Short-term inhalation exposure to cigarette smoke induces oxidative stress and inflammation in lungs without systemic oxidative stress in mice.

Smoking is a well-established risk factor for various pathologies, including pulmonary diseases, cardiovascular disorders, and cancers. The toxic effects of cigarette smoke (CS) are mediated through multiple pathways and diverse mechanisms. A key pathogenic factor is oxidative stress, primarily induced by excessive formation of reactive oxygen species. However, it remains unclear whether smoking directly induces systemic oxidative stress or if such stress is a secondary consequence. This study aimed to determine whether short-term inhalation exposure to CS induces oxidative stress in extrapulmonary organs in addition to the lung in a murine model. In the experiment, 3R4F reference cigarettes were used to generate CS, and 8-week-old male BALB/c mice were exposed to CS at a total particulate matter concentration of either 0 or 800 µg/L for four consecutive days. CS exposure led to an increase in neutrophils, eosinophils, and total cell counts in bronchoalveolar lavage fluid. It also elevated levels of lactate dehydrogenase and malondialdehyde (MDA), markers indicative of tissue damage and oxidative stress, respectively. Conversely, no significant changes were observed in systemic oxidative stress markers such as total oxidant scavenging capacity, MDA, glutathione (GSH), and the GSH/GSSG ratio in blood samples. In line with these findings, CS exposure elevated NADPH oxidase (NOX)-dependent superoxide generation in the lung but not in other organs like the liver, kidney, heart, aorta, and brain. Collectively, our results indicate that short-term exposure to CS induces inflammation and oxidative stress in the lung without significantly affecting oxidative stress in extrapulmonary organs under the current experimental conditions. NOX may play a role in these pulmonary-specific events.

Pulmonary toxicity assessment of polypropylene, polystyrene, and polyethylene microplastic fragments in mice.

Polypropylene (PP), polystyrene (PS), and polyethylene (PE) plastics are commonly used in household items such as electronic housings, food packaging, bottles, bags, toys, and roofing membranes. The presence of inhalable microplastics in indoor air has become a topic of concern as many people spent extended periods of time indoors during the COVID-19 pandemic lockdown restrictions, however, the toxic effects on the respiratory system are not properly understood. We examined the toxicity of PP, PS, and PE microplastic fragments in the pulmonary system of C57BL/6 mice. For 14 days, mice were intratracheally instilled 5 mg/kg PP, PS, and PE daily. The number of inflammatory cells such as macrophages, neutrophils, and eosinophils in the bronchoalveolar lavage fluid (BALF) of PS-instilled mice was significantly higher than that in the vehicle control (VC). The levels of inflammatory cytokines and chemokines in BALF of PS-instilled mice increased compared to the VC. However, the inflammatory responses in PP- and PE-stimulated mice were not significantly different from those in the VC group. We observed elevated protein levels of toll-like receptor (TLR) 2 in the lung tissue of PP-instilled mice and TLR4 in the lung tissue of PS-instilled mice compared with those to the VC, while TLR1, TLR5, and TLR6 protein levels remained unchanged. Phosphorylation of nuclear factor kappa B (NF-κB) and IĸB-α increased significantly in PS-instilled mice compared with that in VC. Furthermore, Nucleotide­binding oligomerization domain­like receptor family pyrin domain­containing 3 (NLRP3) inflammasome components including NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and Caspase-1 in the lung tissue of PS-instilled mice increased compared with that in the VC, but not in PP- and PE-instilled mice. These results suggest that PS microplastic fragment stimulation induces pulmonary inflammation due to NF-ĸB and NLRP3 inflammasome activation by the TLR4 pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00224-x.

Nicotinamide adenine dinucleotide phosphate oxidase 2 deletion attenuates polyhexamethylene guanidine-induced lung injury in mice.

