Publications by authors named "Guan-Hua Du"

308 Publications

TLR4-IN-C34 Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses via Downregulating TLR4/MyD88/NF-κB/NLRP3 Signaling Pathway and Reducing ROS Generation in BV2 Cells.

Inflammation 2021 Nov 2. Epub 2021 Nov 2.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.

TLR4 signal activated by lipopolysaccharide (LPS) is involved in the pathological process of the central nervous system (CNS) diseases and the suppression of TLR4 signal may become an effective treatment. TLR4-IN-C34, a TLR4 inhibitor, is expected to become a candidate compound with anti-neuroinflammatory response. In the present study, the anti-neuroinflammatory effects and possible mechanism of TLR4-IN-C34 were investigated in BV2 microglia cells stimulated by LPS. The results showed that TLR4-IN-C34 decreased the levels of pro-inflammatory factors and chemokines including NO, TNF-α, IL-1β, IL-6, and MCP-1 in the supernatant of LPS-stimulated BV2 cells. Further research indicated that TLR4-IN-C34 suppressed the expression or phosphorylation levels of inflammatory proteins regarding TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In addition, TLR4-IN-C34 reduced ROS production in BV2 cells after LPS treatment. In conclusion, our findings suggest that anti-neuroinflammatory activity of TLR4-IN-C34 may be interrelated to the inhibition of TLR4/MyD88/NF-κB/NLRP3 signaling pathway and reduction of ROS generation.
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http://dx.doi.org/10.1007/s10753-021-01588-8DOI Listing
November 2021

Compound Kushen Injection intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling.

Phytomedicine 2021 Dec 27;93:153781. Epub 2021 Sep 27.

Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan, China. Electronic address:

Background: Hepatocellular carcinoma (HCC) is one of the most extensive and most deadly cancers worldwide. The invasion and metastasis characteristics of HCC dramatically affect the prognosis and survival of HCC patients. Compound Kushen Injection (CKI) is a GMP produced, proverbially applied traditional Chinese medicine formula in China to treat cancer-associated pains, and used as an adjunctive therapy for HCC. Until so far, whether CKI could suppress the metastasis of HCC through regulation of epithelial-mesenchymal transition or metabolic reprogramming is still ambiguous.

Purpose: In this study, the anti-metastasis effects of CKI were clarified and its pharmacological mechanisms were systematically explored.

Methods: Cell invasion and cell adhesion assay were performed in SMMC-7721 cells to assess the anti-metastasis role of CKI, and the histopathological evaluation and biochemical detection were utilized in DEN-induced HCC rats to verify the anti-HCC effect of CKI. Serum and liver samples were analyzed with H NMR metabolomics approach to screen the differential metabolites and further target quantification the content of key metabolites. Finally, western blotting and immunofluorescence assay were applied to verify the crucial signaling pathway involved in metabolites.

Results: CKI markedly repressed the invasion and adhesion in SMMC-7721 cells and significantly improved the liver function of DEN-induced HCC rats. CKI significantly regulated the expression of epithelial-mesenchymal transition (EMT) markers (Vimentin and E-cadherin). Metabolomics results showed that CKI regulated the metabolic reprogramming of HCC by inhibiting the key metabolites (citrate and lactate) and enzymes (HK and PK) in glycolysis process. Importantly, we found that c-Myc mediates the inhibitory effect of CKI on glycolysis. We further demonstrated that CKI inhibits c-Myc expression through modulating Wnt/β-catenin pathway in SMMC-7721 cells and DEN-induced HCC rats. Furthermore, through activating Wnt/β-catenin pathway with LiCl, the inhibitory effects of CKI on HCC were diminished.

Conclusion: Together, this study reveals that CKI intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling pathway. Our research provides a new understanding of the mechanism of CKI against invasion and metastasis of HCC from the perspective of metabolic reprogramming.
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http://dx.doi.org/10.1016/j.phymed.2021.153781DOI Listing
December 2021

Network-Based Identification and Experimental Validation of Drug Candidates Toward SARS-CoV-2 Targeting Virus-Host Interactome.

Front Genet 2021 1;12:728960. Epub 2021 Sep 1.

Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Despite that several therapeutic agents have exhibited promising prevention or treatment on Coronavirus disease-2019 (COVID-19), there is no specific drug discovered for this pandemic. Targeting virus-host interactome provides a more effective strategy for antivirus drug discovery compared with targeting virus proteins. In this study, we developed a network-based infrastructure to prioritize promising drug candidates from natural products and approved drugs targeting host proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We firstly measured the network distances between drug targets and COVID-19 disease module utilizing the network proximity approach, and identified 229 approved drugs as well as 432 natural products had significant associations with SARS-CoV-2. After searching for previous literature evidence, we found that 60.7% (139/229) of approved drugs and 39.6% (171/432) of natural products were confirmed with antivirus or anti-inflammation. We further integrated our network-based predictions and validated anti-SARS-CoV-2 activities of some compounds. Four drug candidates, including hesperidin, isorhapontigenin, salmeterol, and gallocatechin-7-gallate, have exhibited activity on SARS-COV-2 virus-infected Vero cells. Finally, we showcased the mechanism of actions of isorhapontigenin and salmeterol network analysis. Overall, this study offers forceful approaches for identification of drug candidates on COVID-19, which may facilitate the discovery of antiviral drug therapies.
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http://dx.doi.org/10.3389/fgene.2021.728960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440948PMC
September 2021

Aesculin suppresses the NLRP3 inflammasome-mediated pyroptosis via the Akt/GSK3β/NF-κB pathway to mitigate myocardial ischemia/reperfusion injury.

Phytomedicine 2021 Nov 23;92:153687. Epub 2021 Aug 23.

Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.; Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China. Electronic address:

Background: Aesculin (AES), an effective component of Cortex fraxini, is a hydroxycoumarin glucoside that has diverse biological properties. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing 3 (NLRP3) inflammasome has been heavily interwoven with the development of myocardial ischemia/reperfusion injury (MIRI). Nevertheless, it remains unclear whether AES makes a difference to the changes of the NLRP3 inflammasome in MIRI.

Purpose: We used rats that were subjected to MIRI and neonatal rat cardiomyocytes (NRCMs) that underwent oxygen-glucose deprivation/restoration (OGD/R) process to investigate what impacts AES exerts on MIRI and the NLRP3 inflammasome activation.

Methods: The establishment of MIRI model in rats was conducted using the left anterior descending coronary artery ligation for 0.5 h ischemia and then untying the knot for 4 h of reperfusion. After reperfusion, AES were administered intraperitoneally using 10 and 30 mg/kg doses. We evaluated the development of reperfusion ventricular arrhythmias, hemodynamic changes, infarct size, and the biomarkers in myocardial injury. The inflammatory mediators and pyroptosis were also assessed. AES at the concentrations of 1, 3, and 10 μM were imposed on the NRCMs immediately before the restoration process. We also determined the cell viability and cell death in the NRCMs exposed to OGD/R insult. Furthermore, we also analyzed the levels of proteins that affect the NLRP3 inflammasome activation, pyroptosis, and the AKT serine/threonine kinase (Akt)/glycogen synthase kinase 3 beta (GSK3β)/nuclear factor-kappa B (NF-κB) signaling pathway via western blotting.

