Publications by authors named "Dan-Ni Ren"

9 Publications

  • Page 1 of 1

Network pharmacology-based analysis in determining the mechanisms of Huoxin pill in protecting against myocardial infarction.

Pharm Biol 2021 Dec;59(1):1191-1202

Fujian Key Laboratory of Integrative Medicine on Geriatric, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.

Context: Huoxin pill (HXP) is a commonly used TCM prescription for treatment of cardiovascular diseases. However, its mechanism in protecting against myocardial infarction (MI) remains unknown.

Objective: We performed a network pharmacology analysis to explore the bioactive ingredients, therapeutic effects, and mechanisms of HXP in protecting against MI.

Materials And Methods: HPLC was used to identify major bioactive compounds, and overlap with MI target genes were visualised. 10-Week old C57BL/6 mice were randomly assigned as: Sham-operated control, MI + Phosphate buffered saline (PBS), and MI + HXP (3 mg/mL and 9 mg/mL) treatment groups, received oral gavage administration once every two-days starting from 1-week prior to MI, and subsequently MI models were established for one-week before sacrifice.

Results: AKT1, VEGFA, TNF and RELA were identified as core target proteins among eighty-five candidate bioactive compounds identified in HXP with overlapping MI-related genes. HXP protection against MI was mainly via regulation of inflammatory pathways, notably TNF signalling pathway. Mouse models of MI and cardiac myoblasts demonstrated that HXP improved MI-induced injury via improving regulation of inflammatory response.

Discussion And Conclusion: Stellasterol, deoxycholic acid, kaempferol, and quercetin are important active compounds contained in HXP with anti-inflammatory properties in the therapeutic treatment of MI. Due to the straightforward nature and effectiveness of taking oral HXP medications, our findings provide a theoretical basis for the clinical application of HXP in treating patients with angina or myocardial ischaemia. Future research into the combination of surgical procedures or medications that restore blood flow together with HXP as supportive medication would be worthwhile.
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http://dx.doi.org/10.1080/13880209.2021.1964542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425702PMC
December 2021

Babao Dan is a robust anti-tumor agent via inhibiting wnt/β-catenin activation and cancer cell stemness.

J Ethnopharmacol 2021 Nov 28;280:114449. Epub 2021 Jul 28.

Fujian Key Laboratory of Integrative Medicine on Geriatric, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China. Electronic address:

Ethnopharmacological Relevance: Traditional Chinese Medicine (TCM) is being increasingly used worldwide due to its diverse efficacy and relatively low side effects. Babao Dan (BBD) is a well-known TCM formula that is currently used for the effective treatment of various cancers, however its underlying molecular mechanism remains unknown.

Aim Of The Study: Tumor growth and tumor recurrence are characterized by two distinct populations of cells, namely the well-differentiated cancer cells composing the majority of tumor bulk, and cancer stem cells (CSCs) involved in tumor relapse, which are both strongly associated with excessive activation of Wnt/β-catenin signaling. Our study aims to elucidate the underlying molecular mechanisms associated with the anti-tumor proliferative effects of Babao Dan (BBD).

Materials And Methods: We used a hepatoblastoma cell line HepG2 with stem cell-like traits that harbors a constitutively active mutant of β-catenin in order to study the anti-tumor ability of BBD via targeting Wnt/β-catenin signaling.

Results: BBD robustly attenuated both the intrinsic and extrinsic activation of Wnt/β-catenin pathway in HepG2 hepatoblastoma cells, as well as Wnt target genes. Moreover, BBD significantly inhibited both the proliferation of well-differentiated cancer cells, as well as the stem-like property of CSCs as evidenced by EpCAM, a Wnt target gene and a novel marker of cancer cell stemness. In addition, mice administered with BBD using HepG2 cell line derived xenograft model had marked reductions in tumor size and weight, as well as significantly decreased expressions of Wnt target genes and cancer cell stemness.

