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Asian sand dust (ASD), a seasonal dust storm originating from the deserts of China and Mongolia, affects Korea and Japan during the spring, carrying soil particles and a variety of biochemical components. Exposure to ASD has been associated with the onset and exacerbation of respiratory disorders, although the underlying mechanisms remain unclear. This study investigates ASD-induced pulmonary toxicity and its mechanistic pathways, focusing on the role of thioredoxin-interacting protein (TXNIP). Using TXNIP knock-out (KO) mice and adeno-associated virus (AAV)-mediated TXNIP overexpression transgenic mice, we explored how TXNIP modulates ASD-induced pulmonary inflammation. Mice were exposed to ASD via intranasal administration on days 1, 3, and 5 to induce inflammation. ASD exposure led to significant pulmonary inflammation, evidenced by increased inflammatory cell counts and elevated cytokine levels in bronchoalveolar lavage fluid, as well as heightened protein expression of the TXNIP/NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. TXNIP KO mice exhibited attenuated airway inflammation and downregulation of the NLRP3 inflammasome compared to wild-type controls, while AAV-mediated TXNIP overexpression mice showed exacerbated inflammatory responses, including elevated NLRP3 inflammasome expression, compared to AAV-GFP controls. These findings suggest that TXNIP is a key regulator of ASD-induced pulmonary inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Although copper oxide nanoparticles (CuONPs) offer certain benefits to humans, they can be toxic to organs and exacerbate underlying diseases upon exposure. Chronic obstructive pulmonary disease (COPD), induced by smoking, can worsen with exposure to various harmful particles. However, the specific impact of CuONPs on COPD and the underlying mechanisms remain unknown. In this study, we investigated the toxic effects of CuONPs on the respiratory tract, the pathophysiology of CuONPs exposure-induced COPD, and the mechanism of CuONPs toxicity, focusing on thioredoxin-interacting protein (TXNIP) signaling using a cigarette smoke condensate (CSC)-induced COPD model., Results: In the toxicity study, CuONPs exposure induced an inflammatory response in the respiratory tract, including inflammatory cell infiltration, cytokine production, and mucus secretion, which were accompanied by increased TXNIP, NOD-like receptor protein 3 (NLRP3), caspase-1, and interleukin (IL)-1β. In the COPD model, CuONPs exposure induced the elevation of various indexes related to COPD, as well as increased TXNIP expression. Additionally, TNXIP-knockout (KO) mice showed a significantly decreased expression of NLRP3, caspase-1, and IL-1β and inflammatory responses in CuONPs-exposed COPD mice. These results were consistent with the results of an in vitro experiment using H292 cells. By contrast, TNXIP-overexpressed mice had a markedly increased expression of NLRP3, caspase-1, and IL-1β and inflammatory responses in CuONPs-exposed COPD mice., Conclusions: We elucidated the exacerbating effect of CuONPs exposure on the respiratory tract with underlying COPD, as well as related signaling transduction via TXNIP regulation. CuONPs exposure significantly increased inflammatory responses in the respiratory tract, which was correlated with elevated TXNIP-NLRP3 signaling., Competing Interests: Declarations Ethics approval and consent to participate This research was approved by the Institutional Animal Care Use Committee (IACUC) of Chonnam National University (CNU IACUC-YB-2021-146). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Copper oxide nanoparticles (CuO NPs) have seen increasing use across various industries, raising significant concerns about their potential toxicity and the exacerbation of pre-existing conditions like asthma. Asthma, a chronic inflammatory condition of the airways, can be triggered or worsened by environmental factors such as allergens, air pollutants, and chemicals, including nanoparticles. This study aimed to investigate the pulmonary toxicity induced by CuO NPs and their impact on asthma, with a particular focus on the role of thioredoxin-interacting protein (TXNIP). Using an ovalbumin (OVA)-induced asthma model, we found that CuO NP exposure led to significant increases in inflammatory cell infiltration, cytokine production, airway hyperresponsiveness, OVA-specific immunoglobulin (Ig)E levels, and mucus production. These pathological changes were closely associated with the upregulation of TXNIP-related signaling pathways, including phosphorylated apoptosis signal-regulating kinase (p-ASK)1, the Bax/Bcl-2 ratio, and cleaved caspase-3 activation. Complementary in vitro experiments using NCI-H292 respiratory epithelial cells showed that CuO NP treatment enhanced TXNIP signaling and increased mRNA expression and the production of inflammatory cytokines. Notably, TXNIP knockdown significantly attenuated these CuO NP-induced effects. In conclusion, our findings suggest that CuO NP exposure not only induces pulmonary toxicity but also exacerbates asthma, primarily through the activation of the TXNIP signaling pathway.

Asian sand dust (ASD), generated from the deserts of China and Mongolia, affects Korea and Japan during spring and autumn, causing harmful effects on various bio-organs, including the respiratory system, due to its irritants such as fine dust, chemicals, and toxic materials. Here, we investigated the therapeutic effects of silibinin against ASD-induced airway inflammation using mouse macrophage-like cell line RAW264.7 and a murine model. ASD was intranasally administered to mice three times a week and silibinin was administered for 6 days by oral gavage. In ASD-stimulated RAW264.7 cells, silibinin treatment decreased tumor necrosis factor-α production and reduced the expression of p-p65NF-κB, p-p38, and cyclooxygenase (COX)-2, while increasing heme oxygenase (HO)-1 expression. In ASD-exposed mice, silibinin administration reduced inflammatory cell count and cytokines in bronchoalveolar lavage fluid and decreased inflammatory cell infiltration in lung tissue. Additionally, silibinin lowered oxidative stress, as evidenced by decreased 8-hydroxy-2'-deoxyguanosin (8-OHdG) expression and increased HO-1 expression. The expression of inflammatory-related proteins, including p-p65NF-κB, COX-2, and p-p38, was markedly reduced by silibinin administration. Overall, silibinin treatment reduced the expression of p-p65NF-κB, COX-2, and p-p38 in response to ASD exposure, while increasing HO-1 expression both in vitro and in vivo. These findings suggest that silibinin mitigates pulmonary inflammation caused by ASD exposure by reducing inflammatory signaling and oxidative stress, indicating its potential as a therapeutic agent for ASD-induced pulmonary inflammation.

Importance: Porcine epidemic diarrhea virus (PEDV) binds to particular cell surface receptors to penetrate cells. The virus specifically identifies certain carbohydrate structures present on the surface of the cell to facilitate the binding process. Nevertheless, the influence of viral infections on specific alterations of glycoconjugates in the small intestines remains unexplored., Objective: This work aimed to examine the alterations in glycoconjugates in the small intestines of piglets naturally infected with PEDV using lectin histochemistry., Methods: Six piglets including three PEDV-infected and three non-infected piglets were evaluated. Small intestinal samples were histopathologically examined, and lectin histochemistry was performed., Results: Piglets infected with PEDV had significant histological abnormalities in their small intestines, such as pronounced villous atrophy, varying degrees of villous fusion, and diverse mucosal alterations. Specific regions of the duodenum, jejunum, and ileum showed discernible variations in glycoconjugate distribution, as determined by lectin histochemistry. Compared with the controls, the PEDV-infected piglets showed significant changes in N-acetylglucosamine- and galactose-binding lectins (particularly wheat germ agglutinin and Arachis hypogaea (peanut) agglutinin) in multiple intestinal regions., Conclusions and Relevance: These findings can enhance understanding of how viruses such as PEDV impact the glycoconjugate composition of the small intestines and emphasize the potential connection between the pathogenesis of PEDV and glycoconjugate., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

Titanium dioxide nanoparticles (TiO 2 NPs) are used in products that are applied to the human body, such as cosmetics and food, but their biocompatibility remains controversial. Pycnogenol (PYC), a natural extract of pine bark, exerts anti-inflammatory and antioxidant effects. In this study, we investigated whether PYC effectively alleviates pulmonary toxicity induced by airway exposure to TiO 2 NPs, and the beneficial effects of PYC were explained through the analysis of changes to the mechanism of cytotoxicity. TiO 2 NPs induced pulmonary inflammation and mucus production, increased the levels of malondialdehyde, and upregulated thioredoxin-interacting protein (TXNIP) and cleaved-caspase 3 (Cas3) in the lungs of mice. However, PYC treatment reduced the levels of all toxicity markers of TiO 2 NPs and restored glutathione levels. These antioxidant and anti-inflammatory effects of PYC were also demonstrated in TiO 2 NP-exposed human airway epithelial cells by increasing the mRNA levels of antioxidant enzymes and decreasing the expression of TXNIP, cleaved-Cas3, and inflammatory mediators. Taken together, our results showed that PYC attenuated TiO 2 NP-induced lung injury via TXNIP downregulation. Therefore, our results suggest the potential of PYC as an effective anti-inflammatory and antioxidant agent against TiO 2 NP-induced pulmonary toxicity.