Results: We found that AES notably attenuated reperfusion arrhythmias and myocardia damage, improved the hemodynamic function, and ameliorated the inflammatory response and pyroptosis of cardiomyocytes in rats and NRCMs. Additionally, AES reduced the NLRP3 inflammasome activation in rats and NRCMs. AES also enhanced the phosphorylation of Akt and GSK3β, while suppressing the phosphorylation of NF-κB. Moreover, the allosteric Akt inhibitor, MK-2206, abolished the AES-mediated cardioprotection and the NLRP3 inflammasome suppression.

Conclusions: These findings indicate that AES effectively protected cardiomyocytes against MIRI by suppressing the NLRP3 inflammasome-mediated pyroptosis, which may relate to the upregulated Akt activation and disruption of the GSK3β/NF-κB pathway.
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http://dx.doi.org/10.1016/j.phymed.2021.153687DOI Listing
November 2021

RKC-B1 Blocks Activation of NF-κB and NLRP3 Signaling Pathways to Suppress Neuroinflammation in LPS-Stimulated Mice.

Mar Drugs 2021 Jul 28;19(8). Epub 2021 Jul 28.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

RKC-B1 is a novel fermentation product obtained from the marine micromonospora FIM02-523A. Thus far, there have been few reports about the pharmacological activity of RKC-B1. In our present study, we investigated the anti-neuroinflammatory effects and the possible mechanism of RKC-B1 in LPS-stimulated mice. After treatment with RKC-B1, RNA-seq transcriptome of the cerebral cortex tissue was conducted to find the differentially expressed genes (DEGs). Inflammatory cytokines and proteins were evaluated by ELISA and WB. In RNA-seq analysis, there were 193 genes screened as core genes of RKC-B1 for treatment with neuroinflammation. The significant KEGG enrichment signaling pathways of these core genes were mainly included TNF signaling pathway, IL-17 signaling pathway, NOD-like receptor signaling pathway, NF-κB signaling pathway and others. The corresponding top five KEGG enrichment pathways of three main clusters in PPI network of core genes were closely related to human immune system and immune disease. The results showed that RKC-B1 reduced the levels of pro-inflammatory factors (IL-6, IL-1β, MCP-1, and ICAM-1) and the expression of COX2 in cerebral cortex tissue. Additionally, we found that the anti-neuroinflammation activity of RKC-B1 might be related to suppress activating of NF-κB and NLRP3/cleaved caspase-1 signaling pathways. The current findings suggested that RKC-B1 might be a promising anti-neuroinflammatory agent.
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http://dx.doi.org/10.3390/md19080429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398414PMC
July 2021

Benzimidazoles induce concurrent apoptosis and pyroptosis of human glioblastoma cells via arresting cell cycle.

Acta Pharmacol Sin 2021 Aug 25. Epub 2021 Aug 25.

The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.

Glioblastoma multiforme (GBM) is the most malignant and lethal primary brain tumor in adults accounting for about 50% of all gliomas. The only treatment available for GBM is the drug temozolomide, which unfortunately has frequent drug resistance issue. By analyzing the hub genes of GBM via weighted gene co-expression network analysis (WGCNA) of the cancer genome atlas (TCGA) dataset, and using the connectivity map (CMAP) platform for drug repurposing, we found that multiple azole compounds had potential anti-GBM activity. When their anti-GBM activity was examined, however, only three benzimidazole compounds, i.e. flubendazole, mebendazole and fenbendazole, potently and dose-dependently inhibited proliferation of U87 and U251 cells with IC values below 0.26 μM. Benzimidazoles (0.125-0.5 μM) dose-dependently suppressed DNA synthesis, cell migration and invasion, and regulated the expression of key epithelial-mesenchymal transition (EMT) markers in U87 and U251 cells. Benzimidazoles treatment also dose-dependently induced the GBM cell cycle arrest at the G/M phase via the P53/P21/cyclin B1 pathway. Furthermore, the drugs triggered pyroptosis of GBM cells through the NF-κB/NLRP3/GSDMD pathway, and might also concurrently induced mitochondria-dependent apoptosis. In a nude mouse U87 cell xenograft model, administration of flubendazole (12.5, 25, and 50 mg · kg · d, i.p, for 3 weeks) dose-dependently suppressed the tumor growth without obvious adverse effects. Taken together, our results demonstrated that benzimidazoles might be promising candidates for the treatment of GBM.
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http://dx.doi.org/10.1038/s41401-021-00752-yDOI Listing
August 2021

[Research progress of circadian rhythm].

Zhongguo Zhong Yao Za Zhi 2021 Jul;46(13):3240-3248

Modern Research Center for Traditional Chinese Medicine,Shanxi University Taiyuan 030006,China.

Circadian rhythm disorder is a common society issue caused by jet lag,shift work,sleep disruption and changes in food consumption. Light is the major factor affecting the circadian rhythm system. Disruption of the circadian rhythm system can cause damage to the body,leading to some diseases. Maintaining a normal circadian system is of great importance for good health. Ideal therapeutic effect can not only alleviate symptoms of the diseases,but also recovery the disturbed circadian rhythm to normal. The paper summarizes the modeling methods of animal circadian rhythm disorder,diseases of circadian rhythm abnormality,regulation of circadian clock genes and medicine which are related to circadian rhythm to diseases of circadian rhythm disorder.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210308.601DOI Listing
July 2021

Quercetin attenuates ischemia reperfusion injury by protecting the blood-brain barrier through Sirt1 in MCAO rats.

J Asian Nat Prod Res 2021 Jul 22:1-12. Epub 2021 Jul 22.

Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

The purpose of the present study was to examine the protective action and mechanisms of quercetin on the blood-brain barrier (BBB) in rats subjected to transient middle cerebral artery occlusion (tMCAO) and reperfusion. Quercetin (10, 30, 50 mg/kg) was intraperitoneally administered at the onset of reperfusion. The results showed that quercetin significantly reduced cerebral infarct volume, neurological deficit, BBB permeability and ROS generation via Sirt1/Nrf2/HO-1 signaling pathway. Moreover, EX527, a selective inhibitor of Sirt1, reversed these neuroprotective effects. Our findings indicate that quercetin has neuroprotective effects against cerebral ischemia-reperfusion injury by protecting BBB through Sirt1 signaling pathway in MCAO rats.
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http://dx.doi.org/10.1080/10286020.2021.1949302DOI Listing
July 2021

Luteolin alleviates cognitive impairment in Alzheimer's disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation.

