phosphorylation, increased by TGF-ß1 treatment, was strongly inhibited by brevilin A; the expression levels of fibronectin and connective tissue growth factor were also significantly decreased by brevilin A. The present study indicated that brevilin A has a preventive and therapeutic potential against hepatic fibrosis.

Prediction of cerebral perfusion pressure during CPR using electroencephalogram in a swine model of ventricular fibrillation.

BACKGROUND: Measuring the quality of cardiopulmonary resuscitation (CPR) is important for improving outcomes in cardiac arrest. Cerebral perfusion pressure (CePP) could represent cerebral circulation during CPR, but it is difficult to measure non-invasively. In this study, we developed the electroencephalogram (EEG) based brain index (EBRI) derived from EEG signals by machine learning techniques, which could estimate CePP accurately in a porcine cardiac arrest model. METHODS: We conducted a randomised crossover study using nine female pigs. After 1 min of untreated ventricular fibrillation, we performed CPR with 12 different 2-min tilting angle sessions, including two different head-up tilt (HUT) angles (30°, 15°) twice, horizontal angle (0°) four times and two different head-down tilt (HDT) angles (-15°, -30°) twice with the random order. We collected EEG signals using a single channel EEG electrode in real-time during CPR. We derived the EBRI models to predict the CePP classified by the 5 or 10 groups using three different machine learning algorithms, including the support vector machine (SVM), k-nearest neighbour (KNN) and random forest classification (RFC) method. We assessed the accuracy, sensitivity and specificity of each model. RESULTS: The accuracy of the EBRI model using an SVM algorithm in the 5-group CePP classification was 0.935 with a standard deviation (SD) from 0.923 to 0.946. The accuracy in the 10-group classification was 0.904 (SD: 0.896, 0.913). The accuracy of the EBRI using the KNN method in the 5-group classification was 0.927 (SD: 0.920, 0933) and in the 10-group was 0.894 (SD: 0.880, 0.907). The accuracy of the RFC algorithm was 0.947 (SD: 0.931, 0.963) in the 5-group classification and 0.920 (SD: 0.911, 0.929) in the 10-group classification. CONCLUSION: We developed the EBRI model using non-invasive acquisition of EEG signals to predict CePP during CPR. The accuracy the EBRI model was 0.935, 0.927 and 0.947 for each machine learning algorithm, and the EBRI could be used as a surrogate indicator for measuring cerebral perfusion during CPR.

Efficacy of a new dispatcher-assisted cardiopulmonary resuscitation protocol with audio call-to-video call transition.

BACKGROUND: Video call based dispatcher-assisted cardiopulmonary resuscitation (V-DACPR) has been suggested to improve the quality of bystander cardiopulmonary resuscitation. In the current system, dispatchers must convert the audio calls to video calls to provide V-DACPR. We aimed to develop new audio call-to-video call transition protocols and test its efficacy and safety compared to conventional DACPR(C-DACPR). METHODS: This was a randomized controlled simulation trial that compared the quality of bystander chest compression that was performed under three different DACPR protocols: C-DACPR, V-DACPR with rapid transition, and V-DACPR with delayed transition. Adult volunteers excluding healthcare providers were recruited for the trial. The primary outcome of the study was the mean proportion of adequate hand positioning during chest compression. RESULTS: Simulation results of 131 volunteers were analyzed. The mean proportion of adequate hand positioning was highest in V-DACPR with rapid transition (V-DACPR with rapid transition vs. C-DACPR: 92.7% vs. 82.4%, p = 0.03). The mean chest compression depth was deeper in both V-DACPR groups than in the C-DACPR group (V-DACPR with rapid transition vs. C-DACPR: 40.7 mm vs. 35.9 mm, p = 0.01, V-DACPR with delayed transition vs. C- DACPR: 40.9 mm vs. 35.9 mm, p = 0.01). Improvement in the proportion of adequate hand positioning was observed in the V-DACPR groups (r = 0.25, p < 0.01 for rapid transition and r = 0.19, p < 0.01 for delayed transition). CONCLUSION: Participants in the V-DACPR groups performed higher quality chest compression with higher appropriate hand positioning and deeper compression depth compared to the C-DACPR group.