Inhalation of polyhexamethylene guanidine phosphate (PHMG) can cause pulmonary fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are enzymes that produce reactive oxygen species, which may be involved in tissue damage in various lung diseases. To investigate whether the Nox2 isoform of Nox is involved in the progression of PHMG-induced lung damage, we studied the contribution of Nox2 in PHMG-induced lung injury in Nox2-deficient mice. We treated wild-type (WT) and Nox2 knockout mice with a single intratracheal instillation of 1.1 mg/kg PHMG and sacrificed them after 14 days. We analyzed lung histopathology and the number of total and differential cells in the bronchoalveolar lavage fluid. In addition, the expressions of cytokines, chemokines, and profibrogenic genes were analyzed in the lung tissues. Based on our results, Nox2-deficient mice showed less PHMG-induced pulmonary damage than WT mice, as indicated by parameters such as body weight, lung weight, total cell count, cytokine and chemokine levels, fibrogenic mediator expression, and histopathological findings. These findings suggest that Nox2 may have the potential to contribute to PHMG-induced lung injury and serves as an essential signaling molecule in the development of PHMG-induced pulmonary fibrosis by regulating the expression of profibrogenic genes.

The Relationship between Types of Os Trigonum and Findings of Conventional Ankle Magnetic Resonance Imaging: A Study Based on Three-Dimensional Magnetic Resonance Imaging.

This study aimed to investigate the dimensions and types of the os trigonum and evaluate their relationship with various pathologic conditions on the posterior ankle using ankle MRI images. A total of 124 non-contrast-enhanced ankle and foot MR images of 123 consecutive patients were included in this retrospective study. The images were presented randomly, and they contained no patient information. The MR images were retrospectively and independently reviewed by two reviewers with a fellowship-trained musculoskeletal radiologist. The images were classified as type I and II based on the ossicle's medial border overlying the talus's posterior process and the groove for the flexor hallucis longus tendon (FHL). The study revealed that patients with type II os trigonum had a longer transverse diameter of the ossicle than type I, and there were statistically significant differences. Detachment status tended to be less in type I than in type II os trigonum, and the differences between the groups were statistically significant. There were no significant differences between type I and II os trigonum regarding posterior talofibular ligament (PTFL) abnormality, bone marrow edema, FHL tenosynovitis, and posterior synovitis. The study concluded that the os trigonum is a common cause of posterior ankle impingement, and type II os trigonum has a longer transverse diameter of the ossicle than type I.

ChatGPT's Accuracy on Magnetic Resonance Imaging Basics: Characteristics and Limitations Depending on the Question Type.

Our study aimed to assess the accuracy and limitations of ChatGPT in the domain of MRI, focused on evaluating ChatGPT's performance in answering simple knowledge questions and specialized multiple-choice questions related to MRI. A two-step approach was used to evaluate ChatGPT. In the first step, 50 simple MRI-related questions were asked, and ChatGPT's answers were categorized as correct, partially correct, or incorrect by independent researchers. In the second step, 75 multiple-choice questions covering various MRI topics were posed, and the answers were similarly categorized. The study utilized Cohen's kappa coefficient for assessing interobserver agreement. ChatGPT demonstrated high accuracy in answering straightforward MRI questions, with over 85% classified as correct. However, its performance varied significantly across multiple-choice questions, with accuracy rates ranging from 40% to 66.7%, depending on the topic. This indicated a notable gap in its ability to handle more complex, specialized questions requiring deeper understanding and context. In conclusion, this study critically evaluates the accuracy of ChatGPT in addressing questions related to Magnetic Resonance Imaging (MRI), highlighting its potential and limitations in the healthcare sector, particularly in radiology. Our findings demonstrate that ChatGPT, while proficient in responding to straightforward MRI-related questions, exhibits variability in its ability to accurately answer complex multiple-choice questions that require more profound, specialized knowledge of MRI. This discrepancy underscores the nuanced role AI can play in medical education and healthcare decision-making, necessitating a balanced approach to its application.

