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Background:It is unknown whether nasal corticosteroid (NCS) or inhaled corticosteroid (ICS) use impacts the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Objectives:We sought to examine the associations of NCS and ICS use with the risk of SARS-CoV-2 infection among individuals with allergic rhinitis or asthma.Methods:This is a prospective, multicenter, SARS-CoV-2 surveillance study of households with children. Nasal swabs were obtained from participants every 2 weeks with additional collections based on coronavirus disease 2019–related symptoms. In our primary adjusted models, we examined the association of NCS or ICS use at study entry (in participants with allergic rhinitis or asthma, respectively) with the time to the first SARS-CoV-2–positive quantitative PCR testing using Cox proportional hazard regression.Results:There were 2211 participants in the 1113 households included. The associations of NCS and ICS use with the risk of SARS-CoV-2 infection were modified by age (P for both interactions <.05). NCS and ICS use were individually associated with higher risks of SARS-CoV-2 infection among adults (adjusted hazard ratio [aHR] = 1.88, 95% CI: 1.14-3.12, P = .01, and aHR = 2.15, 95% CI: 1.003-4.63, P = .049, respectively). The association of NCS use with the risk of SARS-CoV-2 infection in adults was consistent in a series of sensitivity analyses. There was no association of NCS or ICS use with the risk of SARS-CoV-2 infection in children.Conclusion:Our findings suggest that the risk of SARS-CoV-2 infection is increased in adults who use NCS but not in children. Similar, albeit less consistent, age-dependent findings were observed for ICS use. While the results of this observational study should be interpreted with caution, they emphasize the need to conduct studies to understand potential mechanisms that could explain these findings.

Studies of low basal Jun N-terminal kinase (JNK) activity in non-stressed cells led us to identify a JNK inhibitor that was purified and identified as glutathione S-transferase Pi (GSTp) and was characterized as a JNK-associated protein. UV irradiation or H2O2 treatment caused GSTp oligomerization and dissociation of the GSTp-JNK complex, indicating that it is the monomeric form of GSTp that elicits JNK inhibition. Addition of purified GSTp to the Jun-JNK complex caused a dose-dependent inhibition of JNK activity. Conversely, immunodepleting GSTp from protein extracts attenuated JNK inhibition. Furthermore, JNK activity was increased in the presence of specific GSTp inhibitors and a GSTp-derived peptide. Forced expression of GSTp decreased MKK4 and JNK phosphorylation which coincided with decreased JNK activity, increased c-Jun ubiquitination and decreased c-Jun-mediated transcription. Co-transfection of MEKK1 and GSTp restored MKK4 phosphorylation but did not affect GSTp inhibition of JNK activity, suggesting that the effect of GSTp on JNK is independent of the MEKK1-MKK4 module. Mouse embryo fibroblasts from GSTp-null mice exhibited a high basal level of JNK activity that could be reduced by forced expression of GSTp cDNA. In demonstrating the relationships between GSTp expression and its association with JNK, our findings provide new insight into the regulation of stress kinases.

Risk of cataracts in the Childhood Asthma Management Program Cohort

Chapter 11 - Protective Effect of Polysaccharide from Hizikia fusiformis Against Ethanol-Induced Toxicity

BackgroundExpression of insulin in terminally differentiated non-beta cell types in the pancreas could be important to treating type-1 diabetes. Previous findings led us to hypothesize involvement of kinase inhibition in induction of insulin expression in pancreatic alpha cells.Methodology/Principal FindingsAlpha (αTC1.6) cells and human islets were treated with GW8510 and other small-molecule inhibitors for up to 5 days. Alpha cells were assessed for gene- and protein-expression levels, cell-cycle status, promoter occupancy status by chromatin immunoprecipitation (ChIP), and p53-dependent transcriptional activity. GW8510, a putative CDK2 inhibitor, up-regulated insulin expression in mouse alpha cells and enhanced insulin secretion in dissociated human islets. Gene-expression profiling and gene-set enrichment analysis of GW8510-treated alpha cells suggested up-regulation of the p53 pathway. Accordingly, the compound increased p53 transcriptional activity and expression levels of p53 transcriptional targets. A predicted p53 response element in the promoter region of the mouse Ins2 gene was verified by chromatin immunoprecipitation (ChIP). Further, inhibition of Jun N-terminal kinase (JNK) and p38 kinase activities suppressed insulin induction by GW8510.Conclusions/SignificanceThe induction of Ins2 by GW8510 occurred through p53 in a JNK- and p38-dependent manner. These results implicate p53 activity in modulation of Ins2 expression levels in pancreatic alpha cells, and point to a potential approach toward using small molecules to generate insulin in an alternative cell type.