Allergic asthma, a type of chronic airway inflammation, is a global health concern because of its increasing incidence and recurrence rates. Camellia sinensis L. yields a variety type of teas, which are also used as medicinal plants in East Asia and are known to have antioxidant, anti-inflammatory, and immune-potentiating properties. Here, we examined the constituents of C. sinensis L. extract (CSE) and evaluated the protective effects of CSE on allergic asthma by elucidating the underlying mechanism. To induce allergic asthma, we injected the sensitization solution (mixture of ovalbumin (OVA) and aluminum hydroxide) into mice intraperitoneally on days 0 and 14. Then, the mice were exposed to 1% OVA by a nebulizer on days 21 to 23, while intragastric administration of CSE (30 and 100 mg/kg) was performed each day on days 18 to 23. We detected five compounds in CSE, including (-)-epigallocatechin, caffeine, (-)-epicatechin, (-)-epigallocatechin gallate, and (-)-epicatechin gallate. Treatment with CSE remarkably decreased the airway hyperresponsiveness, OVA-specific immunoglobulin E level, and inflammatory cell and cytokine levels of mice, with a decrease in inflammatory cell infiltration and mucus production in lung tissue. Treatment with CSE also decreased the phosphorylation of nuclear factor-κB (NF-κB) and the expression of matrix-metalloproteinase (MMP)-9 in asthmatic mice. Our results demonstrated that CSE reduced allergic airway inflammation caused by OVA through inhibition of phosphorylated NF-κB and MMP-9 expression., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Asian sand dust (ASD), generally produced in East Asia, including China, Japan, and Korea, directly leads to the development of pulmonary disease and exacerbates underlying pulmonary diseases. Loranthus tanakae Franch. and Sav. is a traditional herbal medicine applied to improve various inflammatory conditions. Here, we evaluated the curative properties of L. tanakae ethanol extract (LTE) against pulmonary inflammation caused by ASD. Additionally, to investigate the mechanism of action of LTE, we performed network pharmacological analysis. ASD was administrated on day 1, 3, and 5 by intranasal instillation, and LTE was orally administered for 6 days. Administration of LTE significantly decreased inflammatory cytokines and the number of inflammatory cells in bronchoalveolar lavage fluid, which was accompanied by a decrease in inflammatory cell accumulation in pulmonary tissue. Administration of LTE decreased the expression of cyclooxygenase2 and matrix metalloproteinase-9 in mice exposed to ASD with the decline in p65 phosphorylation. Additionally, administration of LTE significantly elevated hemeoxygenase (HO)-1 expression in the pulmonary tissue of mice exposed to ASD. These results were consistent with the data of network pharmacological analysis. This experiment showed that LTE attenuated pulmonary inflammation caused by ASD via inhibition of NF-κB and elevation of HO-1. Therefore, LTE may have potential as a therapeutic agent to treat pulmonary inflammation caused by ASD.

Ethnopharmacological Relevance: Melia azedarach L. is a traditional medicinal plant used to control pain, pyrexia, inflammation and bacterial infections that possesses several pharmacological activities, including anti-inflammatory and antioxidant activities. Particularly, the root of M. azedarach was used as expectorant and anti-cough and asthma treatment. Based its properties, M. azedarach is expected to have a potential to treat allergic asthma, chronic inflammatory respiratory disease. However, there is no study on anti-asthmatic effects of M. azedarach and its mechanism of action until now., Aim of the Study: We investigated the active ingredient of M. azedarach fruit extract (MAE) using high-performance liquid chromatography (HPLC) and explored the therapeutic effects of MAE on pulmonary inflammation and mucus hypersecretion using a murine model of ovalbumin (OVA) exposed asthma., Materials and Methods: The ingredients of MAE were analyzed using HPLC. To develop allergic asthma model, the animals were sensitized (days 1 and 14) and the airway was challenged (from day 21-23) using OVA. MAE was administered by oral gavage once a day from day 18-23 at doses of 30 and 100 mg/kg., Results: HPLC analysis revealed the presence of toosendanin in MAE. In asthmatic mice, MAE administration effectively suppressed the inflammatory cell counts in bronchoalveolar lavage fluid (BALF) along with a reduction in airway hyperresponsiveness. Moreover, MAE administration inhibited the production of proinflammatory cytokines and immunoglobulin E in BALF and serum of asthmatic mice, respectively. These results were similar to the results of histological examination showing a reduction in pulmonary inflammation and mucus hypersecretion. MAE elevated the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, and superoxide dismutase 2, which in turn resulted in the suppression of matrix metallopeptidase-9 expression in lung tissue of asthmatic mice., Conclusions: Altogether, MAE successfully inhibited allergic asthma in OVA-exposed mice. Thus, MAE could be a potential therapeutic remedy for treating allergic asthma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Asian sand dust (ASD), also called China dust or yellow dust, mainly occurs in East Asia during spring and autumn. Because ASD enters the body mainly through the respiratory system, it can cause respiratory disorders or worsen underlying diseases. Because of this, it has become an important health concern that threatens the well-being of humans and animals. In this study, we investigated the effects of 15 and 30 mg/kg of Pycnogenol (PYC15 and 30 groups), a pine bark extract, on ASD-induced pulmonary inflammation in mice. We evaluated the inflammatory cell counts, inflammatory cytokines, and matrix-metalloproteinase (MMP)-9 expression in animal models. PYC administration significantly decreased inflammatory cell infiltration into lung tissue; this was accompanied by a reduction in the levels of proinflammatory mediators including interleukin (IL)-1β ( P   <  0.01), IL-6 ( P   <  0.01) and tumour necrosis factor-α ( P   < 0.01) in bronchoalveolar lavage fluids of ASD-exposed mice (ASD group). Histological analysis revealed that PYC suppressed ASD-induced pulmonary inflammation. Moreover, PYC suppressed the levels of matrix-metalloproteinase (MMP)-9 in the lung tissue of ASD-exposed mice, indicating that PYC reduced ASD-induced pulmonary inflammation by suppressing MMP-9. Together, these results indicate that PYC as the potential to treat ASD-driven pulmonary inflammation., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 Pak et al.)

