Publications by authors named "Pengfei Tu"

250 Publications

An integrated biomimetic array chip for establishment of collagen-based 3D primary human hepatocyte model for prediction of clinical drug-induced liver injury.

Biotechnol Bioeng 2021 Sep 3. Epub 2021 Sep 3.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Drug-induced liver injury (DILI) is a leading cause of therapy failure in the clinic and also contributes much to acute liver failure cases. Investigations of predictive sensitivity in animal models have limitations due to interspecies differences. Previously reported in vitro models of liver injury based on primary human hepatocytes (PHHs) cannot meet the requirements of high physiological fidelity, low cost, simple operation, and high throughput with improved sensitivity. Herein, we developed an integrated biomimetic array chip (iBAC) for establishing extracellular matrix (ECM)-based models. A collagen-based 3D PHH model was constructed on the iBAC as a case for the prediction of clinical DILI at throughput. The iBAC has a three-layer structure with a core component of 3D implanting holes. At an initial cell seeding numbers of 5000-10,000, the collagen-based 3D PHH model was optimized with improved and stabilized liver functionality, including cell viability, albumin, and urea production. Moreover, basal activities of most metabolic enzymes on the iBAC were maintained for at least 12 days. Next, a small-scale hepatotoxicity screening indicated that the 3D PHH model on the iBAC was more sensitive for predicting hepatotoxicity than the 2D PHH model on the plate. Finally, a large-scale screening of liver toxicity using 122 clinical drugs further demonstrated that the collagen-based 3D PHH model on the iBAC had superior predictive sensitivity compared to all previously reported in vitro models. These results indicated the importance of 3D collagen for liver physiological functionality and hepatotoxicity prediction. We anticipant it being a promising tool for risk assessment of drug-induced hepatotoxicity with a widespread acceptance in drug industry.
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http://dx.doi.org/10.1002/bit.27931DOI Listing
September 2021

Online pressurized liquid extraction enables directly chemical analysis of herbal medicines: A mini review.

J Pharm Biomed Anal 2021 Aug 19;205:114332. Epub 2021 Aug 19.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China. Electronic address:

Extraction is responsible for transferring components from solid materials into solvent. Tedious extraction procedures are usually involved in liquid chromatography-based chemical analysis of herbal medicines (HMs), resulting in extensive consumptions of organic solvents, time, energy, and materials, as well as the significant chemical degradation risks for those labile compounds. Fortunately, an emerging online pressurized liquid extraction (OLE, also known as online liquid extraction) technique has been developed for the achievement of directly chemical analysis for solid matrices in recent years, and in a short period, this versatile technique has been widely applied for the chemical analysis of HMs. In the present mini-review, we aim to briefly summarize the principles, the instrumentation, along with the application progress of this robust and flexible extraction technique in the latest six years, and the emerging challenges and future prospects are discussed as well. Special attention is paid onto the hyphenation of the versatile OLE module with LC-MS instrument. The described information is expected to introduce a promising OLE approach and to provide the guidance for the achievement of directly chemical analysis of, but not limited to, HMs.
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http://dx.doi.org/10.1016/j.jpba.2021.114332DOI Listing
August 2021

Comparison of the preventive effects of Murraya exotica and Murraya paniculata on alcohol-induced gastric lesions by pharmacodynamics and metabolomics.

J Ethnopharmacol 2021 Aug 24;281:114567. Epub 2021 Aug 24.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address:

Ethnopharmacological Relevance: Multi-source phenomenon is very common for traditional Chinese medicine (TCM). Both Murraya exotica L. (ME) and Murraya paniculata (L.) Jack (MP) are used as the source plants of Murrayae Folium et Cacumen (MFC), a traditional Chinese medicine recorded in Chinese Pharmacopoeia for promoting qi and relieving pain, mainly for the treatment of stomach pain, rheumatism and arthralgia. However, up to now, there has been no comparative study of these two plants on their efficacies and mechanisms, thus, further research is needed to evaluate their similarity and difference in order to judge the reasonability for their common usage.

Aim Of The Study: This study aims to compare the effects and potential mechanisms of ME and MP, the two source plants of MFC on gastric lesions in rats by pharmacodynamics and metabolomics.

Materials And Methods: A rat model of gastric lesions induced by 70% aqueous ethanol and 150 mmol/L HCl was established and adopted to evaluate the gastric protective effects of ME and MP by analysis of the lesion index, histopathological changes (observed by H&E staining and TUNEL staining) and cytokine levels (IL-1β, IL-6, TNF-α, MTL, and GAS). The potential mechanisms were investigated by LC-MS metabolomic analysis of the rat plasma.

Results: ME and MP showed the similar effects on improving the lesions of rat stomachs and reducing the cytokine levels related to inflammation and digestion of rats. The metabolomics results showed that the metabolism of rats with gastric lesions was abnormal mainly in lipid metabolism, energy metabolism, and amino acid metabolism. ME and MP demonstrated a similar metabolic modulation for gastric lesions by acting on the similar pathways and metabolites. Also, PLA2 pathway was proved as an important pathway for ME and MP modulation of glycerophospholipid metabolism in gastric lesions.

Conclusions: Our results proved that it is feasible and reasonable to use both of ME and MP as the source plants of MFC, at least for the treatment of gastric lesions, due to their similar pharmacodynamics and metabolic modulation ability. Moreover, the combination of pharmacodynamics and metabolomics is an efficient means for multi-source TCM study.
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http://dx.doi.org/10.1016/j.jep.2021.114567DOI Listing
August 2021

Therapeutic importance of Zishen Yutai Pill on the female reproductive health: A review.

J Ethnopharmacol 2021 Aug 24;281:114523. Epub 2021 Aug 24.

Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshidong Road, Licheng District, Jinan, 250103, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 Jingshidong Road, Licheng District, Jinan, 250103, China. Electronic address:

Ethnopharmacological Relevance: Zishen Yutai Pill (ZYP) is a widely used Traditional Chinese Medicine in Assisted Reproductive Technology (ART) medications, particularly in China. ZYP has a potential therapeutic role in human reproductive health, including in vitro fertilization embryo transfer and various reproductive disorders. The National Essential Medicine List of China has recently included the ZYP in Obstetrics and Gynecology medicine due to its significance in treating miscarriage and fertility associated disorders. Various clinical studies have demonstrated the importance of ZYP in improving the fertility and pregnancy rate. However, the pharmacological and toxicological actions of ZYP on reproductive health has been scantly reported.