The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson's disease mouse model.

Accumulating evidence suggests that the non-receptor tyrosine kinase c-Abl plays an important role in the progression of Parkinson's disease (PD) and c-Abl inhibition could be neuroprotective in PD and related α-synucleinopathies. Nilotinib, a c-Abl inhibitor, has shown improved motor and cognitive symptoms in PD patients. However, issues concerning blood-brain barrier (BBB) penetration, lack of selectivity and safety still remain. Radotinib HCl is a selective Bcr-Abl kinase inhibitor that not only effectively access the brain, but also exhibits greater pharmacokinetic properties and safety profiles compared to Nilotinib and other c-Abl inhibitors. Here, we show the neuroprotective efficacy of Radotinib HCl, a brain penetrant c-Abl inhibitor, in a pre-clinical model of PD. Importantly, in vitro studies demonstrate that the treatment of Radotinib HCl protects the α-synuclein preformed fibrils (PFF)-induced neuronal toxicity, reduces the α-synuclein PFF-induced Lewy bodies (LB)/Lewy neurites (LN)-like pathology and inhibits the α-synuclein PFF-induced c-Abl activation in primary cortical neurons. Furthermore, administration of Radotinib HCl inhibits c-Abl activation and prevents dopaminergic neuron loss, neuroinflammation and behavioral deficits following α-synuclein PFF-induced toxicity in vivo. Taken together, our findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides an evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD and related α-synucleinopathies.

Effects of emergency department boarding on mortality in patients with ST-segment elevation myocardial infarction.

OBJECTIVE: Patients with ST-segment elevation myocardial infarction (STEMI) are sometimes boarded in the emergency department (ED) after percutaneous coronary intervention (PCI). We evaluated the effects of direct and indirect admission to the CCU on mortality and the effect on length of stay (LOS) in patients with STEMI. METHOD: This was a retrospective observational study of patients with STEMI between Jan 2014 and Nov 2017. The patients were divided into the direct admission (DA) group, who were admitted into the CCU immediately after PCI, and the indirect admission (IA) group, who were admitted after boarding in the ED. The primary endpoint was in-hospital mortality. Secondary endpoints were 3-month mortality, LOS in CCU and hospital, and LOS under intensive care. RESULTS: During the study period, 780 patients were enrolled and analyzed. The in-hospital mortality rate and 3-month mortality rate were 5.9% (46 patients) and 8.5% (66 patients). The DA group and IA group had similar in-hospital and 3-month mortality rates (P = .50, P = .28). The median CCU LOS and hospital LOS was similar for both groups (P = .28, P = .46). However, LOS under in intensive care for the IA group was significantly longer than that of the DA group (DA, 31.9 h; IA, 38.7 h; P < .001). CONCLUSION: This study suggests that direct admission after PCI and indirect admission was not associated with mortality in patients with STEMI. In addition, the stay in ED also appears to be associated with the duration of stay under critical care.

Emergency Department Triage Early Warning Score (TREWS) predicts in-hospital mortality in the emergency department.

AIM: The purpose is to assess the adequacy of the National Early Warning Score (NEWS) in the emergency department (ED) and the usefulness of the Triage in Emergency Department Early Warning Score (TREWS) that has been developed using the NEWS in the ED. METHODS: In this retrospective observational cohort study, we performed univariable and multivariable regression analyses with 81,520 consecutive ED patients to develop a new scoring system, the TREWS. The primary outcome was in-hospital mortality within 24 h, and secondary outcomes were in-hospital mortality within 48 h, 7 days, and 30 days. The prognostic properties of the TREWS were compared with those of the NEWS, Modified Early Warning Score (MEWS), and Rapid Emergency Medicine Score (REMS) using the area under the receiver operating characteristic curve (AUC) technique. RESULTS: The AUC of the TREWS for in-hospital mortality within 24 h was 0.906 (95% CI, 0.903-0.908), those of the NEWS, MEWS, and REMS were 0.878 (95% CI, 0.875-0.881), 0.857 (95% CI, 0.854-0.860), and 0.834 (95% CI, 0.831-0.837), respectively. Differences in the AUC between the TREWS and NEWS, the TREWS and MEWS, and the TREWS and REMS were 0.028 (95% CI, 0.022-0.033; p < .001), 0.049 (95% CI, 0.041-0.057; p < .001), and 0.072 (95% CI, 0.063-0.080; p < .001), respectively. The TREWS showed significantly superior performance in predicting secondary outcomes. CONCLUSION: The TREWS predicts in-hospital mortality within 24 h, 48 h, 7 days, and 30 days better than the NEWS, MEWS, and REMS for patients arriving at the ED.