Ethnopharmacological Relevance: Angelica decursiva Franchet & Savatier is a traditional medicinal plant used to treat asthma, cough, headache, pyrexia and thick phlegm in China, Japan and Korea. A. decursiva contains many types of coumarins, which can exert several pharmacological activities including anti-inflammatory and antioxidant properties for treating various diseases such as pneumonitis, atopic dermatitis, diabetes, and Alzheimer's disease., Aim of the Study: In this study, we analyzed the components of A. decursiva ethanol extract (ADE) by high performance liquid chromatography (HPLC) and investigated the therapeutic effects of ADE against allergic asthma using lipopolysaccharide (LPS) stimulated RAW264.7 cells and an ovalbumin (OVA)-exposed allergic asthma model. To elucidate the mechanism of action of ADE, we examined the protein expression through network pharmacological analysis., Materials and Methods: To establish asthma model, the mice were sensitized on day 0 and 14 via intraperitoneal injection of OVA with aluminum hydroxide. The mice were inhaled with OVA using an ultrasonic nebulizer on day 21, 22 and 23. ADE (50 and 100 mg/kg) was administered to mice by oral gave form day 18-23. On day 24, airway hyperresponsiveness (AHR) was measured using flexivent. On day 25, the mice were sacrificed and collected bronchoalveolar lavage fluids (BALF), serum and lung tissue. In LPS-stimulated RAW264.7 cell, nitric oxide and cytokines were measured. Additionally, expression of nuclear factor erythroid-2-related factor (Nrf2) and suppression of nuclear factor (NF)-κB were detected using double-immunofluorescence., Results: We detected the five coumarin components which included nodakenin, umbelliferon, (-)-marmesin (=nodakenetin), bergapten, and decursin, in ADE by high performance liquid chromatography. Treatment with ADE decreased the production of nitric oxide, interleukin (IL)-6 and tumor necrosis factor (TNF)-α in LPS-stimulated RAW264.7 cells accompanied by the enhanced expression of nuclear factor erythroid-2-related factor (Nrf2) and suppression of nuclear factor (NF)-κB. In the asthma model, the administration of ADE reduced inflammatory cell count and airway hyperresponsiveness in OVA-exposed animals with decreased levels of IL-4, IL-13, and OVA-specific immunoglobulin E. These results were accompanied by the reduction of pulmonary inflammation and mucus secretion. Furthermore, ADE administration inhibited the expression of NF-κB and matrix metalloproteinase (MMP)-9 in OVA-exposed animals, which was consistent with the results of network pharmacological analysis., Conclusion: This study demonstrated that ADE effectively attenuated allergic inflammation induced by OVA inhalation through the enhancement of Nrf2 expression and suppression of NF-κB expression. Therefore, ADE may be a potential therapeutic agent for controlling asthma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Lincomycin (LCM) is an antibiotic used to treat severe bacterial infections in livestock and companion animals. In this study, we aimed to investigate the oral bioavailability of LCM with PK data after IV and PO administration and to compare differences in drug residue patterns in eggs. To ensure food safety, an additional study on egg residue was conducted using 3 different commercial LCM drugs. For bioavailability study, laying hens were divided into oral and intravenous (n = 8/group) groups and received single dose (10 mg/kg) of LCM. The limits of quantification for LCM were 0.729 μg/mL and 0.009 mg/kg in plasma and eggs, respectively. The oral group exhibited a significantly lower average serum drug concentration than the IV group, with a bioavailability of 2.6%. Furthermore, the egg residue profiles confirmed reduced systemic drug exposure after oral administration. For the commercial LCM drug egg residue experiment, laying hens were divided into low- and high-dose groups (n = 12/group) for each drug and treated with the recommended dosage and administration method for each respective drug. The eggs were collected and analyzed until 14 d after the last drug treatment. Despite differences in the LCM content and formulation among commercial drugs, all the tested commercial drugs showed average concentrations below the MRL in eggs within approximately 3 d after the last drug treatment. In this study, we have confirmed that LCM has a low oral absorption rate in laying hens, and this was consistent with the findings from the egg residue profiles. Further studies are requested to elucidate the exact reasons for evidently low oral drug absorption in laying hens., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure to particulate matter is currently recognized as a serious aggravating factor of respiratory diseases. In this study, we investigated the effects of particulate matter (PM) on the respiratory system in BALB/c mice and NCI-H292 cells. PM (0, 2.5, 5 and 20 mg/kg) was administered to mice by intra-tracheal instillation for 7 days. After a 7 day-repeated treatment of PM, we evaluated inflammatory cytokines/cell counts in bronchoalveolar lavage fluid (BALF) and conducted pulmonary histology and functional test. We also investigated the role of TXNIP/NF-κB and SIRT1-mediated p53 and TGF-β/Smad3 pathways in PM-induced airway inflammation and pulmonary dysfunction. PM caused a significant increase in pro-inflammatory cytokines, inflammatory cell counts in bronchoalveolar lavage fluid. PM-mediated oxidative stress down-regulated thioredoxin-1 and up-regulated thioredoxin-interacting protein and activation of nuclear factor-kappa B in the lung tissue and PM-treated NCI-H292 cells. PM suppressed sirtuin1 protein levels and increased p53 acetylation in PM-exposed mice and PM-treated NCI-H292 cells. In addition, PM caused inflammatory cell infiltration and the thickening of alveolar walls by exacerbating the inflammatory response in the lung tissue. PM increased levels of transforming growth factor-β, phosphorylation of Smad3 and activation of α-smooth muscle actin, and collagen type1A2 in PM-exposed mice and PM-treated NCI-H292 cells. In pulmonary function tests, PM exposure impaired pulmonary function resembling pulmonary fibrosis, characterized by increased resistance and elastance of the respiratory system, and resistance, elastance, and damping of lung tissues, whereas decreased compliance of the respiratory system, forced expired volume and forced vital capacity. Overall, PM-mediated oxidative stress caused airway inflammation and pulmonary dysfunction with pulmonary fibrosis via TXNIP pathway/NF-κB activation and modulation of the SIRT1-mediated TGF-β/Smad3 pathways. The results of this study can provide fundamental data on the potential adverse effects and underlying mechanism of pulmonary fibrosis caused by PM exposure as a public health concern. Due to the potential toxicity of PM, people with respiratory disease must be careful with PM exposure., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives : Critically ill surgical patients are susceptible to various postoperative complications, including acute kidney injury (AKI) and multiorgan distress syndrome (MODS). These complications intensify patient suffering and significantly increase morbidity and mortality rates. This study aimed to identify the biomarkers for predicting AKI and MODS in critically ill surgical patients. Materials and Methods : We prospectively enrolled critically ill surgical patients admitted to the intensive care unit via the emergency department between July 2022 and July 2023. A total of 83 patients were recruited, and their data were used to analyze MODS. Three patients who showed decreased creatinine clearance at the initial presentation were excluded from the analysis for AKI. Patient characteristics and laboratory parameters including white blood cell (WBC) count, neutrophil count, delta neutrophil index, urine and serum β2-microglobulin, and urine serum mitochondrial DNA copy number (mtDNAcn) were analyzed to determine the reliable biomarker to predict AKI and MODS. Results : The following parameters were independently correlated with MODS: systolic blood pressure (SBP), initial neutrophil count, and platelet count, according to a logistic regression model. The optimal cut-off values for SBP, initial neutrophil count, and platelet count were 113 mmHg (sensitivity 66.7%; specificity 73.9%), 8.65 (X 3 ) (10 9 /L) (sensitivity 72.2%; specificity 64.6%), and 195.0 (X 3 ) (10 9 /L) (sensitivity 66.7%; specificity 81.5%), respectively. According to the logistic regression model, diastolic blood pressure (DBP) and initial urine mtDNAcn were independently correlated with AKI. The optimal cut-off value for DBP and initial urine mtDNAcn were 68.5 mmHg (sensitivity 61.1%; specificity 79.5%) and 1225.6 copies/μL (sensitivity 55.6%; specificity 95.5%), respectively. Conclusions : SBP, initial neutrophil count, and platelet count were independent predictors of MODS in critically ill patients undergoing surgery. DBP and initial urine mtDNAcn levels were independent predictors of AKI in critically ill surgical patients. Large-scale multicenter prospective studies are needed to confirm our results.

Background: The use of biomarkers to predict patient outcomes may be crucial for patients admitted to the intensive care unit (ICU) following surgery because biomarkers guide clinicians in tailoring treatment plans accordingly. Therefore, we aimed to identify potential biomarkers to predict the prognosis of patients with Fournier's gangrene (FG) admitted to the ICU after surgery., Methods: We enrolled patients with FG admitted to our Hospital between January 2013 and December 2022. We retrospectively analyzed patient characteristics, factors related to management, scores known to be associated with the prognosis of FG, and laboratory data., Results: The study population included 28 survivors and 13 nonsurvivors. The initial serum lactate level taken in the emergency department; white blood cell, neutrophil, and platelet counts; delta neutrophil index and international normalized ratio; albumin, glucose, HCO3, and postoperative lactate levels; and the laboratory risk indicator for necrotizing fasciitis differed between survivors and nonsurvivors. Postoperative lactate and initial albumin levels were independent predictors of mortality in patients with FG. In the receiver operating characteristic curve analysis, the postoperative lactate level was the best indicator of mortality (area under the curve, 0.877; 95% confidence interval, 0.711-1.000). The optimal cutoff postoperative lactate level for predicting mortality was 3.0 mmol/L (sensitivity, 80.0%; specificity, 95.0%)., Conclusions: Postoperative lactate and initial albumin levels could be potential predictors of mortality in patients with FG admitted to the ICU after surgery, and the optimal cutoff postoperative lactate and initial albumin levels to predict mortality were 3.0 mmol/L and 3.05 g/dl, respectively. Large-scale multicenter prospective studies are required to confirm our results.

