Publications by authors named "Wenji Lu"

8 Publications

  • Page 1 of 1

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

Phytomedicine 2021 Jun 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
June 2021

TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity.

J Exp Clin Cancer Res 2020 May 24;39(1):93. Epub 2020 May 24.

School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China.

Background: Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism.

Methods: Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway.

Results: DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/β and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/β and p-NF-κB.

Conclusions: Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.
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http://dx.doi.org/10.1186/s13046-020-01595-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245789PMC
May 2020

Identification of the active compounds and drug targets of Chinese medicine in heart failure based on the PPARs-RXRα pathway.

J Ethnopharmacol 2020 Jul 12;257:112859. Epub 2020 Apr 12.

School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China; College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Ethnopharmacological Relevance: Danqi Pill (DQP), commonly known as a routinely prescribed traditional Chinese medicine (TCM), is composed of Salviae Miltiorrhizae Radix et Rhizoma and Notoginseng Radix et Rhizoma and effective in treating heart failure (HF) clinically due to their multicompound and multitarget properties. However, the exact active compounds and corresponding targets of DQP are still unknown.

Aim Of The Study: This study aimed to investigate active compounds and drug targets of DQP in heart failure based on the PPARs-RXRα pathway.

Materials And Methods: Network pharmacology was used to predict the compound-target interactions of DQP. Left anterior descending (LAD)-induced HF mouse model and oxygen-glucose deprivation/recovery (OGD/R)-induced H9C2 model were constructed to screen the active compounds of DQP.

Results: According to BATMAN-TCM (a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine we previously developed), 24 compounds in DQP were significantly enriched in the peroxisome proliferator activated receptors-retinoid X receptor α (PPARs-RXRα) pathway. Among them, Ginsenoside Rb3 (G-Rb3) had the best pharmacodynamics against OGD/R-induced loss of cell viability, and it was selected to verify the compound-target interaction. In HF mice, G-Rb3 protected cardiac functions and activated the PPARs-RXRα pathway. In vitro, G-Rb3 protected against OGD/R-induced reactive oxygen species (ROS) production, promoted the expressions of RXRα and sirtuin 3 (SIRT3), thereafter improved the intracellular adenosine triphosphate (ATP) level. Immunofluorescent staining demonstrated that G-Rb3 could activate RXRα, and facilitate RXRα shifting to the nucleus. HX531, the specific inhibitor of RXRα, could abolish the protective effects of G-Rb3 on RXRα translocation. Consistently, the effect was also confirmed on RXRα siRNA cardiomyocytes model. Moreover, surface plasmon resonance (SPR) assays identified that G-Rb3 bound directly to RXRα with the affinity of KD = 10 × 10 M.

Conclusion: By integrating network pharmacology and experimental validation, we identified that as the major active compound of DQP, G-Rb3 could ameliorate ROS-induced energetic metabolism dysfunction, maintain mitochondrial function and facilitate energy metabolism via directly targeting on RXRα. This study provides a promising strategy to dissect the effective patterns for TCM and finally promote the modernization of TCM.
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http://dx.doi.org/10.1016/j.jep.2020.112859DOI Listing
July 2020

Qishen Granule alleviates endoplasmic reticulum stress-induced myocardial apoptosis through IRE-1-CRYAB pathway in myocardial ischemia.

J Ethnopharmacol 2020 Apr 13;252:112573. Epub 2020 Jan 13.

College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Ethnopharmacological Relevance: Qishen Granule (QSG) is a prevailing traditional Chinese medicine formula that displays impressive cardiovascular protection in clinical. However, underlying mechanisms by which QSG alleviates endoplasmic reticulum (ER) stress-induced apoptosis in myocardial ischemia still remain unknown.

Aim Of The Study: This study aims to elucidate whether QSG ameliorates ER stress-induced myocardial apoptosis to protect against myocardial ischemia via inositol requiring enzyme 1 (IRE-1)-αBcrystallin (CRYAB) signaling pathway.