Aim Of The Review: This review aims to emphasize the potential therapeutic effect of ZYP in ART and highlight its clinical significance in treating various reproductive disorders linked with hormonal balance, ovarian follicle development, menstrual cycle, uterine function and pregnancy. Additional insights on the safety evaluation of ZYP were elucidated by exploring an array of published experimental studies in various animal models with its molecular mechanism of action.

Materials And Methods: The literature review was conducted across the databases such as PubMed, ScienceDirect, Google Scholar, China Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang Database, International Clinical Trials Registry Platform and Cochrane Central Register of Controlled Trials with no time limit applied. The search terms used in this review include, 'Zishen Yutai Pills' and/or 'reproduction', 'assisted reproductive techniques', 'pregnancy', 'threatened abortion', 'miscarriage', 'fertility', 'infertility', 'disorders', 'women health', 'toxicity', and 'adverse effects'.

Results: ZYP is a combination of fifteen traditional medicines and each of its components has various biological functions in humans. ZYP has improved the fertility and pregnancy rate through in vitro fertilization-embryo transfer. Further, various clinical studies have revealed that ZYP showed the curative effect for miscarriage, recurrent spontaneous abortion, menstrual disorder, luteal dysfunction, diminished ovarian reserve, polycystic ovary syndrome and premature ovarian insufficiency. The intervention of ZYP has multiple roles in reproductive functions such as regulation of ovulation, follicle development, menstrual flow, hormonal balance and endometrial thickness. The reproductive and toxicological reports in various animal models have highlighted the efficacy and safety of ZYP on the reproductive functions.

Conclusion: Nowadays, many problems are associated with maternal health, fertility and reproduction, due to the various physiological and environmental factors. The intervention of ART provides hope to infertile patients. Overall, this review provides insights on the therapeutic importance of ZYP in ART medications and treating various reproductive disorders.
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http://dx.doi.org/10.1016/j.jep.2021.114523DOI Listing
August 2021

Pharmacologically targeting molecular motor promotes mitochondrial fission for anti-cancer.

Acta Pharm Sin B 2021 Jul 21;11(7):1853-1866. Epub 2021 Jan 21.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells. Mitochondrial dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton proteins. Thus, targeting myosin-actin molecular motor is considered as a promising strategy for anti-cancer. In this study, we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics pharmacologically targeting molecular motor. Here, we found J13 could directly target myosin-9 (MYH9)-actin molecular motor to promote mitochondrial fission progression, and markedly inhibited cancer cells survival, proliferation and migration. Mechanism study revealed that J13 impaired MYH9-actin interaction to inactivate molecular motor, and caused a cytoskeleton-dependent mitochondrial dynamics imbalance. Moreover, stable isotope labeling with amino acids in cell culture (SILAC) technology-coupled with pulldown analysis identified HSPA9 as a crucial adaptor protein connecting MYH9-actin molecular motor to mitochondrial fission. Taken together, we reported the first natural small-molecule directly targeting MYH9-actin molecular motor for anti-cancer translational research. Besides, our study also proved the conceptual practicability of pharmacologically disrupting mitochondrial fission/fusion dynamics in human cancer therapy.
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http://dx.doi.org/10.1016/j.apsb.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343112PMC
July 2021

Direct infusion-tandem mass spectrometry combining with data mining strategies enables rapid chemome characterization of medicinal plants: A case study of Polygala tenuifolia.

J Pharm Biomed Anal 2021 Sep 24;204:114281. Epub 2021 Jul 24.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Data-independent MS spectrum acquisition after fragmenting the precursor ion cohort with 1 Da bin, termed as MS/MS, offers an opportunity to achieve rapid chemome characterization when being coupled with direct infusion (DI). Some post-acquisition data processing strategies, such as mass defect filtering (MDF), diagnostic fragment ion filtering (DFIF), and neutral loss filtering (NLF), facilitate data extraction from massive dataset, and moreover, molecular weight (MW) imprinting allows rapid capturing those reported components. Here, DI-MS/MS was employed to acquire cubic spectral dataset, and the strategies such as MW imprinting, MDF, DFIF, and NLF, were subsequently applied to filter the structural information. The integrated pipeline was utilized for the chemome characterization of Polygala tenuifolia, a famous edible medicinal plant. To aid information filtering, an in-house chemical library was built by comprehensively collecting structural information from some available databases. A single analytical run was completed within 5 min. For MS spectrum processing, MW imprinting was firstly applied to capture the compounds in the chemical library, and "five-point" MDF frames were employed to pursue saponins, oligosaccharide esters, and xanthones. Regarding MS spectral plot, DFIF and NLF were deployed to search information-of-interest. Structural identification was accomplished by carefully correlating precursor ions and MS spectra, applying the well-defined mass cracking rules, and referring to literature information as well as available databases. A total of 109 compounds, mainly saponins (40 ones), oligosaccharide esters (29 ones), and xanthones (19 ones), were captured and structurally annotated. MS spectra were also implemented for chemome comparison between Polygala tenuifolia and several similar plants belonging to Polygala genus, resulting in the observation of significant inter- and intra-species differences. Above all, DI-MS/MS is a promising choice for high-throughput chemome profiling of, but not limited to, medicinal plants, in particular when being integrated with post-acquisition data processing strategies.
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http://dx.doi.org/10.1016/j.jpba.2021.114281DOI Listing
September 2021

Molecular cloning and biochemical characterization of a new coumarin glycosyltransferase CtUGT1 from Cistanche tubulosa.

