ITRAQ-Based Proteomics Reveals Gu-Ben-Fang-Xiao Decoction Alleviates Airway Remodeling via Reducing Extracellular Matrix Deposition in a Murine Model of Chronic Remission Asthma.
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ABSTRACT:
SUBMITTER: Xing Q
PROVIDER: S-EPMC8237094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dysbiosis of gut microbiota is a critical factor in the pathogenesis of asthma. Manipulating gut microbiota is a promising therapeutic intervention in asthma, and is being extensively studied. Gu-Ben-Fang-Xiao Decoction (GBFXD), derived from traditional Chinese medicine, is an effective and safe therapeutic formula for asthma in remission stage (ARS). Herein, we showed that GBFXD treatment remarkably alleviated ARS by improving respiratory function and lung histopathology. Asthmatic mice displayed a dysbiosis of gut microbiota, represented by significantly increased abundance of Bacteroidetes and decreased abundance of Firmicutes in gut, while GBFXD treatment reversed the gut dysbiosis in asthmatic mice at phylum, family, and genus levels. Moreover, our data showed that GBFXD treatment increased the abundance of short-chain fatty acid (SCFA)-producing bacteria in asthmatic mice, such as Firmicutes, Lachnospiraceae, and Bifidobacteriaceae, which consequently led to elevated levels of SCFAs. Furthermore, GBFXD treatment significantly enhanced the regulatory T cell differentiation via SCFAs, particularly acetate, in asthmatic mice. More critically, the protective effect of GBFXD was shown to be transmissible among asthmatic mice through co-housing microbiota transplantation. Antibiotic cocktail and acetate replenishment experiments also further substantiated the importance of SCFA-producing gut microbiota in GBFXD action. We, thus, demonstrated for the first time that gut microbiota dysbiosis existed in ARS. GBFXD could ameliorate ARS through the microbiota-acetate-Tregs axis.
| S-EPMC7212778 | biostudies-literature
Project description:Gubenfangxiao decoction (GBFXD) is a traditional Chinese medicine based on a combination of Yu-Ping-Feng-San and Erchen decoctions. GBFXD has been widely used for decades in treating asthma at the Affiliated Hospital of Nanjing University of Chinese Medicine. Previously, GBFXD was found to reduce lung inflammation and airway remodeling; however, the underlying mechanism remains unknown. In this study, the effects of GBFXD on asthmatic mice were evaluated based on pathology and lung function; airway hyperresponsiveness (AHR) and pathology were compared among the two different mouse models utilized. Furthermore, the mechanism of action of GBFXD on asthmatic mice was analyzed using iTRAQ labeling technology combined with ingenuity pathway analysis (IPA). Modeling analysis of pre- and post-treatment proteins identified 75 differentially expressed proteins. These proteins were related to B-cell development, calcium-induced lymphocyte apoptosis, antigen presentation, and Th1 and Th2 activation pathways. Moreover, 68 differentially expressed proteins were identified in the GBFXD treatment group compared with the model group. Upstream regulatory factors predicted that interleukin (IL)-4 (necessary for inducing polarization of type 2 [M2] macrophages), cyclooxygenase, and prostaglandin E2 are significantly elevated in the model group. Based on IPA analysis, it was concluded that several pathways, including mitochondrial dysfunction and oxidative phosphorylation, are closely associated with the therapeutic effects of GBFXD in asthma. Moreover, the differential expression of several proteins, including the M2 markers, MRC1, ARG1, Retnla, Chil3, and CHIA, were validated by western blotting, confirming that GBFXD can reduce airway inflammation, which fits the pattern of an alternative M2 activation state, and attenuate AHR. Overall, our findings indicate that GBFXD significantly suppresses M2 macrophage polarization, providing further insights into the mechanism underlying the protective effects of GBFXD.
| S-EPMC6514195 | biostudies-literature
Project description:Airway remodeling is a main pathological feature of asthma. The current therapy for asthma is mainly targeted for reducing inflammation, not particularly for airway remodeling. Herein, developing alternative and more effective therapy to attenuate remodeling is worthy of further study. Gu-Ben-Fang-Xiao Decoction (GBFXD) has been used to treat asthma for decades effectively and safely. In present study, GBFXD significantly regulated the airway inflammation, collagen deposition and the molecules relevant to airway remodeling such as Vimentin, α-SMA, hydroxyproline (HYP), and E-cadherin in chronic remission asthma (CRA) murine model. Subsequently, we found the overlapping differentially expressed proteins (DEPs) between Model/Control and GBFXD/Model mainly belonged to Collagen and Laminin which were extracellular matrix (ECM) proteins by iTRAQ proteomics. In addition, the KEGG analysis showed GBFXD could regulate pathways related to airway remodeling, such as ECM-receptor interaction, Focal adhesion, and PI3K/AKT signaling pathway which were top three pathways of most DEPs (Model/Control and GBFXD/Model) significantly enriched simultaneously. Further validation research showed GBFXD regulated Reticulon-4 (RTN4), thus suppressing the activation of PI3K/AKT pathway to alleviate the ECM proteins deposition. Thus, our findings indicate GBFXD regulate the PI3K/AKT pathway via RTN4 to improve airway remodeling and provide a new insight into the molecular mechanism of GBFXD for treating CRA.
