Development of highly potent glucocorticoids for steroid-resistant severe asthma

He, Yuanzheng; Shi, Jingjing; Nguyen, Quan; You, Erli; Liu, Hongbo; Ren, Xin; Wu, Zhongshan; Li, Jianshuang; Qiu, Wenli; Khoo, Sok Kean; Yang, Tao; Yi, Wei; Sun, Feng xiang; Xi, Zhijian; Huang, Xiaozhu; Melcher, Karsten; Min, Booki; Xu, H. Eric

doi:10.1073/pnas.1816734116

Cited by 46 publications

(31 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The latest research shows that the new high-efficiency glucocorticoid ligands (such as vsg158) had a very high antiinflammatory effect in animal asthma models, showing an effect 10-fold stronger than that of the widely used and effective asthma drug (fluticasone furoate, FF) and reversed corticosteroid resistance in the animal model of a corticosteroid-resistant type of malignant asthma. Although no clinical experiments were carried out, the research provided a new idea for the treatment of malignant asthma characterized by high mortality [95].…”

Section: Development Potential and Clinical Applications Of Neutrophimentioning

confidence: 99%

The role of NTHi colonization and infection in the pathogenesis of neutrophilic asthma

et al. 2020

View full text Add to dashboard Cite

Asthma is a complex heterogeneous disease. The neutrophilic subtypes of asthma are described as persistent, more severe and corticosteroid-resistant, with higher hospitalization and mortality rates, which seriously affect the lives of asthmatic patients. With the development of high-throughput sequencing technology, an increasing amount of evidence has shown that lower airway microbiome dysbiosis contributes to the exacerbation of asthma, especially neutrophilic asthma. Nontypeable Haemophilus influenzae is normally found in the upper respiratory tract of healthy adults and is one of the most common strains in the lower respiratory tract of neutrophilic asthma patients, in whom its presence is related to the occurrence of corticosteroid resistance. To understand the pathogenic mechanism by which nontypeable Haemophilus influenzae colonization leads to the progression of neutrophilic asthma, we reviewed the previous literature on nontypeable Haemophilus influenzae colonization and subsequent aggravation of neutrophilic asthma and corticosteroid resistance. We discussed nontypeable Haemophilus influenzae as a potential therapeutic target to prevent the progression of neutrophilic asthma.

show abstract

Section: Development Potential and Clinical Applications Of Neutrophimentioning

confidence: 99%

The role of NTHi colonization and infection in the pathogenesis of neutrophilic asthma

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The AGE-RAGE signaling pathway has important protective effects on bones and the heart and participates in oxidative stress response [25] and fibrosis transduction [22]. The cytokine-cytokine receptor interaction is a key pathway for regulating the cellular inflammatory response [28]. IL6, ILIB, CCL2 and other genes occupy a large rectangular area, indicating that there are more pathways connected to these genes.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Dayuanyin in the treatment of coronavirus disease 2019 based on network pharmacology and molecular docking

Ruan

Zhao

et al. 2020

Chin Med

View full text Add to dashboard Cite

Background: At present, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2, is spreading all over the world, with disastrous consequences for people of all countries. The traditional Chinese medicine prescription Dayuanyin (DYY), a classic prescription for the treatment of plague, has shown significant effects in the treatment of COVID-19. However, its specific mechanism of action has not yet been clarified. This study aims to explore the mechanism of action of DYY in the treatment of COVID-19 with the hope of providing a theoretical basis for its clinical application. Methods: First, the TCMSP database was searched to screen the active ingredients and corresponding target genes of the DYY prescription and to further identify the core compounds in the active ingredient. Simultaneously, the Genecards database was searched to identify targets related to COVID-19. Then, the STRING database was applied to analyse protein-protein interaction, and Cytoscape software was used to draw a network diagram. The R language and DAVID database were used to analyse GO biological processes and KEGG pathway enrichment. Second, Auto-Dock Vina and other software were used for molecular docking of core targets and core compounds. Finally, before and after application of DYY, the core target gene IL6 of COVID-19 patients was detected by ELISA to validate the clinical effects. Results: First, 174 compounds, 7053 target genes of DYY and 251 genes related to COVID-19 were selected, among which there were 45 target genes of DYY associated with treatment of COVID-19. This study demonstrated that the use of DYY in the treatment of COVID-19 involved a variety of biological processes, and DYY acted on key targets such as IL6, ILIB, and CCL2 through signaling pathways such as the IL-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and cytokine-cytokine receptor interaction. DYY might play a vital role in treating COVID-19 by suppressing the inflammatory storm and regulating immune function. Second, the molecular docking results showed that there was a certain affinity between the core compounds (kaempferol, quercetin, 7-Methoxy-2-methyl isoflavone, naringenin, formononetin) and core target genes (IL6, IL1B, CCL2). Finally, clinical studies showed that the level of IL6 was elevated in COVID-19 patients, and DYY can reduce its levels.