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects of Camellia sinensis (L.) Kuntze extract (CE) on ovalbumin-induced allergic asthma. The components of CE were analyzed using high-performance liquid chromatography (HPLC) chromatogram patterns, and asthmatic animal models were induced via ovalbumin treatment. The antioxidant and anti-inflammatory effects of CE were evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and nitric oxide (NO) assays. Seven compounds were detected in the CE chromatogram. In the ovalbumin-induced mouse model, CE treatment significantly decreased the inflammation index in the lung tissue. CE also significantly decreased eosinophilia and the production of inflammatory cytokines and OVA-specific IgE in animals with asthma. Collectively, our results indicate that CE has anti-inflammatory and antioxidant activities, and that CE treatment suppresses asthmatic progression, including mucin accumulation, inflammation, and OVA-specific IgE production.

Desertification and desert sandstorms caused by the worsening global warming pose increasing risks to human health. In particular, Asian sand dust (ASD) exposure has been related to an increase in mortality and hospital admissions for respiratory diseases. In this study, we investigated the effects of ASD on metabolic tissues in comparison to diesel particulate matter (DPM) that is known to cause adverse health effects. We found that larger lipid droplets were accumulated in the brown adipose tissues (BAT) of ASD-administered but not DPM-administered mice. Thermogenic gene expression was decreased in these mice as well. When ASD-administered mice were exposed to the cold, they failed to maintain their body temperature, suggesting that the ASD administration had led to impairments in cold-induced adaptive thermogenesis. However, impaired thermogenesis was not observed in DPM-administered mice. Furthermore, mice fed a high-fat diet that were chronically administered ASD demonstrated unexplained weight loss, indicating that chronic administration of ASD could be lethal in obese mice. We further identified that ASD-induced lung inflammation was not exacerbated in uncoupling protein 1 knockout mice, whose thermogenic capacity is impaired. Collectively, ASD exposure can impair cold-induced adaptive thermogenic responses in mice and increase the risk of mortality in obese mice., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Melamine or cyanuric acid alone has low toxicity, but combined exposure to melamine and cyanuric acid was reported to cause unexpected toxicological effects. This study investigated the potential effects and toxic mechanism of combined exposure to melamine and cyanuric acid on placental and fetal development in rats. Exposure to melamine and cyanuric acid caused maternal toxicity manifested by increased abnormal symptoms and decreased body weight gain. Developmental toxic effects included a decrease in placental and fetal weights with increased fetal deaths and post-implantation loss. Melamine and cyanuric acid induced oxidative stress in the developing placenta and fetus. The placentas from rats treated with melamine and cyanuric acid showed shortening of the placental layers with histological changes, decreased cell proliferation, increased apoptotic changes, and decreased insulin-like growth factor (IGF)/IGF-binding proteins (IGFBPs) and placental lactogen (PL) expression levels. Fetuses from melamine- and cyanuric acid-treated dams showed increased apoptotic changes and suppressed cellular proliferation in their livers and vertebrae. Consequently, combined exposure to melamine and cyanuric acid resulted in high levels of oxidative stress and impaired placental development associated with impairment of the IGF/IGFBP and PL systems, resulting in increased apoptotic changes and reduced fetal cell proliferation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The aim of this study was to compare the outcomes of preperitoneal pelvic packing (PPP) and angioembolization (AE) for patients with equivocal vital signs after initial resuscitation. This single-centered retrospective study included information from the database of a regional trauma center from April 2014 to December 2022 for patients with pelvic fractures with a systolic blood pressure of 80-100 mmHg after initial fluid resuscitation. The patients' characteristics, outcomes, and details of AE after resuscitative endovascular balloon occlusion of the aorta (REBOA) placed in zone III were collected. The follow-up duration was from hospital admission to discharge. A total of 65 patients were enrolled in this study. Their mean age was 59.2 ± 18.1 years, and 40 were males. We divided the enrolled patients into PPP ( n = 43) and AE ( n = 22) groups. The median time from emergency department (ED) to procedure and the median duration of ED stay were significantly longer in the AE group than in the PPP group ( p ≤ 0.001 for both). The median mechanical ventilation (MV) duration was significantly shorter ( p = 0.046) in the AE group. The number of patients with complications, overall mortality, and mortality due to hemorrhage did not differ between the two groups. Three patients (13.6%) were successfully treated with AE after REBOA. AE may be beneficial for patients with hemodynamically unstable pelvic fractures who show equivocal vital signs after initial fluid resuscitation in terms of reducing the MV duration and incidence of infectious complications.

Pediatric trauma patients are increasing, and trauma is the leading cause of death in children. Pancreatic injury is known as the fourth most common solid organ injury, but the diagnosis of pancreatic injury is often delayed due to the retroperitoneal location of the pancreas and the low sensitivity and specificity of diagnostic tests. Endoscopic retrograde cholangiopancreatography (ERCP) is an important test for the diagnosis and treatment of various biliary tract and pancreatic diseases. However, cases of performing ERCP in traumatic pancreatic injury in children have been rarely reported. Thus, we aimed to evaluate the usefulness of ERCP in traumatic pancreatic injury in children. Between January 1983 and December 2022, pediatric patients under the age of 18 who were treated for traumatic pancreatic injury at a single institution were recruited and retrospectively analyzed. Patient characteristics and clinical outcomes were assessed. Thirty-one patients were enrolled in this study. Among them, 15 (48.4%) patients underwent ERCP. The time to diet was significantly longer in the ERCP group. There were no statistically significant differences in other characteristics between the ERCP and the non-ERCP group. In nine (60%) patients of the ERCP group, ERCP was used for therapeutic intervention or as a decision-making tool for surgery, and was used to resolve pancreas-related complications. ERCP may be useful for the diagnosis and treatment of traumatic pancreatic injury in children. In addition, ERCP can be safely applied in children, and complications related to ERCP also may not increase. When obscure pancreatic injury is suspected, it is necessary to consider performing ERCP.