Hepatoprotective Potency of Chrysophanol 8-O-Glucoside from Rheum palmatum L. against Hepatic Fibrosis via Regulation of the STAT3 Signaling Pathway.

Rhubarb is a well-known herb worldwide and includes approximately 60 species of the Rheum genus. One of the representative plants is Rheum palmatum, which is prescribed as official rhubarb due to its pharmacological potential in the Korean and Chinese pharmacopoeia. In our bioactive screening, we found out that the EtOH extract of R. palmatum inhibited hepatic stellate cell (HSC) activation by transforming growth factor ß1 (TGF-ß1). Chemical investigation of the EtOH extract led to the isolation of chrysophanol 8-O-glucoside, which was determined by structural analysis using NMR spectroscopic techniques and electrospray ionization mass spectrometry (ESIMS). To elucidate the effects of chrysophanol 8-O-glucoside on HSC activation, activated LX-2 cells were treated for 48 h with chrysophanol 8-O-glucoside, and α-SMA and collagen, HSC activation markers, were measured by comparative quantitative real-time PCR (qPCR) and western blotting analysis. Chrysophanol 8-O-glucoside significantly inhibited the protein and mRNA expression of α-SMA and collagen compared with that in TGF-ß1-treated LX-2 cells. Next, the expression of phosphorylated SMAD2 (p-SMAD2) and p-STAT3 was measured and the translocation of p-STAT3 to the nucleus was analyzed by western blotting analysis. The expression of p-SMAD2 and p-STAT3 showed that chrysophanol 8-O-glucoside strongly downregulated STAT3 phosphorylation by inhibiting the nuclear translocation of p-STAT3, which is an important mechanism in HSC activation. Moreover, chrysophanol 8-O-glucoside suppressed the expression of p-p38, not that of p-JNK or p-Erk, which can activate STAT3 phosphorylation and inhibit MMP2 expression, the downstream target of STAT3 signaling. These findings provided experimental evidence concerning the hepatoprotective effects of chrysophanol 8-O-glucoside against liver damage and revealed the molecular basis underlying its anti-fibrotic effects through the blocking of HSC activation.

Akt and Notch pathways mediate polyhexamethylene guanidine phosphate-induced epithelial-mesenchymal transition via ZEB2.

Polyhexamethylene guanidine phosphate (PHMG-p), an antimicrobial additive, was used as a humidifier disinfectant in Korea and caused severe lung injuries, including lung fibrosis, in hundreds of victims. As PHMG-p-induced lung fibrosis is different from that induced by known fibrogenic agents such as bleomycin, it is important to understand the molecular mechanisms underlying this effect. A recent study showed that epithelial-mesenchymal transition (EMT) could play key roles in PHMG-p-induced pulmonary fibrosis. Therefore, we aimed to characterize the molecular mechanisms associated with PHMG-p-induced EMT. We observed EMT, macrophage infiltration, and fibrosis in mouse lung tissues after intratracheal instillation of PHMG-p. Furthermore, PHMG-p-induced EMT was observed in A549 cells by the evaluation of cell morphology and quantitation of mRNA and protein expression. The use of EMT inhibitors revealed that PHMG-p induced EMT through the activation of Akt and Notch signaling. Moreover, the transcription factor ZEB2 was observed in PHMG-p-treated A549 cells and mouse lungs. The results indicated that upstream regulators, including Akt and Notch 1, acted as intracellular effectors that triggered ZEB2 expression after exposure to PHMG-p. Attenuation of PHMG-p-induced EMT following inhibition or silencing of Akt and Notch signaling or ZEB2 implied that PHMG-p-induced EMT was a result of Akt, Notch, and ZEB2 activation. Our findings showed that PHMG-p induced EMT through Akt/Notch signaling pathways and that ZEB2 played an important role in PHMG-p-induced lung toxicity. This study will help to understand the mechanisms of action of PHMG-p associated with lung fibrogenesis.