Disruption of phosphofructokinase activity and aerobic glycolysis in human bronchial epithelial cells by atmospheric ultrafine particulate matter.

Exposure to ambient ultrafine particulate matter (UPM) causes respiratory disorders; however, the underlying molecular mechanisms remain unclear. In this study, we synthesized simulated UPM (sUPM) with controlled physicochemical properties using the spark-discharge method. Subsequently, we investigated the biological effects of sUPM using BEAS-2B human bronchial epithelial cells (HBECs) and a mouse intratracheal instillation model. High throughput RNA-sequencing and bioinformatics analyses revealed that dysregulation of the glycolytic metabolism is involved in the inhibited proliferation and survival of HBECs by sUPM treatment. Furthermore, signaling pathway and enzymatic analyses showed that the treatment of BEAS-2B cells with sUPM induces the inactivation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB, also known as AKT), resulting in the downregulation of phosphofructokinase 2 (PFK2) S483 phosphorylation, PFK enzyme activity, and aerobic glycolysis in HBECs in an oxidative stress-independent manner. Additionally, intratracheal instillation of sUPM reduced the phosphorylation of ERK, AKT, and PFK2, decreased proliferation, and increased the apoptosis of bronchial epithelial cells in mice. The findings of this study imply that UPM induces pulmonary toxicity by disrupting aerobic glycolytic metabolism in lung epithelial cells, which can provide novel insights into the toxicity mechanisms of UPM and strategies to prevent their toxic effects.

The Development and Validation of an AI Diagnostic Model for Sacroiliitis: A Deep-Learning Approach.

PURPOSE: Sacroiliitis refers to the inflammatory condition of the sacroiliac joints, frequently causing lower back pain. It is often associated with systemic conditions. However, its signs on radiographic images can be subtle, which may result in it being overlooked or underdiagnosed. This study aims to utilize artificial intelligence (AI) to create a diagnostic tool for more accurate sacroiliitis detection in radiological images, with the goal of optimizing treatment plans and improving patient outcomes. MATERIALS AND METHOD: The study included 492 patients who visited our hospital. Right sacroiliac joint films were independently evaluated by two musculoskeletal radiologists using the Modified New York criteria (Normal, Grades 1-4). A consensus reading resolved disagreements. The images were preprocessed with Z-score standardization and histogram equalization. The DenseNet121 algorithm, a convolutional neural network with 201 layers, was used for learning and classification. All steps were performed on the DEEP:PHI platform. RESULT: The AI model exhibited high accuracy across different grades: 94.53% (Grade 1), 95.83% (Grade 2), 98.44% (Grade 3), 96.88% (Grade 4), and 96.09% (Normal cases). Sensitivity peaked at Grade 3 and Normal cases (100%), while Grade 4 achieved perfect specificity (100%). PPVs ranged from 82.61% (Grade 1) to 100% (Grade 4), and NPVs peaked at 100% for Grade 3 and Normal cases. The F1 scores ranged from 64.41% (Grade 1) to 95.38% (Grade 3). CONCLUSIONS: The AI diagnostic model showcased a robust performance in detecting and grading sacroiliitis, reflecting its potential to enhance diagnostic accuracy in clinical settings. By facilitating earlier and more accurate diagnoses, this model could substantially impact treatment strategies and patient outcomes.

Size- and oxidative potential-dependent toxicity of environmentally relevant expanded polystyrene styrofoam microplastics to macrophages.

