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1.
Phytomedicine ; 118: 154941, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37451150

ABSTRACT

BACKGROUND: Asthma is a chronic inflammatory disorder in airways with typical pathologic features of airflow limitation, airway inflammation and remodeling. Icariside II (IS), derived from herbal medicine Herba Epimedii, exerts an anti-inflammatory property. However, underlying mechanisms with specifically targeted molecular expression by IS in asthma have not been fully understood, and whether IS could inhibit remodeling and EMT still remains unclear. PURPOSE: The study aimed to clarify therapeutic efficacy of IS for attenuating airway inflammation and remodeling in asthma, and illustrate IS-regulated specific pathway and target proteins through TMT-based quantitative proteomics. STUDY DESIGN AND METHODS: Murine model of chronic asthma was constructed with ovalbumin (OVA) sensitization and then challenge for 8 weeks. Pulmonary function, leukocyte count in bronchoalveolar lavage fluid (BALF), lung histopathology, inflammatory and fibrotic cytokines, and markers of epithelial-mesenchymal transition (EMT) were evaluated. TMT-based quantitative proteomics were performed on lung tissues to explore IS-regulated proteins. RESULTS: IS contributed to alleviative airway hyperresponsiveness (AHR) evidenced by declined RL and increased Cdyn. After IS treatment, we observed a remarked down-regulation of leukocyte count, inflammatory cytokines in BALF, and peribronchial inflammation infiltration. Goblet cell hyperplasia, mucus secretion and peribronchial collagen deposition were attenuated, with the level of TGF-ß and MMP-9 in BALF declined. Furthermore, IS induced a rise of Occludin and E-cadherin and a decline of N-cadherin and α-SMA in lung tissues. These results proved the protective property of IS against airway inflammation, remodeling and EMT. To further investigate underlying mechanisms of IS in asthma treatment, TMT-based quantitative proteomics were performed and 102 overlapped DEPs regulated by IS were identified. KEGG enrichment exhibited these DEPs were enriched in lysosome, phagosome and autophagy, in which LAMP2, CTSD and CTSS were common DEPs. WB, q-PCR and IHC results proofed expressional alteration of these proteins. Besides, IS could decrease Beclin-1 and LC3B expression with increasing p62 expression thus inhibiting autophagy. CONCLUSIONS: The study demonstrated IS could ameliorate AHR, airway inflammation, remodeling and EMT in OVA-induced chronic asthma mice. Our research was the first to reveal that inhibition of LAMP2, CTSD and CTSS expression in autophagy contributed to the therapeutic efficacy of IS to asthma.


Subject(s)
Asthma , Proteomics , Mice , Animals , Ovalbumin , Asthma/drug therapy , Asthma/metabolism , Lung/pathology , Inflammation/metabolism , Bronchoalveolar Lavage Fluid , Cytokines , Disease Models, Animal , Mice, Inbred BALB C
2.
Ther Adv Respir Dis ; 17: 17534666231155748, 2023.
Article in English | MEDLINE | ID: mdl-36942731

ABSTRACT

BACKGROUND: To better understand the development of therapy for asthma, grasp the core paradigm associated with the transformation of cognition of asthma treatment and asthma, explore potential and effective therapies for asthma, discover new biomarkers and mechanisms related to asthma treatment, find novel targets for anti-asthma drugs, and predict the future trends of asthma therapy, we used a bibliometric analysis to research articles related to the therapies for asthma published from 1983 to 2022. METHODS: A comprehensive search was conducted to analyze the articles associated with therapy for asthma with the help of the Web of Science Core Collection (WOSCC) database from January 1, 1983 to August 14, 2022. The CiteSpace 6.1.R2 software and VOS viewer 6.1.8 software were utilized to analyze the overall structure of the network, network clusters, links between clusters, key nodes, and pathways. RESULTS: A total of 3902 publications related to therapies on asthma were published in 3211 academic journals by a total of 14,655 authors in 3476 organizations from 87 countries or regions from 1983 to 2022. The United States published the most articles (n = 1143), followed by England (n = 574) and China (n = 405). However, the centrality of China was 0.4, higher than the United States (centrality = 0.16) and Singapore (centrality = 0.11). Akdis Cezmi published the most papers. Journal of Allergy and Clinical Immunology published the most studies on therapies for asthma. Asthma was the most frequent keyword (n = 594). The betweenness centrality value of keywords that were greater than 0.1 included airway inflammation (centrality = 0.22), double blind (centrality = 0.18), asthma (centrality = 0.17), inflammation (centrality = 0.12), and inhaled corticosteroid (centrality = 0.11). CONCLUSIONS: The results from this biometric review provide insight into the development of therapy for asthma, the paradigm of recognition of this field, the approach of discovering new targets, exploration and combination of new mechanisms, and the frontier trend of this field in future.