Acta Pharmacol Sin 2021 Jul 15. Epub 2021 Jul 15.

School of Pharmacy, Henan University, Kaifeng, 475004, China.

Luteolin is a flavonoid in a variety of fruits, vegetables, and herbs, which has shown anti-inflammatory, antioxidant, and anti-cancer neuroprotective activities. In this study, we investigated the potential beneficial effects of luteolin on memory deficits and neuroinflammation in a triple-transgenic mouse model of Alzheimer's disease (AD) (3 × Tg-AD). The mice were treated with luteolin (20, 40 mg · kg · d, ip) for 3 weeks. We showed that luteolin treatment dose-dependently improved spatial learning, ameliorated memory deficits in 3 × Tg-AD mice, accompanied by inhibiting astrocyte overactivation (GFAP) and neuroinflammation (TNF-α, IL-1β, IL-6, NO, COX-2, and iNOS protein), and decreasing the expression of endoplasmic reticulum (ER) stress markers GRP78 and IRE1α in brain tissues. In rat C6 glioma cells, treatment with luteolin (1, 10 µM) dose-dependently inhibited LPS-induced cell proliferation, excessive release of inflammatory cytokines, and increase of ER stress marker GRP78. In conclusion, luteolin is an effective agent in the treatment of learning and memory deficits in 3 × Tg-AD mice, which may be attributable to the inhibition of ER stress in astrocytes and subsequent neuroinflammation. These results provide the experimental basis for further research and development of luteolin as a therapeutic agent for AD.
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http://dx.doi.org/10.1038/s41401-021-00702-8DOI Listing
July 2021

Chrysomycin A Attenuates Neuroinflammation by Down-Regulating NLRP3/Cleaved Caspase-1 Signaling Pathway in LPS-Stimulated Mice and BV2 Cells.

Int J Mol Sci 2021 Jun 24;22(13). Epub 2021 Jun 24.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

Chrysomycin A (Chr-A), an antibiotic chrysomycin, was discovered in 1955 and is used to treat cancer and tuberculosis. In the present study, the anti-neuroinflammatory effects and possible mechanism of Chr-A in BALB/c mice and in BV2 microglia cells stimulated by lipopolysaccharide (LPS) were investigated. Firstly, the cortex tissues of mice were analyzed by RNA-seq transcriptome to identify differentially expressed genes (DEGs) regulated by Chr-A in LPS-stimulated mice. Inflammatory cytokines and inflammatory proteins were detected by enzyme-linked immunosorbent assay and Western blot. In RNAseq detection, 639 differential up-regulated genes between the control group and LPS model group and 113 differential down-regulated genes between the LPS model group and Chr-A treatment group were found, and 70 overlapping genes were identified as key genes for Chr-A against neuroinflammation. Subsequent GO biological process enrichment analysis showed that the anti-neuroinflammatory effect of Chr-A might be related to the response to cytokine, cellular response to cytokine stimulus, and regulation of immune system process. The significant signaling pathways of KEGG enrichment analysis were mainly involved in TNF signaling pathway, cytokine-cytokine receptor interaction, NF-κB signaling pathway, IL-17 signaling pathway and NOD-like receptor signaling pathway. Our results of in vivo or in vitro experiments showed that the levels of pro-inflammatory factors including NO, IL-6, IL-1β, IL-17, TNF-α, MCP-1, CXCL12, GM-CSF and COX2 in the LPS-stimulated group were higher than those in the control group, while Chr-A reversed those conditions. Furthermore, the Western blot analysis showed that its anti-neuroinflammation appeared to be related to the down-regulation of NLRP3/cleaved caspase-1 signaling pathway. The current findings provide new insights into the activity and molecular mechanisms of Chr-A for the treatment of neuroinflammation.
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http://dx.doi.org/10.3390/ijms22136799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268846PMC
June 2021

Baicalein Delays HO-Induced Astrocytic Senescence through Inhibition of Senescence-Associated Secretory Phenotype (SASP), Suppression of JAK2/STAT1/NF-κB Pathway, and Regulation of Leucine Metabolism.

ACS Chem Neurosci 2021 07 21;12(13):2320-2335. Epub 2021 Jun 21.

Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China.

Baicalein is an active ingredient extracted from the dried roots of the Georgi. It has been demonstrated to improve memory impairment in multiple animal models; however, the underlying mechanisms remain ambiguous. The accumulation of senescent astrocytes and senescence-associated secretory phenotype (SASP) secreted by senescent astrocytes has been deemed as potential contributors to neurodegenerative diseases. Therefore, this study explored the protective effects of baicalein against astrocyte senescence and investigated the molecular mechanisms and metabolic mechanisms of baicalein against astrocyte senescence. Our results demonstrated that treatment with baicalein protects T98G cells from HO-induced damage, delays cell senescence, inhibits the secretion of SASP (IL-6, IL-8, TNF-α, CXCL1, and MMP-1), and inhibits SASP-related pathways NF-κB and JAK2/STAT1. H NMR metabolomics analysis and correlation analysis revealed that leucine was significantly correlated with SASP factors. Further study demonstrated that supplement with leucine could restrain SASP secretion, and baicalein could significantly increase leucine level through down-regulation of BCAT1 and up-regulation of SLC7A5 expression. The above results revealed that baicalein exerted protective and antisenescence effects in HO-induced T98G cells possibly through inhibition of SASP, suppression of JAK2/STAT1/NF-κB pathway, and regulation of leucine metabolism. Consistent results were obtained in primary astrocytes of newborn SD rats, which suggests that baicalein significantly increases viabilities, delays senescence, inhibits IL-6 secretion, and increases leucine level in HO-induced primary astrocytes.
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http://dx.doi.org/10.1021/acschemneuro.1c00024DOI Listing
July 2021

Pinocembrin attenuates hemorrhagic transformation after delayed t-PA treatment in thromboembolic stroke rats by regulating endogenous metabolites.

Acta Pharmacol Sin 2021 Aug 15;42(8):1223-1234. Epub 2021 Apr 15.

Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Hemorrhagic transformation (HT) is a common serious complication of stroke after thrombolysis treatment, which limits the clinical use of tissue plasminogen activator (t-PA). Since early diagnosis and treatment for HT is important to improve the prognosis of stroke patients, it is urgent to discover the potential biomarkers and therapeutic drugs. Recent evidence shows that pinocembrin, a natural flavonoid compound, exerts anti-cerebral ischemia effect and expands the time window of t-PA. In this study, we investigated the effect of pinocembrin on t-PA-induced HT and the potential biomarkers for HT after t-PA thrombolysis, thereby improving the prognosis of stroke. Electrocoagulation-induced thrombotic focal ischemic rats received intravenous infusion of t-PA (10 mg/kg) 6 h after ischemia. Administration of pinocembrin (10 mg/kg, iv) prior t-PA infusion significantly decreased the infarct volume, ameliorated t-PA-induced HT, and protected blood-brain barrier. Metabolomics analysis revealed that 5 differential metabolites in the cerebral cortex and 16 differential metabolites in serum involved in amino acid metabolism and energy metabolism were significantly changed after t-PA thrombolysis, whereas pinocembrin administration exerted significant intervention effects on these metabolites. Linear regression analysis showed that lactic acid was highly correlated to the occurrence of HT. Further experiments confirmed that t-PA treatment significantly increased the content of lactic acid and the activity of lactate dehydrogenase in the cerebral cortex and serum, and the expression of monocarboxylate transporter 1 (MCT 1) in the cerebral cortex; pinocembrin reversed these changes, which was consistent with the result of metabolomics. These results demonstrate that pinocembrin attenuates HT after t-PA thrombolysis, which may be associated with the regulation of endogenous metabolites. Lactic acid may be a potential biomarker for HT prediction and treatment.
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http://dx.doi.org/10.1038/s41401-021-00664-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285418PMC
August 2021

A metabolic data-driven systems pharmacology strategy for decoding and validating the mechanism of Compound Kushen Injection against HCC.

J Ethnopharmacol 2021 Jun 20;274:114043. Epub 2021 Mar 20.

Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China. Electronic address:

Ethnopharmacological Relevance: Compound Kushen Injection (CKI) is a widely used TCM formula for treatment of carcinomatous pain and tumors of digestive system including hepatocellular carcinoma (HCC). However, the potential mechanisms of CKI for treatment of HCC have not been systematically and deeply studied.

Aim Of Study: A metabolic data-driven systems pharmacology approach was utilized to investigate the potential mechanisms of CKI for treatment of HCC.

Materials And Methods: Based on phenotypic data generated by metabolomics and genotypic data of drug targets, a propagation model based on Dijkstra program was proposed to decode the effective network of key genotype-phenotype of CKI in treating HCC. The pivotal pathway was predicted by target propagation mode of our proposed model, and was validated in SMMC-7721 cells and diethylnitrosamine-induced rats.

Results: Metabolomics results indicated that 12 differential metabolites, and 5 metabolic pathways might be involved in the anti-HCC effect of CKI. A total of 86 metabolic related genes that affected by CKI were obtained. The results calculated by propagation model showed that 6475 shortest distance chains might be involved in the anti-HCC effect of CKI. According to the results of propagation mode, EGFR was identified as the core target of CKI for the anti-HCC effect. Finally, EGFR and its related pathway EGFR-STAT3 signaling pathway were validated in vivo and in vitro.

Conclusion: The proposed method provides a methodological reference for explaining the underlying mechanism of TCM in treating HCC.
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http://dx.doi.org/10.1016/j.jep.2021.114043DOI Listing
June 2021

Remarkable inhibition effects of afatinib alone or combining with paclitaxel in esophageal squamous cell carcinoma.

J Gastroenterol Hepatol 2021 Sep 1;36(9):2513-2522. Epub 2021 Apr 1.

State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background And Aim: Chemotherapy drugs do not work well in esophageal squamous cell carcinoma (ESCC), and none of the targeted drugs have been applied in clinic. This study aims to identify effective targeted drugs and related biomarkers for the treatment of ESCC.

Methods: The effect of 40 Food and Drug Administration-approved small-molecule inhibitors was first tested in five ESCC cell lines. CCK8 assays and xenografts derived from ESCC cell lines were performed to evaluate the anti-ESCC effects of inhibitors or chemotherapeutic agents in vitro and in vivo, respectively. Immunohistochemistry was utilized to analyze the p-EGFR expression in tissues. Western blot combining with gray analysis was conducted to detect the expression of interest protein. Flow cytometry and immunofluorescence assay were used to analyze apoptosis, cell cycle, and mitotic changes after drug treatment.

Results: Afatinib showed remarkable effects on inhibiting ESCC cells with higher expression of p-EGFR. Results from combinatorial screening in ESCC cells expressing lower phosphorylation level of EGFR showed that paclitaxel and afatinib presented a significant synergistic inhibitory effect (P < 0.001). Molecular analysis revealed that paclitaxel sensitized afatinib by activating EGFR, and afatinib in combination with paclitaxel effectively blocked MAPK pathway and induced G2/M cell arrest and apoptosis that is an indicator of mitotic catastrophe.

Conclusions: Our data demonstrate that afatinib is an effective drug for patients with ESCC expressing higher phosphorylation level of EGFR. And for patients with lower p-EGFR in tumors, paclitaxel in combination with afatinib might be a promising therapeutic strategy in ESCC.
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http://dx.doi.org/10.1111/jgh.15490DOI Listing
September 2021

Author Correction: Salvianolic acid A prevented cerebrovascular endothelial injury caused by acute ischemic stroke through inhibiting the Src signaling pathway.

Acta Pharmacol Sin 2021 Jun;42(6):1014

Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

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http://dx.doi.org/10.1038/s41401-020-00607-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149382PMC
June 2021

A Novel Strategy for Decoding and Validating the Combination Principles of Huanglian Jiedu Decoction From Multi-Scale Perspective.

Front Pharmacol 2020 4;11:567088. Epub 2020 Dec 4.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Traditional Chinese medicine (TCM) formulas treat complex diseases through combined botanical drugs which follow specific compatibility rules to reduce toxicity and increase efficiency. "Jun, Chen, Zuo and Shi" is one of most used compatibility rules in the combination of botanical drugs. However, due to the deficiency of traditional research methods, the quantified theoretical basis of herbal compatibility including principles of "Jun, Chen, Zuo and Shi" are still unclear. Network pharmacology is a new strategy based on system biology and multi-disciplines, which can systematically and comprehensively observe the intervention of drugs on disease networks, and is especially suitable for the research of TCM in the treatment of complex diseases. In this study, we systematically decoded the "Jun, Chen, Zuo and Shi" rules of Huanglian Jiedu Decoction (HJD) in the treatment of diseases for the first time. This interpretation method considered three levels of data. The data in the first level mainly depicts the characteristics of each component in single botanical drug of HJD, include the physical and chemical properties of component, ADME properties and functional enrichment analysis of component targets. The second level data is the characterization of component-target-protein (C-T-P) network in the whole protein-protein interaction (PPI) network, mainly include the characterization of degree and key communities in C-T-P network. The third level data is the characterization of intervention propagation properties of HJD in the treatment of different complex diseases, mainly include target coverage of pathogenic genes and propagation coefficient of intervention effect between target proteins and pathogenic genes. Finally, our method was validated by metabolic data, which could be used to detect the components absorbed into blood. This research shows the scientific basis of "Jun-Chen-Zuo-Shi" from a multi-dimensional perspective, and provides a good methodological reference for the subsequent interpretation of key components and speculation mechanism of the formula.
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http://dx.doi.org/10.3389/fphar.2020.567088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789881PMC
December 2020

Hypoglycemic activity of puerarin through modulation of oxidative stress and mitochondrial function via AMPK.