2021-09-09 | PXD020711 | Pride
Project description:Psoriasis is an immune-mediated chronic inflammatory skin disease primarily mediated by the activation of interleukin (IL)-17-producing T cells. Traditional Chinese Medicine (TCM) represents one of the most effective complementary and alternative medicine (CAM) agents for psoriasis, which provides treasured sources for the development of anti-psoriasis medications. Xiao-Yin-Fang (XYF) is an empirically developed TCM formula that has been used to treat psoriasis patients in Shanghai Changhai Hospital for over three decades. Imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was utilized to investigate the therapeutic effects of XYF by the assessment of disease severity and skin thickness. Flow cytometric assay was performed to explore the influence of XYF on skin-related immunocytes, primarily T cells. And, RNA sequencing analysis was employed to determine the alternation in gene expression upon XYF therapy. We discovered that XYF alleviated psoriasis-like skin inflammation mainly through suppressing dermal and draining lymph-node IL-17-producing γδT (γδT17) cell polarization. Moreover, XYF therapy ameliorated the relapse of psoriasis-like dermatitis and prohibited dermal γδT cell reactivation. Transcriptional analysis suggested that XYF might regulate various inflammatory signaling pathways and metabolic processes. In conclusion, our results clarified the therapeutic efficacy and inner mechanism of XYF therapy in psoriasis, which might promote its clinical application in psoriasis patients and facilitate the development of novel anti-psoriasis drugs based on the bioactive components of XYF.
| S-EPMC8087247 | biostudies-literature
Project description:Ethnopharmacological relevance: Gubenfangxiao decoction (GBFXD) is a traditional Chinese medicine formula derived from Yupingfensan, an ancient formula widely used to treat respiratory diseases such as repeated respiratory infection, allergic rhinitis, bronchitis, and asthma. In recent years, GBFXD has been applied to efficaciously and safely treat asthma. However, the mechanism of GBFXD is still not fully elucidated. Aim of the study: A label-free proteomic method was to employed to explore the protective mechanism of GBFXD in respiratory syncytial virus (RSV)-ovalbumin (OVA)-induced chronic persistent asthmatic mice. Materials and methods: After RSV-OVA challenge, mice were orally administered GBFXD at a dose of 36 g/kg/d accompanied with OVA nasal spray once every 3 days for 28 days. The label-free proteomics-based liquid chromatography-tandem mass spectrometry method was used to explore the differentially abundant proteins (DAPs) in the serum from model mice compared with that in control mice (M:C), and in GBFXD-treated mice compared with that in model mice (G:M). We utilized OmicsBean (http://www.omicsbean.cn), a multi-omics data analysis platform, to perform bioinformatics analysis of DAPs. Enzyme-linked immunosorbent assay and Western Blotting were performed to measure the levels of related proteins and verify the results of proteomics analysis. Results: A total of 69 significant DAPs were identified including 39 in M:C, 46 in G:M, and 16 common differential proteins. Bioinformatics analysis revealed that the DAPs of M:C were mainly involved in inflammatory response and were related to lipid metabolism. However, the DAPs of G:M mostly participated in stress response, inflammatory response, and epithelial cell proliferation. Serum levels of Apoa-1, Apoc-1, Cfd, and Lrg1, EGFR and Lrg1 in the lungs were consistent with the results of proteomic analysis. Apoa-1 and Apoc-1 are closely related to cholesterol transport, lipid metabolism balance, and airway epithelial integrity; Cfd participates in immune response, affecting the occurrence and development of inflammation; EGFR and Lrg1 are involved in epithelial cell proliferation, influencing the process of airway remodeling. Conclusions: GBFXD may affect inflammatory and immune responses of asthma by regulating cholesterol transport and complement factor activation. Furthermore, it could repair damaged airway epithelium and avoid airway remodeling to prevent and treat asthma.