Inflammatory bowel diseases could be diagnosed in major measure by diagnostic imaging; however, radiation exposure in the intestine may also contribute to the progression of these pathologies. To better understand the impact of radiation in the presence of bowel disease, we administered dextran sodium sulfate (DSS) to C57BL/6 mice to induce colitis and exposed to radiation at abdominal area. We observed that abdominal irradiation (13 Gy) aggravates the DSS-induced decrease in survival rate (0%), body weight (74.54 ± 3.59%) and colon length (4.98 ± 0.14 cm). Additionally, abdominal irradiation markedly increased in colonic inflammation levels (3.16 ± 0.16) compared with that of DSS-induced sham mice. Furthermore, abdominal irradiation also increased the mRNA expression levels of inflammatory genes, such as cyclooxygenase-2 (13.10 folds), interleukin-6 (48.83 folds) and tumor necrosis factor-alpha (42.97 folds). We conclude that abdominal irradiation aggravates the detrimental effects of DSS-induced colitis in mice, which might be a useful guideline for inflammatory bowel disease patients., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aluminum oxide nanoparticles (Al 2 O 3 NPs) have recently been reported to cause an inflammatory response in the lungs, and studies are being conducted on their adverse effects, especially in patients with underlying lung diseases such as asthma. However, the underlying mechanism of asthma aggravation caused by Al 2 O 3 NPs remains unclear. This study investigated whether Al 2 O 3 NPs exacerbate ovalbumin (OVA)-induced asthma and focused on the correlation between toll-like receptor 4 (TLR4) signaling and Al 2 O 3 NP-induced asthma exacerbation. Al 2 O 3 NP exposure in asthmatic mice resulted in increased inflammatory cell counts in the lungs, airway hyperresponsiveness, and increased levels of inflammatory cytokines compared with only OVA-induced mice, and excessive secretion of mucus was observed in the airways. Moreover, Al 2 O 3 NP exposure in OVA-induced mice increased the expression levels of TLR4, phospho-nuclear transcription factor-kappa B (p-NFκB), myeloid differentiation factor 88 (MyD88), and phospho-NF kappa B inhibitor alpha (p-IκBα). Furthermore, in the lungs of TLR4 knockout mice exposed to Al 2 O 3 NPs and in a human airway epithelial cell line with down regulated TLR4, the expression levels of MyD88, p-NFκB, and p-IκBα were decreased, and asthma-related allergic responses were reduced. Therefore, we demonstrated that TLR4 is important for aggravation of asthma induced by Al 2 O 3 NPs, and this study provides useful information regarding as yet undiscovered novel target signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: The delta neutrophil index represents the fraction of circulating immature granulocytes and is a marker of infection and sepsis. Our study aimed to evaluate the usefulness of the delta neutrophil index in predicting mortality in patients with Fournier's gangrene., Methods: We enrolled patients with Fournier's gangrene who were admitted to the Wonju Severance Christian Hospital (Wonju, Korea) between September 2010 and December 2021. We retrospectively analyzed the patients' characteristics, factors related to management, scoring systems such as the Fournier's Gangrene Severity Index, and laboratory data measured at initial presentation., Results: There were 58 (68.2%) survivors and 27 (31.8%) non-survivors. The initial levels of serum lactate, hemoglobin, delta neutrophil index, albumin, international normalized ratio, creatinine, Fournier's Gangrene Severity Index, Uludag Fournier's Gangrene Severity Index, and prognostic nutritional index differed between survivors and non-survivors. Age, international normalized ratio, and delta neutrophil index were independent predictors of mortality in Fournier's gangrene. In receiver operating characteristic curve analysis, delta neutrophil index on the day of admission was the best indicator of mortality (area under the curve, 0.804; 95% confidence interval [0.679-0.929]). The optimal cutoff for delta neutrophil index in predicting mortality was 11.25% (sensitivity, 74.1%; specificity, 91.4%). The initial delta neutrophil index was the best indicator of mortality (area under the curve, 0.804; 95% confidence interval 0.679-0.929)., Conclusion: The delta neutrophil index can be useful for predicting mortality in patients with Fournier's gangrene. A delta neutrophil index >11.25% at initial presentation is a reliable predictor of Fournier's gangrene., (© 2022 The Japanese Urological Association.)

Loranthus tanakae Franch. & Sav. found in China, Japan, and Korea is traditionally used for managing arthritis and respiratory diseases. In this study, we analyzed the components of L. tanakae 70% ethanol extract (LTE) and investigated the therapeutic effects of LTE on pulmonary inflammation using cells exposed to cigarette smoke condensate (CSC) and lipopolysaccharide (LPS) in vitro and in vivo in mice and performed a network analysis between components and genes based on a public database. We detected quercitrin, afzelin, rhamnetin 3-rhamnoside, and rhamnocitrin 3-rhamnoside in LTE, which induced a significant reduction in inflammatory mediators including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and inflammatory cells in CSC exposed H292 cells and in mice, accompanied by a reduction in inflammatory cell infiltration into lung tissue. In addition, LTE increased translocation into the nuclei of nuclear factor erythroid-2-related factor 2 (Nrf2). By contrast, the activation of nuclear factor (NF)-κB, induced by CSC exposure, decreased after LTE application. These results were consistent with the network pharmacological analysis. In conclusion, LTE effectively attenuated pulmonary inflammation caused by CSC+LPS exposure, which was closely involved in the enhancement of Nrf2 expression and suppression of NF-κB activation. Therefore, LTE may be a potential treatment option for pulmonary inflammatory diseases including chronic obstructive pulmonary disease (COPD).

This study investigated the potential effects of China dust (CD) exposure on cyclophosphamide (CP)-induced testicular toxicity in mice, focusing on spermatogenesis and oxidative damage. CP treatment reduced testicular and epididymal weight and sperm motility and enhanced sperm abnormality. Histopathological examination presented various morphological alterations in the testis, including increased exfoliation of spermatogenic cells, degeneration of early spermatogenic cells, vacuolation of Sertoli cells, a decreased number of spermatogonia/spermatocytes/spermatids, along with a high number of apoptotic cells. In addition, the testis exhibited reduced glutathione (GSH) levels and glutathione reductase (GR) activity and enhanced malondialdehyde (MDA) concentration. Meanwhile, CD exposure exacerbated testicular histopathological alterations induced by CP. CD exposure also aggravated oxidative damage by increasing the lipid peroxidative product MDA and decreasing GSH levels and antioxidant enzyme activities in the testis. These results suggest that CD exposure exacerbates CP-induced testicular toxicity in mice, which might be attributed to the induction of lipid peroxidation and reduced antioxidant activity., Competing Interests: Competing interestsThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s) under exclusive licence to Korean Society of Toxicology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Systemic arterial hypertension is a health condition causing target organ damage (TOD) in dogs. Early and effective treatment is essential to prevent hypertensive emergencies and to reduce the risk of TOD. This study investigated the diseases underlying hypertension and compared the short-term efficacy of antihypertensive drugs in dogs. We evaluated the medical records of client-owned dogs treated with antihypertensive drugs between 2017 and 2018. The study included 75 dogs diagnosed with systemic arterial hypertension (systolic blood pressure ≥150 mmHg). The dogs were classified based on treatment with the following antihypertensive drugs: calcium channel blocker amlodipine, angiotensin-converting enzyme inhibitor ramipril, and angiotensin receptor blocker telmisartan, either as monotherapy or combination therapy (telmisartan + amlodipine or ramipril + amlodipine). Systolic blood pressure was measured using an indirect Doppler method over 4 weeks. Naturally acquired hyperadrenocorticism was the most common disorder to be diagnosed in conjunction with systemic hypertension. In the telmisartan group, the systolic blood pressure decreased more rapidly for 3 weeks compared to ramipril. The combination of telmisartan and amlodipine showed the greatest decrease in systolic blood pressure throughout the 4-week treatment period. This study is meaningful as it suggests guidelines for the use of various antihypertensive drugs in dogs., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

We investigated the effects of low dose rate radiation (LDR) on M1 and M2 macrophages in an ovalbumin-induced mouse model of allergic airway inflammation and asthma. After exposure to LDR (1 Gy, 1.818 mGy/h) for 24 days, mice were euthanized and the changes in the number of M1 and M2 macrophages in the bronchoalveolar lavage fluid and lung, and M2-associated cytokine levels, were assessed. LDR treatment not only restored the M2-rich microenvironment but also ameliorated asthma-related progression in a macrophage-dependent manner. In an ovalbumin-induced mouse model, LDR treatment significantly inhibited M2, but not M1, macrophage infiltration. M2-specific changes in macrophage polarization during chronic lung disease reversed the positive effects of LDR. Moreover, the levels of cytokines, including chemokine (C-C motif) ligand (CCL) 24, CCL17, transforming growth factor beta 1, and matrix metalloproteinase-9, decreased in ovalbumin-sensitized/challenged mice upon exposure to LDR. Collectively, our results indicate that LDR exposure suppressed asthmatic progression, including mucin accumulation, inflammation, and Type 2 T helper (Th2) cytokine (interleukin (IL)-4 and IL-13) production. In conclusion, LDR exposure decreased Th2 cytokine secretion in M2 macrophages, resulting in a reduction in eosinophilic inflammation in ovalbumin-sensitized/challenged mice., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

The prevalence of asthma is gradually increasing, and endangers human health. Many therapeutic agents have been developed to address this concern. Cinnamomum cassia (L.) J.Presl is a traditional herbal remedy in China, Japan, and Korea and used mainly to control common cold, cough, pneumonitis and fever in Donguibogam, a medical encyclopedia of Korea. Therefore, we investigated whether C. cassia (L.) J.Presl extract (CCE) confers protective effects on asthma model induced by ovalbumin (OVA). The animals were received intraperitoneal administration of OVA on day 1 and 14, and then subjected to OVA inhalation from day 21-23. They were orally treated CCE (30 and 100 mg/kg) from day 18-23. CCE administration decreased allergic responses, including airway hyperresponsiveness, eosinophilia, inflammatory cytokine production, and immunoglobulin E in OVA-exposed mice, along with the decline in inflammatory cell count and mucus secretion in respiratory tract. Additionally, CCE suppressed MAPK phosphorylation and MMP-9 expression in OVA-exposed mice. Overall, CCE treatment attenuated allergic responses induced by OVA exposure, which may be connected to the suppression of MAPK phosphorylation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lim, Kim, Lee, Kim, Lee, Pak, Shin and Kim.)