Guanidine-based disinfectants, polyhexamethylene guanidine-phosphate (PHMG-P), polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) induced epithelial-mesenchymal transition in A549 alveolar epithelial cells.

Abstracts Objective: The major active ingredient of humidifier disinfectant, polyhexamethylene guanidine-phosphate (PHMG-P), caused hundreds of deaths with pulmonary fibrosis. However, structurally similar guanidine-based disinfectants are still in use in various fields. Moreover, as they are precursors of excellent antimicrobial compounds, new chemicals with guanidine-based structures have been synthesized and introduced. In this study, we evaluated pulmonary fibrotic responses induced by PHMG-P, polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) and their toxicity mechanisms in type II alveolar epithelial A549 cells. Materials and methods: Cellular damage was compared by using the cytotoxicity test (WST-1 assay) and plasma membrane toxicity tests (Lactate dehydrogenase leakage detection assay and plasma membrane staining). As a measure of fibrotic response, induction of the epithelial-mesenchymal transition (EMT) was evaluated by measuring E-cadherin and α-smooth muscle actin (α-SMA) protein expression (epithelial and mesenchymal marker, respectively). Results: All tested compounds showed membrane damage; PHMG-P and PGH induced the highest and lowest damage, respectively. Moreover, they induced EMT when the test chemicals were treated with similar cytotoxic concentrations. Conclusions: Our study indicates that three guanidine-based disinfectants are potential fibrosis-inducing chemicals that induce EMT through cellular damage. Therefore, use of guanidine-based polymers should be strictly regulated by considering their potential adverse effects on the lungs.

The ratio of N-terminal pro-B-type natriuretic peptide to troponin I for differentiating acute coronary syndrome.

INTRODUCTION: It is difficult to differentiate whether coronary or non-coronary causes in patients with elevated troponin I (TnI) in emergency department (ED). The aim of this study was to develop a clinical decision tool for differentiating a coronary cause in the patients with elevated TnI. METHODS: This was a retrospective observational study that enrolled consecutive ED patients. Patients were included in the study if they were ≥16 years of age, had admitted through ED with a medical illness, and TnI levels at initial evaluation in the ED were ≥0.2 ng/mL. Patients diagnosed with ST elevation myocardial infarction or congestive heart failure were excluded. Coronary angiography, electrocardiogram, laboratory results, echocardiography, and clinical characteristics were analyzed. RESULTS: Among the included 1441 patients, 603 and 838 patients were categorized into an acute coronary syndrome (ACS) group and non-acute coronary syndrome (non-ACS) group, respectively. The ratio of N-terminal pro-Btype natriuretic peptide (NT-proBNP) to TnI was significantly higher in the non-ACS group compared to the ACS group. The AUC of NT-proBNP/TnI (0.805, 95% CI, 0.784-0.826) was significantly superior to that of NT-proBNP/creatinine kinase-MB, TnI, and NT-proBNP. The patients of the non-ACS group with high levels of TnI and BNP showed more critically ill manifestation at the time of presentation and higher mortality. CONCLUSION: NT-proBNP/TnI may help to distinguish medical patients with elevated TnI whether the elevated TnIs were caused from ACSs or from conditions other than ACS.

Suppression of 6-Hydroxydopamine-Induced Oxidative Stress by Hyperoside Via Activation of Nrf2/HO-1 Signaling in Dopaminergic Neurons.