2019-09-26 | PXD013244 | Pride
Project description:IntroductionGu-Ben-Ke-Chuan (GBKC) decoction, a well-known prescription composed of seven herbs, has been widely used for treating chronic bronchitis (CB). However, the pharmacological constituents of GBKC and the underlying mechanisms by which these components act on CB remain unclear.MethodsUltra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap) was first employed to rapidly identify compounds from GBKC. Thereafter, network pharmacology and molecular docking analyses were performed to identify the potential active constituents, candidate targets, and major pathways. Finally, the affinities between the key compounds and targets were verified via surface plasmon resonance (SPR) analysis. In addition, the anti-inflammatory effect of GBKC was verified using an LPS-induced inflammatory cell model based on the predicted results.ResultsA total of 53 major compounds were identified in the GBKC decoction. After network pharmacology-based virtual screening, 141 major targets and 39 main compounds were identified to be effective in the treatment of CB. The major targets were highly enriched in the tumor necrosis factor (TNF) signaling pathway, suggesting that GBKC could attenuate the inflammatory response in patients with CB. Furthermore, molecular docking results indicated that 20 pairs of components and target proteins relevant to the TNF pathway exhibited notable interactions. Among them, eight compound-target pairs exhibited good affinity as per SPR analysis. In addition, the production of interleukin 6 and TNF-α in LPS-induced MH-S cells was suppressed after GBKC treatment.ConclusionThis study successfully clarified the mechanism of action of GBKC against CB, which demonstrated that the integrated strategy described above is reliable for identifying the active compounds and mechanisms responsible for the pharmacological activities of GBKC decoction.
| S-EPMC8055291 | biostudies-literature
Project description:BackgroundJian-Gan-Xiao-Zhi decoction (JGXZ), composed of Salvia miltiorrhiza Bunge, Panax notoginseng, Curcuma zedoaria, and other 9 types of herbs, has demonstrated beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the mechanisms behind JGXZ's impact on NAFLD remain unknown.MethodsIn this study, a NAFLD rat model induced by a high-fat diet (HFD) received oral treatment of JGXZ (8 or 16 g crude herb/kg) for 12 weeks. The therapeutic effects of JGXZ on NAFLD model rats were investigated through blood lipid levels and pathological liver changes. 16S rRNA analysis was used to study the changes in gut microbiota after JGXZ treatment. The expressions of occludin and tight junction protein 1 (ZO-1) in the colon were investigated using immunostaining to study the effects of JGXZ on gut permeability. The anti-inflammatory effects of JGXZ were also studied through measuring the levels of IL-1β, IL-6, and TNF-α in the serum and liver.ResultsJGXZ treatment could decrease body weight and ameliorate dyslipidemia in NAFLD model rats. H&E and Oil Red O staining indicated that JGXZ reduced steatosis and infiltration of inflammatory cells in the liver. 16S rRNA analysis showed that JGXZ impacted the diversity of gut microbiota, decreasing the Firmicutes-to-Bacteroidetes ratio, and increasing the relative abundance of probiotics, such as Alloprevotella, Lactobacillus, and Turicibacter. Gut permeability evaluation found that the expressions of ZO-1 and occludin in the colon were increased after JGXZ treatment. Moreover, JGXZ treatment could decrease the levels of IL-1β, IL-6, and TNF-α in the serum and liver.ConclusionsOur study illustrated that JGXZ could ameliorate NAFLD through modulating gut microbiota, decreasing gut permeability, and alleviating inflammatory response.
| S-EPMC8007356 | biostudies-literature
Project description:Adult mammalian heart repair after myocardial damage is highly inefficient due to the post-mitotic nature of cardiomyocytes. Interestingly, in traditional Chinese medicine (TCM), there are reported effective treatments of myocardial infarction (MI) and heart failure in adult humans by oral intake of a TCM concoction named Gu Ben Pei Yuan San (GBPYS), which is composed of Panax ginseng, velvet antler, Gekko gecko Linnaeus tail, human placenta, Trogopterus dung, Panax notoginseng, and amber. We fed mice with GBPYS after myocardial damages through everyday self-feeding. We then examined the effect of everyday oral intake of GBPYS on improving cardiac function and myocardial repair in adult mice after apical resection or MI. We found that long-term oral intake of GBPYS significantly improved cardiac function after myocardial damages in adult mice. BrdU, phospho-histone 3, and AuroraB staining indicated increased cell proliferation at the border zone of MI after TCM feeding. GBPYS feeding reduced organ inflammation, induced angiogenesis, and is non-toxic to mice after long-term oral intake. Further, serum derived from TCM-fed MI rats promoted division of both neonatal rat cardiomyocytes and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes in vitro. Oral intake of GBPYS improved heart repair after myocardial damages in adult mice. Our results suggest that there are substances present in GBPYS that help improve adult mammalian heart repair after MI. Also, it could be a good choice of non-invasive alternative therapy for myocardial damages and heart failure after rigorous clinical study in the future.
