The severity of the coronavirus disease (COVID-19) is associated with various comorbidities. However, no studies have yet demonstrated the potential risk of respiratory failure and mortality in ...COVID-19 patients with pre-existing asthma. We selected 7272 adult COVID-19 patients from the Korean Health Insurance Review and Assessment COVID-19 database for this nationwide retrospective cohort study. Among these, 686 patients with asthma were assessed by their severities and evaluated by the clinical outcome of COVID-19 compared to patients without asthma. Of 7272 adult COVID-19 patients, 686 with asthma and 6586 without asthma were compared. Asthma was not a significant risk factor for respiratory failure or mortality among all COVID-19 patients (odds ratio OR = 0.99, P = 0.997 and OR = 1.06, P = 0.759) after adjusting for age, sex, and the Charlson comorbidity score. However, a history of acute exacerbation (OR = 2.63, P = 0.043) was significant risk factors for death among COVID-19 patients with asthma. Asthma is not a risk factor for poor prognosis of COVID-19. However, asthma patients who had any experience of acute exacerbation in the previous year before COVID-19 showed higher COVID-19-related mortality, especially in case of old age and male sex.
Underlying chronic respiratory disease may be associated with the severity of coronavirus disease 2019 (COVID-19). This study investigated the impact of chronic obstructive pulmonary disease (COPD) ...on the risk for respiratory failure and mortality in COVID-19 patients. A nationwide retrospective cohort study was conducted in 4610 patients (≥ 40 years old) infected with COVID-19 between January 20 and May 27, 2020, using data from the Ministry of Health and Welfare and Health Insurance Review and Assessment Service in Korea. The clinical course and various clinical features were compared between COPD and non-COPD patients, and the risks of respiratory failure and all-cause mortality in COPD patients were analyzed using a multivariate logistic regression model. Among 4610 COVID-19 patients, 4469 (96.9%) and 141 (3.1%) were categorized into the non-COPD and COPD groups, respectively. The COPD group had greater proportions of older (≥ 60 years old) (78.0% vs. 45.2%, P < 0.001) and male (52.5% vs. 36.6%, P < 0.001) patients than the non-COPD group. Relatively greater proportions of patients with COPD received intensive critical care (7.1% vs. 3.7%, P = 0.041) and mechanical ventilation (5.7% vs. 2.4%, P = 0.015). Multivariate analyses showed that COPD was not a risk factor for respiratory failure but was a significant independent risk factor for all-cause mortality (OR = 1.80, 95% CI 1.11-2.93) after adjustment for age, sex, and Charlson Comorbidity Index score. Among COVID-19 patients, relatively greater proportions of patients with COPD received mechanical ventilation and intensive critical care. COPD is an independent risk factor for all-cause mortality in COVID-19 patients in Korea.
Pure and CuO-loaded In2O3 nanofibers were prepared by electrospinning and their H2S sensing characteristics were investigated. The loading of CuO on In2O3 nanofibers significantly enhanced the gas ...response (ratio of the resistance in air to that in gas) toward 5ppm H2S from 515 to 1.16×105 at 150°C. The CuO-loaded In2O3 nanofibers also exhibited high gas response (9.17×103 toward 5ppm H2S) at room temperature. The CuO-loaded In2O3 nanofibers showed ultrahigh selectivity to H2S concerning interferences with NO2, H2, CO, NH3, C2H5OH, C3H6O, TMA, C7H8, and C8H10 at room temperature and 150°C. The operation of the sensor using pulse heating was suggested reliable H2S sensing with complete recovery. The ultrasensitivie and ultraselective H2S sensing characteristics are explained in terms of the creation and disruption of p–n junctions in the presence and absence of H2S, respectively, the high specific surface area provided by the networks of one-dimensional polycrystalline nanofibers, and the abundance of p–n junctions due to the uniform mixing between p-CuO and n-In2O3 nanograins within the nanofibers.
Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness ...the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC
values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.
Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by ...acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress-PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i.
Background Allergic rhinitis (AR) and asthma are 2 entities of allergic airway diseases that frequently occur together, which is referred to as united airways . In contrast to this general concept, ...we hypothesized that innate immunity of the upper and lower airways is respectively distinctive, because the immunologic conditions of the nasal and lung mucosa as well as the functions of the immune cells within their epithelia are different. Objective We wanted to identify distinctive mechanisms of innate immunity in the nose and lung mucosa, which are responsible for house dust mite (HDM)–induced AR and allergic asthma (AA), respectively. Methods We constructed a mouse model of AR or AA induced by sensitization and consequent provocation with HDM extracts. Results HDM-derived β-glucans, rather than LPS, were proven to be essential to activating innate immunity in the nasal mucosa and triggering AR, which depended on Toll-like receptor 2 (TLR2), but not on TLR4; however, the LPS/TLR4 signaling axis, rather than β-glucans/TLR2, was critical to HDM-induced AA. These differences were attributed to the specific role of β-glucans and LPS in inducing the surface expression of TLR2 and TLR4 and their translocation to lipid rafts in nasal and bronchial epithelial cells, respectively. We also showed that dual oxidase 2–generated reactive oxygen species mediate both β-glucan–induced TLR2 activation and LPS-induced TLR4 activation. Conclusions We describe a novel finding of distinctive innate immunity of the nose and lungs, respectively, which trigger AR and AA, by showing the critical role of HDM-induced TLR activation via dual oxidase 2–mediated reactive oxygen species.