Fitoterapia 2021 Sep 20;153:104995. Epub 2021 Jul 20.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China. Electronic address:

UDP-glycosyltransferases (UGTs) are an important and functionally diverse family of enzymes involved in secondary metabolite biosynthesis. Coumarin is one of the most common skeletons of natural products with candidate pharmacological activities. However, to date, many reported GTs from plants mainly recognized flavonoids as sugar acceptors. Only limited GTs could catalyze the glycosylation of coumarins. In this study, a new UGT was cloned from Cistanche tubulosa, a valuable traditional tonic Chinese herb, which is abundant with diverse glycosides such as phenylethanoid glycosides, lignan glycosides, and iridoid glycosides. Sequence alignment and phylogenetic analysis showed that CtUGT1 is phylogenetically distant from most of the reported flavonoid UGTs and adjacent to phenylpropanoid UGTs. Extensive in vitro enzyme assays found that although CtUGT1 was not involved in the biosynthesis of bioactive glycosides in C. tubulosa, it could catalyze the glucosylation of coumarins umbelliferone 1, esculetine 2, and hymecromone 3 in considerable yield. The glycosylated products were identified by comparison with the reference standards or NMR spectroscopy, and the results indicated that CtUGT1 can regiospecifically catalyze the glucosylation of hydroxyl coumarins at the C7-OH position. The key residues that determined CtUGT1's activity were further discussed based on homology modeling and molecular docking analyses. Combined with site-directed mutagenesis results, it was found that H19 played an irreplaceable role as the crucial catalysis basis. CtUGT1 could be used in the enzymatic preparation of bioactive coumarin glycosides.
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http://dx.doi.org/10.1016/j.fitote.2021.104995DOI Listing
September 2021

Pharmacokinetics/pharmacometabolomics-pharmacodynamics reveals the synergistic mechanism of a multicomponent herbal formula, Baoyuan decoction against cardiac hypertrophy.

Biomed Pharmacother 2021 Jul 7;139:111665. Epub 2021 May 7.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People's Republic of China. Electronic address:

Multicomponent herbal formulas (MCHFs) have earned a wide reputation for their definite efficacy in preventing or treating chronic complex diseases. However, holistic elucidation of the causal relationship between the bioavailable ingredients of MCHFs and their multitarget interactions is very challenging. To solve this problem, pharmacokinetics/pharmacometabolomics-pharmacodynamics (PK/PM-PD) combined with a multivariate biological correlation-network strategy was developed and applied to a classic MCHF, Baoyuan decoction (BYD), to clarify its active components and synergistic mechanism against cardiac hypertrophy (CH). First, multiple plasma metabolic biomarkers for β-adrenergic agonist-induced CH rats were identified by using untargeted metabolomic profiling, and then, these CH-associated endogenous metabolites and the absorbed BYD-compounds in plasma at different treatment stages after oral administration of BYD were analyzed by using targeted PK and PM. Second, the dynamic relationship of BYD-related compounds and CH-associated endogenous metabolites and signaling pathways was built by using multivariate and bioinformatic correlation analysis. Finally, metabolic-related PD indicators were predicted and further verified by biological tests. The results demonstrated that the bioavailable BYD-compounds, such as saponins and flavonoids, presented differentiated and distinctive metabolic features and showed positive or negative correlations with various CH-altered metabolites and PD-indicators related to gut microbiota metabolism, amino acid metabolism, lipid metabolism, energy homeostasis, and oxidative stress at different treatment stages. This study provides a novel strategy for investigating the dynamic interaction between BYD and the biosystem, providing unique insight for disclosing the active components and synergistic mechanisms of BYD against CH, which also supplies a reference for other MCHF related research.
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http://dx.doi.org/10.1016/j.biopha.2021.111665DOI Listing
July 2021

: A new host for .

Heliyon 2021 Jun 19;7(6):e07368. Epub 2021 Jun 19.

State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.

has been historically used in traditional Chinese medicine for supplementing kidney (yang) function, benefiting blood and essence, and moistening intestines in order to pass stool. Its host, , is an important pioneer plant used for windbreaks and sand dune fixation, which are strategies used for the control desertification. For a long time, it has been considered that can only parasitize . In this study, morphological identification, gene barcoding identification and inoculation experiment were carried out, we finally found that can also parasitize is a species of Chenopodiaceae with a wide range of adaptability. Compared with , it has more biomass and a wider range of ecological adaptability, making it more suitable for the industrial production of . In addition, we also found that the concentration of active components was higher in parasitized on than in those parasitized on ; this finding further suggests that the application of on a larger scale warrants further exploration.
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http://dx.doi.org/10.1016/j.heliyon.2021.e07368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246398PMC
June 2021

[Chemome profiling of Pien-Tze-Huang by online pressurized liquid extraction-ultra-high performance liquid chromatography-ion trap-time-of-flight mass spectrometry].

Se Pu 2021 May;39(5):478-487

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.

Pien-Tze-Huang is one of the most famous traditional Chinese medicine prescriptions and consists of several precious medicinal materials, such as Notoginseng Radix et Rhizoma, Bovis Calculus, Snake Gall, and Moschus. However, its formula has not been completely revealed. It is mainly applied for the treatment of acute and chronic viral hepatitis, carbuncle, and boils caused by blood stasis, unknown swelling, bruises, and various inflammation disorders. The chemical composition of Pien-Tze-Huang is extremely complicated. Thus far, extensive attention has been paid to the principal chemical families in Pien-Tze-Huang, such as ginsenosides, bile acids, and muscone derivatives. Comprehensive chemical profiling, although of immense importance for systematic quality control, has not been achieved. Therefore, we configured a platform, namely online pressurized liquid extraction-ultra-high-performance liquid chromatography-ion trap-time-of-flight mass spectrometry (online PLE-UHPLC-IT-TOF-MS), to characterize the chemical profile of Pien-Tze-Huang in detail as well as to conduct source attribution, aiming to clarify the chemome of Pien-Tze-Huang and to provide a reliable method for quality assessment. A sub-microgram amount of Pien-Tze-Huang powder (0.3 mg) was placed in a hollow guard column, which was subsequently filled with clear silica gel. Filter membranes were used to seal the extraction vessel. The vessel was then placed in an adapted guard column holder and maintained in a thermal column oven (70 ℃). Metal tubing was used to connect the outlet of the guard column holder to the mass spectrometer. The extraction phase was maintained for 3 min by employing 0.1%(v/v) formic acid aqueous solution as the extraction solvent with a flow rate of 0.2 mL/min. Moreover, a six-port two-position electronic valve was introduced to automatically switch the system from extraction to elution phases. Within the elution phase, 0.1%(v/v) formic acid aqueous solution and acetonitrile composed the mobile phase, and the extracts were eluted with a gradient program. Because of the elevated temperature and pressure, the physical and chemical properties of water, especially polarity and solubility, were modified. Therefore, warm water could be an eligible green solvent to achieve wide polarity-spanned extraction. In addition, IT-TOF-MS was employed to acquire tandem mass spectrometry information. The mass fragmentation pathways of saponins and bile acids were carefully studied. Finally, according to authentic compounds, mass fragmentation pathways, reference information in the literature, and accessible databanks, a total of 73 signals were observed from Pien-Tze-Huang, of which 71 components were tentatively identified and assigned. Among them, 36 were from Notoginseng Radix et Rhizoma, 15 from Snake Gall, and 9 from Bovis Calculus, while the occurrences of the other 11 components were synergistically contributed by both Bovis Calculus and Snake Gall, through retrieving the in-house chemical database that was built by considering all accessible chemical information from Notoginseng Radix et Rhizoma, Bovis Calculus, Snake Gall, and Moschus. The other two compounds were assigned as unknown compounds. However, none of the components were assigned to Moschus because they mainly contained hydrophobic compounds, such as cycloketones, cholesterol, and sterols, among others, and it was difficult to detect them with the current measurement program. The extraction efficiency of online PLE was assessed by comparing it with the efficiency obtained from ultrasonication at the same time. According to base peak ion current chromatograms (BPCs) and mass spectrometry information, the efficiency of online PLE was greater than that of ultrasonic extraction, even through direct analysis. Online PLE-UHPLC-IT-TOF-MS is not only a tool fit for the concept of green analytical chemistry, but also a reliable analytical pipeline for the direct characterisation of other complicated matrixes. Above all, this study clarified the chemome of Pien-Tze-Huang and provided meaningful information for the quality control of this famous TCM prescription.
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http://dx.doi.org/10.3724/SP.J.1123.2020.10011DOI Listing
May 2021