Materials And Methods: Left anterior descending (LAD) ligation induced-ischemic heart model and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 cells injury model were established to clarify the effects and potential mechanism of QSG. Ethanol extracts of QSG (2.352 g/kg) were orally administered for four weeks and Ginaton Tablets (100 mg/kg) was selected as a positive group in vivo. In vitro, QSG (800 μg/ml) or STF080310 (an inhibitor of IRE-1, 10 μM) was co-cultured under OGD/R in H9C2 cells. Inhibition of IRE-1 was conducted in H9C2 cells to further confirm the exact mechanism. Finally, to define the active components of anti-cardiomyocyte apoptosis in QSG which absorbed into the blood, we furtherly used the OGD/R-induced cardiomyocyte apoptosis model to evaluate the effects.

Results: QSG treatment improved cardiac function, ameliorated inflammatory cell infiltration and myocardial apoptosis. Similar effects were revalidated in OGD/R-induced H9C2 injury model. Western blots demonstrated QSG exerted anti-apoptotic effects by regulating apoptosis-related proteins, including increasing Bcl-2 and caspase 3/12, reducing the expressions of Bax and cleaved-caspase 3/12. Mechanistically, the IRE-1-CRYAB signaling pathway was significantly activated by QSG. Co-treatment with STF080310, the IRE-1 specific inhibitor significantly compromised the protective effects of QSG in vitro. Especially, the active components of QSG including Formononetin, Tanshinone IIA, Tanshinone I, Cryptotanshinon and Harpagoside showed significantly anti-apoptosis effects.

Conclusion: QSG protected against ER stress-induced myocardial apoptosis via the IRE-1-CRYAB pathway, which is proposed as a promising therapeutic target for myocardial ischemia.
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http://dx.doi.org/10.1016/j.jep.2020.112573DOI Listing
April 2020

Baoyuan decoction ameliorates apoptosis via AT1-CARP signaling pathway in H9C2 cells and heart failure post-acute myocardial infarction rats.

J Ethnopharmacol 2020 Apr 10;252:112536. Epub 2020 Jan 10.

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

Ethnopharmacological Relevance: Previous studies have approved that Baoyuan decoction (BYD) exerted remarkable cardioprotective effects on heart failure (HF) due to its anti-apoptotic properties. As a novel biomarker and target of HF, Cardiac ankyrin repeat protein (CARP) can exacerbate apoptosis via activation by angiotensin type 1 receptor (AT1) and subsequently deteriorate heart function. Transcriptome results in our previous study indicated BYD was beneficial to HF post-acute myocardial infarction (AMI) with a promising effect on CARP. However, the mechanism remains to be validated.

Aim Of The Study: This study aims to elucidate whether BYD ameliorates apoptosis to protect against HF via AT1-CARP signaling pathway.

Materials And Methods: Left anterior descending ligation was applied to induce an HF rat model, Ang Ⅱ-stimulated H9C2 cells apoptotic model and overexpression of Ankrd1/CARP H9C2 cells were established to clarify the effects and potential mechanism of BYD. Ethanol extracts of BYD (0.64; 1.28; 2.57 g/kg) were orally administered for four weeks and Fosinopril (4.67 mg/kg) was selected as a positive group in vivo. In vitro, BYD (400, 600, 800 μg/ml) or RNH6270 (an inhibitor of AT1, 1 μM) was co-cultured with Ang Ⅱ stimulation for 48 h in H9C2 cells. Overexpression of Ankrd1/CARP was conducted by transient transfection with H9C2 cells to further confirm the exact mechanism. Finally, to define the active ingredients of anti-cardiomyocyte apoptosis in BYD, we furtherly used the Ang Ⅱ-induced cardiomyocyte apoptosis model to evaluate the effects.