Expanded polystyrene (EPS), also known as Styrofoam, is a widespread global pollutant, and its lightweight floating property increases its chances of weathering by abrasion and ultraviolet (UV) irradiation, resulting in microplastics. Herein, we investigated the effects of particle size ((1 µm versus 10 µm), UV irradiation (pristine versus UV oxidation), and origin (secondary versus primary) on the toxicity of Styrofoam microplastics. The target cells used in this study were selected based on human exposure-relevant cell lines: differentiated THP-1 cells for macrophages, Caco-2 for enterocytes, HepG2 for hepatocytes, and A549 for alveolar epithelial cells. In the differentiated THP-1 cells, the levels of cytotoxicity and inflammatory cytokines showed size- (1 µm > 10 µm), UV oxidation- (UV > pristine), and origin- (secondary > primary) dependency. Furthermore, the intrinsic oxidative potential of the test particles was positively correlated with cellular oxidative levels and toxicity endpoints, suggesting that the toxicity of Styrofoam microplastics also follows the oxidative stress paradigm. Additionally, all microplastics induced the activation of the pyrin domain-containing protein 3 (NLRP3) inflammasome and the release of interleukin-1ß (IL-1ß). These results imply that weathering process can aggravate the toxicity of Styrofoam microplastics due to the increased oxidative potential and decreased particle size.

Effects of stabilizer magnesium nirate on CMIT/MIT-induced respiratory toxicity.

Despite a humidifier disinfectant (HD) product containing chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) with approximately 22% magnesium nitrate as a stabilizer, no report on the effects of magnesium nitrate on the respiratory toxicity of CMIT/MIT is available. In this study, Kathon CG and Proclin 200, containing approximately 1.5% CMIT/MIT with different magnesium nitrate concentrations (22.6% and 3%, respectively), were used to compare respiratory effects after intratracheal instillation (ITI) in C57BL/6 mice. C57BL/6 mice were randomized into groups of saline control, magnesium nitrate, Kathon CG, and Proclin 200 with 1.14 mg/kg of CMIT/MIT as the active ingredient, and administration was performed 6 times in a 2-3 day-interval in 2 weeks in all groups. Differential cell count analysis, cytokine analysis, and histological analysis of lung tissue were performed to characterize the injury features. Both Kathon and Proclin 200 induced an increase in inflammatory cell levels in the bronchoalveolar lavage (BAL) fluid, in particular, eosinophils and type 2 T helper cell (Th2)-secreted cytokines. All histopathological changes including granulomatous inflammation, mixed inflammatory cell infiltration, mucous cell hyperplasia, eosinophil infiltration, and pulmonary fibrosis were induced with similar frequency and severity in Kathon CG and Proclin 200 groups. Our results suggested that magnesium nitrate did not affect CMIT/MIT-induced lung injury in the intratracheally instilled model. Further inhalation studies are needed to determine the distribution and toxicity differences of CMIT/MIT in the lungs according to the magnesium nitrate concentration.

Establishment of an artificial particulate matter-induced lung disease model through analyzing pathological changes and transcriptomic profiles in mice.

Particulate matter (PM), an environmental risk factor, is linked with health risks such as respiratory diseases. This study aimed to establish an animal model of PM-induced lung injury with artificial PM (APM) and identify the potential of APM for toxicological research. APM was generated from graphite at 600 °C and combined with ethylene. We analyzed diesel exhaust particulate (DEP) and APM compositions and compared toxicity and transcriptomic profiling in lungs according to the exposure. For the animal study, C57BL/6 male mice were intratracheally administered vehicle, DEP, or APM. DEP or APM increased relative lung weight, inflammatory cell numbers, and inflammatory protein levels compared with the vehicle control. Histological assessments showed an increase in particle-pigment alveolar macrophages and slight inflammation in the lungs of DEP and APM mice. In the only APM group, granulomatous inflammation, pulmonary fibrosis, and mucous hyperplasia were observed in the lungs of some individuals. This is the first study to compare pulmonary toxicity between DEP and APM in an animal model. Our results suggest that the APM-treated animal model may contribute to understanding the harmful effects of PM in toxicological studies showing that APM can induce various lung diseases according to different doses of APM.

Comparative study of lung toxicity of E-cigarette ingredients to investigate E-cigarette or vaping product associated lung injury.