[Production of curcumin by engineered Escherichia coli].

Sheng Wu Gong Cheng Xue Bao 2021 Jun;37(6):2077-2084

Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.

Curcumin is exclusively isolated from Zingiberaceae plants with a broad spectrum of bioactivities. In the present study, we used the diketide-CoA synthase (DCS) and curcumin synthase (CURS) genes to construct a non-natural fusion gene encoding diketide-CoA synthase::curcumin synthase (DCS::CURS). This fusion protein, together with the acetyl coenzyme A carboxylase (ACC) and the 4-coumarate coenzyme A ligase (4CL), were introduced into Escherichia coli for the production of curcumin from ferulic acid. The process is divided into two stages, the growth stage using LB medium and the fermentation stage using the modified M9 medium. The yield of curcumin reached 386.8 mg/L by optimizing the induction of protein expression in the growth stage, and optimizing the inoculum volume, medium composition and fermentation time in the fermentation stage, as well as the addition of macroporous resin AB-8 into the second medium to attenuate the toxicity of the end product. The exploitation of the non-natural fusion protein DCS::CURS for the production of curcumin provides a new alternative to further promoting the production of curcumin and the related analogues.
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http://dx.doi.org/10.13345/j.cjb.200825DOI Listing
June 2021

Baoyuan decoction (BYD) attenuates cardiac hypertrophy through ANKRD1-ERK/GATA4 pathway in heart failure after acute myocardial infarction.

Phytomedicine 2021 Aug 1;89:153617. Epub 2021 Jun 1.

Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address:

Background: The pathological cardiac functions of ankyrin repeat domain 1 (ANKRD1) in left ventricle can directly aggravate cardiac hypertrophy (CH) and fibrosis through the activation of extracellular signal-regulated kinase (ERK)/ transcription factor GATA binding protein 4 (GATA4) pathway, and subsequently contribute to heart failure (HF). Baoyuan Decoction (BYD), which is a famous classic Chinese medicinal formulation, has shown impressive cardioprotective effects clinically and experimentally. However, the knowledge is still limited in its underlying mechanisms against HF.

Purpose: To explore whether BYD plays a protective role against HF by attenuating CH via the ANKRD1-ERK/GATA4 pathway.

Methods: In vivo, HF rat models were prepared using left anterior descending coronary artery (LADCA) ligation. Rats in the BYD group were administered a dosage of 2.57 g/kg of BYD for 28 days, while in the positive control group rats were given 4.67 mg/kg of Fosinopril. In vitro, a hypertrophic model was constructed by stimulating H9C2 cells with 1 uM Ang II. An ANKRD1-overexpressing cell model was established through transient transfection of ANKRD1 plasmid into H9C2 cells. Subsequently, BYD intervention was performed on the cell models to further elucidate its effects and underlying mechanism.

Results: In vivo results showed that BYD significantly improved cardiac function and inhibited pathological hypertrophy and fibrosis in a rat model of HF post-acute myocardial infarction (AMI). Noticeably, label-free proteomic analysis demonstrated that BYD could reverse the CH-related biological turbulences, mainly through ANKRD1-ERK/GATA4 pathway. Further in vitro results validated that the hypertrophy was attenuated by BYD through suppression of AT1R, ANKRD1, Calpain1, p-ERK1/2 and p-GATA4. The results of in vitro model indicated that BYD could reverse the outcome of transfected over-expression of ANKRD1, including down-regulated expressions of ANKRD1, p-ERK1/2 and p-GATA4.

Conclusion: BYD ameliorates CH and improves HF through the ANKRD1-ERK/GATA4 pathway, providing a novel therapeutic option for the treatment of HF.
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http://dx.doi.org/10.1016/j.phymed.2021.153617DOI Listing
August 2021

Cephalotaxine Inhibits the Survival of Leukemia Cells by Activating Mitochondrial Apoptosis Pathway and Inhibiting Autophagy Flow.