Several studies on the potential adverse effects of aluminum oxide nanoparticles (Al 2 O 3 NPs) have reported conflicting results. The present study investigated the potential adverse effects of Al 2 O 3 NPs in Sprague-Dawley rats following 28-day repeated oral administration. In addition, we aimed to determine the target organ and no-observed-adverse-effect level (NOAEL) of Al 2 O 3 NPs. Al 2 O 3 NPs was administered once daily by gavage to male and female rats at dose levels of 0, 500, and 1000 mg/kg/day for 28 days. There were no treatment-related adverse effects as indicated by the clinical signs, body weight, food consumption, urinalysis, ophthalmology, hematology, serum biochemistry, gross pathology, organ weight, and histopathology at all the tested doses. Under the experimental conditions of the present study, 28-day repeated oral administration of Al 2 O 3 NPs at doses of up to 1000 mg/kg/day did not induce any treatment-related systemic toxicity in male and female rats. The NOAEL of Al 2 O 3 NPs was set at 1000 mg/kg/day in both male and female rats and no target organs were identified., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The airway epithelium maintains tight barrier integrity to prevent penetration of pathogens; thus, impairment of the barrier function is an important and common histological feature in asthmatic patients. Proteolytic allergens from fungi, pollen, and house dust mites can disrupt epithelial barrier integrity, but the mechanism remains unclear. Aspergillus oryzae protease (AP)-induced mitochondrial reactive oxygen species (ROS) contribute to the epithelial inflammatory response. However, as mitochondrial ROS affect various cellular functions, such as metabolism, cell death, cell proliferation, and redox homeostasis through signal transduction, it is difficult to understand the detailed action mechanism of AP by measuring changes in a single gene or protein of a specific signaling pathway. Moreover, mitochondrial ROS can directly oxidize DNA to activate transcription, thereby affecting the expression of various genes at the transcriptional level. Therefore, we conducted whole-genome analysis and used a network-based approach to understand the effect of AP and AP-induced mitochondrial ROS in human primary airway epithelial cells and to evaluate the mechanistic basis for AP-mediated epithelial barrier dysfunction. Our results indicate that production of mitochondrial ROS following AP exposure induce mitochondrial dysfunction at an early stage. Over time, changes in genome expression were further expanded without remaining mitochondrial ROS. Specifically, genes involved in the apoptotic functions and intercellular junctions were affected, consequently impairing the cellular barrier integrity. This change was recovered by scavenging mitochondrial ROS at an early point after exposure to AP. In conclusion, our findings indicate that instantly increased mitochondrial ROS at the time of exposure to allergenic proteases consequently induces epithelial barrier dysfunction at a later time point, resulting in pathological changes. These data suggest that antioxidant therapy administered immediately after exposure to proteolytic antigens may be effective in maintaining epithelial barrier function., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study investigated the potential adverse effects of aluminum chloride (AlCl 3 ) following a 4-week repeated oral administration in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 100, 300, and 900 mg/kg/day for 4 weeks. After administration of AlCl 3 at 900 mg/kg/day, treatment-related systemic toxicity manifested as significant increases in salivation incidence, neutrophil percentage, reticulocytes, serum triglyceride, adrenal gland and liver weights, and single-hepatocyte necrosis, as well as significant decreases in body weight gain, food intake, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration (MCHC), lymphocyte percentage, serum total protein and albumin, and thymus weight in male rats; and significant increases in salivation incidence, serum triglyceride, and liver weight, as well as a significant decrease in lymphocyte percentage in female rats. At 300 mg/kg/day, a significant decrease in MCHC was found in male rats, but not in female rats. However, this finding was not toxicologically significant because the reduction was minimal and was not accompanied by changes in any other parameters. No treatment-related effects were observed in the 100 mg/kg/day group of both genders. Under the experimental conditions of this study, the target organs of AlCl 3 were determined to be the blood, liver, and thymus in rats. The no-observed-adverse-effect level was found to be 300 mg/kg/day in rats of both genders.

We evaluated the potential genotoxic effects of the nutrient supplement SUNACTIVE Zn-P240 in vitro and in vivo. Genotoxicity tests were performed at the Korea Testing and Research Institute, a GLP certification institution. A bacterial reverse mutation test was performed using the pre-incubation method, while the in vitro chromosome aberration test was performed using a cultured Chinese hamster lung cell line in the presence or absence of metabolic activation. The in vivo micronucleus test was performed using ICR mice. The bacterial reverse mutation test revealed that SUNACTIVE Zn-P240 did not induce genetic mutations at the tested doses in Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and Escherichia coli (WP2 uvrA ) tester strains. Meanwhile, the results of the in vitro chromosomal aberration and in vivo micronucleus tests revealed that SUNACTIVE Zn-P240 did not induce chromosomal aberrations. These results suggest that SUNACTIVE Zn-P240 did not exhibit mutagenic or clastogenic properties in vitro and in vivo., Competing Interests: Conflict of interestThe authors do not have any conflicts of interests to declare., (© The Author(s) under exclusive licence to Korean Society of Toxicology 2022.)

Background: Phlomis umbrosa Turczaninow has been used as a tradition herbal medicine for treating various inflammatory diseases., Purpose: In present study, we explored the effects of P. umbrosa on asthma induced by ovalbumin (OVA) and elucidated the mechanism via in vivo verification and network pharmacology prediction., Methods: The animals were intraperitoneally injected OVA on day 1 and 14, followed by OVA inhalation on days 21, 22, and 23. The animals were daily treated P. umbrosa extract (PUE, 20 and 40 mg/kg) by oral gavage from day 18 to day 23., Results: PUE significantly decreased airway hyperresponsiveness, eosinophilia, and the production of inflammatory cytokines and OVA specific immunoglobulin E in animals with asthma, along with a reduction in airway inflammation and mucus secretion in lung tissue. In network analysis, antiasthmatic effects of PUE were closely related with suppression of mitogen-activated protein kinases and matrix metalloproteinases (MMPs). Consistent with the results from network analysis, PUE suppressed the phosphorylation of ERK and p65, which was accompanied by a decline in MMP-9 expression., Conclusion: Administration of PUE effectively reduced allergic responses in asthmatic mice, which was associated with the suppressed phosphorylation of ERK and p65, and expression of MMP-9. These results indicate that PUE has therapeutic potential to treat allergic asthma., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Silica dioxide nanoparticles (SiONPs) have been increasingly used in various industries; however, this has raised concerns regarding their potential toxicity. SiONPs are also a major component in the Asian sand dust that causes pulmonary diseases among the general public. Melatonin exerts some inhibitory effects against lung inflammation. In this study, we explored the therapeutic properties of melatonin against lung inflammation using an SiONPs-induced lung inflammation murine model and SiONPs-stimulated H292 cells, human airway epithelial cell line, by focusing on the involvement of thioredoxin-interacting protein (TXNIP) in the modulation of the MAPKs/AP-1 axis. We induced an inflammatory response by exposing mouse lungs and the H292 cells to SiONPs and confirmed the anti-inflammatory effect of melatonin. Melatonin inhibited the expression of various inflammatory mediators, including TNF-α , IL-6 , and IL-1β , in SiONPs-exposed mice and SiONPs-stimulated H292 cells; this inhibition contributed to a decline in inflammatory cell accumulation in the lung tissues. Furthermore, melatonin treatment decreased the expression of MAPKs and AP-1 by downregulating TXNIP, eventually decreasing the production of SiONPs-induced inflammatory mediators. Overall, these data suggest that melatonin reduces SiONPs-induced lung inflammation by downregulating the TXNIP/MAPKs/AP-1 signalling pathway, thereby supporting the use of melatonin as an effective approach to control SiONPs-induced lung inflammation.