No comparative study has yet been performed on the respiratory effects of individual E-cigarette ingredients. Here, lung toxicity of individual ingredients of E-cigarette products containing nicotine or tetrahydrocannabinol was investigated. Mice were intratracheally administered propylene glycol (PG), vegetable glycerin (VG), vitamin E acetate (VEA), or nicotine individually for two weeks. Cytological and histological changes were noticed in PG- and VEA-treated mice that exhibited pathophysiological changes which were associated with symptoms seen in patients with symptoms of E-cigarette or Vaping Use-Associated Lung Injuries (EVALI) or E-cigarette users. Compared to potential human exposure situations, while the VEA exposure condition was similar to the dose equivalent of VEA content in E-cigarettes, the PG condition was about 47-137 times higher than the dose equivalent of the daily PG intake of E-cigarette users. These results reveal that VEA exposure is much more likely to cause problems related to EVALI in humans than PG. Transcriptomic analysis revealed that PG exposure was associated with fibrotic lung injury via the AKT signaling pathway and M2 macrophage polarization, and VEA exposure was associated with asthmatic airway inflammation via the mitogen-activated protein kinase signaling pathway. This study provides novel insights into the pathophysiological effects of individual ingredients of E-cigarettes.

Effects of maternal cigarette smoke exposure on the progression of nonalcoholic steatohepatitis in offspring mice.

Cigarette smoke (CS) is a dominant carcinogenic agent in a variety of human cancers. CS exposure during pregnancy can adversely affect the fetus. Non-alcoholic fatty liver disease (NAFLD) is considered as a hepatic manifestation of a metabolic disorder, and ranges from simple steatosis to cirrhosis leading to hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is a more severe phase of NAFLD. Recently, there is increasing apprehension about the CS-related chronic liver diseases. Therefore, we examined whether maternal CS exposure could affect the pathogenesis of NASH in offspring. Mainstream CS (MSCS) was exposed to pregnant C57BL/6 mice via nose-only inhalation for 2 h/day, 5 days/week for 2 weeks from day 6 to 17 of gestation at 0, 300, or 600 µg/L. Three-week-old male offspring mice were fed methionine and choline-supplemented (MCS) diet or methionine and choline-deficient including high-fat (MCDHF) diet for 6 weeks to induce NASH. Maternal MSCS exposure increased the severity of NASH by increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic total cholesterol (TC) and triglyceride (TG) levels, pro-inflammation, fibrosis, and steatosis in offspring mice. Especially, maternal MSCS exposure significantly downregulated the phosphorylation of AMP-activated protein kinase (AMPK) in MCDHF diet-fed offspring mice. Subsequently, the protein levels of sterol regulatory element-binding protein (SREBP)-1c and stearoyl-CoA desaturase-1 (SCD1) were upregulated by maternal MSCS exposure. In conclusion, maternal MSCS exposure exacerbates the progression of NASH by modulating lipogenesis on offspring mice. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-022-00153-1.

Polypropylene nanoplastic exposure leads to lung inflammation through p38-mediated NF-κB pathway due to mitochondrial damage.

BACKGROUND: Polypropylene (PP) is used in various products such as disposable containers, spoons, and automobile parts. The disposable masks used for COVID-19 prevention mainly comprise PP, and the disposal of such masks is concerning because of the potential environmental pollution. Recent reports have suggested that weathered PP microparticles can be inhaled, however, the inhalation toxicology of PP microparticles is poorly understood. RESULTS: Inflammatory cell numbers, reactive oxygen species (ROS) production, and the levels of inflammatory cytokines and chemokines in PP-instilled mice (2.5 or 5 mg/kg) increased significantly compared to with those in the control. Histopathological analysis of the lung tissue of PP-stimulated mice revealed lung injuries, including the infiltration of inflammatory cells into the perivascular/parenchymal space, alveolar epithelial hyperplasia, and foamy macrophage aggregates. The in vitro study indicated that PP stimulation causes mitochondrial dysfunction including mitochondrial depolarization and decreased adenosine triphosphate (ATP) levels. PP stimulation led to cytotoxicity, ROS production, increase of inflammatory cytokines, and cell deaths in A549 cells. The results showed that PP stimulation increased the p-p38 and p-NF-κB protein levels both in vivo and in vitro, while p-ERK and p-JNK remained unchanged. Interestingly, the cytotoxicity that was induced by PP exposure was regulated by p38 and ROS inhibition in A549 cells. CONCLUSIONS: These results suggest that PP stimulation may contribute to inflammation pathogenesis via the p38 phosphorylation-mediated NF-κB pathway as a result of mitochondrial damage.