Conclusion: Our findings elucidated the underlying molecular mechanisms associated with the robust anti-tumor effects of BBD via potent inhibition of Wnt/β-catenin signaling, and implicate its use in the clinical treatment of cancers.
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http://dx.doi.org/10.1016/j.jep.2021.114449DOI Listing
November 2021

IGFBP-4 enhances VEGF-induced angiogenesis in a mouse model of myocardial infarction.

J Cell Mol Med 2020 08 28;24(16):9466-9471. Epub 2020 Jun 28.

Fujian Key Laboratory of Integrative Medicine on Geriatric, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.

Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor, however its ability in promoting therapeutic angiogenesis following myocardial infarction (MI) is limited. Here, we aimed to investigate whether dual treatment with insulin-like growth factor binding protein-4 (IGFBP-4), an agent that protects against early oxidative damage, can be effective in enhancing the therapeutic effect of VEGF following MI. Combined treatment with IGFBP-4 enhanced VEGF-induced angiogenesis and prevented cell damage via enhancing the expression of a key angiogenic factor angiopoietin-1. Dual treatment with the two agents synergistically decreased cardiac fibrosis markers collagen-I and collagen-III following MI. Importantly, while the protective action of IGFBP-4 occurs at an early stage of ischemic injury, the action of VEGF occurs at a later stage, at the onset angiogenesis. Our findings demonstrate that VEGF treatment alone is often not enough to protect against oxidative stress and promote post-ischemic angiogenesis, whereas the combined treatment with IGFBP4 and VEGF can utilize the dual roles of these agents to effectively protect against ischemic and oxidative injury, and promote angiogenesis. These findings provide important insights into the roles of these agents in the clinical setting, and suggest new strategies in the treatment of ischemic heart disease.
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http://dx.doi.org/10.1111/jcmm.15516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417680PMC
August 2020

Deletion of low-density lipoprotein-related receptor 5 inhibits liver Cancer cell proliferation via destabilizing Nucleoporin 37.

Cell Commun Signal 2019 12 27;17(1):174. Epub 2019 Dec 27.

Fujian Key Laboratory of Integrative Medicine on Geriatric, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Minhou Shangjie, Fuzhou, 350122, Fujian, China.

Background: LRP5/6 are co-receptors in Wnt/β-catenin pathway. Recently, we discovered multiple β-catenin independent functions of LRP5/6 in tumor cells and in the diseased heart. Nucleoporin 37 (NUP37) is an important component of the nuclear pore complex (NPC), whose elevated expression is associated with worsened prognosis in liver cancer. Previous studies have shown that NUP37 interacted with YAP and activated YAP/TEAD signaling in liver cancer. Our preliminary findings showed a nuclear location of LRP5. We thus tested the hypothesis that LRP5 may act as a genuine regulator of YAP/TEAD signaling via modulating NUP37 in a β-catenin-independent way.

Methods: We performed siRNA knockdown of LRP5, LRP6, or β-catenin in liver cancer HepG2 cells to determine the effect on tumor cell proliferation. Protein expressions and interaction between LRP5 and NUP37 were determined using immunoprecipitation and western blot analyses.

Results: HepG2 cell proliferation was markedly inhibited by knockdown of LRP5 but not LRP6 or β-catenin, suggesting that LRP5 has a specific, β-catenin-independent role in inhibiting HepG2 cell proliferation. Knockdown of NUP37 by siRNA inhibited the proliferation of HepG2 cells, whereas overexpression of NUP37 reversed the decrease in cell proliferation induced by LRP5 knockdown. Immunoprecipitation assays confirmed that LRP5 bound to NUP37. Furthermore, LRP5 overexpression restored NUP37 knockdown-induced downregulation of YAP/TEAD pathway.

Conclusions: LRP5 deletion attenuates cell proliferation via destabilization of NUP37, in a β-catenin-independent manner. LRP5 therefore acts as a genuine regulator of YAP/TEAD signaling via maintaining the integrity of the NPC, and implicates a therapeutic strategy in targeting LRP5 for inhibiting liver cancer cell proliferation.
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http://dx.doi.org/10.1186/s12964-019-0495-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935199PMC
December 2019

LRP6 Ectodomain Prevents SDF-1/CXCR4-Induced Breast Cancer Metastasis to Lung.