Molecules 2021 May 18;26(10). Epub 2021 May 18.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

Cephalotaxine (CET) is a natural alkaloid with potent antileukemia effects. However, its underlying molecular mechanism has not been well understood. In this study, we verified that CET significantly inhibited the viability of various leukemia cells, including HL-60, NB4, Jurkat, K562, Raji and MOLT-4. RNA-sequencing and bioinformatics analysis revealed that CET causes mitochondrial function change. Mechanism research indicated that CET activated the mitochondrial apoptosis pathway by reducing the mitochondrial membrane potential, downregulating anti-apoptotic Bcl-2 protein and upregulating pro-apoptotic Bak protein. In addition, the autophagy signaling pathway was highly enriched by RNA-seq analysis. Then, we found that CET blocked the fluorescence colocation of MitoTracker Green and LysoTracker Red and upregulated the level of LC3-II and p62, which indicated that autophagy flow was impaired. Further results demonstrated that CET could impair lysosomal acidification and block autophagy flow. Finally, inhibiting autophagy flow could aggravate apoptosis of HL-60 cells induced by CET. In summary, this study demonstrated that CET exerted antileukemia effects through activation of the mitochondria-dependent pathway and by impairing autophagy flow. Our research provides new insights into the molecular mechanisms of CET in the treatment of leukemia.
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http://dx.doi.org/10.3390/molecules26102996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158396PMC
May 2021

Shotgun chemome characterization of Artemisia rupestris L. Using direct infusion-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jun 12;1176:122735. Epub 2021 May 12.

Key Laboratory of Ethnomedicine (Minzu University of China) Ministry of Education, School of Pharmacy, Minzu University of China, Beijing 100081, China. Electronic address:

In comparison of liquid chromatography, direct infusion is a superior choice to achieve high-throughput measurements. The specificity and selectivity of tandem mass spectrometry (MS/MS) actually result in a so-called MS separation potential when chemical characterization of herbal medicines. Here, a MS/MS program was introduced to promote DI-MS/MS to be an eligible tool for shotgun chemome characterization of Artemisia rupestris L. that is currently drawing worldwide interests because of the promising antiviral activity. After MS spectral acquisition for the crude extract, the gas phase fractionation concept enabled the precursor ion cohort sequentially entered the collision cell with a stepped unit mass window (step-size as 1 Da) to generate MS spectra, thus generating a unique property integrating the advantages of both data-dependent and data-independent acquisition manners. Even though being free of chromatographic separation, spectrometric separations were accomplished for by MS/MS program unless the components shared identical nominal molecular weights. Extensive efforts such as the correlations of MS signals with MS spectra, structural annotations of fragment ion species, information retrieval in some accessible databases, and referring to the literature data, were devoted for chemical characterization, and as a result, 44 compounds, in total, were structurally identified from 50% aqueous methanol exact of A. rupestris, including 8 caffeoyl quinic acid derivatives, 13 flavonoids, 15 monomeric and dimeric sesquiterpenoids, 4 fatty acids, 2 penylpropanoids, along with 2 other compounds. However, isomers were assigned as an isomeric mixture because their precursor ions always co-existed in a single mass window. Above all, DI-MS/MS provides an alternative tool for chemome characterization of herbal medicines, in particular when the great measurement workload for a large sample cohort, attributing to the high-throughput advantage.
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http://dx.doi.org/10.1016/j.jchromb.2021.122735DOI Listing
June 2021

Involvement of Nrf2-HO-1/JNK-Erk Signaling Pathways in Aconitine-Induced Developmental Toxicity, Oxidative Stress, and ROS-Mitochondrial Apoptosis in Zebrafish Embryos.

Front Pharmacol 2021 21;12:642480. Epub 2021 Apr 21.

Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.

Aconitine (AC), one of the bioactive diterpenoid alkaloids extracted from plants, is widely used in traditional herbal medicine to treat various diseases. Emerging evidence indicates that AC has attracted great interest for its wide cardiotoxicity and neurotoxicity. However, the toxic effects of AC on embryonic development and its underlying mechanisms remain unclear. Here, a developmental toxicity assay of AC was performed on zebrafish embryos from 4 to 96 h post fertilization (hpf), and its underlying mechanisms were discussed. AC exposure impaired the cardiac, liver, and neurodevelopment. Especially, a high dose of AC (7.27 and 8.23 μM) exposure resulted in malformations at 72 and 96 hpf, including reduced body length, curved body shape, pericardial edema, yolk retention, swim bladder and brain developmental deficiency, and degeneration of dopaminergic neurons. High-concentration AC exposure caused a deficient cardiovascular system with cardiac dysfunctions, increased heart rates at 72 and 96 hpf, and reduced locomotor behavior at 120 hpf. AC treatment significantly increased the ROS level and triggered cell apoptosis in the heart and brain regions of embryos at 96 hpf in 7.27 and 8.23 μM AC treatment zebrafish. Oxidative stress was confirmed by reduced levels of T-SOD activity associated with accumulation of lipid peroxidation in larvae. The expression levels of oxidative stress-related genes (, , , and ) and were significantly downregulated at 96 hpf. The expression pattern of JNK and mitochondrial apoptosis-related genes (, , , , and ) was significantly upregulated. Taken together, all these parameters collectively provide the first evidence of AC-induced developmental toxicity in zebrafish embryo/larvae through ROS-medicated mitochondrial apoptosis involving Nrf2/HO-1 and JNK/Erk pathways.
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http://dx.doi.org/10.3389/fphar.2021.642480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097150PMC
April 2021

Three Pairs of Enantiomeric Sesquiterpenoids from .

J Org Chem 2021 05 29;86(10):7263-7270. Epub 2021 Apr 29.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, P. R. China.

Three pairs of enantiomeric sesquiterpenoids, (∓)-syringanoid A ( and ) and (±)-pinnatanoids A ( and ) and B ( and ), that represent an unprecedented 5/4/6 tricyclic backbone and a rare 6/7 bicyclic backbone, respectively, were isolated from the peeled stems of . The structures were elucidated by extensive spectroscopic analysis, single-crystal X-ray diffraction, a modified Mosher's method, and quantum chemical calculations. A plausible biotransformation pathway for - was proposed, and their cardiomyocyte-protective and anti-inflammatory activities were evaluated.
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http://dx.doi.org/10.1021/acs.joc.1c00267DOI Listing
May 2021

Global identification of the cellular targets for a multi-molecule system by a photochemically-induced coupling reaction.