Inhalation toxicity of polyhexamethylene guanidine-phosphate in rats: A 4-week inhalation exposure and 24-week recovery period study.

Humidifier disinfectant (HD) is a causative agent of atypical lung injury reported in 2011 in South Korea, and various diseases caused by HD after exposure cessation have been reported to date. However, there is limited research on most of the reported diseases in terms of their association with HD exposure, and information on the progression of diseases caused by HD exposure is also limited. Therefore, we investigated the effects of HD inhalation on the body in rats. Rats were exposed to 0.15, 0.50, and 1.60 mg/m3 polyhexamethylene guanidine-phosphate (PHMG-p), which is the major component of HDs and most closely related to HD-associated lung injury. We conducted necropsy four times during the recovery period (0, 4, 12, and 24 weeks) and evaluated general systemic toxicities. There were significant changes in the mortality rate, body weight, and food consumption in the PHMG-p-exposed groups. Hematology revealed changes in hemoglobin level, hematocrit, red blood cell, reticulocyte, and white blood cell counts until 12 weeks of the recovery period. PHMG-p induced a delay in prothrombin time until 12 weeks of the recovery period. The aspartate aminotransferase, alanine aminotransferase, total bilirubin, and triglyceride levels were higher in the PHMG-p-exposed groups than in the control group at week 4 of the recovery period, and these parameters normalized after 12 weeks of the recovery period. Histopathological examination in PHMG-p exposed groups revealed several changes in the lungs, including the presence of alveolar macrophages, chronic inflammation, squamous metaplasia, alveolar emphysema, and pulmonary fibrosis. The severity of these symptoms was maintained or exacerbated till 24 weeks. Overall, PHMG-p inhalation can induce irreversible histological changes in the lungs and cause various types of damage throughout the body, even after exposure ends.

Pulmonary Toxicity of Polystyrene, Polypropylene, and Polyvinyl Chloride Microplastics in Mice.

Globally, plastics are used in various products. Concerns regarding the human body's exposure to plastics and environmental pollution have increased with increased plastic use. Microplastics can be detected in the atmosphere, leading to potential human health risks through inhalation; however, the toxic effects of microplastic inhalation are poorly understood. In this study, we examined the pulmonary toxicity of polystyrene (PS), polypropylene (PP), and polyvinyl chloride (PVC) in C57BL/6, BALB/c, and ICR mice strains. Mice were intratracheally instilled with 5 mg/kg of PS, PP, or PVC daily for two weeks. PS stimulation increased inflammatory cells in the bronchoalveolar lavage fluid (BALF) of C57BL/6 and ICR mice. Histopathological analysis of PS-instilled C57BL/6 and PP-instilled ICR mice showed inflammatory cell infiltration. PS increased the NLR family pyrin domain containing 3 (NLRP3) inflammasome components in the lung tissue of C57BL/6 and ICR mice, while PS-instilled BALB/c mice remained unchanged. PS stimulation increased inflammatory cytokines, including IL-1ß and IL-6, in BALF of C57BL/6 mice. PP-instilled ICR mice showed increased NLRP3, ASC, and Caspase-1 in the lung tissue compared to the control groups and increased IL-1ß levels in BALF. These results could provide baseline data for understanding the pulmonary toxicity of microplastic inhalation.