Chronic obstructive pulmonary disease (COPD) is a significant disease threatening human health. Currently, roflumilast, a phosphodiesterase (PDE)4 inhibitor, is recommended as a therapeutic agent for COPD. In this study, we investigated the therapeutic effects of melatonin against COPD, focusing on determining whether it is a PDE4 inhibitor via in vivo and in vitro experiment using cigarette smoke (CS) and cigarette smoke condensate (CSC), respectively. In the in vivo experiments, melatonin treatment reduced inflammatory responses, including inflammatory cell counts. Melatonin treatment also suppressed the CS-exposure-induced upregulation of cytokine and matrix metalloproteinase (MMP)-9, reduced the PDE4B expression, and elevated cAMP levels. In addition, these effects were synergistic, as melatonin and roflumilast cotreatment eventually ameliorated the CS-exposure-induced worsening of lung function. In the CSC-stimulated NCI-H292 cells, melatonin inhibited elevation in the levels of inflammatory cytokines, MMP-9, and PDE4, and elevated cAMP levels. Furthermore, melatonin and roflumilast cotreatment was more effective on inflammatory responses than only melatonin or roflumilast treatment. Our results indicate that melatonin relieves inflammatory response and loss of lung function in COPD, which is associated with decreased PDE4 expression. Therefore, we suggest that melatonin is a putative candidate for the treatment of COPD.

Cimicifugae Rhizoma has been used as a medicinal herb for fever, pain, and inflammation in East Asia. We conducted this study because the effect of Cimicifugae Rhizoma extract (CRE) on allergic asthma has not yet been evaluated. To induce allergic airway inflammation, we intraperitoneally injected ovalbumin (OVA) mixed with aluminum hydroxide into mice twice at intervals of 2 weeks (Days 0 and 14) and then inhaled them thrice with 1% OVA solution using a nebulizer (Days 21 to 23). CRE (30 and 100 mg/kg) was administered orally daily for 6 days (Days 18 to 23). The mice showed remarkable reduction in allergic inflammation at 100 mg/kg of CRE, as evidenced by decreased inflammatory cell counts, pro-inflammatory cytokine levels, OVA-specific immunoglobulin E level, airway hyperresponsiveness, and production of mucus. Additionally, these effects were involved with the enhancement of heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase (NQO1), and nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduction of nuclear factor-κB (NF-κB) phosphorylation and matrix metalloproteinase-9 expression. Our findings indicated that CRE effectively protected against OVA-induced inflammation and oxidative stress via upregulation of the Nrf2/HO-1/NQO1 signaling and downregulation of NF-κB phosphorylation in asthma caused by OVA.

This study was conducted to investigate the potential toxicity of repeated oral dose of SUNACTIVE Zn-P240, a new type of zinc supplement, in Sprague-Dawley rats. SUNACTIVE Zn-P240 was administered once daily by gavage at doses of 0, 500, 1000, and 2000 mg/kg/day for each group over a 28-day period. At 2000 mg/kg/day, there were increases in serum alkaline phosphatase (ALP) and alanine aminotransferase, liver weight, histopathological changes in stomach, liver, and pancreas and decreases in body weight, food consumption, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein (TP), and albumin. At 1000 mg/kg/day, there was an increase in the serum ALP level and there were decreases in the MCV, MCH, and TP. There were no treatment-related adverse effects in the 500 mg/kg/day group. Under the present experimental conditions, the target organs in rats were determined to be the stomach, pancreas, liver, and erythrocyte and the no-observed-adverse-effect level (NOAEL) in rats was considered to be 500 mg/kg/day., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Titanium dioxide nanoparticles (TiO 2 NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO 2 NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO 2 NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO 2 NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO 2 NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO 2 NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO 2 NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO 2 NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO 2 NP-mediated respiratory toxicity.

Protaetia brevitarsis seulensis is an animal-based medicine used traditionally in China, Japan, and Korea to treat hepatic disorders; it has been shown to possess various pharmacological effects such as antibacterial and antioxidant activities. In this study, we investigated the effects of P .  brevitarsis on a testosterone-induced benign prostatic hyperplasia (BPH) rat model. To establish the BPH model, the animals were administered a subcutaneous injection of testosterone daily for 28 days. P .  brevitarsis was administered by oral gavage at doses of 12.5, 25, and 50 mg/kg for 28 days, along with testosterone injection. P .  brevitarsis treatment markedly decreased the absolute and relative prostate weight of BPH animals. The levels of dihydrotestosterone was reduced in P .  brevitarsis -treated animals compared to those in the BPH animals. Histological analysis of the prostate showed that P .  brevitarsis treatment effectively suppressed the testosterone-induced hyperplasia of prostatic epithelial cells, which was accompanied by reductions in the PCNA and Ki-67 expressions in prostatic tissues. These results indicate that P .  brevitarsis effectively suppresses testosterone-induced development of BPH, and thus, is a potential therapeutic agent for BPH., Competing Interests: The authors declare that they do not have any conflict of interest., (© 2021 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Purpose: Traumatic kidney injury can be treated surgically or nonsurgically. Nonsurgical treatment options include angiography, embolization, and conservative treatment. We aimed to identify factors that help in making clinical decisions on treatment plans for patients with traumatic kidney injury caused by blunt trauma., Methods: The study included 377 patients aged ≥18 years with traumatic kidney injury caused by blunt abdominal trauma admitted to the emergency room of Wonju Severance Christian Hospital between January 2008 and July 2020. Medical records, laboratory test results, and computed tomography results were retrospectively reviewed., Results: Multivariable logistic analysis showed diastolic blood pressure at admission and disruption of Gerota's fascia were significantly associated with surgical treatment, and that perinephric hematoma rim distance was the only significant indicator favoring embolization. Receiver operating characteristic curve analysis showed that angiography and embolization should be considered when hematoma size exceeds 2.97 cm., Conclusion: When a patient with traumatic kidney injury due to blunt trauma visits an emergency room, even when vital signs are stable, Gerota's fascia should be checked by computed tomography prior to deciding on surgical treatment, and angiographic embolization should be considered if perinephric hematoma rim distance exceeds 2.97 cm., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2021, the Korean Surgical Society.)

Yijin-tang is an oriental traditional herb used to treat inflammatory diseases. In the present study, we investigated the protective effects of Yijin-tang water extract (YTE) using an ovalbumin- (OVA-) induced asthma model, focusing on the antioxidant and anti-inflammatory properties of the herb. BALB/c mice were intraperitoneally injected with OVA on days 0 and 14 and then challenged with OVA on days 21, 22, and 23. The animals were orally administered YTE (200 and 400 mg/kg) from days 18 to 23, and this was found to significantly decrease airway hyperresponsiveness and release of inflammatory cells, cytokines, and OVA-specific immunoglobulin E in mice with asthma. In addition, YTE was associated with a marked reduction in airway inflammation and mucus production in lung tissue of mice with asthma. Furthermore, YTE suppressed the expression of matrix metalloproteinase-9 and phosphorylation of ERK in the lungs, which in turn led to a reduction in inducible nitric oxide synthases and an elevation in reduced glutathione and heme oxygenase-1. In conclusion, YTE effectively suppressed allergic responses in mice with asthma and the effect was closely related to antioxidant and anti-inflammatory properties of the herb. Our results indicate that YTE may be a potential agent for the treatment of allergic asthma., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Se-Jin Lee et al.)

Shape memory materials have been successfully applied to minimally invasive implantation of medical devices. However, organ-movement-specific shape programing at a microscale level has never been demonstrated despite significant unmet needs. As vein-to-artery grafting induces vein dilation and stenosis, a polymeric self-enclosable external support (SES) is designed to wrap the vascular out-wall. Its micropores are programmed to increase sizes and interconnections upon dilation. Vessel dilation promotes venous maturation, but overdilation induces stenosis by disturbed blood flow. Therefore, the unique elastic shape-fixity of SES provides a foundation to enable a stable microscale shape transition by maintaining the vein dilation. The shape transition of micropore architecture upon dilation induces beneficial inflammation, thereby regenerating vasa vasorum and directing smooth muscle cell migration toward adventitia with the consequent muscle reinforcement of veins. This game-changer approach prevents the stenosis of vein-to-artery grafting by rescuing ischemic disorders and promoting arterial properties of veins., (© 2021 The Authors. Small published by Wiley-VCH GmbH.)