The chemiresistive sensing characteristics of metal oxide gas sensors depend closely on ambient humidity. Herein, we report that gas sensors using Tb-doped SnO2 yolk–shell spheres can be used for ...reliable acetone detection, regardless of the variations in humidity. Pure SnO2 and Tb-doped SnO2 yolk–shell spheres were prepared via ultrasonic spray pyrolysis and their chemiresistive sensing characteristics were studied. The sensor resistance and gas response of the pure SnO2 yolk–shell spheres significantly changed and deteriorated upon exposure to moisture. In stark contrast, the Tb-doped SnO2 yolk–shell spheres exhibited similar gas responses and sensor resistances in both dry and humid relative humidity (RH) 80% atmospheres. In addition, the Tb-doped SnO2 yolk–shell sensors showed a high gas response (resistance ratio) of 1.21 to the sub-ppm-levels (50 ppb) of acetone with low responses to the other interference gases. The effects of Tb oxide and the chemical interactions among the Tb oxide, SnO2, and water vapor on this humidity-independent gas sensing behavior of the Tb-doped SnO2 yolk–shell sensors were investigated. This strategy can provide a new road to achieve highly sensitive, selective, and humidity-independent sensing of acetone, which will facilitate miniaturized and real-time exhaled breath analysis for diagnosing diabetes.
The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a critical transcriptional coactivator that maintains metabolic homeostasis and energy expenditure by cooperating ...with various transcription factors. Recent studies have shown that PGC1α deficiency promotes lung cancer metastasis to the bone through activation of TCF4 and TWIST1-mediated epithelial–mesenchymal transition (EMT), which is suppressed by the inhibitor of DNA binding 1 (ID1); however, it is not clear which transcription factor participates in PGC1α-mediated EMT and lung cancer metastasis. Here, we identified forkhead box A1 (FOXA1) as a potential transcription factor that coordinates with PGC1α and ID1 for EMT gene expression using transcriptome analysis. Cooperation between FOXA1 and PGC1α inhibits promoter occupancy of TCF4 and TWIST1 on CDH1 and CDH2 proximal promoter regions due to increased ID1, consequently regulating the expression of EMT-related genes such as CDH1, CDH2, VIM, and PTHLH. Transforming growth factor beta 1 (TGFβ1), a major EMT-promoting factor, was found to decrease ID1 due to the suppression of FOXA1 and PGC1α. In addition, ectopic expression of ID1, FOXA1, and PGC1α reversed TGFβ1-induced EMT gene expression. Our findings suggest that FOXA1- and PGC1α-mediated ID1 expression involves EMT by suppressing TCF4 and TWIST1 in response to TGFβ1. Taken together, this transcriptional framework is a promising molecular target for the development of therapeutic strategies for lung cancer metastasis.
An ideal root canal sealer creates a bacteria-resistant seal and exhibits antimicrobial activity, biocompatibility, and osteoconductivity. The aim of this study was to assess the effects of 3 root ...canal sealers on cell viability, inflammatory response, and osteogenic potential in MC3T3-E1 cells.
AH Plus (Dentsply Caulk, Milford, DE), MTA Fillapex (Angelus Solucxoes Odontologicas, Londrina, Brazil), and EndoSequence BC (Brasseler, Savannah, GA) were mixed according to the manufacturer's instructions, and samples were prepared as extraction media (final dilution: 1/10). Lipopolysaccharide (LPS) (100 ng/mL) treatment was used to induce an inflammatory response in this study. Cell viability was evaluated using the Water soluble tetrazolium-1 (WST-1) assay. The levels of inflammatory mediators (interleukin 6 and tumor necrosis factor alpha) and osteogenic marker genes (ALP and OCN) were measured by reverse-transcription polymerase chain reaction and real-time polymerase chain reaction. Osteogenic potential was evaluated by alkaline phosphatase staining and alizarin red staining.
Calcium silicate–based sealers such as MTA Fillapex and EndoSequence BC showed strong cell viability compared with AH Plus. AH Plus, MTA Fillapex, and EndoSequence BC decreased the levels of LPS-induced inflammatory mediators (P < .05). The expression of osteogenic marker genes, alkaline phosphatase activity, and mineralized nodule formation decreased with LPS treatment. However, AH Plus and calcium silicate–based sealers increased the osteogenic potential reduced by LPS treatment (P < .05).
Calcium silicate–based sealers exhibit anti-inflammatory effects and induce osteogenic differentiation in MC3T3-E1 cells.
•We evaluated the biocompatibility, anti-inflammatory, and osteogenic effects of calcium silicate–based root canal sealers.•Calcium silicate–based sealers showed good cell viability compared with epoxy resin–based sealer.•The expression of osteogenic marker genes, ALP activity, and mineralized nodule formation decreased by lipopolysaccharide (LPS) treatment, but calcium silicate–based sealers and epoxy/amine resin–based sealer increased osteogenic potential and mineralization reduced by LPS treatment.
Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory ...responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces "mitochondrial priming" by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.
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