Biodistribution and respiratory toxicity of chloromethylisothiazolinone/methylisothiazolinone following intranasal and intratracheal administration.

A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution and potential harmful effects on human health, especially respiratory effects, were not yet identified in sufficient detail. The purpose of this study was to investigate whether a biocide comprising a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) could reach the lungs and induce lung injury when exposure occurs by two administration routes involving the respiratory tract: intratracheal and intranasal instillation. To investigate the biodistribution of CMIT/MIT, we quantified the uptake of 14C-labeled CMIT/MIT in experimental animals for up to seven days after intratracheal and intranasal instillation. In the toxicity study, lung injury was assessed in mice using total inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung histopathology. The results of the biodistribution study indicated that CMIT/MIT were rapidly distributed throughout the respiratory tract. Using quantitative whole-body autoradiogram analysis, we confirmed that following intranasal exposure, CMIT/MIT reached the lungs via the respiratory tract (nose-trachea-lung). After 5 min post intratracheal and intranasal instillation, the amount of radiotracer ([14C]CMIT/MIT) in the lungs was 2720 ng g-1 and 752 ng g-1 tissue, respectively, and lung damage was observed. A higher amount of the radiotracer resulted in higher toxicity. Both intratracheal and intranasal instillation of CMIT/MIT increased inflammatory cell counts in the BALF and induced injuries in the alveoli. The frequency and the severity scores of injuries caused by intratracheal instillation were approximately-four to five times higher than those induced by intranasal instillation. Therefore, we concluded that CMIT/MIT could reach the lungs following nasal and intratracheal exposure and cause lung injuries, and the extent of injury was dependent on the exposure dose.

Intratracheal exposure to polyhexamethylene guanidine phosphate disrupts coordinate regulation of FXR-SHP-mediated cholesterol and bile acid homeostasis in mouse liver.

A public health crisis in the form of a significant incidence of fatal pulmonary disease caused by repeated use of humidifier disinfectants containing polyhexamethylene guanidine phosphate (PHMG) recently arose in Korea. Although the mechanisms of pulmonary fibrosis following respiratory exposure to PHMG are well described, distant-organ effect has not been reported. In this study, we investigated whether intratracheal administration of PHMG affects liver pathophysiology and metabolism. Our PHMG mouse model showed a significant decrease in liver cholesterol level. An mRNA-seq analysis of liver samples revealed an alteration in the gene expression associated with cholesterol biosynthesis and metabolism to bile acids. The expression of genes involved in cholesterol synthesis was decreased in a real-time PCR analysis. To our surprise, we found that the coordinate regulation of cholesterol and bile acid homeostasis was completely disrupted. Despite the decreased cholesterol synthesis and low bile acid levels, the farnesoid X receptor/small heterodimer partner pathway, which controls negative feedback of bile acid synthesis, was activated in PHMG mice. As a consequence, gene expression of Cyp7a1 and Cyp7b1, the rate-limiting enzymes of the classical and alternative pathways of bile acid synthesis, was significantly downregulated. Notably, the changes in gene expression were corroborated by the hepatic concentrations of the bile acids. These results suggest that respiratory exposure to PHMG could cause cholestatic liver injury by disrupting the physiological regulation of hepatic cholesterol and bile acid homeostasis.

Coconut Oil Alleviates the Oxidative Stress-Mediated Inflammatory Response via Regulating the MAPK Pathway in Particulate Matter-Stimulated Alveolar Macrophages.

