Yange Tian

Systems pharmacology-based dissection of mechanisms of Chinese medicinal formula Bufei Yishen as an effective treatment for chronic obstructive pulmonary disease.

The present work adopted a systems pharmacology-based approach to provide new insights into the active compounds and therapeutic targets of Bufei Yishen formula (BYF) for the treatment of chronic obstructive pulmonary disease (COPD). In addition, we established a rat model of cigarette smoke- and bacterial infection-induced COPD to validate the mechanisms of BYF action that were predicted in systems pharmacology study. The systems pharmacology model derived 216 active compounds from BYF and 195 potential targets related to various diseases. The compound-target network showed that each herbal drug in the BYF formula acted on similar targets, suggesting potential synergistic effects among these herbal drugs. The ClueGo assay, a Cytoscape plugin, revealed that most targets were related to activation of MAP kinase and matrix metalloproteinases. By using target-diseases network analysis, we found that BYF had great potential to treatment of multiple diseases, such as respiratory tract diseases, immune system, and cardiovascular diseases. Furthermore, we found that BYF had the ability to prevent COPD and its comorbidities, such as ventricular hypertrophy, in vivo. Moreover, BYF inhibited the inflammatory cytokine, and hypertrophic factors expression, protease-antiprotease imbalance and the collagen deposition, which may be the underlying mechanisms of action of BYF.

Systems pharmacology-based approach for dissecting the active ingredients and potential targets of the Chinese herbal Bufei Jianpi formula for the treatment of COPD

Background The Chinese herbal Bufei Jianpi formula (BJF) provides an effective treatment option for chronic obstructive pulmonary disease (COPD). However, the systems-level mechanism underlying the clinical effects of BJF on COPD remains unknown. Methods In this study, a systems pharmacology model based on absorption filtering, network targeting, and systems analyses was applied specifically to clarify the active compounds and therapeutic mechanisms of BJF. Then, a rat model of cigarette smoke- and bacterial infection-induced COPD was used to investigate the therapeutic mechanisms of BJF on COPD and its comorbidity. Results The pharmacological system successfully identified 145 bioactive ingredients from BJF and revealed 175 potential targets. There was a significant target overlap between the herbal constituents of BJF. These results suggested that each herb of BJF connected with similar multitargets, indicating potential synergistic effects among them. The integrated target–disease network showed that BJF probably was efficient for the treatment of not only respiratory tract diseases but also other diseases, such as nervous system and cardiovascular diseases. The possible mechanisms of action of BJF were related to activation of inflammatory response, immune responses, and matrix metalloproteinases, among others. Furthermore, we demonstrated that BJF treatment could effectively prevent COPD and its comorbidities, such as ventricular hypertrophy, by inhibition of inflammatory cytokine production, matrix metalloproteinases expression, and other cytokine production in vivo. Conclusion This study using the systems pharmacology method, in combination with in vivo experiments, helped us successfully dissect the molecular mechanism of BJF for the treatment of COPD and predict the potential targets of the multicomponent BJF, which provides a new approach to illustrate the synergetic mechanism of the complex prescription and discover more effective drugs against COPD.

System biology analysis of long-term effect and mechanism of Bufei Yishen on COPD revealed by system pharmacology and 3-omics profiling

System pharmacology identified 195 potential targets of Bufei Yishen formula (BYF), and BYF was proven to have a short-term therapeutic effect on chronic obstructive pulmonary disease (COPD) rats previously. However, the long-term effect and mechanism of BYF on COPD is still unclear. Herein, we explored its long-term effect and underlying mechanism at system level. We administered BYF to COPD rats from week 9 to 20, and found that BYF could prevent COPD by inhibiting the inflammatory cytokines expression, protease-antiprotease imbalance and collagen deposition on week 32. Then, using transcriptomics, proteomics and metabolomics analysis, we identified significant regulated genes, proteins and metabolites in lung tissues of COPD and BYF-treated rats, which could be mainly attributed to oxidoreductase-antioxidant activity, focal adhesion, tight junction or lipid metabolism. Finally, based on the comprehensive analysis of system pharmacology target, transcript, protein and metabolite data sets, we found a number of genes, proteins, metabolites regulated in BYF-treated rats and the target proteins of BYF were involved in lipid metabolism, inflammatory response, oxidative stress and focal adhension. In conclusion, BYF exerts long-term therapeutic action on COPD probably through modulating the lipid metabolism, oxidative stress, cell junction and inflammatory response pathways at system level.