Subject(s)
Asthma , Humans , Asthma/diagnosis , Asthma/drug therapy , China , Databases, Factual , England , Inflammation , Randomized Controlled Trials as Topic
3.
Int Immunopharmacol ; 115: 109670, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36603356

ABSTRACT

Acupuncture has been frequently used in China for the treatment asthma for thousands of years. Ferroptosis was recently revealed to be involved in several pathological conditions including asthma. However, the detailed links between ferroptosis and airway inflammation in asthma, as well as the detailed regulation of acupuncture on these disorders remains unclear. Our results demonstrated that the non-haem Fe2+ level increased markedly in the lung tissue of mouse asthma model, and positively correlated with RL and IL-4 level in BALF. Furthermore, lipid peroxidation markers MDA and GSSG increased remarkably in OVA-induced experimental asthma mice. Up-regulation of lipid peroxidation associated proteins ACSL4 and15-LO1 was also observed in OVA-induced experimental asthma mice. To demonstrate the role of ferroptosis in asthma and the effect of acupuncture on these disorders, ferroptosis-induction agent erastin and ferroptosis-inhibition agent fer-1 were used, and our data demonstrated that erastin could augment lung inflammation and lipid peroxidation in OVA induced asthma model. Fer-1 was able to relieve AHR, lung inflammation, non-haem Fe2+ level, lipid peroxidation and ferroptosis related pathway ACSL4-15LO1 in OVA-induced experimental asthma mice. Acupuncture treatment alleviated RL, lung inflammation as well as type 2 cytokines IL-4 and IL-13 levels induced by OVA inhalation. What's more, acupuncture significantly reduced the MDA and GSSG levels, the non-haem Fe2+ level and ACSL4-15-LO1 proteins expression. Acupuncture also relieved erastin-induced exacerbation in lung inflammation and lipid peroxidation in ferroptosis. Acupuncture treatment could relieve ferroptosis related exacerbation in airway inflammation. Our study provided insights into the underlying mechanisms for the protective effects of acupuncture and highlighted a therapeutic potential of acupuncture treatment in the attenuation of lipid peroxidation and ferroptosis in asthma.


Subject(s)
Acupuncture Therapy , Anti-Asthmatic Agents , Asthma , Ferroptosis , Pneumonia , Animals , Mice , Anti-Asthmatic Agents/therapeutic use , Anti-Asthmatic Agents/pharmacology , Asthma/therapy , Asthma/drug therapy , Coenzyme A Ligases/metabolism , Coenzyme A Ligases/pharmacology , Disease Models, Animal , Glutathione Disulfide/adverse effects , Inflammation , Interleukin-4/pharmacology , Ovalbumin/therapeutic use , Pneumonia/drug therapy , Arachidonate 15-Lipoxygenase/metabolism
4.
Front Immunol ; 13: 988573, 2022.
Article in English | MEDLINE | ID: mdl-36524132

ABSTRACT

Asthma is a complex and heterogeneous disease with multicellular involvement, and knowledge gaps remain in our understanding of the pathogenesis of asthma. Efforts are still being made to investigate the immune pathogenesis of asthma in order to identify possible targets for prevention. Single cell RNA sequencing (scRNA-seq) technology is a useful tool for exploring heterogeneous diseases, identifying rare cell types and distinct cell subsets, enabling elucidation of key processes of cell differentiation, and understanding regulatory gene networks that predict immune function. In this article, we provide an overview of the importance of scRNA-seq for asthma research, followed by an in-depth discussion of the results in recent years, in order to provide new ideas for the pathogenesis, drug development and treatment of asthma.


Subject(s)
Asthma , Single-Cell Analysis , Humans , Single-Cell Analysis/methods , Gene Regulatory Networks , RNA/genetics , Asthma/genetics
5.
Biomed Pharmacother ; 153: 113516, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36076514

ABSTRACT

Ferroptosis, an iron-dependent form of regulated cell death, was recently demonstrated to be closely associated with the immune system. Regulators of ferroptosis may be the cells and secretions of the immune system. Ferroptosis has contributed to the progression of various diseases, namely, cancer, ischemia, and degenerative diseases. However, research on the relationship between ferroptosis and asthma remains fragmented. Non-immune cells associated with asthma are also closely associated with ferroptosis. Further studies on cross-linking asthma inflammation with ferroptosis signaling pathways could help identify several key molecules, known as ferroptosis regulators, that regulate asthma. Ferroptosis provides a new perspective to interpret and understand the manifestations of asthma, potential drug discovery targets, and new therapeutic options to effectively intervene in the imbalance caused by abnormal inflammation in asthma. Thus, the pathogenesis of ferroptosis and its contribution to the pathogenesis of asthma is essential in deepening the understanding and improving the prognosis and cure rate of the patients. Herein, we introduce the main molecular mechanisms of ferroptosis and asthma, describe the relationship between ferroptosis and asthma based on their common regulatory cells or molecules, and discuss potential drug discovery targets and therapeutic applications of ferroptosis in the context of immunomodulation and symptom alleviation.