Chem Commun (Camb) 2021 Apr 19;57(28):3449-3452. Epub 2021 Mar 19.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

Current target identification strategies mainly focus on single compounds. However, no practical experimental methodologies have been developed for multi-molecule systems. Herein, we established a cellular target identification technology for a multi-molecule system by preparing 4,4'-dihydroxybenzophenone (DHBP)-bound FeO nanoparticles (NPs) with photochemically induced crosslinking capacity. DHBP-bound NPs reacted with the chemicals from the medicinal plant extract as a multi-molecule system under ultraviolet radiation by forming carbon-carbon bonds, thus generating extract-crosslinked NPs for capturing target proteins from cell lysates. The technology, which is named the Zhao-Yao (ZY) strategy, may promote the comprehensive interpretation of the pharmacological mechanism of multi-molecule systems via the global identification of cellular targets.
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http://dx.doi.org/10.1039/d1cc00392eDOI Listing
April 2021

Direct Flavonoid-Focused Chemical Comparison among Three Plants by Online Liquid Extraction-High Performance Liquid Chromatography-Tandem Mass Spectrometry.

Molecules 2021 Mar 10;26(6). Epub 2021 Mar 10.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.

It is usually a tedious task to profile the chemical composition of a given herbal medicine (HM) using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) due to the time-consuming sample preparation and laborious post-acquisition data processing procedures. Even worse, some labile compounds may face degradation risks when exposed to organic solvents for a relatively long period. As one of the most popular HMs, the promising therapeutic benefits of Epimedii Herba (Chinese name: ) are well defined; however, the chemical profile, and in particular those flavonoids that have been claimed to be responsible for the efficacy, remains largely unknown. Attempts are devoted here to achieve direct LC-MS measurement and efficient post-acquisition data processing, and chemome comparison among three original sources of Epimedii Herba, such as (Esa), (Epu), and (Eko) was employed to illustrate the strategy utility. A home-made online liquid extraction (OLE) module was introduced at the front of the analytical column to comprehensively transfer the compounds from raw materials onto the LC-MS instrument. A mass defect filtering approach was programmed to efficiently mine the massive LC-MS dataset after which a miniature database was built involving all chemical information of flavonoids from the genus to draw a pentagonal frame to rapidly capture potential quasi-molecular ions (mainly [M-H]). A total of 99 flavonoids (66 in Esa, 84 in Eko, and 66 in Epu) were captured, and structurally annotated by summarizing the mass fragmentation pathways from the mass spectrometric data of authentic compounds and an in-house data library as well. Noteworthily, neutral loss of 144 Da was firstly assigned to the neutral cleavage of rhamnosyl residues. Significant species-differences didn't occur among their chemical patterns. The current study proposed a robust strategy enabling rapid chemical profiling of, but not limited to, HMs.
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http://dx.doi.org/10.3390/molecules26061520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998785PMC
March 2021

Oleanane-type saponins and prosapogenins from Albizia julibrissin and their cytotoxic activities.

Phytochemistry 2021 May 23;185:112674. Epub 2021 Mar 23.

State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China. Electronic address:

Two undescribed oleanane-type saponins, julibrosides K-L, along with three undescribed oleanane-type prosapogenins, julibrosides M-O, were isolated from the stem bark of Albizia julibrissin Durazz. and the mild alkaline hydrolysate of the total saponin, respectively. Their structures were established by extensive analysis of 1D and 2D NMR experiments (COSY, TOCSY, HSQC, HMBC, and HSQC-TOCSY) and mass spectrometry. Furthermore, the cytotoxic activities of the isolated compounds against BGC-823, A549, HCT-116, and HepG2 cell lines were evaluated, and julibroside L showed significant cytotoxic activities against the four cancer cell lines with IC values of 5.77, 4.80, 4.26, and 4.93 μM, respectively.
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http://dx.doi.org/10.1016/j.phytochem.2021.112674DOI Listing
May 2021

Simultaneous determination of eight tryptic peptides in musk using high-performance liquid chromatography coupled with tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 May 9;1171:122624. Epub 2021 Mar 9.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China. Electronic address:

In comparison of herbal medicines, less attention has been paid onto animal medicines, partially attributing to the protein-enriched property. Particularly, it is still challenging to conduct quality evaluation for the animal medicines because of the lack of a fit-for-purpose analytical tool. Herein, an attempt was made to propose a workflow allowing the quality assessment of animal medicines by LC-MS/MS, and musk that is one of the most precious traditional Chinese medicines was employed as a representative case for utility illustration. After the extraction of protein from musk with a well-defined protocol, tryptic digestion was conducted to hydrolyze proteins into peptides, and the peptide-enriched sample was subjected to nanoLC-Orbitrap MS measurement. The tandem mass spectral dataset was retrieved in Human Swiss-Prot FASTA database, and the sequences together with the sources of 733 tryptic peptides, in total, were annotated. Because of the abundant distributions, eight peptides were chosen as the analytes for quantitative measurements, and their quantitative MS parameters, such as ion transitions and collision energies, were rapid optimized in an authentic compound-free manner using online energy-resolved MS (ER-MS). On the other side, the annotated peptides were structurally consolidated via synthesizing reference peptides. When the synthetic peptides were applied for parameter optimization with the authentic compound-dependent manner, the values were almost identical with those from online ER-MS measurements. After being validated with diverse assays, the developed method was applied for the simultaneous determination of eight peptides in 28 batches of musk samples, including captive (C1-C18) and wild ones (W1-W10). Significant differences took place for the content patterns of concerned tryptic peptides between the captive and wild musk samples. Trace distributions occurred for DVDAAYMNK in most batches. Captive samples were rich of QSLEASLAETEGR, TLLDIDNTR, and EVATNSELVQSGK, whereas wild samples were able to accumulate YLGYLEQLLR. Together, the present study provided a meaningful approach for the quality evaluation of musk, as well as other peptide-enriched animal medicines, even if the absences of authentic peptides.
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http://dx.doi.org/10.1016/j.jchromb.2021.122624DOI Listing
May 2021

NOGEA: A Network-oriented Gene Entropy Approach for Dissecting Disease Comorbidity and Drug Repositioning.

Genomics Proteomics Bioinformatics 2021 Mar 17. Epub 2021 Mar 17.

College of Life Science, Northwest University, Xi'an 710069, China; College of Life Science, Northwest A & F University, Yangling 712100, China; State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang 222001, China. Electronic address:

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes on the interactome network, which provides a new way for predicting drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.
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http://dx.doi.org/10.1016/j.gpb.2020.06.023DOI Listing
March 2021

Correction: Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity.

Signal Transduct Target Ther 2021 Mar 12;6(1):120. Epub 2021 Mar 12.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.