Chin J Nat Med 2020 Nov;18(11):818-826

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China. Electronic address:

Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known about its direct effects on diabetes. The aim of our study is to investigate its antidiabetic effect in vivo and in vitro, and explore the underlying mechanism. We used type I diabetic mice induced by streptozotocin to observe the effects of puerarin on glucose metabolism. In addition, oxidative stress and hepatic mitochondrial respiratory activity were evaluated in type I diabetic mice. In vitro, glucose consumption in HepG2 cells was assayed along with the qPCR detection of glucogenesis genes expression. Moreover, ATP production was examined and phosphorylation of AMPK was determined using Western blot. Finally, the molecular docking was performed to predict the potential interaction of puerarin with AMPK utilizing program LibDock of Discovery Studio 2018 software. The results showed that puerarin improved HepG2 glucose consumption and upregulated the glucogenesis related genes expression. Also, puerarin lowered fasting and fed blood glucose with improvement of glucose tolerance in type I diabetic mice. Further mechanism investigation showed that puerarin suppressed oxidative stress and improved hepatic mitochondrial respiratory function with enhancing ATP production and activating phosphorylation of AMPK. Docking study showed that puerarin interacted with AMPK activate site and enhancing phosphorylation. Taken together, these findings indicated that puerarin exhibited the hypoglycemic effect through attenuating oxidative stress and improving mitochondrial function via AMPK regulation, which may serve as a potential therapeutic option for diabetes treatment.
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http://dx.doi.org/10.1016/S1875-5364(20)60022-XDOI Listing
November 2020

Recent developments in natural products for white adipose tissue browning.

Chin J Nat Med 2020 Nov;18(11):803-817

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China. Electronic address:

Excess accumulation of white adipose tissue (WAT) causes obesity which is an imbalance between energy intake and energy expenditure. Obesity is a serious concern because it has been the leading causes of death worldwide, including diabetes, stroke, heart disease and cancer. Therefore, uncovering the mechanism of obesity and discovering anti-obesity drugs are crucial to prevent obesity and its complications. Browning, inducing white adipose tissue to brown or beige (brite) fat which is brown-like fat emerging in WAT, becomes an appealing therapeutic strategy for obesity and metabolic disorders. Due to lack of efficacy or intolerable side-effects, the clinical trials that promote brown adipose tissue (BAT) thermogenesis and browning of WAT have not been successful in humans. Obviously, more specific means still need to be developed to activate browning of white adipose tissue. In this review, we summarized seven kinds of natural products (alkaloids, flavonoids, terpenoids, long chain fatty acids, phenolic acids, else and extract) promoting white adipose tissue browning which can ameliorate the metabolic disorders, including obesity, dislipidemia, insulin resistance and diabetes. Since natural products are important drug sources and the browning property plays a significant role in not only obesity treatment but also in type 2 diabetes (T2DM) improvement, natural products of inducing browning may be an irreplaceable drug discovery orientation for obesity, diabetes and even other metabolic disorders.
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http://dx.doi.org/10.1016/S1875-5364(20)60021-8DOI Listing
November 2020

Salvianolic acid A prevented cerebrovascular endothelial injury caused by acute ischemic stroke through inhibiting the Src signaling pathway.

Acta Pharmacol Sin 2021 Mar 10;42(3):370-381. Epub 2020 Dec 10.

Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Stroke is an acute cerebrovascular disease caused by ruptured or blocked blood vessels. For the prevention of ischemic stroke, the coagulation state of blood and cerebrovascular protection should be considered. Our previous study has shown that salvianolic acid A (SAA), which is a water-soluble component from the root of Salvia Miltiorrhiza Bge, prevents thrombosis with a mild inhibitory effect on platelet aggregation. In this study we investigated the preventive effects of SAA on cerebrovascular endothelial injury caused by ischemia in vivo and oxygen-glucose deprivation (OGD) in vitro, and explored the underlying mechanisms. An autologous thrombus stroke model was established in SD rats by electrocoagulation. SAA (10 mg/kg) was orally administered twice a day for 5 days before the operation. The rats were sacrificed at 24 h after the operation. We showed that pretreatment with SAA significantly improved the neurological deficits, intracerebral hemorrhage, BBB disruption, and vascular endothelial dysfunction as compared with model group. In human brain microvascular endothelial cells (HBMECs), pretreatment with SAA (10 μM) significantly inhibited OGD-induced cell viability reduction and degradation of tight junction proteins (ZO-1, occludin, claudin-5). Furthermore, we found that SAA inhibited the upregulation of Src signaling pathway in vivo and vitro and reversed the increased expression of matrix metalloproteinases (MMPs) after ischemic stroke. In conclusion, our results suggest that SAA protects cerebrovascular endothelial cells against ischemia and OGD injury via suppressing Src signaling pathway. These findings show that pretreatment with SAA is a potential therapeutic strategy for the prevention of ischemic stroke.
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http://dx.doi.org/10.1038/s41401-020-00568-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027612PMC
March 2021

EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers.

Acta Pharmacol Sin 2021 Jul 14;42(7):1171-1179. Epub 2020 Oct 14.

The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China.

Triple-negative breast cancer (TNBC) is characterized by low expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), which is the most aggressive subtype with poor outcome among breast cancers. The underlying mechanisms of TNBC remain unclear and there is a lack of biomarkers. In this study we conducted an in silico assay and found that FOXC1 was highly expressed in ER/PR/HER2 breast cancers, which was confirmed by qRT-PCR, immunohistochemistry, and Western blot analysis. FOXC1 was more highly expressed in TNBCs than the other breast cancers. Kaplan-Meier plotter revealed that expression of FOXC1 was associated with overall survival (OS) of patients with breast cancers. Expression of FOXC1 was reversely associated with level of H3K27me3, which was methylated by EZH2. In MCF-7 and T47D cells, inhibition of EZH2 by DZNeP or GSK343 concentration- and time-dependently increased expression of FOXC1. Finally, we demonstrated that the expression of FOXC1 was associated with resistance of doxorubicin treatment of breast cancer cells. In conclusion, these results suggest that FOXC1 may be a potential biomarker or drug target for TNBCs, and that downregulation of FOXC1 could have therapeutic value in treatment of TNBCs.
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http://dx.doi.org/10.1038/s41401-020-00543-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209002PMC
July 2021

Cryptotanshinone alleviates chemotherapy-induced colitis in mice with colon cancer via regulating fecal-bacteria-related lipid metabolism.