show abstract

“…Based on the HDM-induced asthma recurrence model, we compared the efficiency of YPFS administered in remission versus three medications applied in clinical including dexamethasone, salbutamol and montelukast. Since lung inflammation is the significant cause of asthma, antiinflammation corticosteroids are the most commonly used medications to control the attack of asthma (He et al, 2019). In particular, b 2 agonists like salbutamol and (or) leukotriene receptor antagonists represented by montelukast might be used as the combination of corticosteroids to control moderate-tosevere asthma (Pedersen and O'Byrne, 2012;Bateman et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…However, the clinical application of these agents still encounters three main problems or obstacles. First of all, patients with severe asthma may have steroid resistance (He et al, 2019). Second, these medications are developed to control asthma symptoms instead of curing the disease.…”

Section: Discussionmentioning

confidence: 99%

A Chinese Prescription Yu-Ping-Feng-San Administered in Remission Restores Bronchial Epithelial Barrier to Inhibit House Dust Mite-Induced Asthma Recurrence

et al. 2020

View full text Add to dashboard Cite

Clinically, the treatments against asthma like b 2 agonist focus on controlling the symptoms rather than inhibiting recurrence radically. This study aims to evaluate the efficacy and mechanism of a potent Chinese prescription Yu-Ping-Feng-San (YPFS) against asthma recurrence. We here established an optimized house dust mite (HDM)-induced asthma recurrence mice model with typical asthmatic responses such as significantly augmented airway hyperresponsiveness (AHR), elevated serum IgE, pulmonary type 2 cytokines IL-5 and IL-13 levels, pathological changes including thickening bronchial wall, inflammatory infiltration of lung tissue, etc. Moreover, all typical asthmatic pathological features were prominently alleviated by YPFS applied during remission phase ahead of second elicitation, which was even more effective than three different types of medications dexamethasone, montelukast and salbutamol, which were commonly applied in clinical practice, administered during recurrence phase. Besides, we found that desmoglein 1 (DSG1) remained deficient when asthmatic responses regressed whereas tight junction (TJ) claudin 1 (CLDN1) or adherin junction (AJ) E-cadherin restored spontaneously. In vitro, DSG1 interference resulted in increased thymic stromal lymphopoietin (TSLP) secretion, and epithelial barrier compromise evidenced by significantly elevated transepithelial electrical resistance (TEER) and increased 4-kDa FITC-dextran influx. YPFS could downregulate TSLP production and restore HDM-induced DSG1 deficiency and barrier destruction, which was further reversed by shDSG1. Collectively, administration of YPFS in remission prominently alleviated HDM-induced asthma relapse by restoring DSG1 and decreasing TSLP overexpression, which might be the key factors contributing to chronic asthma relapse. Our data not only demonstrated the pivotal role of DSG1 in asthma pathogenesis, but also provided a novel and potent therapeutic strategy against chronic asthma.

show abstract

Development of highly potent glucocorticoids for steroid-resistant severe asthma

Abstract: This article contains supporting information online at www.pnas.org/lookup/suppl/

Cited by 46 publications

References 24 publications

The role of NTHi colonization and infection in the pathogenesis of neutrophilic asthma

The role of NTHi colonization and infection in the pathogenesis of neutrophilic asthma

Mechanism of Dayuanyin in the treatment of coronavirus disease 2019 based on network pharmacology and molecular docking

A Chinese Prescription Yu-Ping-Feng-San Administered in Remission Restores Bronchial Epithelial Barrier to Inhibit House Dust Mite-Induced Asthma Recurrence

Contact Info

Product

Resources

About