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http://dx.doi.org/10.1038/s41392-021-00533-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955056PMC
March 2021

Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity.

Signal Transduct Target Ther 2021 Feb 19;6(1):71. Epub 2021 Feb 19.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.

Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α' subunit (CK2α') as a direct cellular target, and genetic knockdown of CK2α' abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α' conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α'/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α' mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.
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http://dx.doi.org/10.1038/s41392-020-00447-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893052PMC
February 2021

(+/-)-Alashanoid N, Two Enantiomeric Sesquiterpenes from Syringa pinnatifolia.

Chem Biodivers 2021 Mar 12;18(3):e2001065. Epub 2021 Feb 12.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China.

Two enantiomeric humulane sesquiterpenes, namely (+)-alashanoid N (1a) and (-)-alashanoid N (1b), along with two known analogs ((2R,3R,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (2) and (2R,3S,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (3)), were described from the peeled stems of a folk Mongolian herbal medicine Syringa pinnatifolia. Their structures were characterized based on UV, IR, NMR, and HR-ESI-MS data analyses, and the absolute configurations were determined by data analysis of X-ray diffraction and quantum chemical calculations. (+/-)-Alashanoid N showed inhibition against NO production in RAW 264.7 macrophage cells with IC values of 90.1 μM and 71.7 μM, and protective effect against oxygen-glucose deprivation injury to H9c2 cells at a concentration of 20 μM and 5 μM, respectively.
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http://dx.doi.org/10.1002/cbdv.202001065DOI Listing
March 2021

Total glycosides and polysaccharides of Cistanche deserticola prevent osteoporosis by activating Wnt/β-catenin signaling pathway in SAMP6 mice.

J Ethnopharmacol 2021 May 5;271:113899. Epub 2021 Feb 5.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address:

Ethnopharmacological Relevance: Traditional Chinese medicine Cistanche deserticola Y. C. Ma has effect of "tonifying kidney and strengthening bone". However, the specific active extracts of C. deserticola and mechanisms for treatment of osteoporotic are not clear.

Aim Of The Study: We wanted to identify the effective component extracts of C. deserticola for the treatment of osteoporosis and the potential mechanisms.

Materials And Methods: Our group researched the extracts of C. deserticola with anti-osteoporotic activity, including total glycosides (TGs), polysaccharides (PSs), and oligosaccharides (OSs) in senescence accelerated mouse prone 6 (SAMP6) mice. The Goldner's Trichrome, Van Gieson's (VG), Safranin O-Fast Green staining and Von Kossa staining were performed to investigate the bone structure formation and calcium deposits. Serum was collected for detecting biochemical markers. Bone micro-architecture was detected by micro-CT. Expressions of bone morphogenetic protein-2 (BMP-2), osteocalcin (OCN), osteoprotegerin (OPG), receptor activator of nuclear factor-κ B ligand (RANKL), p-glycogen synthetase kinase-3β (p-GSK-3β), and p-β-catenin were analyzed by western blotting and immunohistochemistry.

Results: TGs and PSs ameliorated bone histopathological damages, promoted the formation of new bone, collagenous fiber, and chondrocytes, and accelerated the calcium deposits. Moreover, they remarkable altered the biomarkers of bone turnover and effectively ameliorated bone microarchitecture. The further mechanisms study showed that TGs and PSs significantly decreased the expressions of RANKL, p-β-catenin, as well as up-regulated the expression of BMP-2, OCN, OPG, and p-GSK-3β (Ser9).

Conclusion: The findings of this study suggest that TGs and PSs can promote osteoblastogenic bone formation and improve bone microstructure damage in SAMP6 mice, and their therapeutic effect on osteoporosis is via activating Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1016/j.jep.2021.113899DOI Listing
May 2021

Cistanches Herba, from an endangered species to a big brand of Chinese medicine.

Med Res Rev 2021 05 31;41(3):1539-1577. Epub 2021 Jan 31.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Cistanches Herba (CH, Chinese name: Roucongrong), is a very precious, tonic Chinese medicine. Cistanche deserticola and Cistanche tubulosa are the two commonly used species and authenticated in Chinese Pharmacopoeia. Due to the parasitic nature of Cistanche plants, the wild source was once endangered and listed in the Appendix II of Convention on International Trade in Endangered Species of Wild Fauna and Flora. However, after continuously struggling in the past decades, CH has grown up to a big brand of Chinese medicine featured with the cultivation area as 1.26 million mu, the annual output as 6000 tons, and the related industrial output value as more than 20 billion China Yuan, attributing to large-scale cultivation and in-depth phytochemical and pharmacological investigations. Noteworthily, great achievements have reached concerning the research and development of relevant products, such as modern drugs, traditional Chinese medicine prescriptions, and dietary supplements. The current review summarizes the research progresses concerning the distribution and cultivation, phytochemistry, pharmacology, metabolism and product development of CH in the past decades, and the emerging challenges and developing prospects are discussed as well.
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http://dx.doi.org/10.1002/med.21768DOI Listing
May 2021

Integrated Strategy Drives Direct Infusion-Tandem Mass Spectrometry as an Eligible Tool for Shotgun Pseudo-Targeted Metabolomics of Medicinal Plants.

Anal Chem 2021 02 13;93(4):2541-2550. Epub 2021 Jan 13.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, East Road of North 3rd Ring, Chaoyang District, Beijing 100029, China.

Direct infusion (DI) has an extraordinary high-throughput advantage. Pseudo-targeted metabolomics (PTM) has been demonstrated integrating the merits of both nontargeted and targeted metabolomics. Herein, we attempted to implant DI into the PTM concept to configure a new strategy allowing shotgun PTM. First, a versatile MS/MSALL program was applied to acquire MS and MS spectra. Second, online energy-resolved MS (online ER-MS) was conducted to obtain breakdown graph as well as optimal collision energy (OCE) for each ion transition paired by precursor ion and the dominant product ion. Third, selected reaction monitoring (SRM) was responsible to output a quantitative dataset with a constant length. Moreover, breakdown graph also served as orthogonal structural evidence when matching MS spectra between DI-MS/MS and an in-house library to strengthen structural annotation confidence. To evaluate and illustrate the utility of the new strategy toward shotgun PTM of medicinal plants, in-depth chemome comparison was conducted within three species, all of which are edible medicinal plants and playing essential roles for turning the deserts into the oases. A total of 185 variables participated in the quantitative measurement program. Each diagnostic ion pair was featured with an OCE. Significant species differences occurred, and echinacoside, acteoside, isoacteoside, 2'-acetyl-acteoside, tubuloside B, mannitol, sucrose, betaine, malate, as well as choline were found to be confirmative chemical markers offering primary contributions toward the species discrimination. After cross-validation with LC-MS/MS, DI-MS/MS fortified with the new strategy is an eligible tool for shotgun PTM, beyond plants.
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http://dx.doi.org/10.1021/acs.analchem.0c04602DOI Listing
February 2021

Different regulatory effects of CD40 ligand and B-cell activating factor on the function of B cells.