High mobility group 1 protein (HMGB1), a highly conserved nuclear DNA‐binding protein and inflammatory mediator, has been recently found to be involved in angiogenesis. Our previous study has demonstrated the elevation of HMGB1 in the tissue of perforated disc of temporomandibular joint (TMJ). Here, we investigated a novel mediator of HMGB1 in regulating hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) to mediate angiogenesis in perforated disc cells of TMJ. HMGB1 increased the expression of HIF‐1α and VEGF in a dose‐ and time‐dependent manner in these cells. Moreover, immunofluorescence assay exhibits that the HIF‐1α were activated by HMGB1. In addition, HMGB1 activated extracellular signal‐related kinase 1/2 (Erk1/2), Jun N‐terminal kinase (JNK), but not P38 in these cells. Furthermore, both U0126 (ErK inhibitor) and SP600125 (JNK inhibitor) significantly suppressed the enhanced production of HIF‐1α and VEGF induced by HMGB1. Tube formation of human umbilical vein endothelial cells (HUVECs) was significantly increased by exposure to conditioned medium derived from HMGB1‐stimulated perforated disc cells, while attenuated with pre‐treatment of inhibitors for VEGF, HIF‐1α, Erk and JNK, individually. Therefore, abundance of HMGB1 mediates activation of HIF‐1α in disc cells via Erk and JNK pathway and then, initiates VEGF secretion, thereby leading to disc angiogenesis and accelerating degenerative change of the perforated disc.

Evidence from several studies indicates that expression of interleukin-1beta (IL-1beta) and IL-1 type I receptor is particularly high in hippocampus, and it has recently been shown that the concentration of IL-1beta is increased in the hippocampus of the aged rat. Here we report that this increase is coupled with an increase in expression of IL-1 type I receptor and increased activity of IL-1 receptor-associated kinase. The evidence presented indicates that the age-related increase in activity of the mitogen-activated protein kinases, Jun N-terminal kinase (JNK) and p38, was accompanied by enhanced caspase-3 activity. Analysis of colocalization of activated caspase-3 with activated p38 (p-p38) suggested that p-p38 was necessary for activation of caspase-3; while in vitro analysis indicated that the IL-1beta-induced increase in caspase-3 activity was abrogated by the p38 inhibitor, SB203580. The IL-1beta-induced increase in caspase-3 activity in vitro was also abrogated by vasoactive intestinal peptide, which is a JNK inhibitor; however, colocalization of activated JNK (p-JNK) and activated caspase-3 did not clearly identify JNK as an upstream activator of caspase-3. We propose that these changes are indicative of cell death in aged hippocampus and suggest that they contribute to the age-related decrease in long-term potentiation in perforant path granule cell synapses.

Idiopathic pulmonary fibrosis (IPF) is a condition that results in the progressive deterioration of lung function with poor prognosis. The current study is aimed at exploring how microRNA-448 (miR-448) targeting ABCC3 affects fibroblast proliferation, apoptosis, and collagen synthesis of mice with IPF via the Jun N-terminal kinase (JNK) signaling pathway. Bioinformatics and dual-luciferase polymerase chain reaction were used to predict the relationship of miR-448 and ABCC3. The expression of miR-448 and ABCC3 was detected in IPF tissues. Using IPF mouse models, lung fibroblasts for the experiments were treated with miR-448 mimic, miR-448 inhibitor, si-ABCC3, or SP600125 (inhibitor of JNK) to evaluate the cell proliferation and apoptosis in response to miR-448. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to identify the expression of miR-448, ABCC3, and the activation of the JNK signaling pathway. ABCC3 was targeted and downregulated by miR-448 based on bioinformatics prediction and dual-luciferase reporter gene assay. Additionally, miR-448 was found to be highly expressed in IPF lung tissues with low expression levels of ABCC3. In response to the treatment of miR-448 mimic or si-ABCC3, lung fibroblasts exhibited decreased cell proliferation and increased apoptotic rates, whereas the miR-448 inhibitor reversed the conditions. Notably, we also found that miR-448 mimic inhibited the JNK signaling pathway. In conclusion, by using miR-448 to target and downregulate ABCC3 to block the JNK signaling pathway in mice with IPF, we found an increase in fibroblast apoptosis, inhibited cell proliferation, and decreased collagen synthesis of fibroblasts.

The treatment of choice for allergic bronchopulmonary aspergillosis (ABPA) is oral corticosteroids (OCS). However, they are associated with numerous adverse effects. Inhaled corticosteroids (ICS) are associated with fewer side-effects; however, their role in the management of ABPA remains controversial. In this retrospective study, we evaluate the role of high doses of ICS in serological ABPA (ABPA-S). Patients with ABPA-S were treated with a combination of formoterol/budesonide (24-1600 micrograms per day), and followed up with history, physical examination, chest radiograph and total IgE levels at 6, 12, 18 and 24 weeks. Asthma control was evaluated using the Global Initiative for Asthma (GINA) criteria. OCS were initiated if the IgE levels continued to rise after six months of therapy with ICS. There were 8 men and 13 women with a mean (SD) age of 39.3 (12.9) years. There was subjective improvement in all patients treated with ICS but none had complete control of asthma. After six months of therapy with ICS, the median IgE levels increased by 99.3%. After the initiation of OCS, there was complete resolution of asthma symptoms in 19 patients, and IgE levels fell by a median of 52.6% at six weeks. The median duration of follow-up was 15 months after OCS therapy. Eighteen patients achieved complete remission and three patients had a relapse in the first three months after stopping OCS. One patient required long-term OCS and was classified as glucocorticoid-dependent ABPA. High doses of ICS alone have no role in the management of ABPA-S and should not be used as first-line therapy. In patients receiving OCS or alternate therapy, ICS can be used as an add-on therapy for the control of symptoms of asthma.