Subject(s)
Asthma , Ferroptosis , Asthma/drug therapy , Humans , Inflammation/drug therapy , Iron/metabolism , Signal Transduction
6.
Phytomedicine ; 104: 154252, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35752075

ABSTRACT

BACKGROUND: Despite the substantial amount of efforts made to reduce morbidity and improve respiratory management, asthma control remained a major challenge for severe patients. Plant isoflavones, one of the most estrogenic compounds, are considered a potential alternative therapy for asthma. Iristectorigenin A, a naturally occurring isoflavone, is extracted from a variety of medical plants and its biological activity has not been reported previously. PURPOSE: In present study, we aim to reveal the potential therapeutic role of Iristectorigenin A against acute asthmatic mice. STUDY DESIGN: We established ovalbumin (OVA) induced asthmatic murine model and orally administrated Iristectorigenin A at concentration of 5 and 10 mg/kg and dexamethasone as a positive control substance. METHODS: Asthmatic murine model was established with OVA sensitization and challenge. Lung function was assessed with FinePoint Ventilation system recording lung resistance (RI) and lung compliance (Cydn). White cells were sorted and counted in BALF. Histopathological assessment was conducted by H&E, PAS, and Masson's trichrome staining on paraffin embedded lung tissues. BALF content of IL-4, IL-5, IL-33, IL-13, INF-γ, IL-9 and serum IgE, IgG1 were measured using ELISA kit. Expression levels of mRNAs associated with inflammatory cytokines and goblet cell metaplasia were evaluated via quantitative RT-PCR. Protein expression levels of FOXA3, MUC5AC, SPDEF were estimated by immunohistochemistry on lung tissue, while NOTCH1 and NOTCH2 expressions were evaluated by western blotting analysis. RESULTS: Iristectorigenin A resulted in improved airway hyperresponsiveness (AHR) mirrored by decreased RI and increased Cydn. With Iristectorigenin A, we also observed reduced number of BALF leukocytes, improved inflammatory cell infiltration in lung tissue, decreased content of BALF IL-4, IL-5, IL-33, but not IL-13, INF-γ, IL-9, and their mRNA levels, along with decreased levels of OVA-specific IgE, IgG1 in asthmatic mice. Additionally, Iristectorigenin A exhibited significant therapeutic potential on attenuating mucus production reflected by mitigated FOXA3 and MUC5AC immunostaining on the airway epithelium, as well as decreased mRNAs associated with goblet cell metaplasia. At last, a decrease in elevated expression level of NOTCH2, but not NOTCH1, in asthmatic mice lung tissue was observed by western blotting analysis. CONCLUSION: Our study provides strong evidence that Iristectorigenin A can be potential therapeutic agent ameliorating airway inflammation and mucus hypersecretion in allergic asthma. This is a first research reported the potential of Iristectorigenin A as an alternative therapeutic agent.


Subject(s)
Asthma , Interleukin-33 , Animals , Asthma/drug therapy , Bronchoalveolar Lavage Fluid , Disease Models, Animal , Immunoglobulin E , Immunoglobulin G , Inflammation/drug therapy , Interleukin-33/metabolism , Interleukin-4/metabolism , Interleukin-5/metabolism , Interleukin-9/metabolism , Interleukin-9/therapeutic use , Lung/pathology , Metaplasia/metabolism , Metaplasia/pathology , Mice , Mice, Inbred BALB C , Mucus , Ovalbumin , Phenotype
7.
Front Pharmacol ; 13: 834009, 2022.
Article in English | MEDLINE | ID: mdl-35273507

ABSTRACT

Growing evidence suggests that long non-coding RNAs (lncRNAs) play a key role in the pathogenesis of asthma. Although some differentially expressed lncRNAs have been identified in asthmatic patients, many asthma-related lncRNAs have not been annotated. In the present study, six patients and three healthy subjects were randomly selected from 34 asthmatic patients and 17 healthy subjects. Second-generation high-throughput sequencing was performed on their peripheral blood samples. There were 1,137 differentially expressed lncRNAs in the asthma patients compared to in the healthy controls, of which 485 were upregulated and 652 were downregulated. The top 30 enriched GO and KEGG terms were identified, and the cytosolic ribosome (GO:0022626) and ribosome (hsa03010) were associated with the most differentially expressed lncRNAs. The top 10 differentially expressed lncRNAs associated with asthma were verified by an lncRNA-mRNA co-expression network and RT-qPCR. Seven of the these (NONHSAT015495.2, MSTRG.71212.2, NONHSAT163272.1, NONHSAT181891.1, NONHSAT190964.1, ENST00000564809, and NONHSAT076890.2) were down-regulated in the peripheral blood of asthmatic patients, which was consistent with the sequencing results. Three patients and three healthy subjects were randomly selected from the remaining subjects to verify these seven lncRNAs by RT-qPCR, which further confirmed the sequencing results. Public database GSE106230 was also in agreement with the FPKM (Fragments Per kilobase of exon model per Million mapped reads) trends of ENST00000564809, NONHSAT015495.2, NONHSAT181891.1, and NONHSAT190964.1. In conclusion, the present study identified seven lncRNAs that may serve as potential biological markers for asthma.