Int Immunopharmacol 2021 Feb 2;91:107337. Epub 2021 Jan 2.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. Electronic address:

CD40 ligand (CD40L) and B-cell activating factor (BAFF) play important roles in the function of B cells. However, the difference of their regulatory effects remains obscure. In this study, we used anti-CD40 to imitate CD40L and investigated the different regulatory effects of CD40L and BAFF on the function of B cells. In the functional analyses, both anti-CD40 and BAFF significantly enhanced the survival and differentiation of B cells, and slightly increased the activation and proliferation. However, in the transcriptome analysis, anti-CD40 and BAFF exerted very different regulation on the gene expression profile of B cells. Anti-CD40 upregulated the expression of genes related to the adaptive immune function of B cells, but BAFF enhanced the genes associated with the innate immune function. Furthermore, the effect analysis of the combination of anti-CD40 or BAFF with anti-IgM also demonstrated that anti-CD40 could cooperate with anti-IgM to promote the proliferation of B cells, but BAFF could not do it. The mechanism study revealed that the different effects of anti-CD40 and BAFF on B cells were resulting from the different modulation on NF-кB, ERK1/2, and PI3K-AKT signaling pathways. Collectively, the results suggest that CD40L mainly promotes adaptive immune function of B cells, but BAFF primarily enhances innate immune function.
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http://dx.doi.org/10.1016/j.intimp.2020.107337DOI Listing
February 2021

Liquid chromatography-three-dimensional mass spectrometry enables confirmative structural annotation of cistanoside F metabolites in rat.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jan 26;1162:122457. Epub 2020 Nov 26.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, PR China.

Clarification the existence forms, including prototype and metabolite(s) is the prerequisite for understanding in-depth the therapeutic mechanisms of a given agent, particularly when oral administration. However, it is still a long distance for unambiguous structural identification of metabolites even employing the cutting-edge MS/MS technique, and the determinant obstacle is produced by its inherent isomer-blind disadvantage. To tackle with this drawback, online energy-resolved mass spectrometry (online ER-MS) was introduced to enable isomeric discrimination after that high-resolution MS/MS provided empirical molecular formula as well as substructures. In-depth metabolic characterization of cistanoside F (CF), an effective natural product, was conducted as a proof-of-concept for the new strategy namely three-dimensional MS that was configured by MS, MS and online ER-MS as 1st, 2nd, and 3rd dimensions, respectively. Sensitive metabolite detection was assisted by predictive multiple-reaction monitoring function on Qtrap-MS, and the empirical formulas of all metabolites were calculated from the quasi-molecular ions yielded from IT-TOF-MS. Subsequently, substructures of each metabolite were constructed by combining the calculated element compositions and the well-defined mass fragmentation pathways. Finally, online ER-MS was responsible to generate optimal collision energies for bonds-of-interest, and enabled rational selection among candidate structures. A total of thirteen metabolites were detected and confirmatively identified in rat after oral treatment of CF using LC-3D MS. Acyl-migration, hydrolysis and sulfation played key roles for the metabolic fate of CF. More importantly, LC-3D MS is an eligible tool to achieve confidence-enhanced structural annotation of metabolites in biological matrices because of the unique isomeric differentiation ability from online ER-MS.
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http://dx.doi.org/10.1016/j.jchromb.2020.122457DOI Listing
January 2021

Confirmative Structural Annotation for Metabolites of ()-7,3'-Dihydroxy-4'-methoxy-8-methylflavane, A Natural Sweet Taste Modulator, by Liquid Chromatography-Three-Dimensional Mass Spectrometry.

J Agric Food Chem 2020 Nov 21;68(44):12454-12466. Epub 2020 Oct 21.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.

Flavonoids occupy the largest family of natural products and possess a broad spectrum of health benefits. Their metabolites are sometimes the truly effective molecules . It is still challenging, however, to unambiguously identify flavonoid metabolites using conventional LC-MS/MS. Herein, we aimed to pursue auxiliary structural clues to / values in both MS and MS spectra through LC coupled to three-dimensional MS (LC-3D MS). MS, as the first dimension, was in charge of suggesting theoretical molecular formulas, MS, the as second dimension, was responsible for offering substructures, and exactly, online energy-resolved MS (ER-MS), as the third dimension, provided optimal collision energies (OCEs) that reflected the linkage manners among the substructures. Metabolic characterization of a natural sweet taste modulator, namely, ()-7,3'-dihydroxy-4'-methoxy-8-methylflavane (DHMMF), was conducted as a proof-of-concept. Extensive efforts, such as full MS and MS scans on IT-TOF-MS and predictive selected-reaction monitoring mode on Qtrap-MS, were made for in-depth metabolite mining. Seventeen metabolites (-) were captured from DHMMF-treated biological samples, including 17 (-), 10 (, , , , and ), and 2 ( and ) metabolites from urine, plasma, and feces, respectively. Their structures were configured by integrating MS, MS, and OCE information. Except , all metabolites were new compounds. LC-MS/MS-guided chromatographic purification yielded three glucuronyl-conjugated metabolites (, , and ), and NMR spectroscopic assays consolidated the structures transmitted from LC-3D MS. Demethylation, glucuronidation, and sulfation occurred as the primary metabolic pathways of DHMMF. Above all, LC-3D MS bridged LC-MS/MS from putatively structural annotation toward confidence-enhanced identification, beyond the metabolite characterization of flavonoids.
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http://dx.doi.org/10.1021/acs.jafc.0c05154DOI Listing
November 2020
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