Integrating 3-omics data analyze rat lung tissue of COPD states and medical intervention by delineation of molecular and pathway alterations

Chronic obstructive pulmonary disease (COPD) is a serious health problem. However, the molecular pathogenesis of COPD remains unknown. Here, we explored the molecular effects of cigarette smoke and bacterial infection in lung tissues of COPD rats. We also investigated therapeutic effects of aminophylline (APL) on the COPD rats and integrated transcriptome, proteome, and metabolome data for a global view of molecular mechanisms of COPD progression. Using molecular function and pathway analyses, the genes and proteins regulated in COPD and APL-treated rats were mainly attributed to oxidoreductase, antioxidant activity, energy and fatty acid metabolism. Furthermore, we identified hub proteins such as Gapdh (glyceraldehyde-3-phosphate dehydrogenase), Pkm (pyruvate kinase isozymes M1/M2), and Sod1 (superoxide dismutase 1), included in energy metabolism and oxidative stress. Then, we identified the significantly regulated metabolic pathways in lung tissues of COPD- and APL-treated rats, such as arachidonic acid, linoleic acid, and α-linolenic acid metabolism, which belong to the lipid metabolism. In particular, we picked the arachidonic acid metabolism for a more detailed pathway analysis of transcripts, proteins, and metabolites. We could observe an increase in metabolites and genes involved in arachidonic acid metabolism in COPD rats and the decrease in these in APL-treated rats, suggesting that inflammatory responses were up-regulated in COPD rats and down-regulated in APL-treated rats. In conclusion, these system-wide results suggested that COPD progression and its treatment might be associated with oxidative stress, lipid and energy metabolism disturbance. Additionally, we demonstrated the power of integrated omics for the elucidation of genes, proteins, and metabolites’ changes and disorders that were associated with COPD.

Dusuqing granules (DSQ) suppress inflammation in Klebsiella pneumonia rat via NF-κB/MAPK signaling

BackgroundDusuqing granules (DSQ) have been used in the treatment of bacterial pneumonia clinically, with remarkable benefits. This study was initiated to explore the effects of DSQ on pulmonary inflammation by regulating nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) signaling in bacterial pneumonia rats.MethodsRat model was duplicated with Klebsiella pneumonia by a one-time intratracheal injection. Rats were randomized into control, model, DSQ and levofloxacin (LVX) groups. After administrated with appropriate medicines for 7 days, lung tissues were harvested and prepared for pathological analysis, and interleukin (IL)-1, IL-6, monocyte chemotactic protein (MCP)-1and macrophage inflammatory protein (MIP)-2 detections. NF-κB mRNA was measured by real-time qPCR, and the phosphorylation and total proteins of P38MAPK, JNK46/54, ERK42/44 were determined by Western blotting.ResultsMarked pathological impairments were observed in model rats, whereas were improved in DSQ group. The cytokines levels, NF-κB mRNA expression and the phosphorylation of P38MAPK, JNK46/54 and ERK42/44 proteins were significantly higher in model group, and were significantly depressed in DSQ group.ConclusionThe protective effects of DSQ on Klebsiella pneumonia might be attributed to its inactivative effects of NF-κB/ MAPK pathway.

Bufei Yishen granules combined with acupoint sticking therapy suppress oxidative stress in chronic obstructive pulmonary disease rats: Via regulating peroxisome proliferator-activated receptor-gamma signaling

ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine (TCM) is clinically used under the guidance of its unique theory system. Bufei Yishen (BY) granules, an oral Chinese herbal formula, is confirmed effective for treating the syndrome of lung-kidney qi deficiency in chronic obstructive pulmonary disease (COPD) patients. Shu-Fei Tie ointment is another prescription for acupoint sticking (AS) therapy based on the theory of treating an internal disease by external treatment on proper acupoints. The beneficial effects of BY granules combined with Shu-Fei Tie have been proved in previous clinical trials. However, the underlying mechanism remains unclear. The present study was initiated to explore the antioxidative mechanism of the integrated therapy of BY granules and acupoint sticking via regulating by peroxisome proliferator activated receptor-gamma (PPARγ) signaling in a cigarette-smoke/bacterial exposure induced COPD rat model. MATERIALS AND METHODS Rats were randomized into Control, Model, BY, AS, BY+AS and aminophylline (APL) groups. COPD rats were induced by cigarette-smoke and bacterial exposures, and were administrated with normal saline, BY granules, AS, BY+AS or aminophylline from week 9 and sacrificed at week 20. Activity of superoxide dismutase (SOD) and levels of methane dicarboxylic aldehyde (MDA) in peripheral blood and bronchoalveolar lavage fluid (BALF) were determined by hydroxylamine and thiobarbituric acid methods. The gene and protein expressions of PPARγ in the lung tissues were analyzed by quantitative polymerase chain reaction and western blot. RESULTS Serum and BALF SOD decreased significantly in Model group (P<0.01), while MDA increased (P<0.01). Compared to COPD rats, serum SOD was higher in all treatment groups (P<0.01), and BALF SOD was higher in BY and BY+AS groups (P<0.01); serum and BALF MDA was lower in all treatment groups (P<0.01). Serum and BALF SOD was higher in BY+AS group than in AS group, while MDA was lower (P<0.05). BALF SOD increased in BY+AS group compared with APL group, while MDA decreased (P<0.05). PPARγ mRNA and protein and the phosphorylation of PPARγ (p-PPARγ) decreased in COPD rats (P<0.01), and increased in all treatment groups (P<0.01). PPARγ mRNA was higher in BY+AS group than in AS group (P<0.05), PPARγ and p-PPARγ were higher in BY+AS group than in AS and APL groups (P<0.05, P<0.01); PPARγ protein was higher in BY group than in APL group (P<0.05). CONCLUSION Bufei Yishen granules, Shu-Fei Tie and their combination have beneficial effects in stable COPD, and can attenuate the oxidative stress, and the activation of PPARγ signaling might be involved in the underlying mechanisms, but there are no obvious synergistic effect of Bufei Yishen granules and Shu-Fei Tie.

Combining systems pharmacology, transcriptomics, proteomics, and metabolomics to dissect the therapeutic mechanism of Chinese herbal Bufei Jianpi formula for application to COPD.

Bufei Jianpi formula (BJF) has long been used as a therapeutic agent in the treatment of COPD. Systems pharmacology identified 145 active compounds and 175 potential targets of BJF in a previous study. Additionally, BJF was previously shown to effectively prevent COPD and its comorbidities, such as ventricular hypertrophy, by inhibition of inflammatory cytokine production, matrix metalloproteinases expression, and other cytokine production, in vivo. However, the system-level mechanism of BJF for the treatment of COPD is still unclear. The aim of this study was to gain insight into its system-level mechanisms by integrating transcriptomics, proteomics, and metabolomics together with systems pharmacology datasets. Using molecular function, pathway, and network analyses, the genes and proteins regulated in COPD rats and BJF-treated rats could be mainly attributed to oxidoreductase activity, antioxidant activity, focal adhesion, tight junction, or adherens junction. Furthermore, a comprehensive analysis of systems pharmacology, transcript, protein, and metabolite datasets is performed. The results showed that a number of genes, proteins, metabolites regulated in BJF-treated rats and potential target proteins of BJF were involved in lipid metabolism, cell junction, oxidative stress, and inflammatory response, which might be the system-level therapeutic mechanism of BJF treatment.

Restoring Th17/Treg balance via modulation of STAT3 and STAT5 activation contributes to the amelioration of chronic obstructive pulmonary disease by Bufei Yishen formula

