Global Proteomics Deciphered Novel-Function of Osthole Against Pulmonary Arterial Hypertension

Li, Yao; Yang, Yi; He, Guanhong; Ou, Chunqing; Wang, Lin-Lin; Liu, Kaixuan

doi:10.1038/s41598-018-23775-8

Cited by 26 publications

(16 citation statements)

References 37 publications

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“…In agreement with previous work, peroxisome proliferator-activated receptor (PPAR)-γ was identified as an important regulator of CTSS expression in SMCs [115,116]. Yao et al reported that osthole, a novel hypotensive agent purified from the Chinese medical plan Angelica pubescens Maxim, down-regulated MCT-induced CTSS levels while reducing PAH [117].…”

Section: Pulmonary Arterial Hypertension (Pah)supporting

confidence: 86%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment. Proteases in pulmonary diseases Research in the last 60 years has demonstrated that proteases are critical contributors to pulmonary disease pathophysiology. Initially known as protein-degrading enzymes with a restricted spectrum of substrates, recent studies have revealed that the diversity of protease substrates and biological effects triggered by their processing is vast [1, 2]. Proteases are primarily known for their matrix degradation capabilities, but also play significant roles in other biological mechanisms such as angiogenesis, growth factor bioavailability, cytokine processing, receptor shedding and activation, as well as cellular processes including migration, proliferation, invasion, and survival [3]. Importantly, protease activity requires tight regulation, and disruption of the close interplay between proteases, substrates and inhibitors may contribute to the pathogenesis and progression of a variety of pulmonary diseases, including muco-inflammatory diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), as well as infection [4]. In pulmonary diseases with a high neutrophil burden such as CF, a protease:antiprotease imbalance is frequently observed. The activity of proteases such as neutrophil elastase (NE) in the respiratory tract is regulated by antiproteases, such as α1-antitrypsin (A1AT) [5], secretory leukoprotease inhibitor (SLPI) [6] and elafin [7]. However, in diseases like CF, the antiproteases are overburdened by their cognate proteases and this imbalance can result in chronic airway inflammation, decreased mucociliary clearance, mucus obstruction, extracellular matrix (ECM) remodeling, increased susceptibility to infection and impaired immune responses [8].

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Section: Pulmonary Arterial Hypertension (Pah)supporting

confidence: 86%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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“…A previous study exploited an iTRAQ-based proteomic method to investigate the therapeutic actions and associated mechanisms of osthole in rats with PAH induced by experimental monocrotaline (MCT). This study reported that the complement and coagulation cascade pathway was significantly disordered in PAH lungs [4]. In our sequencing data, within this pathway, the Kng1 and Thbd genes were the most significantly upregulated and downregulated genes, respectively.…”

Section: Discussionmentioning

confidence: 74%

Revealing the pathogenic changes of PAH based on multiomics characteristics

et al. 2019

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Background Pulmonary artery hypertension (PAH), which is characterized by an increase in pulmonary circulation blood pressure, is a fatal disease, and its pathogenesis remains unclear. Methods In this study, RNA sequencing (RNA-seq), tandem mass tags (TMT) and reduced representation bisulfite sequencing (RRBS) were performed to detect the levels of mRNA, protein, and DNA methylation in pulmonary arteries (PAs), respectively. To screen the possible pathways and proteins related to PAH, pathway enrichment analysis and protein–protein interaction (PPI) network analysis were performed. For selected genes, differential expression levels were confirmed at both the transcriptional and translational levels by real-time PCR and Western blot analyses, respectively. Results A total of 362 differentially expressed genes (|Fold-change| > 1.5 and p < 0.05), 811 differentially expressed proteins (|Fold-change| > 1.2 and p < 0.05) and 76,562 differentially methylated regions (1000 bp slide windows, 500 bp overlap, p < 0.05, and |Fold-change| > 1.2) were identified when the PAH group (n = 15) was compared with the control group (n = 15). Through an integrated analysis of the characteristics of the three omic analyses, a multiomics table was constructed. Additionally, pathway enrichment analysis showed that the differentially expressed proteins were significantly enriched in five Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathways and ten Gene Ontology (GO) terms for the PAH group compared with the control group. Moreover, protein–protein interaction (PPI) networks were constructed to identify hub genes. Finally, according to the genes identified in the PPI and the protein expression fold-change, nine key genes and their associated proteins were verified by real-time PCR and Western blot analyses, including Col4a1, Itga5, Col2a1, Gstt1, Gstm3, Thbd, Mgst2, Kng1 and Fgg. Conclusions This study conducted multiomic characteristic profiling to identify genes that contribute to the hypoxia-induced PAH model, identifying new avenues for basic PAH research. Electronic supplementary material The online version of this article (10.1186/s12967-019-1981-5) contains supplementary material, which is available to authorized users.

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“…Osthole is a natural coumarin present in the medicinal plant Cnidium monnieri. Because osthole demonstrates significant protective effects in animal models of hepatic diseases (30,31), cancer (54), diabetes (27,28), osteoarthritis (55), cardiovascular (56,57) and allergic diseases (18,34), it is a promising natural lead compound for drug discovery. Herein we demonstrate that osthole inhibits mast cell activation via MRGPRX2.…”

Section: Discussionmentioning

confidence: 99%

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

et al. 2020

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Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca 2+ mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 in vitro. Osthole also inhibits MrgprB2-(mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.

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Global Proteomics Deciphered Novel-Function of Osthole Against Pulmonary Arterial Hypertension

Cited by 26 publications

References 37 publications

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Revealing the pathogenic changes of PAH based on multiomics characteristics

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

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