Publications by authors named "Shengjun Fan"

20 Publications

  • Page 1 of 1

A novel risk score predicts prognosis in melanoma: The combination of three tumor-infiltrating immune cells and four immune-related genes.

Clin Immunol 2021 Jul 8;228:108751. Epub 2021 May 8.

Department of Pharmacology and Department of Pathology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China. Electronic address:

Tumor-infiltrating immune cells (TIICs) and immune-related genes (IRGs) of melanoma are associated with prognosis. However, whether the combination of TIICs and IRGs can be used as prognostic clinical biomarkers are still unknown. Here, we downloaded transcription profile of melanoma from TCGA. Then, three TIICs and four IRGs that associated with the overall survival were used to constructed the Immune Cell Score (ICS) and Immune Gene Score (IGS) respectively. Next, to improve the accuracy of ICS and IGS for melanoma prognostic, we combined the ICS and IGS constructed the Immune Cell and Gene Score (ICGS) model. ICGS had higher accuracy and predictive ability than ICS or IGS. Meanwhile, ICGS model reliability was validated by two independent datasets of melanoma. Functional enrichment and protein-protein interaction network analysis based on ICGS were performed to identify T cell mediated immune and inflammatory response are highly associated with melanoma.
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http://dx.doi.org/10.1016/j.clim.2021.108751DOI Listing
July 2021

PINK1-Dependent Mitophagy Regulates the Migration and Homing of Multiple Myeloma Cells via the MOB1B-Mediated Hippo-YAP/TAZ Pathway.

Adv Sci (Weinh) 2020 Mar 23;7(5):1900860. Epub 2020 Jan 23.

Division of Hematologic Malignancies and Cellular Therapy Department of Medicine Duke University Medical Center Durham NC 27710 USA.

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN-induced putative kinase 1 (PINK1)-dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1-dependent mitophagy markers and parkin RBR E3 ubiquitin protein ligase ( in CD138 plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1-dependent mitophagy with carbonylcyanide--chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of accelerates myeloma development in a spontaneous X-box binding protein-1 spliced isoform () transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1-dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)-mediated Hippo pathway and the subsequent downregulation of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) expression. These data provide direct evidence that PINK1-dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target.
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http://dx.doi.org/10.1002/advs.201900860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055555PMC
March 2020

The novel small molecular BH3 mimetics SM3 and its regulation of cell apoptosis and autophagy.

Biochem Biophys Res Commun 2019 09 11;517(1):15-22. Epub 2019 Jul 11.

Department of Pharmacology, School of Basic Medical Science, Peking University and Institute of System Biomedicine, Peking University, Beijing, 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. Electronic address:

Bcl-2 family proteins play an important role in regulation of the cell survival and death. The inhibition of the anti-apoptotic proteins of Bcl-2 family leads to the apoptosis of cancer. BH3 mimetics have been developed targeting anti-apoptotic proteins of Bcl-2 family as small molecular drugs. It has been proved that BH3 mimetics has effect on apoptosis and proliferation in leukemia and some of them has been used in phase one or two clinical trials. Besides, with the development of the research on autophagic cell death, the antagonism and the synergism of autophagy and apoptosis is significant in cell death. As a hub of these two pathways of cell death, Bcl-2 protein is a potential target in basic research and clinical applications. In our studies, we found 32 potential BH3 mimetics compounds from 140,000 small molecular compounds via pharmacophore-based virtual screening. Furthermore, we demonstrated SM3, one of the 32 potential BH3 mimetics, induced autophagy and apoptosis simultaneously in dose-time dependence in A549 cell. SM3 induced apoptosis by intrinsic apoptosis pathway and induced autophagy by weakening the interaction between Beclin-1 and Bcl-2 complex. We wish to provide evidences and clues for the structural optimizing and further study of new compounds in the future.
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http://dx.doi.org/10.1016/j.bbrc.2019.06.068DOI Listing
September 2019

FOXO1 inhibition potentiates endothelial angiogenic functions in diabetes via suppression of ROCK1/Drp1-mediated mitochondrial fission.

Biochim Biophys Acta Mol Basis Dis 2018 Jul 11;1864(7):2481-2494. Epub 2018 Apr 11.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China. Electronic address:

Diabetes-induced endothelial cell (EC) dysfunction and neovascularization impairment constitute vascular complications with limited treatment regimens. Transcription factor FOXO1 is a key angiogenic regulator and plays a pathologic role in progression of diabetes. The present study was designed to determine the involvement of FOXO1 in impaired EC function and post-ischemic neovascularization in diabetes and investigate underlying mechanisms. We found that FOXO1-selective inhibitor AS1842856 improved blood flow recovery and capillary density in ischemic hindlimb, and rescued the delay of wound closure with a concomitant augmentation of mean perfusion rate in diabetic mice. In vitro, treatment with AS1842856 or FOXO1 siRNA abrogated high glucose-induced apoptosis and ameliorated capillary tube formation in human umbilical vein endothelial cells (HUVECs). FOXO1 inhibition relieved alterations in mitochondrial networks and significantly suppressed the overproduction of mitochondrial reactive oxygen species (mtROS) induced by high glucose in ECs. Expression of dynamin-related protein-1 (Drp1) and phosphorylation at Ser616, a protein required for mitochondrial fission, were enhanced by hyperglycemia, which could be neutralized by FOXO1 inhibition. Moreover, the transcription of Rho-associated coiled-coil containing protein kinase 1 (ROCK1), which phosphorylates Drp1 at Ser616, was shown by luciferase assay to be directly regulated by FOXO1. These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in ECs, and FOXO1 may serve as a therapeutic target for microvascular complications of diabetes.
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http://dx.doi.org/10.1016/j.bbadis.2018.04.005DOI Listing
July 2018

Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma.