Pharmacol Res 2021 01 4;163:105232. Epub 2020 Oct 4.

Beijing Key Laboratory of Drug Targets Identification and Research and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nongtan Street, Beijing, 100050, China. Electronic address:

Patients with colorectal cancer treated with 5-fluorouracil (5-FU) and irinotecan (CPT-11) exhibit a risk for chemotherapy-induced colitis (CIC) that may lead to fatal consequences. Cryptotanshinone (CTS) is a natural compound extracted from the root of Salvia miltiorrhiza Bunge that shows potent antitumor activities. We previously reported CTS relieved 5-FU/ CPT-11 induced colitis in tumor-free mice. In this study, we studied the effect of CTS on 5-FU/ CPT-11 induced colitis in mice with colitis associated colon cancer (CAC). The effects of CTS on CIC were evaluated by disease activity index (DAI) and histological assessment via hematoxylin-and-eosin staining. Serum lipids and lipid-metabolic enzymes were detected by commercial kits. Fecal microbial diversity was detected by 16S ribosomal RNA gene sequencing. To find the role of fecal bacteria in CAC mice with 5-FU/ CPT-11 induced colitis, pseudo-germ-free mice were established by intragastric administration of mixed antibiotics. Except for decreasing tumor number (3 ± 1 vs 6 ± 1, p < 0.05), CTS significantly alleviated DAI (1.9 ± 0.6 vs 2.6 ± 0.5, p < 0.05) and regulated serum lipids in CAC mice with 5-FU/ CPT-11induced colitis. Compared with model group, CTS significantly increased serum triglycerides (TG) (1.13 ± 0.26 mM vs 0.79 ± 0.03 mM, p < 0.05), high density lipoprotein (HDL) (3.88 ± 0.1 mM vs 3.28 ± 0.05 mM, p < 0.001) and oxidized low-density lipoprotein (oxLDL) (288.12 ± 65.92 ng/mL vs 150.72 ± 42.13 ng/mL, p < 0.05) level but decreased serum adiponectin level (1177.47 ± 179.2 pg/mL vs 1523.43 ± 91.8 pg/mL, p < 0.05). Among fecal bacteria significantly correlated with lipid metabolism, CTS significantly decreased the abundance of g__norank_f__Muribaculaceae (21.15 % ± 5.7 % vs 41.84 ± 12.0 %, p < 0.01) but increased that of g_Lactobacillus (11.13 % ± 6.6 % vs 5.7 % ± 4.6 %, p < 0.05), g__Alistipes (3.66 % ± 0.7 % vs 1.47 % ± 1,0%, p < 0.01) and g__Odoribacter (1.31 % ± 0.7 % vs 0.30 % ± 0.2 %, p < 0.01). In addition, the development of CIC and abnormal lipid metabolism were significantly prevented in pseudo-germ-free mice. Therefore, we concluded CTS alleviated 5FU/CPT-11 induced colitis in CAC mice via regulating fecal flora associated lipid metabolism.
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http://dx.doi.org/10.1016/j.phrs.2020.105232DOI Listing
January 2021

Pinocembrin Ameliorates Cognitive Impairment Induced by Vascular Dementia: Contribution of Reelin-dab1 Signaling Pathway.

Drug Des Devel Ther 2020 4;14:3577-3587. Epub 2020 Sep 4.

Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, People's Republic of China.

Background: As a substrate of apoER2, Reelin has been verified to exert neuroprotection by preventing memory impairment. Pinocembrin is the most abundant natural flavonoid found in propolis, and it has been used to exert neuroprotection, blood-brain barrier protection, anti-oxidation, and inflammation diminishing, both in vitro and in vivo. However, the roles and molecular mechanisms of pinocembrin in neurobehavioral outcomes and neuronal repair after vascular dementia are still under investigation.

Purpose: To explore the role of pinocembrin in the involvement of the Reelin-dab1 signaling pathway in improving memory impairment, both in cell culture and animals experiments.

Material And Methods: Behavioral tests were conducted on day 48 to confirm the protection of pinocembrin against cognitive impairment. Cell and molecular biology experiments demonstrated that the Reelin-dab1 pathway mediates the underlying mechanism of cognitive improvement by pinocembrin.

Results: It was showed that pinocembrin alleviated learning and memory deficits induced by vascular dementia, by inducing the expression of Reelin, apoER2, and p-dab1 in the hippocampus. The expression of Reelin and p-dab1 was both inhibited following Reelin RNA interference in SH-SY5Y prior to oxygen glucose deprivation (OGD) injury, suggesting that Reelin played a core role in pinocembrin's effect on OGD in vitro.

Conclusion: Pinocembrin improves the cognition via the Reelin-dab1 signaling pathway.
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http://dx.doi.org/10.2147/DDDT.S249176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481311PMC
July 2021

DL0410 ameliorates cognitive disorder in SAMP8 mice by promoting mitochondrial dynamics and the NMDAR-CREB-BDNF pathway.

Acta Pharmacol Sin 2021 Jul 31;42(7):1055-1068. Epub 2020 Aug 31.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Alzheimer's disease (AD) is a worldwide problem and there are no effective drugs for AD treatment. Previous studies show that DL0410 is a multi-target, anti-AD agent. In this study, we investigated the therapeutic effect of DL0410 and its action mechanism in SAMP8 mice. DL0410 (1-10 mg·kg·d) was orally administered to 8-month-old SAMP mice (SAMP8) for 8 weeks. We showed that DL0410 administration effectively ameliorated the cognitive deficits in the Morris water maze test, novel object recognition test, and nest building test. We revealed that DL0410 dose-dependently increased the expression levels of the mitochondrial proteins (PGC-1α, Mitofusin 2, OPA1, and Drp1), and subsequently ameliorated the processes of mitochondrial biosynthesis, fusion, and fission in the cortex and hippocampus of SAMP8 mice. Furthermore, DL0410 administration promoted the expression of synaptic proteins (synaptophysin and PSD95) in the brain of SAMP8 mice, and upregulated the protein phosphorylation in NMDAR-CAMKII/CAMKIV-CREB pathway responsible for the synaptic plasticity. DL0410 administration dose-dependently increased the expression of BDNF and TrkB, and the neurotrophic effect was mediated via the ERK1/2 and PI3K-AKT-GSK-3β pathways. DL0410 administration upregulated Bcl-2, increased the Bcl-2/Bax ratio and the level of caspase 3 and PARP-1, alleviating neuronal apoptosis. We proposed that the NMDAR-CREB-BDNF pathway might establish a positive feedback loop between synaptic plasticity and neurotrophy, with CREB at the center. In summary, DL0410 promotes synaptic function and neuronal survival, thus ameliorating cognitive deficits in SAMP8 mice via improved mitochondrial dynamics and increased activity of the NMDAR-CREB-BDNF pathway. DL0410 is a promising candidate to treat aging-related AD, and deserves more research and development in future.
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http://dx.doi.org/10.1038/s41401-020-00506-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209040PMC
July 2021

Integrated network pharmacology and metabolomics to dissect the combination mechanisms of Bupleurum chinense DC-Paeonia lactiflora Pall herb pair for treating depression.