ETHNOPHARMACOLOGY RELEVANCE Bufei Yishen formula (BYF), a Traditional Chinese Medicine (TCM), has been extensively applied in clinical treatment of chronic obstructive pulmonary disease (COPD) and provides an effective treatment strategy for the syndrome of lung-kidney qi deficiency in COPD patients. Here, we investigated its anti-COPD mechanism in COPD rats in relation to the balance between T helper (Th) 17 cells and regulatory T (Treg) cells. METHODS Rat model of cigarette smoke- and bacterial infection-induced COPD was established, and orally treated with BYF for 12 consecutive weeks. Then, the rats were sacrificed, their lung tissues were removed for histological analysis, and spleens and mesenteric lymph nodes (MLNs) were collected to evaluate the Th17 and Treg cells. RESULTS Oral treatment of BYF markedly suppressed the disease progression and alleviated the pathological changes of COPD. It also decreased the bronchoalveolar lavage fluid (BALF) levels of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α and Th17-related IL-17A, and induced a significant increase in Treg-related IL-10. Furthermore, BYF treatment obviously decreased the proportion of CD4+RORγt+ T (Th17) cell and increased the proportion of CD4+CD25+Foxp3+ T (Treg) cell, leading to restore the Th17/Treg balance. BYF treated groups also decreased RORγt and increased Foxp3 expression in the spleens and MLNs. BYF further inhibited the phosphorylation of signal transducer and activator of transcription-3 (STAT3) and boosted the phosphorylation of STAT5, that were critical transcription factors for TH17 and Treg differentiation. CONCLUSION these results demonstrated that BYF exerted its anti-COPD efficacy by restoring Th17/Treg balance via reciprocally modulating the activities of STAT3 and STAT5 in COPD rats, which may help to elucidate the underlying immunomodulatory mode of BYF on COPD treatment.

Integration of transcriptomics, proteomics, metabolomics and systems pharmacology data to reveal the therapeutic mechanism underlying Chinese herbal Bufei Yishen formula for the treatment of chronic obstructive pulmonary disease

Bufei Yishen formula (BYF) is a traditional Chinese medicine formula, which has long been used as a therapeutic agent for the treatment of chronic obstructive pulmonary disease (COPD). Systems pharmacology has previously been used to identify the potential targets of BYF, and an experimental study has demonstrated that BYF is able to prevent COPD. In addition, the transcriptomic and metabolomic profiles of lung tissues from rats with COPD and BYF-treated rats have been characterized. The present study aimed to determine the therapeutic mechanisms underlying the effects of BYF on COPD treatment by integrating transcriptomics, proteomics and metabolomics, together with systems pharmacology datasets. Initially, the proteomic profiles of rats with COPD and BYF-treated rats were analyzed. Subsequently, pathway and network analyses were conducted to integrate three-omics data; the results demonstrated that the genes, proteins and metabolites were predominantly associated with oxidoreductase activity, antioxidant activity, focal adhesion and lipid metabolism. Finally, a comprehensive analysis of systems pharmacology, transcriptomic, proteomic and metabolomic datasets was performed, and numerous genes, proteins and metabolites were found to be regulated in BYF-treated rats; the potential target proteins of BYF were involved in lipid metabolism, inflammatory response, oxidative stress and focal adhesion. In conclusion, BYF exerted beneficial effects against COPD, potentially by modulating lipid metabolism, the inflammatory response, oxidative stress and cell junction pathways at the system level.

miRNA-206 regulates human pulmonary microvascular endothelial cell apoptosis via targeting in chronic obstructive pulmonary disease: SUN et al.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death due to tis high morbidity and mortality. microRNAs have emerged as new biomarkers for the prognosis and diagnosis of patients with COPD. In this study, we aimed to investigate the expression of microRNA‐206 (miR‐206) in lung tissues from COPD patients and to explore the regulatory role of miR‐206 in the human pulmonary microvascular endothelial cells (HPMECs). Our results showed that cigarette smoke extract (CSE) promoted cell apoptosis, increased caspase‐3 activity, and upregulated the expression of miR‐206 in HPMECs, which was significantly reversed by the miR‐206 knockdown. Transfection with miR‐206 mimics led to cell apoptosis and was closely related to changes in the protein expression levels of caspase‐3, caspase‐9, and Bcl‐2 in HPMECs. Further bioinformatics prediction analysis revealed that the 3′‐untranslated region (3′UTR) of Notch3 and vascular endothelial growth factor‐A (VEGFA) harbored miR‐206‐binding sites, and overexpression of miR‐206 repressed the luciferase activity of the vectors containing Notch3 and VEGFA 3′UTR. Overexpression of either Notch3 or VEGFA attenuated miR‐206‐induced cell apoptosis in HPMECs. More importantly, miR‐206 expression was upregulated in the lung tissues from COPD patients and was positively corrected with forced expiratory volume 1% predicted in COPD patients, while Notch3 and VEGFA mRNA levels were downregulated and were negatively correlated with the expression level of miR‐206 in the lung tissues from COPD patients. In conclusion, our results showed that miR‐206 was upregulated in COPD patients and CSE‐treated HPMECs, promoted cell apoptosis via directly targeting Notch3 and VEGFA in HPMECs.