8.
Int J Biol Sci ; 18(5): 2060-2074, 2022.
Article in English | MEDLINE | ID: mdl-35342361

ABSTRACT

Although cisplatin is the most effective first-line drug in the management of advanced non-small cell lung cancer (NSCLC), drug resistance remains a major clinical challenge. There is increasing evidence that icariside II (IS) exhibits antitumour activity in a variety of cancers. In the current study, we investigated the anticancer effects of icariside II combined with cisplatin and elucidated the underlying mechanism in NSCLC. Here, we showed that cotreatment with IS and cisplatin inhibited cell proliferation and induced cellular apoptosis. Using mRNA sequencing (mRNA-seq), we identified differentially expressed genes (DEGs) in which there was an enrichment in PERK-mediated unfolded protein response (UPR) signalling. The western blot results revealed that IS activated endoplasmic reticulum (ER) stress, including three branches of UPR signalling, PERK, IRE1 and ATF6, and the downstream PERK-eIF2α-ATF4-CHOP pathway, thus potentiating the apoptosis induced by cisplatin. In addition, the combination of IS with cisplatin significantly reduced xenograft tumour growth in C57BL/6 and BALB/c nude mice in vivo. Notably, the combination therapy displayed no evident toxicity. Taken together, IS enhances cisplatin-induced apoptosis partially by promoting ER stress signalling in NSCLC, suggesting that combination treatment with IS and cisplatin is a novel potential therapeutic strategy for NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Apoptosis , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Cisplatin/pharmacology , Cisplatin/therapeutic use , Endoplasmic Reticulum Stress , Flavonoids , Humans , Lung Neoplasms/drug therapy , Mice , Mice, Inbred C57BL , Mice, Nude , RNA, Messenger , eIF-2 Kinase/genetics , eIF-2 Kinase/metabolism
9.
Biomed Res Int ; 2022: 1764104, 2022.
Article in English | MEDLINE | ID: mdl-35281601

ABSTRACT

Allergic asthma is associated with T helper (Th) 2 cell-biased immune responses and characterized by the airway hyperresponsiveness (AHR). Studies have shown that the acupoint catgut-embedding therapy (ACE) has a therapeutic effect on allergic asthma. However, the relevant mechanism is poorly understood. In present study, female BALB/c mice were sensitized and challenged with ovalbumin (OVA) to establish a model of allergic asthma. AHR was evaluated by using airway resistance (R L ) and lung dynamic compliance (Cdyn). Airway inflammation and mucus hypersecretion were observed by HE and PAS staining. Inflammatory cells were counted, and related cytokines in bronchoalveolar lavage fluid (BALF) were detected by enzyme-linked immunosorbent assay (ELISA). Pulmonary group 2 innate lymphoid cell (ILC2s) proportions were analyzed by flow cytometry. The expression of nuclear factor κB (NF-κB) and cyclooxygenase-2 (COX-2) was detected by immunostaining. Our results showed that OVA induction resulted in a significant increase in R L , accompanied by a significant decrease in Cdyn. The levels of interleukin- (IL-) 4, IL-13, OVA-specific IgE in BALF, and the percentage of ILC2 in the lungs were markedly increased accompanied by a significant decreased in interferon-γ (IFN-γ). Furthermore, the expressions of p-NF-κB p65 and COX-2 in airways were significantly upregulated. After ACE treatment, the indicators above were significantly reversed. In conclusion, ACE treatment inhibited the secretion of Th2 cytokines and the proliferation of ILC2s in the lungs, thereby dampening the inflammatory activity in allergic asthma. The underlying mechanism might be related to the inhibition of NF-κB/COX-2 pathway.


Subject(s)
Asthma , NF-kappa B , Acupuncture Points , Animals , Asthma/drug therapy , Asthma/therapy , Bronchoalveolar Lavage Fluid , Catgut , Cyclooxygenase 2/metabolism , Cytokines/metabolism , Disease Models, Animal , Female , Immunity, Innate , Lung/metabolism , Lymphocytes/metabolism , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Ovalbumin
10.
Phytomedicine ; 95: 153803, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34785105

ABSTRACT

BACKGROUND: Jia-Wei Bu-Shen-Yi-Qi formula (JWBSYQF), a Chinese herbal formula, is a commonly used prescription for treating asthma patients. However, the targeted proteins associated with JWBSYQF treatment remain unknown. PURPOSE: Present study aims to evaluate the therapeutic efficacy of JWBSYQF and identify the targeted proteins in addition to functional pathways. STUDY DESIGN: The ovalbumin (OVA)-induced murine asthma model was established to explore the therapeutic effect of JWBSYQF treatment. Proteomic profiling and quantifications were performed using data-independent acquisition (DIA) methods. Differentially expressed proteins (DEPs) were validated via western blot (WB) and immunohistochemistry (IHC). METHODS: A murine asthma model was made by OVA sensitization and challenge, and JWBSYQF (2.25, 4.50, 9,00 g/kg body weight) or dexamethasone (1 mg/ kg body weight) were administered orally. Airway hyperresponsiveness (AHR) to methacholine (Mch), inflammatory cell counts and classification in bronchoalveolar lavage fluid (BALF), lung histopathology, and cytokine levels were measured. Furthermore, DIA proteomic analyses were performed to explore the DEPs targeted by JWBSYQF and were further validated by WB and IHC. RESULTS: Our results exhibited that JWBSYQF attenuated AHR which was mirrored by decreased airway resistance and increased lung compliance. In addition, JWBSYQF-treated mice showed reduced inflammatory score, mucus hypersecretion, as well as reduced the number of BALF leukocytes along with decreased content of BALF Th2 inflammatory cytokines (IL-4, IL-5, IL-13) and serum IgE. Proteomics analysis identified 704 DEPs between the asthmatic mice and control group (MOD vs CON), and 120 DEPs between the JWBSYQF-treatment and the asthmatic mice (JWB-M vs MOD). A total of 33 overlapped DEPs were identified among the three groups. Pathway enrichment analysis showed that DEPs were significantly enriched in IL-17 signaling pathway, in which DEPs, Lcn2, TGF-ß1, Gngt2, and Ppp2r5e were common DEPs between three experimental groups. WB and IHC results further validated expressional levels and tendency of these proteins. Our results also showed that JWBSYQF affects mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways, that are activated by IL-17 signaling. CONCLUSION: The present study suggested that JWBSYQF could attenuate AHR and airway inflammation in OVA-induced asthmatic mice. In addition, proteomics analysis revealed that suppression of IL-17 signaling pathways contributes to the therapeutic effects of JWBSYQF.