J Ethnopharmacol 2021 Jan 15;264:113281. Epub 2020 Aug 15.

Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China; Shanxi Key Laboratory of Active Constituents Research and Utilization of TCM, Shanxi University, Taiyuan, China. Electronic address:

Ethnopharmacological Relevance: The compatibility of Bupleurum chinense DC (Chaihu)-Paeonia lactiflora Pall (Baishao) is one of the most accepted herb pairs in traditional Chinese medicine (TCM) prescriptions for treating depression. However, the combination mechanisms of this herb pair for anti-depression remain unclear.

Materials And Methods: In this study, the combined effect of Chaihu-Baishao was evaluated by the chronic unpredictable mild stress (CUMS) rat model. Secondly, network pharmacology was constructed to dissect the united mechanisms. Based on the results of network pharmacology analysis, plasma metabolomics based on ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was performed to discover the collaborative effect on metabolite regulation. Furthermore, the targets from network pharmacology and the metabolites from metabolomics were jointly analyzed to select crucial metabolism pathways by MetaScape. Finally, the key metabolic enzymes and metabolites were experimentally validated by ELISA.

Results: The antidepressant effect of Chaihu-Baishao herb pair was significantly better than Chaihu or Baishao in sucrose preference test (SPT), open-field test (OFT), and forced swim test (FST). In network pharmacology, herb pair played synergetic effect through regulating shared pathways, such as MAPK signaling pathway and arachidonic acid metabolism, etc. Besides, by metabolomics, the herb pair improved more metabolites (14) than a single herb (10 & 9) and has a stronger regulation effect on metabolites. Correspondingly, herb pair adjusted more metabolism pathways (5) than individual herb (4 & 4). Furthermore, the arachidonic acid metabolism was selected as crucial metabolism pathways by a joint analysis of 199 targets and 14 metabolites. The results showed that herb pair regulated arachidonic acid metabolism by synergetic reducing the level of arachidonic acid, and inhibiting the enzyme activity of prostaglandin-endoperoxide synthase 1 (PTGS1) and prostaglandin-endoperoxide synthase 2 (PTGS2).

Conclusions: This work provided an integrated strategy for revealing the combination mechanisms of Chaihu-Baishao herb pair for treating depression, and also a rational way for clarifying the composition rules of TCM.
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http://dx.doi.org/10.1016/j.jep.2020.113281DOI Listing
January 2021

Purity and Uncertainty Study of CRM Betulin by DSC.

Nat Prod Bioprospect 2020 Oct 18;10(5):317-324. Epub 2020 Aug 18.

Beijing City Key Laboratory of Drug Target and Screening Research, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.

Betulin (BE) can be obtained from many plants, such as those belonging Betulaceae family, and pharmacological investigations showed its notable biological properties and good potential for food and pharmaceutical development. We investigated the homogeneity, stability, purity, and uncertainty of a newly certified reference material (CRM) of BE. The certified purity value for the CRM of BE was 99.56% with an extended uncertainty of 0.07% (k = 2, P = 0.95), as determined by differential scanning calorimetry (DSC). In this study, DSC was used for the first time for purity determination of BE. Given its high accuracy, precision, and reproducibility, DSC can be used as an alternative technique for purity determination of CRMs in the pharmaceutical and food industry.
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http://dx.doi.org/10.1007/s13659-020-00261-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520392PMC
October 2020

Uncovering the Complexity Mechanism of Different Formulas Treatment for Rheumatoid Arthritis Based on a Novel Network Pharmacology Model.

Front Pharmacol 2020 10;11:1035. Epub 2020 Jul 10.

Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Hong Kong, Hong Kong.

Traditional Chinese medicine (TCM) with the characteristics of "multi-component-multi-target-multi-pathway" has obvious advantages in the prevention and treatment of complex diseases, especially in the aspects of "treating the same disease with different treatments". However, there are still some problems such as unclear substance basis and molecular mechanism of the effectiveness of formula. Network pharmacology is a new strategy based on system biology and poly-pharmacology, which could observe the intervention of drugs on disease networks at systematical and comprehensive level, and especially suitable for study of complex TCM systems. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, causing articular and extra articular dysfunctions among patients, it could lead to irreversible joint damage or disability if left untreated. TCM formulas, Danggui-Sini-decoction (DSD), Guizhi-Fuzi-decoction (GFD), and Huangqi-Guizhi-Wuwu-Decoction (HGWD), et al., have been found successful in controlling RA in clinical applications. Here, a network pharmacology-based approach was established. With this model, key gene network motif with significant (KNMS) of three formulas were predicted, and the molecular mechanism of different formula in the treatment of rheumatoid arthritis (RA) was inferred based on these KNMSs. The results show that the KNMSs predicted by the model kept a high consistency with the corresponding C-T network in coverage of RA pathogenic genes, coverage of functional pathways and cumulative contribution of key nodes, which confirmed the reliability and accuracy of our proposed KNMS prediction strategy. All validated KNMSs of each RA therapy-related formula were employed to decode the mechanisms of different formulas treat the same disease. Finally, the key components in KNMSs of each formula were evaluated by experiments. Our proposed KNMS prediction and validation strategy provides methodological reference for interpreting the optimization of core components group and inference of molecular mechanism of formula in the treatment of complex diseases in TCM.
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http://dx.doi.org/10.3389/fphar.2020.01035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365894PMC
July 2020

[Study on difference of chemical compositions of Guilingji before and after alchemy based on mass spectrometry and multivariate statistical analysis].

Zhongguo Zhong Yao Za Zhi 2020 Jun;45(12):2872-2880

Modern Research Center for Traditional Chinese Medicine, Shanxi University Taiyuan 030006, China Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050, China.

UPLC-Q-Orbitrap MS/MS and ICP-MS coupled with multivariate statistical analysis was employed to explore the differences in chemical compositions of Guilingji(GLJ) before and after alchemy.The changes in organic chemical compositions and inorganic elements were observed and 39 differential organic compositions were found in GLJ after alchemy, 24 compounds of which were identified. The differential compositions of GLJ included violet ketones, chalcones, amides, and fatty acids whose contents were increased after alchemy, as well as flavones, isoflavones, dihydroflavones, flavonoid glycosides, and coumarins whose content were decreased after alchemy. This study showed 6 inorganic elements filtered out as markers for distinguishing GLJ before and after alchemy, including B, Si, Mg, K, Cr, and Ni.The contents of Mg, K, Cr and Ni were increased while the contents of B and Si were decreased after alchemy.The difference of the contents after alchemy changed the cold and hot properties of the compound, showing the decrease of dryness, and the hot property was changed to warm and neutral properties; in addition, the membrane permeability and absorption of the compound compositions were improved. In this study, we preliminarily investigated the changes of chemical compositions in GLJ before and after alchemy as well as the effects of alchemy on physical and chemical properties and cold-heat nature of GLJ, laying a foundation for further clarifying the scientific connotation of alchemy process.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200328.311DOI Listing
June 2020

Potential quality evaluation approach for the absolute growth years' wild and transplanted Astragali Radix based on anti-heart failure efficacy.