Exposure to particulate matter (PM) is related to various respiratory diseases, and this affects the respiratory immune system. Alveolar macrophages (AMs), which are defenders against pathogens, play a key role in respiratory inflammation through cytokine production and cellular interactions. Coconut oil demonstrates antioxidant and anti-inflammatory properties, and it is consumed worldwide for improved health. However, reports on the protective effects of coconut oil on the PM-induced respiratory immune system, especially in AMs, are limited. In this study, we generated artificial PM (APM) with a diameter approximately of 30 nm by controlling the temperature, and compared its cytotoxicity with diesel exhaust particles (DEP). We also investigated the antioxidant and anti-inflammatory effects of coconut oil in APM− and DEP−stimulated AMs, and the underlying molecular mechanisms. Our results showed that APM and DEP had high cytotoxicity in a dose-dependent manner in AMs. In particular, APM or DEP at 100 µg/mL significantly decreased cell viability (p < 0.05) and significantly increased oxidative stress markers such as reactive oxygen species (p < 0.01); the GSSH/GSH ratio (p < 0.01); and cytokine production, such as tumor necrosis factor-α (p < 0.001), interleukin (IL)-1ß (p < 0.001), and IL-6 (p < 0.001). The expression of the genes for chemokine (C-X-C motif) ligand-1 (p < 0.05) and monocyte chemoattractant protein-1 (p < 0.001); and the proteins toll-like receptor (TLR) 4 (p < 0.01), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (p < 0.001), p38 (p < 0.001); and extracellular receptor-activated kinase (p < 0.001), were also upregulated by PM. These parameters were reversed upon treatment with coconut oil in APM− or DEP−stimulated AMs. In conclusion, coconut oil can reduce APM− or DEP−induced inflammation by regulating the TLR4/MAPK pathway in AMs, and it may protect against adverse respiratory effects caused by PM exposure.

Bean Extract-Based Gargle for Efficient Diagnosis of Active COVID-19 Infection Using Rapid Antigen Tests.

The antigen-based rapid diagnostic test (Ag-RDT) using saliva specimens is fast, noninvasive, and suitable for SARS-CoV-2 self-testing, unlike nasopharyngeal swab (NPS) testing. We evaluated a novel Beanguard gargle (BG)-based virus collection method that can be applied to Ag-RDT as an alternative to the current RT-PCR with an NPS for early diagnosis of COVID-19. This clinical trial comprised 102 COVID-19-positive patients hospitalized after a governmental screening process and 100 healthy individuals. Paired NPS and BG-based saliva specimens from COVID-19 patients and healthy individuals were analyzed using NPS-RT-PCR, BG-RT-PCR, and BG-Ag-RDTs, whose diagnostic performance for detecting SARS-CoV-2 was compared. BG-Ag-RDTs showed high sensitivity (97.8%) and specificity (100%) in 45 patients within 6 days of illness and detected all cases of SARS-CoV-2 Alpha and Delta variants. In 11 asymptomatic active COVID-19 cases, both BG-Ag-RDTs and BG-RT-PCR showed sensitivities and specificities of 100%. Sensitivities of BG-Ag-RDT and BG-RT-PCR toward salivary viral detection were highly concordant, with no discrimination between symptomatic (97.0%), asymptomatic (100%), or SARS-CoV-2 variant (100%) cases. The intermolecular interactions between SARS-CoV-2 spike proteins and truncated canavalin, an active ingredient from the bean extract (BE), were observed in terms of physicochemical properties. The detachment of the SARS-CoV-2 receptor-binding domain from hACE2 increased as the BE concentration increased, allowing the release of the virus from hACE2 for early diagnosis. Using BG-based saliva specimens remarkably enhances the Ag-RDT diagnostic performance as an alternative to NPS and enables noninvasive, rapid, and accurate COVID-19 self-testing and mass screening, supporting efficient COVID-19 management. IMPORTANCE An Ag-RDT is less likely to be accepted as an initial test method for early diagnosis owing to its low sensitivity. However, our self-collection method, Ag-RDT using BG-based saliva specimens, showed significantly enhanced detection sensitivity and specificity toward SARS-CoV-2 including the Alpha and Delta variants in all patients tested within 6 days of illness. The method represents an attractive alternative to nasopharyngeal swabs for the early diagnosis of symptomatic and asymptomatic COVID-19 cases. The evidence suggests that the method could have a potential for mass screening and monitoring of COVID-19 cases.