Use of High-Dose Inhaled Corticosteroids and Risk of Corticosteroid-Related Adverse Events in Asthma Findings From the NORDSTAR Cohort.

Anti-Inflammatory Treatment After Discharge Home from the Emergency Department in Adults with Acute Asthma

<b>Aim:</b> Even if international guidelines are developed to align routine care to best current evidence, differences may arise from health system specific factors. ASTROLAB, a FP7 European project assessing the safety of long acting β2-agonists (LABA), included a cohort of persistent asthma patients in France and in the United Kingdom (UK) based on 4 therapy patterns: LABA without inhaled corticosteroid (IC), IC without LABA, LABA and IC as separate inhalers or LABA/IC fixed-dose combinations (FDC). In this analysis, we compared IC therapy patterns and cotherapies between the two national IC without LABA cohorts. <b>Method:</b> Patients (6-40 years) were selected from prescribed LABA and/or IC ≥6 months with the same therapy pattern initially described during the 12 months selection period. THIN prescription data were used for the UK and claims data for France. <b>Results:</b> Among eligible UK (n=29,812) and French (n=2,048) patients, more UK patients received IC without LABA (63.0% vs 23.4%), while the FDC group was predominant in France (64.4% vs 33.3%). In the IC without LABA group, patients received similar numbers of IC prescriptions (UK) or dispensations (France) over 12 months (4.3 vs. 4.0, p=0.12). However, IC canisters with lower IC dosages/inhalation were more frequent in the UK. More French patients received leukotriene-receptor antagonists (18.6% vs 8.3%, p&lt;0.0001) and oral corticosteroids (51.9% vs 15.5%, p&lt;0.0001). Conversely, most patients in both countries received short-acting beta-agonists (94.6% vs 90.7% p=0.0651). <b>Conclusion:</b> Marked differences in asthma therapy patterns appeared between France and the UK, among IC-treated patients. <b>Acknowledgment:</b> Project funded by the EC (GA n°282593).

Ovarian cancer is the most common gynecological malignancy that causes cancer-related deaths in women today; this being the case, developing an understanding of ovarian cancer has become one of the major driving forces behind cancer research overall. Moreover, such research over the last 20 years has shown that the Jun N-terminal kinase (JNK) signaling pathway plays an important role in regulating cell death, survival, growth and proliferation in the mitogen-activated protein kinases (MAPK) signaling pathway, an important pathway in the formation of cancer. Furthermore, the JNK signaling pathway is often regulated by an abnormal activation in human tumors and is frequently reported in the literature for its effect on the progression of ovarian cancer. Although the FDA has approved some JNK inhibitors for melanoma, the agency has not approved JNK inhibitors for ovarian cancer. However, there are some experimental data on inhibitors and activators of the JNK signaling pathway in ovarian cancer, but related clinical trials need to be further improved. Although the Jun N-terminal kinase (JNK) signaling pathway is implicated in the formation of cancer in general, research has also indicated that it has a role in suppressing cancer as well. Here, we summarize this seemingly contradictory role of the JNK signaling pathway in ovarian cancer, that ‘seesaws’ between promoting and suppressing cancer, as well as summarizing the application of several JNK pathway inhibitors in cancer in general, and ovarian cancer in particular.

Inhaled corticosteroids (ICS) treatment for asthma control is generally focused on lung function and symptoms, but inadequately correlated with airway inflammation. To compare asthma control in a group of patients whose treatment was based on fraction of exhaled nitric oxide (FENO) and sputum eosinophils (intervention group) with a group in whom treatment was based on clinical score (control group). Study design and primary outcome: Randomized parallel-group longitudinal 24-month study including 5 visits every 6 months. A combination of asthma exacerbation rate and symptom score at 24 months was the primary outcome. Fourteen patients with eosinophilic asthma per group were included. In the intervention group, exacerbation rate/patient/year was reduced at 12 months (0.82) (-73%) and, to a greater extent at 24 months (0.5) (-84%) compared with baseline (3.21, p<0.01). In the control group, a significant reduction in exacerbation rate/patient/year was only observed between month 12 (3.0) and 24 (2.0, -33%, p<0.01). At 24 months, exacerbation rate was lower (-75%) in the intervention (0.5) than in the control group (2.0, p<0.05). Compared with baseline, mean symptom scores at 24 months were reduced in both groups (intervention group: -72%; control group: - 60%), but were lower in the intervention (8.1±1.0, p<0.05; -27%) than in the control group (11±2.6). ICS dose gradually increased in both groups throughout the study, with no between-group differences. Compared with conventional strategy, longitudinal monitoring of FENO and sputum eosinophils improves eosinophilic asthma control in terms of reduced symptoms and exacerbations without additional increase e in ICS treatment.

Is there an association between inhaled corticosteroids and bone density in postmenopausal women?