| S-EPMC6541202 | biostudies-literature
Project description:BackgroundZhuang-Gu-Fang (ZGF) has been proved to treat osteoporosis in ovariectomized rats by increasing osteogenic related factors Leptin, Ghrelin and Peptide YY(PYY). However, the mechanism of ZGF in the treatment of diabetic osteoporosis (DOP) remains unclear. The aim of this study was to explore the therapeutic effect of ZGF on DOP and its potential molecular mechanism.MethodsUsing GK rats as models, the pharmacodynamic effects of ZGF on bone loss were evaluated by hematoxylin-eosin (H&E) staining and micro-computed.tomography (micro-CT). The expression levels of CD31 and endomucin (Emcn) were detected by immunofluorescence to assess the role of ZGF in angiogenic osteogenic coupling. Finally, real-time quantitative PCR (RT-PCR) and Western Blot (WB)were used to detect the expression levels of osteogenic and angiogenesis-related genes and proteins Notch1, Noggin and vascular endothelial growth factor (VEGF).ResultsAdministration of ZGF demonstrated a significant mitigation of bone loss attributable to elevated glucose levels. H&E staining and micro-CT showed that ZGF notably improved the integrity of the trabecular and cortical bone microarchitecture. Moreover, ZGF was found to augment the density of type H vessels within the bone tissue, alongside elevating the expression levels of Osterix, a transcription factor pivotal for bone formation. Furthermore, our findings suggest that ZGF facilitates the activation of the Notch1/Noggin/VEGF pathway, indicating a potential mechanism through which ZGF exerts its osteoprotective effects.ConclusionOur results suggest that ZGF potentially facilitates the formation of type H vessels through the Notch1/Noggin/VEGF pathway. This action not only enhances angiogenic-osteogenic coupling but also contributes to the improvement of bone structure and density. Consequently, ZGF emerges as a promising therapeutic agent for the prevention and management of DOP, offering a novel approach by leveraging angiogenesis-dependent osteogenesis.
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Project description:Alzheimer's disease (AD) has become a worldwide disease that is harmful to human health and brings a heavy economic burden to healthcare system. Xiao-Xu-Ming Decoction (XXMD) has been widely used to treat stroke and other neurological diseases for more than 1000 years in China. However, the synergistic mechanism of the constituents in XXMD for the potential treatment of AD is still unclear. Therefore, the present study aimed to predict the potential targets and uncover the material basis of XXMD for the potential treatment of AD. A network pharmacology-based method, which combined data collection, drug-likeness filtering and absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties filtering, target prediction and network analysis, was used to decipher the effect and potential targets of XXMD for the treatment of AD. Then, the acetylcholinesterase (AChE) inhibitory assay was used to screen the potential active constituents in XXMD for the treatment of AD, and the molecular docking was furtherly used to identify the binding ability of active constituents with AD-related target of AChE. Finally, three in vitro cell models were applied to evaluate the neuroprotective effects of potential lead compounds in XXMD. Through the China Natural Products Database, Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database, Traditional Chinese Medicine (TCM)-Database @Taiwan and literature, a total of 1481 compounds in XXMD were finally collected. After ADME/T properties filtering, 908 compounds were used for the further study. Based on the prediction data, the constituents in XXMD formula could interact with 41 AD-related targets. Among them, cyclooxygenase-2 (COX-2), estrogen receptor α (ERα) and AChE were the major targets. The constituents in XXMD were found to have the potential to treat AD through multiple AD-related targets. 62 constituents in it were found to interact with more than or equal to 10 AD-related targets. The prediction results were further validated by in vitro biology experiment, resulting in several potential anti-AD multitarget-directed ligands (MTDLs), including two AChE inhibitors with the IC50 values ranging from 4.83 to 10.22 μM. Moreover, fanchinoline was furtherly found to prevent SH-SY5Y cells from the cytotoxicities induced by sodium nitroprusside, sodium dithionate and potassium chloride. In conclusion, XXMD was found to have the potential to treat AD by targeting multiple AD-related targets and canonical pathways. Fangchinoline and dauricine might be the potential lead compounds in XXMD for the treatment of AD.
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