In our ongoing research to discover natural products with neuroprotective effects, hyperoside (quercetin 3-O-galactoside) was isolated from Acer tegmentosum, which has been used in Korean traditional medicine to treat liver-related disorders. Here, we demonstrated that hyperoside protects cultured dopaminergic neurons from death via reactive oxygen species (ROS)-dependent mechanisms, although other relevant mechanisms of hyperoside activity remain largely uncharacterized. For the first time, we investigated the neuroprotective effects of hyperoside on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in neurons, and the possible underlying mechanisms. Hyperoside significantly ameliorated the loss of neuronal cell viability, lactate dehydrogenase release, excessive ROS accumulation and mitochondrial membrane potential dysfunction associated with 6-OHDA-induced neurotoxicity. Furthermore, hyperoside treatment activated the nuclear erythroid 2-related factor 2 (Nrf2), an upstream molecule of heme oxygenase-1 (HO-1). Hyperoside also induced the expression of HO-1, an antioxidant response gene. Remarkably, we found that the neuroprotective effects of hyperoside were weakened by an Nrf2 small interfering RNA, which blocked the ability of hyperoside to inhibit neuronal death, indicating the vital role of HO-1. Overall, we show that hyperoside, via the induction of Nrf2-dependent HO-1 activation, suppresses neuronal death caused by 6-OHDA-induced oxidative stress. Moreover, Nrf2-dependent HO-1 signaling activation represents a potential preventive and therapeutic target in Parkinson's disease management.

ß-Peltoboykinolic Acid from Astilbe rubra Attenuates TGF-ß1-Induced Epithelial-to-Mesenchymal Transitions in Lung Alveolar Epithelial Cells.

Epithelial-to-mesenchymal transition (EMT) is increasingly recognized as contributing to the pathogenesis of idiopathic pulmonary fibrosis. Therefore, novel plant-based natural, active compounds have been sought for the treatment of fibrotic EMT. The aim of the present study was to investigate the inhibitory effects of Astilbe rubra on TGF-ß1-induced EMT in lung alveolar epithelial cells (A549). A. rubra was subjected to extraction using 70% ethanol (ARE), and ethanol extracts of the aerial part and that of the rhizome were further partitioned using various solvents. Protein expression and cell motility were investigated to evaluate the inhibitory effects of ARE on EMT. EMT occurred in A549 cells treated with TGF-ß1, but was prevented by co-treatment with ARE. The dichloromethane fractions showed the strongest inhibitory effect on TGF-ß1-induced EMT. ß-Peltoboykinolic acid was isolated from the dichloromethane fractions of A. rubra by activity-oriented isolation. ß-Peltoboykinolic acid not only attenuated TGF-ß1-induced EMT, but also the overproduction of extracellular matrix components including type I collagen and fibronectin. The Smad pathway activated by TGF-ß1 was inhibited by co-treatment with ß-peltoboykinolic acid. Taken together, these results indicate that ß-peltoboykinolic acid from A. rubra and dichloromethane fractions shows potential as an antifibrotic agent in A549 cells treated with TGF-ß1.

The impact of the improvement in internal medicine consultation process on ED length of stay.

INTRODUCTION: Although consultations are essential for delivering safe, high-quality care to patients in emergency departments, they contribute to emergency department patient flow problems and overcrowding which is associated with several adverse outcomes, such as increases in patient mortality and poor quality care. This study aimed to investigate how time flow metrics including emergency department length of stay is influenced by changes to the internal medicine consultation policy. METHOD: This study is a pre- and post-controlled interventional study. We attempted to improve the internal medicine consultation process to be more concise. After the intervention, only attending emergency physicians consult internal medicine chief residents, clinical fellows, or junior staff of each internal medicine subspecialty who were on duty when patients required special care or an admission to internal medicine. RESULTS: Emergency department length of stay of patients admitted to the department of internal medicine prior to and after the intervention decreased from 996.94min to 706.62min. The times from consultation order to admission order and admission order to emergency department departure prior to and after the intervention were decreased from 359.59min to 180.38min and from 481.89min to 362.37min, respectively. The inpatient mortality rates and Inpatient bed occupancy rates prior to and after the intervention were similar. CONCLUSION: The improvements in the internal medicine consultation process affected the flow time metrics. Therefore, more comprehensive and cooperative strategies need to be developed to reduce the time cycle metrics and overcrowding of all patients in the emergency department.