Chin J Nat Med 2020 Jun;18(6):460-471

Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering Ministry, Shanxi University, Taiyuan 030006, China. Electronic address:

The quality of Astragali Radix (AR) was closely related to the growth period. However, the current commodity grades of AR were only divided by diameter but not directly related to the growth period, which leads to the contradiction between the grade standard and the quality evaluation index. Therefore, solving this problem will be the key for the quality evaluation of AR. The present study established a potential quality evaluation approach for the absolute growth years' wild Astragali Radix (WAR) and transplanted Astragali Radix (TAR) based on the chemical components and anti-heart failure efficacy through adopting a bare-handed sections approach to rapidly identify the growth years of WAR. In this study, the absolute growth years of WAR were obtained by identifying the growth rings of 1-6 growth years root through the methods. The contents of flavonoids and saponins in 2-6 growth years' WAR were determined by HPLC-UV-ELSD. The contents of 12 chemical components and the anti-fatigue failure effects of WAR (4-year-old) and TAR were compared on rat models of heart failure induced by doxorubicin. Meanwhile, NMR-based untargeted metabolomics studies were performed to investigate the regulative effects of WAR and TAR. The result shows that the numbers of growth rings were consistent with the actual growth periods of AR. The HPLC-UV-ELSD determination indicated that the content of total flavonoids in WAR was significantly higher than that in TAR. Pharmacodynamics analysis revealed that the effects of WAR on cardiac function parameters (EF, FS and LVIDs), contents of serum CK and BNP were superior to those of TAR. 13 metabolites of heart were identified that had a higher rate of change in WAR group than TAR. Overall, a rapid identification method for the growth years of WAR was established, and the fact that WAR were significantly better than TAR in the heart failure rats was first proved in the paper. This study provided a scientific basis for establishing a novel commodity specification and grade of AR for clinical rational drug use.
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http://dx.doi.org/10.1016/S1875-5364(20)30053-4DOI Listing
June 2020

Avasimibe exerts anticancer effects on human glioblastoma cells via inducing cell apoptosis and cell cycle arrest.

Acta Pharmacol Sin 2021 Jan 25;42(1):97-107. Epub 2020 May 25.

The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China.

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, but there is no effective drug available for GBM. Avasimibe is a potent inhibitor of acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1), which was used to treat atherosclerosis. Experimental evidence and bioinformatics have shown that avasimibe has anticancer activity. In this study we investigated the anticancer effects of avasimibe on human glioblastoma cells and the underlying mechanisms. Our results showed that avasimibe dose-dependently inhibited the proliferation of U251 and U87 human glioblastoma cells with IC values of 20.29 and 28.27 μM, respectively, at 48 h. Avasimibe (7.5, 15, 30 μM) decreased the DNA synthesis, and inhibited the colony formation of the tumor cells. Treatment of avasimibe also dose-dependently increased the apoptotic rate of tumor cells, decreased the mitochondrial membrane potential, induced the activity of caspase-3/7, and increased the protein expression of cleaved caspase-9, cleaved PARP and Bax in U251 and U87 cells. RNA-sequencing analyses revealed that avasimibe suppressed the expression of CDK2, cyclin E1, CDK4, cyclin D, CDK1, cyclin B1, Aurora A, and PLK1, while induced the expression of p53, p21, p27, and GADD45A, which was validated by Western blot analysis. These results demonstrated that avasimibe induced mitochondria-dependent apoptosis in glioblastoma cells, which was associated with arresting the cell cycle at G0/G1 phase and G2/M phase by regulating the p53/p21 pathway, p53/GADD45A and Aurora A/PLK1 signaling pathways. In U87 xenograft nude mice model, administration of avasimibe (15, 30 mg·kg·d, ip, for 18 days) dose-dependently inhibit the tumor growth. Taken together, our results demonstrated that avasimibe might be a promising chemotherapy drug in the treatment of GBM.
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http://dx.doi.org/10.1038/s41401-020-0404-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921416PMC
January 2021

Dihydrotanshinone attenuates chemotherapy-induced intestinal mucositis and alters fecal microbiota in mice.

Biomed Pharmacother 2020 Aug 22;128:110262. Epub 2020 May 22.

Beijing Key Laboratory of Drug Targets Research and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nongtan Street, Beijing, 100050, China. Electronic address:

Chemotherapy-induced intestinal mucositis (CIM) is a principal reason for reduced living quality of patients undergoing chemotherapy. Growing evidence showed gut microbiota played an important role in the development of intestinal mucositis. Dihydrotanshinone I (DHTS) is a liposoluble extract of Salvia miltiorrhiza Bunge with many bioactivities. Here we investigated the effect of DHTS on intestinal mucositis induced by 5-fluorouracil and irinotecan in mice. We detected the degree of intestinal mucosal damage and inflammatory response in CIM mice with or without DHTS administration. The body weight and disease activity index (DAI) of mice were monitored each day. H&E staining was used to evaluate pathological damage. The contents of interleukin 6 (IL-6), tumor necrosis factor (TNFα), diacylglycerol (DAO) and triglyceride (TG) in serum were determined by commercial kits. We also investigated the changes of fecal microbiota by 16S rRNA high-throughput sequencing. Spearman correlation analysis was used to evaluate the correlation between fecal microbiota and inflammatory factors. Tax4Funwas performed to infer the potential function of the microbial community. Results showed DHTS significantly reduced DAI, intestinal mucosal damage and inflammatory response in CIM mice by decreasing serum IL-6 and TNFα. In addition, there is an intense correlation between fecal microbiota and inflammatory factors. DHTS efficiently reversed disordered fecal microflora close to normal and increased the abundance of g__Akkermansia. DHTS also enriched bacterial species which promote butyric acid metabolism or negatively correlated with inflammatory factors. Besides, species enriched by DHTS in fecal microbiota were probably involved in glutamine production and ammonia oxidation. In conclusion, our study provides evidence that DHTS effectively attenuates CIM induced by 5-fluorouracil and irinotecan in mice. Regulation of the composition and function of fecal microbiota probably plays a critical role in the therapeutic effect of DHTS in CIM mice.
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http://dx.doi.org/10.1016/j.biopha.2020.110262DOI Listing
August 2020
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