Subject(s)
Asthma , Drugs, Chinese Herbal/pharmacology , Interleukin-17 , Proteomics , Signal Transduction , Animals , Asthma/drug therapy , Bronchoalveolar Lavage Fluid , Cytokines , Disease Models, Animal , Lung , Mice , Mice, Inbred BALB C , Ovalbumin
11.
Front Immunol ; 12: 740571, 2021.
Article in English | MEDLINE | ID: mdl-34737744

ABSTRACT

Allergic asthma is well known as a common respiratory disorder comprising an allergic inflammatory nature and excessive immune characteristic. N6-methyladenosine (m6A) methylation is an RNA epigenetic modification that post-transcriptionally regulates gene expression and function by affecting the RNA fate. Currently, m6A methylation is gaining attention as a mechanism of immunoregulation. However, whether m6A methylation engages the pathological process of asthma remains uncertain. Here, we present the m6A methylomic landscape in the lung tissues of ovalbumin-induced acute asthma mice using MeRIP-seq and RNA-seq. We identified 353 hypermethylated m6A peaks within 329 messenger RNAs (mRNAs) and 150 hypomethylated m6A peaks within 143 mRNAs in the lung tissues of asthmatic mice. These differentially methylated mRNAs were found to be involved in several immune function-relevant signaling pathways. In addition, we predicted 25 RNA-binding proteins that recognize the differentially methylated peak sites by exploring public databases, and the roles of these proteins are mostly related to mRNA biogenesis and metabolism. To further investigate the expression levels of the differentially methylated genes, we performed combined analysis of the m6A methylome and transcriptome data and identified 127 hypermethylated mRNAs (107 high and 20 low expression) and 43 hypomethylated mRNAs with differential expressions (9 high and 34 low expression). Of these, there are a list of mRNAs involved in immune function and regulation. The present results highlight the essential role of m6A methylation in the pathogenesis of asthma.


Subject(s)
Adenosine/metabolism , Asthma/genetics , Hypersensitivity/genetics , Lung/physiology , Adenosine/analogs & derivatives , Allergens/immunology , Animals , DNA Methylation , Disease Models, Animal , Epigenesis, Genetic , Epigenome , Female , Gene Expression Profiling , Humans , Immunity/genetics , Mice , Mice, Inbred BALB C , Ovalbumin/immunology , Signal Transduction/genetics
12.
Exp Ther Med ; 22(6): 1483, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34765024

ABSTRACT

Previous studies have indicated that allergens such as house dust mites (HDM) in the environment can induce allergic asthma. Ferroptosis is a newly discovered form of regulatory cell death characterized by aberrant lipid peroxidation and the accumulation of reactive oxygen species (ROS) in cells. However, whether ferroptosis participates in the pathological process of asthma remains to be elucidated. The present study used a HDM-induced mouse asthma model to determine the effect of HDM exposure on allergic asthma and its underlying mechanisms. Female BALB/c mice were intranasally exposed to HDM to induce allergic asthma. Airway hyperresponsiveness (AHR), lung inflammation, mucus secretion, IgE levels, cytokine levels and inflammatory cell counts in bronchoalveolar lavage fluid (BALF) were investigated. In addition, the morphological changes of mitochondria, ROS levels, glutathione (GSH) levels and changes in ferroptosis pathway proteins were also determined in murine lungs. As a result, HDM exposure significantly increased AHR, inflammatory cell infiltration and mucus secretion around the airways. Furthermore, elevated IgE levels in the BALF, lung eosinophilia and a concomitant increase in IL-13 and IL-5 levels in BALF were observed. HDM inhalation increased ROS and decreased GSH levels in the lungs. HDM inhalation induced dysmorphic small mitochondria with decreased crista, as well as condensed, ruptured outer membranes. Western blotting demonstrated that the activities of glutathione peroxidase 4 and catalytic subunit solute carrier family 7 member 11 were significantly decreased, and that protein expression levels of acyl-CoA synthetase long-chain family member 4 and 15 lipoxygenase 1 were upregulated compared with mice in the normal control group. Overall, these results indicated that the AHR, airway inflammation, lipid peroxidation and ROS levels increased in HDM-induced asthma, and that HDM inhalation induced ferroptosis in the lungs, which helped to form an improved understanding of the pathogenesis of allergic asthma.

