Chemical proteomics unveils that seventy flavors pearl pill ameliorates ischemic stroke by regulating oxidative phosphorylation.

Ischemic stroke has high mortality and morbidity rates and is the second leading cause of death in the world, but there is no definitive medicine. Seventy Flavors Pearl Pill (SFPP) is a classic formula in Tibetan Medicine. Clinical practice has shown the attenuation effect of SFPP on blood pressure disorders, strokes and their sequelae and other neurological symptoms, but its mechanism remains to be elucidated. In this study, we established three animal models in vivo and three cell models to evaluate the anti-hypoxia, anti-ischemia, and reperfusion injury prevention effects of SFPP. Quantitative proteomics revealed that oxidative phosphorylation (OXPHOS) is essential for SFPP's efficacy. Then, cysteine-activity based protein profiling technology, which reflects redox stress at the proteome level, was employed to illustrate that SFPP brought functional differences of critical proteins in OXPHOS. In addition, quantitative metabolomics revealed that SFPP affects whole energy metabolism with OXPHOS as the core. Finally, we performed a compositional identification of SFPP to initially explore the components of potential interventions in OXPHOS. These results provide new perspectives and tools to explore the mechanism of herbal medicine. The study suggests that OXPHOS could be a potential target for further research and intervention of ischemic stroke treatment.

Proteomics and Metabolomics Unveil Codonopsis pilosula (Franch.) Nannf. Ameliorates Gastric Precancerous Lesions via Regulating Energy Metabolism.

Objective: This study aimed to systematically evaluate the efficacy of Codonopsis pilosula (Franch.) Nannf. (Codonopsis Radix, CR) and reveal the mechanism of its effects on suppressing Gastric Precancerous Lesions. Methods: First, we established the GPL rat model which was induced by N-methyl-N'-nitro-N-nitrosoguanidine, a disordered diet, and 40% ethanol. The CR's anti-Gastric Precancerous Lesions effect was comprehensively evaluated by body weight, pathological section, and serum biochemical indexes. Then, quantitative proteomics and metabolomics were conducted to unveil the disturbed protein-network and pharmacodynamic mechanism. Furthermore, serum pharmacology was employed to confirm that CR's anti-gastritis and anti-cancer phenotype in cell models. Results: In animal models, CR had been shown to control inflammation and ameliorate Gastric Precancerous Lesions. Considering the combination of proteomics and metabolomics, we found that CR could significantly reverse the biological pathways related to energy metabolism which were disturbed by the Gastric Precancerous Lesions model. Furthermore, the results of serum pharmacology indicated that the Codonopsis Radix containing serum could ameliorate gastritis injury and selectively inhibit the proliferation of gastric cancer cells rather than normal cells, which was closely related to ATP production in the above mentioned cells. Conclusion: In summary, CR exerted anti-Gastric Precancerous Lesions effects by ameliorating gastritis injury and selectively inhibiting the proliferation of gastric cancer cells rather than normal cells. Proteomics and metabolomics unveiled that its efficacy was closely related to its regulation of the energy-metabolism pathway. This research not only provided new ideas for exploring the mechanism of complex systems such as Chinese herbals but also benefited the treatment strategy of Gastric Precancerous Lesions via regulating energy metabolism.

Quantitative Proteomics Revealed the Pharmacodynamic Network of Bugu Shengsui Decoction Promoting Osteoblast Proliferation.

Background and Objective: With high morbidity and disability, osteoporosis is a worldwide bone metabolism disease, regulated by complex pathological processes. Insufficient osteogenesis is greatly essential to osteoporosis. Traditional Chinese Medicine, a complex natural herbal medicine system, has increasingly attracted attention all over the world. Bugu Shengsui Decoction, a compound formula for osteoporosis, has significant clinical effects in the treatment of osteoporosis. Yet the detailed mechanisms are unclear. Thus, we investigated the effects and mechanism of Bugu Shengsui Decoction on osteoporotic rats and osteoblasts in vitro. Methods: In this study, we evaluated the effect of Bugu Shengsui Decoction in an animal model of orchiectomy. Multi-pharmacology indexes revealed that Bugu Shengsui Decoction obviously improved bone metabolism, bone mineral density, bone morphology, and biomechanics in the castrated rats. Then, serum pharmacology was employed to unveil that Bugu Shengsui Decoction promoted the proliferation and differentiation of osteoblasts. Moreover, quantitative proteomics combined with RNA interference assay was used to analyze and verify the pathway and key targets in pro-proliferation of MC3T3-E1 cells. Results: Bugu Shengsui Decoction obviously improved the worse parameters of bone metabolism, bone mineral density, bone morphology, and biomechanics in a castrated rat model. In vitro, Bugu Shengsui Decoction exerted proliferation- and differentiation-promoting effects of osteoblasts induced by serum starvation. Moreover, quantitative proteomics analysis combined with RNA interfere assay illustrated that Bugu Shengsui Decoction promoted osteogenesis via the PI3K-AKT pathway. Conclusion: Summarily, our discoveries certify that Bugu Shengsui Decoction is an effective treatment for osteoporosis via PI3K-AKT. This study is not only a beneficial attempt to explore the detailed mechanism of Traditional Chinese formula but also will provide inspiration for the treatment strategy of osteoporosis.