Results: Echocardiography and TUNEL results showed that BYD in different doses remarkably improved heart function and inhibited apoptosis in vivo. Further study demonstrated that AT1 and CARP expressions in cardiac tissue were suppressed by BYD, accompanied with upregulation of B cell lymphoma-2 (Bcl-2) and downregulation of several pro-apoptotic molecules, including p53, Bcl-2 Associated X Protein (Bax) and Cleaved caspase 3. In parallel with the vivo experiment, in vitro research indicated BYD dramatically reduced the apoptotic cells and regulated expressions of critical apoptosis-related molecules mediated through downregulation of AT1 and CARP simultaneously which were consistent with the results in vivo experiment. Transiently transfected CARP over-expression further confirmed that BYD could suppress severe cardiomyocytes apoptosis induced by overexpression of CARP. Especially, the active ingredients of BYD including Astragaloside IV, Ginsenoside Rg3, Rb1, Rc and Re showed significantly anti-apoptosis effects.

Conclusion: BYD improves cardiac function and protects against cardiomyocytes injury by inhibiting apoptosis via regulating the AT1-CARP signaling pathway.
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http://dx.doi.org/10.1016/j.jep.2019.112536DOI Listing
April 2020

Phenylethanol glycosides from Cistanche tubulosa improved reproductive dysfunction by regulating testicular steroids through CYP450-3β-HSD pathway.

J Ethnopharmacol 2020 Apr 24;251:112500. Epub 2019 Dec 24.

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:

Ethnopharmacological Relevance: Cistanche tubulosa (Schenk) R. Wight has been used frequently in traditional folk medicine for treatment of male sexual dysfunction (MSD). Phenylethanol glycosides, the main components of C. tubulosa, possess a variety of pharmacological activities due to their multiple properties. However, the underlying mechanism by which phenylethanol glycosides from C. tubulosa (CPhGs) regulates testicular steroids has not been elucidated to date.

Aim Of The Study: This study is to determine whether CPhGs promotes the reproductive functions of mice through CYP450-3β-HSD pathway of testosterone synthesis.

Materials And Methods: The major compositions of C. tubulosa (CPhGs) were quantified by high performance liquid chromatography (HPLC). The model of reproductive injury in mice were induced by injection of hydrocortisone (HCT). Different doses of CPhGs (72, 145 and 289 mg/kg) and testosterone propionate (TP, positive control drug) were administrated intragastrically for 14 d. The reproductive functions (erectile incubation period, capture and ejaculation incubation period, number of captures and ejaculations) and organ weights (testicle, epididymis, seminal vesicle and penis) were then determined. The levels of luteinizing hormone and testosterone in serum were quantified by radioimmunoassay. The key enzymes in testosterone synthesis pathways such as steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side chain cleavage enzyme (P450scc/CYP11A1) and 3β-hydroxysteroid dehydrogenase (3β-HSD) in the testis were assessed by immunofluorescence (IF) staining or/and Western blot (WB) analysis.

Results: The results illustrated that the low dose of CPhGs (72 mg/kg) had no significant protective effect against the reproductive injury caused by HCT, while the moderate dose of CPhGs (145 mg/kg) improved the damaged reproductive ability and the declined levels of luteinizing hormone and testosterone in the model mice (P < 0.001, P < 0.05, respectively). In particular, high dose of CPhGs (289 mg/kg) was most effective in improving HCT-induced changes in body weight (P < 0.01), reducing the incubation period of the erectile (P < 0.001), capture (P < 0.05) and ejaculation (P < 0.01), and increasing the number of captures and ejaculations (P < 0.01, P < 0.05, respectively). The weights of testcle, epididymis, seminal vesicle and penis (P < 0.001, P < 0.01, P < 0.01, P < 0.001, respectively) were improved by high dose of CPhGs. The levels of testosterone and its upstream luteinizing hormone were up-regulated by high dose of CPhGs (P < 0.001). Meanwhile, the expressions of the key steroidogenic enzymes including CYP11A1 and 3β-HSD were significantly up-regulated after CPhGs treatment (P < 0.001), demonstrated that CPhGs exerted the effect through enhancing testosterone biosynthesis via CYP450-3β-HSD pathway.