Every year, hundreds of thousands of people die because of metastatic brain cancer. Most metastatic cancer research uses 2D cell culture or animal models, but they have a few limitations, such as difficulty reproducing human tissue structures. This study developed a simple 3D in vitro model to better replicate brain metastasis using human cancer cells and human embryonic stem cell-derived cerebral organoids (metastatic brain cancer cerebral organoid [MBCCO]). The MBCCO model successfully reproduced metastatic cancer processes, including cell adhesion, proliferation, and migration, in addition to cell-cell interactions. Using the MBCCO model, we demonstrated that lung-specific X protein (LUNX) plays an important role in cell proliferation and migration or invasion. We also observed astrocyte accumulation around and their interaction with cancer cells through connexin 43 in the MBCCO model. We analyzed whether the MBCCO model can be used to screen drugs by measuring the effects of gefitinib, a well-known anticancer agent. We also examined the toxicity of gefitinib using normal cerebral organoids (COs). Therefore, the MBCCO model is a powerful tool for modeling human metastatic brain cancer in vitro and can also be used to screen drugs., (© 2020 Federation of American Societies for Experimental Biology.)

The aim of the present study was to establish an integrated network of DNA methylation and RNA expression in an ovalbumin (OVA)‑induced asthma model, and to investigate the epigenetically‑regulated genes involved in asthma development. Genome‑wide CpG‑DNA methylation profiling was conducted through the use of a methylated DNA immunoprecipitation microarray and RNA sequencing was performed using three lung samples from mice with OVA‑induced asthma. A total of 35,401 differentially methylated regions (DMRs) were identified between mice with OVA‑induced asthma and control mice. Of these, 3,060 were located in promoter regions and 370 of the genes containing these DMRs demonstrated an inverse correlation between methylation and gene expression. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified that 368 genes were upregulated or downregulated in OVA‑induced asthma samples, including genes involved in 'chemokine signalling pathway', 'focal adhesion', 'leukocyte transendothelial migration' and 'vascular smooth muscle contraction signaling' pathways. Integrated network analysis identified four hub genes, consisting of three upregulated genes [forkhead box O1 (FOXO1), SP1 transcription factor (SP1) and amyloid β precursor protein (APP)], and one downregulated gene [RUNX family transcription factor 1 (RUNX1)], all of which demonstrated an association between DNA methylation and gene expression. These genes were highly interconnected nodes in the Ingenuity Pathway Analysis module and were functionally significant. A total of four interconnected hub genes, FOXO1, RUNX1, SP1 and APP, were identified from the integrated DNA methylation and gene expression networks involved in asthma development. These results suggested that modulating these four genes could effectively control the development of asthma.

Purpose: Elderly individuals have comorbidities that can adversely affect surgical outcomes. Some studies reported that elderly patients with hepatocellular carcinoma (HCC) have higher liver- and non-liver-related deaths. Therefore, palliative treatments are preferred in these patients. We compared surgical treatment outcomes between young and old age groups., Methods: In total, 233 liver resections were performed in patients with HCC from March 2012 to December 2018. We retrospectively reviewed medical records. The old age group was defined as patients aged more than 70 years. We compared perioperative characteristics and surgical outcomes and analyzed the prognostic factors for disease-free survival (DFS) and overall survival (OS) rates., Results: The young and old age group included 184 and 49 patients, respectively. Preoperative characteristics were similar. Major liver resection rate was similar (young age group, 26.1% vs. old age group, 20.4%), but the operation time was a little bit shorter in old age group. Major postoperative complications were 23 (12.5%) and 9 (18.4%) in the young and old age group (P = 0.351). Median non-liver-related overall survival were 80 and 76 months (P = 0.889) and liver-related OS were 76 and 76 months (P = 0.514) in the young and old age groups, respectively. Age was not an independent risk factor for DFS and OS., Conclusion: Elderly patients showed similar non-liver- and liver-related OS rates as young patients after liver resection. Postoperative complications were also similar. If elderly patients are well selected, they can receive curative treatment and show good surgical outcomes., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2020, the Korean Surgical Society.)

Kidney transplantations using expanded criteria donors (ECD) are being increasingly adopted, but no consensus tools are available to evaluate donor kidney status. Beta-2 microglobulin (B2MG) is a marker of kidney function, and herein, we evaluate the usefulness of assessing B2MG to evaluate donor kidney status. Fifty-seven kidney transplantations were performed from March 2017 to April 2019. Medical records were retrospectively reviewed, and relationships between clinical and laboratory variables and transplant outcomes were investigated. Thirty-eight patients received a standard criteria donor kidney and 19 patients an ECD kidney. Ten patients experienced delayed graft function (DGF), but no patient experienced primary nonfunction. Of the parameters studied, only donor renal replacement therapy (RRT) [odds ratio (OR) 24.162; p = 0.018] and donor serum B2MG (OR 22.685; p = 0.022) significantly predicted DGF. The presence of either of these two risk factors can better reflect the condition of the donor than previous classification. However, on their last follow-up creatinine and estimated glomerular filtration rate values in those with or without these risk factors were not significantly different. For an ECD with a B2MG level of <7.18 and no history of RRT, kidney transplantation can be undertaken without considering the possibility of kidney discard.

Silica dioxide nanoparticles (SiONPs) are mainly used in the rubber industry; however, they are a major air pollutant in Asia. Thus, extensive research on this issue is required. In this study, we investigated the effects of SiONPs on asthma aggravation and elucidated the underlying mechanism using ovalbumin (OVA)-induced asthmatic mice model and in NCI-H292 cells. Mice exposed to SiONPs showed markedly increased Penh values, inflammatory cell counts, and inflammatory cytokine levels compared to OVA-induced asthmatic mice. Exposure to SiONPs also induced additional airway inflammation and mucus secretion with increases in protein expression levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, and interleukin (IL)-1β compared to those in OVA-induced asthmatic mice. Treatment of SiONPs in NCI-H292 cells also significantly increased mRNA expression levels of inflammatory cytokines accompanied with elevation in the levels of TXNIP, NLRP3 inflammasome, and IL-1β proteins in a concentration-dependent manner. Taken together, exposure to SiONPs aggravated asthma development, which is closely related to inflammasome activation. Our results provide useful information about the toxicological effects of SiONPs on asthma exacerbation and suggest the need to avoid SiONP exposure especially in individuals with respiratory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Silica dioxide nanoparticles (SiONPs) have been applied to several fields, such as drug delivery and gene therapy. However, SiONPs are a constituent of fine dust and can induce excessive inflammatory responses in the lungs via the airways. Silibinin, a major component of silymarin, has been known for its anti-oxidant and anti-inflammatory effects. In the present study, we explored the protective effects of silibinin against SiONPs-induced airway inflammation and explored its underlying mechanism of action, focusing on thioredoxin-interacting protein (TXNIP)/mitogen-activated protein kinases (MAPKs) in vitro and in vivo. In SiONPs-stimulated NCI-H292 airway epithelial cells, silibinin treatment effectively suppressed the elevation of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β, which was accompanied by the reduction in the expression of TXNIP, MAPKs, and activator protein-1 (AP-1). In SiONPs-treated mice, silibinin administration inhibited the increase in inflammatory cell counts and proinflammatory mediators, and it alleviated airway inflammation by SiONPs exposure. In addition, silibinin administration effectively suppressed the elevation of TXNIP/MAPKs/AP-1 signaling by SiONPs exposure. Taken together, silibinin effectively inhibited SiONPs-induced inflammatory responses, and this effect was closely related to the inhibition of TXNIP/MAPK/AP-1 signaling. These results suggested that silibinin might be useful for reducing pulmonary inflammation induced by SiONPs.