13.
Mol Med Rep ; 24(5)2021 11.
Article in English | MEDLINE | ID: mdl-34542166

ABSTRACT

Cycloastragenol (CAG), a secondary metabolite from the roots of Astragalus zahlbruckneri, has been reported to exert anti­inflammatory effects in heart, skin and liver diseases. However, its role in asthma remains unclear. The present study aimed to investigate the effect of CAG on airway inflammation in an ovalbumin (OVA)­induced mouse asthma model. The current study evaluated the lung function and levels of inflammation and autophagy via measurement of airway hyperresponsiveness (AHR), lung histology examination, inflammatory cytokine measurement and western blotting, amongst other techniques. The results demonstrated that CAG attenuated OVA­induced AHR in vivo. In addition, the total number of leukocytes and eosinophils, as well as the secretion of inflammatory cytokines, including interleukin (IL)­5, IL­13 and immunoglobulin E were diminished in bronchoalveolar lavage fluid of the OVA­induced murine asthma model. Histological analysis revealed that CAG suppressed inflammatory cell infiltration and goblet cell secretion. Notably, based on molecular docking simulation, CAG was demonstrated to bind to the active site of autophagy­related gene 4­microtubule­associated proteins light chain 3 complex, which explains the reduced autophagic flux in asthma caused by CAG. The expression levels of proteins associated with autophagy pathways were inhibited following treatment with CAG. Taken together, the results of the present study suggest that CAG exerts an anti­inflammatory effect in asthma, and its role may be associated with the inhibition of autophagy in lung cells.


Subject(s)
Anti-Asthmatic Agents/pharmacology , Asthma/etiology , Autophagy/drug effects , Drugs, Chinese Herbal/pharmacology , Sapogenins/pharmacology , Animals , Asthma/drug therapy , Asthma/metabolism , Autophagy-Related Proteins/antagonists & inhibitors , Autophagy-Related Proteins/chemistry , Autophagy-Related Proteins/metabolism , Biomarkers , Biopsy , Bronchial Hyperreactivity/drug therapy , Bronchial Hyperreactivity/etiology , Bronchial Hyperreactivity/metabolism , Bronchoalveolar Lavage Fluid , Cytokines/metabolism , Disease Management , Disease Models, Animal , Disease Susceptibility , Female , Immunoglobulin E/blood , Immunoglobulin E/immunology , Immunohistochemistry , Inflammation Mediators/metabolism , Mice , Microtubule-Associated Proteins/antagonists & inhibitors , Microtubule-Associated Proteins/chemistry , Microtubule-Associated Proteins/metabolism , Sapogenins/chemistry , Structure-Activity Relationship
14.
Biomed Pharmacother ; 137: 111383, 2021 May.
Article in English | MEDLINE | ID: mdl-33761604

ABSTRACT

Although considerable advance has been made in diagnosing and treating, asthma is still a serious public health challenge. Traditional Chinese medicine (TCM) is an effective therapy of complementary and alternative medicine. More and more scientific evidences support the use of TCM for asthma treatment, and active ingredients from Chinese medicine plants are becoming a hot issue. PURPOSE OF REVIEW: To summarize the frontier knowledge on the function and underlying mechanisms of the active ingredients in asthma treatments and provide a fully integrated, reliable reference for exploring innovative treatments for asthma. METHODS: The cited literature was obtained from the PubMed and CNIK databases (up to September 2020). Experimental studies on the active ingredients of Chinese medicine and their therapeutic mechanisms were identified. The key words used in the literature retrieval were "asthma" and "traditional Chinese medicine" or "Chinese herbal medicine". The literature on the active ingredients was then screened manually. RESULTS: We summarized the effect of these active ingredients on asthma, primarily including the effect through which these ingredients can regulate the immunologic equilibrium mechanism by acting on a number of signalling pathways, such as Notch, JAK-STAT-MAPK, adiponectin-iNOS-NF-κB, PGD2-CRTH2, PI3K/AKT, Keap1-Nrf2/HO-1, T-bet/Gata-3 and Foxp3-RORγt, thereby regulating the progression of asthma. CONCLUSION: The active ingredients from Chinese medicine have multilevel effects on asthma by regulating the immunologic equilibrium mechanism or signalling pathways, giving them great clinical value. However, the safety and functional mechanism of these ingredients still must be further determined.


Subject(s)
Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Drugs, Chinese Herbal/chemistry , Medicine, Chinese Traditional , Plants, Medicinal/chemistry , Animals , Anti-Asthmatic Agents/chemistry , Humans
15.
Article in English | MEDLINE | ID: mdl-33531915

ABSTRACT

Airway remodeling is one of the typical pathological characteristics of asthma, while the structural changes of the airways in asthma are complex, which impedes the development of novel asthma targeted therapy. Our previous study had shown that Bu-Shen-Yi-Qi formula (BSYQF) could ameliorate airway remodeling in chronic asthmatic mice by modulating airway inflammation and oxidative stress in the lung. In this study, we analysed the lung transcriptome of control mice and asthmatic mouse model with/without BSYQF treatment. Using RNA-sequencing (RNA-seq) analysis, we found that 264/1746 (15.1%) of transcripts showing abnormal expression in asthmatic mice were reverted back to completely or partially normal levels by BSYQF treatment. Additionally, based on previous results, we identified 21 differential expression genes (DEGs) with fold changes (FC) > (±) 2.0 related to inflammatory, oxidative stress, mitochondria, PI3K/AKT, and MAPK signal pathways which may play important roles in the mechanism of the anti-remodeling effect of BSYQF treatment. Through inputting 21 DEGs into the IPA database to construct a gene network, we inferred Adipoq, SPP1, and TNC which were located at critical nodes in the network may be key regulators of BSYQF's anti-remodeling effect. In addition, the quantitative real-time polymerase chain reaction (qRT-PCR) result for the selected four DEGs matched those of the RNA-seq analysis. Our results provide a preliminary clue to the molecular mechanism of the anti-remodeling effect of BSYQF in asthma.