Conclusions: CPhGs could significantly protect against HCT-induced deleterious reproductive dysfunction and testis injury. The protective effects were exerted by up-regulating synthesis of testosterone via the CYP450-3β-HSD pathway in Leydig cells.
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http://dx.doi.org/10.1016/j.jep.2019.112500DOI Listing
April 2020

Qishen Granule Improved Cardiac Remodeling Balancing M1 and M2 Macrophages.

Front Pharmacol 2019 25;10:1399. Epub 2019 Nov 25.

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

Macrophages play a pivotal role in myocardial remodeling (MR) process which could eventually lead to heart failure. Splenic monocytes could be mobilized and recruited under inflammatory conditions and differentiated into different types of macrophages in heart tissues. Inflammatory M1 macrophages could aggravate tissue damage whereas M2 macrophages could promote angiogenesis and tissue repair process. Unbalanced ratio of M1/M2 macrophages may eventually lead to adverse remodeling. Therefore, regulating differentiation and activities of macrophages are potential strategies for the management of myocardial remodeling. Qishen Granule (QSG) is an effective Chinese medicine for treating heart failure. Our previous studies demonstrated that QSG could inhibit myocardial fibrosis through regulating secretion of cytokines and activation of macrophages. However, the detailed effects of QSG on had not been elucidated yet. In this study, we aimed to explore the effect of QSG on the release of splenic monocytes, the recruitment of monocytes into heart tissues and the differentiation of macrophages under ischemic conditions. Our results showed that QSG could suppress the release of monocytes from the spleen and recruitment of monocytes to heart tissues inhibiting splenic angiotensin (Ang) II/AT1-cardiac monocyte chemotactic protein (MCP)-1/CC chemokine receptor 2 (CCR2) pathway. The anti-fibrotic effect of QSG was exerted by inhibiting M1 macrophage-activated transforming growth factor (TGF)-β1/Smad3 pathway. Meanwhile, QSG could promote angiogenesis by promoting differentiation of M1 macrophages into M2 macrophages. Our results suggest that compounds of Chinese medicine have synergistic effects on cardiac and splenic organs through regulating differentiation of monocytes/macrophages in inhibiting myocardial remodeling.
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http://dx.doi.org/10.3389/fphar.2019.01399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886583PMC
November 2019

BYD Ameliorates Oxidative Stress-Induced Myocardial Apoptosis in Heart Failure Post-Acute Myocardial Infarction via the P38 MAPK-CRYAB Signaling Pathway.

Front Physiol 2018 8;9:505. Epub 2018 May 8.

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

Heart failure (HF) post-acute myocardial infarction (AMI) contributes to increasing mortality and morbidity worldwide. Baoyuan decoction (BYD) is a well-known traditional Chinese medicine formula that exhibits myocardial protection clinically. The aim of this study was to identify the effects of BYD on oxidative stress-induced apoptosis in HF post-AMI and characterize the underlying mechanism. In our study, we constructed left anterior descending (LAD)-induced AMI rat models and a macrophage-conditioned media (CM)-induced H9C2 injury model. , BYD could protect cardiac functions, decrease inflammatory cell infiltration and inhibit oxidative stress-induced apoptosis. , BYD inhibited cellular apoptosis and regulated the expressions of key apoptotic molecules, including reducing the expression of B cell lymphoma-2 (Bcl-2) associated X protein (Bax) and cleaved caspase-3 and -9. Interestingly, the P38 mitogen-activated protein kinase (MAPK)-αB-crystallin (CRYAB) signaling pathway was activated by BYD treatment, and the P38 MAPK inhibitor SB203580 could reverse the protective effects of BYD. This study identified that BYD protected against oxidative stress-induced myocardial apoptosis via the P38 MAPK-CRYAB pathway. CRYAB may become a novel therapeutic target for AMI.
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http://dx.doi.org/10.3389/fphys.2018.00505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999PMC
May 2018
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