Clin Cancer Res 2019 08 22;25(15):4832-4845. Epub 2019 Apr 22.

Clinical and Translational Research Center, Research Institute of Heart Failure Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Tongji University School of Medicine, Shanghai, China.

Purpose: Lung metastasis is an important cause of breast cancer-related deaths, in which SDF-1/CXCR4 signaling pathway plays a critical role. Single transmembrane protein LRP6 is viewed as an oncogene via activating the Wnt/β-catenin signaling pathway. Our work aims to investigate the relationship between SDF-1/CXCR4 and LRP6 in breast cancer lung metastasis.

Experimental Design: We examined the expressions and functions of SDF-1/CXCR4 and LRP6 as well as their relationship in breast cancer and .

Results: LRP6 ectodomain (LRP6N) directly bound to CXCR4 and competitively prevented SDF-1 binding to CXCR4. LRP6N prevented SDF-1/CXCR4-induced metastasis to lung and prolonged survival in mice bearing breast tumors, whereas LRP6 knockdown activated SDF-1/CXCR4 signal transduction and promoted lung metastasis and tumor death. Furthermore, patients with breast cancer with high CXCR4 expression had poor prognosis, which was exacerbated by low LRP6 expression but improved by high LRP6 expression. Interestingly, a secreted LRP6N was found in the serum of mice and humans, which was downregulated by the onset of cancer metastasis in both mice bearing breast cancer as well as in patients with breast cancer.

Conclusions: LRP6N might be a promising diagnostic marker for the early detection of breast cancer metastasis as well as an inhibitor of SDF-1/CXCR4-induced breast cancer metastasis. LRP6N also provides an interesting link between Wnt signaling and SDF-1/CXCR4 signaling, the two key pathways involved in cancer development.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3557DOI Listing
August 2019

Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin.

Circulation 2016 Dec 1;134(24):1991-2007. Epub 2016 Nov 1.

From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory of Signaling and Disease Research, The School of Life Sciences and Technology, Tongji University, China (Zhenping Liu, C.J.); State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Sciences, Fudan University, Shanghai, China (Y.Y., T.Z.); and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (J.W., Y. Zou).

Background: Myocardial infarction is one of the leading causes of morbidity and mortality worldwide, triggering irreversible myocardial cell damage and heart failure. The role of low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) as coreceptors of the Wnt/β-catenin pathway in the adult heart remain unknown. Insulin-like growth factor binding protein 4 and dickkopf-related protein 1 (Dkk1) are 2 secreted LRP5/6 binding proteins that play a crucial role in heart development through preventing Wnt/β-catenin pathway activation. However, their roles in the adult heart remain unexplored.

Methods: To understand the role of LRP5/6 and β-catenin in the adult heart, we constructed conditional cardiomyocyte-specific LRP5/6 and β-catenin knockout mice and induced surgical myocardial infarction. We also directly injected recombinant proteins of insulin-like growth factor binding protein 4 and Dkk1 into the heart immediately following myocardial infarction to further examine the mechanisms through which these proteins regulate LRP5/6 and β-catenin.

Results: Deletion of LRP5/6 promoted cardiac ischemic insults. Conversely, deficiency of β-catenin, a downstream target of LRP5/6, was beneficial in ischemic injury. It is interesting to note that although both insulin-like growth factor binding protein 4 and Dkk1 are secreted Wnt/β-catenin pathway inhibitors, insulin-like growth factor binding protein 4 protected the ischemic heart by inhibiting β-catenin, whereas Dkk1 enhanced the injury response mainly through inducing LRP5/6 endocytosis and degradation.

Conclusions: Our findings reveal previously unidentified dual roles of LRP5/6 involved in the cardiomyocyte response to ischemic injury. These findings suggest new therapeutic strategies in ischemic heart disease by fine-tuning LRP5/6 and β-catenin signaling within the Wnt/β-catenin pathway.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024441DOI Listing
December 2016

LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis.