16.
Int Immunopharmacol ; 94: 107460, 2021 May.
Article in English | MEDLINE | ID: mdl-33621850

ABSTRACT

Allergic asthma is a common chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway remodeling. Autophagy is a highly conserved intracellular degradation pathway in eukaryotic cells. There is growing evidence suggesting that dysregulation of autophagy is involved in the pathological process of asthma. Luteolin is a typical flavonoid compound with anti-inflammatory, anti-allergic and immune-enhancing functions. Previous studies have shown that luteolin can attenuate airway inflammation and hypersensitivity in asthma. However, whether luteolin can play a role in treating asthma by regulating autophagy remains unclear. The aim of the present study was to evaluate the therapeutic effect of luteolin on ovalbumin (OVA)-induced asthmatic mice, observe its effect on the level of autophagy in lung tissues, and further elucidate its underlying mechanism. The results showed that OVA-induced mice developed airway hyperresponsiveness, mucus over-production and collagen deposition. The number of inflammatory cells, levels of interleukin (IL)-4, IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF) and OVA-specific IgE in serum were significantly increased. Furthermore, the infiltration of inflammatory cells was observed along with the activation of autophagy in lung tissues. Luteolin treatment significantly inhibited the OVA-induced inflammatory responses and the level of autophagy in lung tissues as well. Moreover, luteolin activated the PI3K/Akt/mTOR pathway and inhibited the Beclin-1-PI3KC3 protein complex in lung tissues of asthmatic mice. In conclusion, this study explored the regulatory mechanism of luteolin on autophagy in allergic asthma, providing biologic evidence for its clinical application.


Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Autophagy/drug effects , Luteolin/therapeutic use , Allergens , Animals , Anti-Asthmatic Agents/pharmacology , Asthma/immunology , Beclin-1/immunology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cell Line , Cytokines/immunology , Female , Luteolin/pharmacology , Mice, Inbred BALB C , Ovalbumin , Phosphatidylinositol 3-Kinases/immunology , Proto-Oncogene Proteins c-akt/immunology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/immunology
17.
Biomed Pharmacother ; 134: 111001, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33341053

ABSTRACT

Asthma is a chronic airway inflammatory disease and acupuncture is frequently used in patients suffering from asthma in clinic. However, the regulatory mechanism of acupuncture treatment in asthma is not fully elucidated. We sought to investigate the effectiveness of acupuncture on asthma and the associated regulatory mechanism. An ovalbumin (OVA)-induced mouse asthma model was established and the effect of acupuncture on airway hyperresponsiveness (AHR), mucus hypersecretion and inflammation was assessed. Tandem mass tag (TMT)-based quantitative proteomics analysis of lung tissue and bioinformatics analysis were performed. Our results revealed that the OVA-induced mouse asthma model was successfully established with the significantly elevated AHR to methacholine (Mch), and acupuncture was effective in attenuation of AHR to Mch, peribronchial and perivascular inflammation and mucus production. The inflammatory cells around the airways, mucous secretion as well as levels of IgE, CCL5, CCL11, IL-17A in bronchoalveolar lavage fluid (BALF) and IL-4, IL-5 and IL-13 levels in serum were siginificantly inhibited by acupuncture. TMT-based quantitative proteomics analysis found that a total of 6078 quantifiable proteins were identified, and 564 (334 up-regulated and 230 down regulated) differentially expressed proteins (DEPs) were identified in OVA-induced asthma model group (A) versus normal control group (NC). Acupuncture treatment resulted in 667 DEPs (416 up-regulated and 251 down regulated) compared with A group, and 86 overlapping DEPs were identified in NC, A and AA groups. Among the 86 overlapping DEPs, we identified 41 DEPs regulated by acupuncture. Based on the above data, we performed a systematic bioinformatics analysis of the 41 DEPs, and results showed that these 41 DEPs were predominantly related to 4 KEGG pathways including SNARE interactions in vesicular transport, ferroptosis, endocrine and other factor-regulated calcium reabsorption, and protein digestion and absorption. DEPs of SLC3A2 and ATP1A3 expression levels were verified by immumohistochemical staining. Mice in OVA-induced asthma model group had elevated SLC3A2 and ATP1A3 expression and acupuncture had the ability to downregulate SLC3A2 and ATP1A3 protein expression. Furthermore, acupuncture reduced the MDA level and increased the GSH and SOD levels in the lung tissue. Taken together, our data suggested that acupuncture was effective in treating asthma by attenuation of AHR, mucus secretion and airway inflammation, and the mechanism was associated with regulation of ferroptosis, SLC3A2 and ATP1A3 protein expression as well as oxidative stress. Results from our experiments revealed the anti-inflammatory effect of acupuncture in OVA-induced mouse asthma model, leading to a more effective approach to be chosen by patients in clinic.