Network pharmacology unveils spleen-fortifying effect of Codonopsis Radix on different gastric diseases based on theory of "same treatment for different diseases" in traditional Chinese medicine.

Objective: "Same treatment for different diseases" is a unique treatment strategy under the guidance of traditional Chinese medicine (TCM) theory. Codonopsis Radix (Codonopsis pilosula, Dangshen in Chinese) with spleen-fortifying effect was employed to understand the strategy of "Same treatment for different diseases", based on its common mechanism in the treatment of gastric diseases including gastric ulcer, gastritis and gastric cancer via network pharmacology research. Methods: Network pharmacology research methods were used to analyze the interaction network and potential mechanisms of Dangshen in treating gastric ulcer, gastritis and gastric cancer. The active components and their target proteins of Dangshen were integrated from TCMSP, BATMAN-TCM databases. The targets of gastric ulcer, gastritis and gastric cancer were collected through GeneCards, PubMed, TDD and DisGeNET Database. Through screening, the key components and the key targets of Dangshen in treating gastric ulcer, gastritis and gastric cancer were obtained. After KEGG pathway analysis and GO analysis, the important pathways and biological processes were analyzed. Results: Through data and literature mining, the common and specific pharmaceutical effects and mechanism of Dangshen were summarized in these three gastric lesions. It was shown that Dangshen mainly acted on gastric ulcer, gastritis and gastric cancer through the overall regulation of the PI3K-AKT signaling pathway. With the development of the disease, it will gradually increase the control of inflammation through TNF, NF-κB and other inflammation-related signaling pathways to reduce inflammatory damage. For tumorigenesis, it pays more attention to inhibiting the ErbB signaling pathways to reduce the proliferation and migration of tumor cells. In addition, Dangshen's regulation of HIF-1 signaling pathway may also be beneficial for the treatment of gastric ulcer, gastritis and gastric cancer. Conclusion: Dangshen achieves spleen-fortifying effect on gastric diseases including gastric ulcer, gastritis and gastric cancer through multiple targets in multiple pathways, especially PI3K-AKT pathway and HIF-1 pathway. It could provide a scientific basis for understanding the strategy of "Same treatment for different diseases" in traditional Chinese medicine.

Common mechanism of Citrus Grandis Exocarpium in treatment of chronic obstructive pulmonary disease and lung cancer.

Objective: "Same treatment for different diseases" is a unique treatment strategy in traditional Chinese medicine. Two kinds of malignant respiratory diseases endanger human health-chronic obstructive pulmonary disease (COPD) and lung cancer. Citrus Grandis Exocarpium (Huajuhong in Chinese, HJH), a famous herbal, is always applied by Chinese medicine practitioners to dispersion the lung to resolve phlegm based on "syndrome differentiation and treatment" theory. However, the common mechanism for HJH's treatment of COPD and lung cancer is not clear. Methods: In this study, based on network pharmacology and molecular docking technology, the common mechanism of HJH in the treatment of COPD and lung cancer was studied. The active ingredients and related targets of HJH were integrated from TCMSP, BATMAN-TAM, STP, and Pubchem databases. The standard names of these targets were united by UniProt database. Targets of COPD and lung cancer were enriched through GeneCards, NCBI (Gene), Therapeutic Target Database, and DisGeNET (v7.0) databases. Then the intersection targets of HJH and diseases were obtained. The STRING network and the Cytoscape 3.7.2 were used to construct PPI network, the DAVID database was used to perform GO and KEGG analysis. Then Cytoscape 3.6.1 was used to build "ingredient-target-signal pathway" network. Finally, AutoDock 1.5.6 software was used to perform molecular docking of key proteins and molecules. Results: Eleven active ingredients in HJH were obtained by searching the database, corresponding to 184 HJH-COPD-lung cancer targets intersection. The results of biological network analysis showed that naringenin, the active component in HJH, could mainly act on target proteins such as AKT1, EGFR. Then through positive regulation of vasoconstriction and other biological processes, naringenin could regulate estrogen signaling pathway, VEGF signaling pathway, HIF-1 signaling pathway, ErbB signaling pathway, PI3K-Akt signaling pathway to play an important role in the treatment of both COPD and lung cancer. Conclusion: Network pharmacology was employed to systematically investigate the active ingredients and targets of HJH in treatment of COPD and lung cancer. And then, the common pharmacodynamic network of HJH for the two malignant respiratory diseases was firstly described. Furthermore, naringenin was proved to strongly bind with AKT1 and EGFR. It may provide the scientific basis for understanding the "Same treatment for different diseases" strategy in traditional Chinese medicine and inspirit subsequent drug discovery for COPD, lung cancer and other malignant lung diseases.