Nat Commun 2015 Apr 22;6:6906. Epub 2015 Apr 22.

1] Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China [2] Tongji University School of Medicine, Shanghai, China.

How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood. Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. Importantly, through direct binding to Frz, LRP5/6 are able to prevent Frz-regulated non-canonical pathway activation and further non-canonical pathway-mediated tumour metastasis. Knockdown of endogenous LRP5/6 promotes otherwise-nonaggressive tumour cells to migrate in vitro, whereas a soluble recombinant protein of LRP6 ectodomain suppresses migration and metastasis of otherwise-aggressive tumour cells in vitro and in vivo. Furthermore, the expression level of membrane LRP5/6 correlates inversely with metastasis in mouse and human breast cancer. Our study suggests a previously unrecognized mode of receptor interaction, revealing the mechanism of LRP5/6 in inhibition of non-canonical pathway, and a possible clinical use of the LRP6 ectodomain to impede metastasis.
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http://dx.doi.org/10.1038/ncomms7906DOI Listing
April 2015

LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation.

Cell Signal 2014 May 8;26(5):1068-74. Epub 2014 Jan 8.

Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China; Tongji University School of Medicine, Shanghai, China. Electronic address:

Canonical Wnt/β-catenin signaling pathway plays important roles in multiple aspects of cellular responses in development and diseases. It is currently thought that Wnt receptor Frizzled (Frz) exists separately to Wnt coreceptors LRP5 and LRP6 (LRP5/6), and that Wnt-Frz-LRP5/6 triple complex formation bridged by Wnt ligand is needed for canonical pathway activation. We recently showed that Frz and LRP5/6 interact with each other in the absence of Wnt ligand binding and this interaction maintains the Frz-LRP5/6 complex in an inactive state. Here, we further show that Wnt ligand stimulation induces conformational change of the Frz-LRP6 complex and leads to hexamer formation containing the core LDLR domain-mediated LRP6 homodimer that is stabilized by two pairs of Wnt3a and Frz8, that is, Wnt3a-Frz8-LRP6-LRP6-Frz8-Wnt3a. This LDLR-mediated LRP6 dimerization is essential for robust canonical Wnt pathway activation. Our study thus suggests a previously unrecognized mode of receptor interaction in Wnt signal initiation.
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http://dx.doi.org/10.1016/j.cellsig.2013.12.020DOI Listing
May 2014

Comparative analysis of thymidylate synthase at the protein, mRNA, and DNA levels as prognostic markers in colorectal adenocarcinoma.

J Surg Oncol 2009 Dec;100(7):546-52

Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, South Korea.

Background And Objectives: To determine the best routinely available molecular methodology for assessing thymidylate synthase (TS) as a prognostic marker in colorectal adenocarcinoma, TS was examined at the protein, mRNA, and DNA levels. Direct comparison of these routinely available assays has not been systematically studied across a large colon cancer patient cohort with long-term follow-up.

Methods: We studied 150 surgically resected colorectal adenocarcinoma patients who received postoperative 5-Fluorouracil (5-FU) chemotherapy. TS immuunohistochemistry and real-time quantitative RT-PCR and PCR genotyping on patient-matched tumor and normal tissues were performed.

Results: Surprisingly, mRNA values in normal tissue varied from 0.11 to 62.0 and significantly correlated with mRNA values of matched tumor tissues. Although higher tumor/normal ratios of mRNA expression trended toward poorer patient survival, neither this nor TS immunohistochemistry results were statistically significant predictors. TS tumor genotype was generally concordant with matched normal tissues. Further, the 2R/3R genotype of 5'-TSER was significantly correlated with poorer patient survival (P = 0.0249) and was also an independent prognostic marker on multivariate analysis.

Conclusion: TS genotyping on paraffin-embedded fixed tissues proved to be the most useful method for prediction of outcome of 5-FU treatment in patients with colorectal adenocarcinoma.
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http://dx.doi.org/10.1002/jso.21383DOI Listing
December 2009
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