Subject(s)
Acupuncture Therapy/methods , Asthma/therapy , Fusion Regulatory Protein 1, Heavy Chain/metabolism , Inflammation/therapy , Sodium-Potassium-Exchanging ATPase/metabolism , Animals , Asthma/metabolism , Bronchoalveolar Lavage Fluid , Cytokines/metabolism , Disease Models, Animal , Female , Inflammation/metabolism , Lung/metabolism , Methacholine Chloride/metabolism , Mice , Mice, Inbred BALB C , Mucus/metabolism , Ovalbumin/adverse effects , Proteomics , Respiratory Hypersensitivity/therapy
18.
J Ethnopharmacol ; 266: 113343, 2021 Feb 10.
Article in English | MEDLINE | ID: mdl-32991972

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Loki Zupa (LKZP) decoction is one of the herbal prescriptions in traditional Uyghur medicine, which is commonly used for treating airway abnormality. However, underlying pathological mechanism and pathways involved has not been well studied. OBJECTIVES: In this paper, we aim to further confirmed the anti-inflammatory and anti-fibrotic role of LKZP decoction in airway, and uncover the passible mechanism involved via comprehensive quantitative proteomic DIA-MS analysis. MATERIALS AND METHODS: Mice asthmatic model was established with sensitizing and challenging with OVA. Lung function, pathological status, and inflammatory cytokines were assessed. Total of nine lung tissues were analyzed using proteomic DIA-MS analysis and 18 lung tissues were subjected to PRM validation. RESULTS: Total of 704 differentially expressed proteins (DEPs) (363 up regulated, 341 down regulated) were quantified in comparison of asthmatic and healthy mice, while 152 DEPs (91 up regulated, 61 down regulated) were quantified in LKZP decoction treated compared to asthmatic mice. Total of 21 proteins were overlapped between three groups. ECM-receptor interaction was significantly enriched and commonly shared between downregulated DEPs in asthma and upregulated DEPs in LKZP decoction treated mice. Total of 20 proteins were subjected to parallel reaction monitoring (PRM) analysis and 16 of which were quantified. At last, two proteins, RMB 10 and COL6A6, were validated with significant difference (P < 0.001) in protein abundance. CONCLUSIONS: Our results suggest that attenuated airway inflammation and fibrosis caused by LKZP decoction may associated with ECM-receptor interaction and RMB 10 and COL6A6 may be targeted by LKZP decoction in OVA-induced asthmatic mice.


Subject(s)
Anti-Asthmatic Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Asthma/drug therapy , Drugs, Chinese Herbal/pharmacology , Animals , Anti-Asthmatic Agents/isolation & purification , Anti-Inflammatory Agents/isolation & purification , Cytokines/metabolism , Disease Models, Animal , Female , Inflammation/drug therapy , Inflammation/pathology , Medicine, Chinese Traditional/methods , Mice , Mice, Inbred BALB C , Ovalbumin , Proteomics , Receptors, Cell Surface/metabolism
19.
Front Pharmacol ; 11: 533841, 2020.
Article in English | MEDLINE | ID: mdl-33013383

ABSTRACT

Allergic asthma has been considered as a respiratory disorder with pathological features of airway inflammation and remodeling, which involves oxidative stress. Formononetin (FMT) is a bioactive isoflavone obtained from Chinese herb Radix Astragali, and has been reported to have notable anti-inflammatory and antioxidant effects in several diseases. The purpose of our study was to elaborate the effects of FMT on asthma and the underlying mechanisms. To establish allergic asthma model, BALB/c mice were given ovalbumin (OVA) sensitization and challenge, treated with FMT (10, 20, 40 mg/kg) or dexamethasone (2 mg/kg). The effects of FMT on lung inflammation and oxidative stress were assessed. In OVA-induced asthmatic mice, FMT treatments significantly ameliorated lung function, alleviated lung inflammation including infiltration of inflammatory cells, the elevated levels of interleukin (IL)-4, IL-5, and IL-13, immunoglobulin (Ig) E, C-C motif chemokine ligand 5 (CCL5, also known as RANTES), CCL11 (also called Eotaxin-1), and IL-17A. In addition, FMT treatments eminently blunted goblet cell hyperplasia and collagen deposition, and remarkably reduced oxidative stress as displayed by decreased reactive oxygen species (ROS), and increased superoxide diamutase (SOD) activity. Furthermore, to clarify the potential mechanisms responsible for the effects, we determined the inflammation and oxidation-related signaling pathway including nuclear factor kappa ß (NF-κB), c-Jun N-terminal kinase (JNK), and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). FMT treatments appeared to dramatically inhibit the activation of NF-κB and JNK, significantly elevated the expression of heme oxygenase 1 (HO-1) but failed to activate expression of Nrf2. In conclusion, our study suggested that FMT had the therapeutic effects in attenuating airway inflammation and oxidative stress in asthma.

20.
Mediators Inflamm ; 2020: 7835284, 2020.
Article in English | MEDLINE | ID: mdl-32922208

ABSTRACT

Asthma is associated with innate and adaptive immunity mediated by immune cells. T cell or macrophage dysfunction plays a particularly significant role in asthma pathogenesis. Furthermore, crosstalk between them continuously transmits proinflammatory or anti-inflammatory signals, causing the immune cell activation or repression in the immune response. Consequently, the imbalanced immune microenvironment is the major cause of the exacerbation of asthma. Here, we discuss the role of T cells, macrophages, and their interactions in asthma pathogenesis.


Subject(s)
Asthma/metabolism , Macrophages/metabolism , T-Lymphocytes/metabolism , Animals , Asthma/physiopathology , Humans , Immunity, Innate/physiology , Macrophages/physiology , T-Lymphocytes/physiology
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