J Hematol Oncol 2018 02 27;11(1):29. Epub 2018 Feb 27.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, 3961, Durham, NC, 27710, USA.

Background: Although current chemotherapy using bortezomib (Velcade) against multiple myeloma in adults has achieved significant responses and even remission, a majority of patients will develop acquired resistance to bortezomib. Increased thioredoxin level has been reported to be associated with carcinogenesis; however, the role of thioredoxin in bortezomib drug resistance of myeloma remains unclear.

Methods: We generated several bortezomib-resistant myeloma cell lines by serially passaging with increased concentrations of bortezomib over a period of 1.5 years. Thioredoxin expression was measured by real-time PCR and western blot.

Results: The role of thioredoxin in the survival of bortezomib-resistant myeloma cells was determined by specific shRNA knockdown in vitro and in vivo. Thioredoxin inhibitor (PX12) was used to determine the effectiveness of thioredoxin inhibition in the treatment of bortezomib-resistant myeloma cells. The effect of thioredoxin inhibition on mitophagy induction was examined. The correlation of thioredoxin expression with patient overall survival was interrogated. Thioredoxin expression was significantly upregulated in bortezomib-resistant myeloma cells and the change correlated with the increase of bortezomib concentration. Thioredoxin gene knockdown using specific shRNA sensitized bortezomib-resistant myeloma cells to bortezomib efficiency in vitro and in vivo. Similarly, pharmacological inhibition with PX12 inhibited the growth of bortezomib-resistant myeloma cells and overcame bortezomib resistance in vitro and in vivo. Furthermore, inhibition of thioredoxin resulted in the activation of mitophagy and blockage of mitophagy prevented the effects of PX12 on bortezomib-resistant myeloma cells, indicating that mitophagy is the important molecular mechanism for the induction of cell death in bortezomib-resistant myeloma cells by PX12. Moreover, inhibition of thioredoxin resulted in downregulation of phosphorylated mTOR and ERK1/2. Finally, thioredoxin was overexpressed in primary myeloma cells isolated from bortezomib-resistant myeloma patients and overexpression of thioredoxin correlated with poor overall survival in patients with multiple myeloma.

Conclusions: Our findings demonstrated that increased thioredoxin plays a critical role in bortezomib resistance in multiple myeloma through mitophagy inactivation and increased mTOR and ERK1/2 phosphorylation. Thioredoxin provides a potential target for clinical therapeutics against multiple myeloma, particularly for bortezomib-resistant/refractory myeloma patients.
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http://dx.doi.org/10.1186/s13045-018-0575-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828316PMC
February 2018

A class of stochastic Gronwall's inequality and its application.

J Inequal Appl 2018 10;2018(1):336. Epub 2018 Dec 10.

School of Mathematics, China University of Mining and Technology, Xuzhou, China.

This paper puts forward the basic form of stochastic Gronwall's inequality and uses, respectively, the iterative method, the integral method and the martingale representation method to prove it. Then it presents an application to prove a comparison theorem of solutions for one-dimensional backward stochastic differential equations under the stochastic Lipschitz condition.
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http://dx.doi.org/10.1186/s13660-018-1932-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290671PMC
December 2018

Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells.

Oncol Rep 2017 May 21;37(5):3019-3025. Epub 2017 Mar 21.

Department of Pharmacology, School of Basic Medical Sciences, Peking University and State Key Laboratory of Natural and Biomimetic Drugs, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, P.R. China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors of the digestive system, but the mechanisms of its development and progression are unclear. Inflammation is thought to be fundamental to pancreatic cancer development and caffeic acid phenethyl ester (CAPE) is an active component of honey bee resin or propolis with anti-inflammatory and anticancer activities. We investigated the inhibitory effects of CAPE on cell growth and migration induced by human neutrophil elastase (HNE) and report that HNE induced cancer cell migration at low doses and growth at higher doses. In contrast, lower CAPE doses inhibited migration and higher doses of CAPE inhibited the growth induced by HNE. HNE activity was significantly inhibited by CAPE (7.5-120 µM). Using quantitative real-time PCR and western blotting, we observed that CAPE (18-60 µM) did not affect transcription and translation of α1-antitrypsin (α1-AT), an endogenous HNE inhibitor. However, in an in silico drug target docking model, we found that CAPE directly bound to the binding pocket of HNE (25.66 kcal/mol) according to CDOCKER, and the residue of the catalytic site stabilized the interaction between CAPE and HNE as evidenced by molecular dynamic simulation. Response unit (RU) values of surface plasmon resonance (SPR) significantly increased with incremental CAPE doses (7.5-120 µM), indicating that CAPE could directly bind to HNE in a concentration-dependent manner. Thus, CAPE is an effective inhibitor of HNE via direct interaction whereby it inhibits the migration and growth of PANC-1 cells in a dose-dependent manner.
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http://dx.doi.org/10.3892/or.2017.5516DOI Listing
May 2017

Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1.

Oncotarget 2016 Dec;7(52):86225-86238

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.

Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer.
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http://dx.doi.org/10.18632/oncotarget.13368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349909PMC
December 2016

Bisdemethoxycurcumin exerts pro-apoptotic effects in human pancreatic adenocarcinoma cells through mitochondrial dysfunction and a GRP78-dependent pathway.

Oncotarget 2016 Dec;7(50):83641-83656

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.

Pancreatic cancer is a highly aggressive malignancy, which is intrinsically resistant to current chemotherapies. Herein, we investigate whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, potentiates gemcitabine in human pancreatic cancer cells. The result suggests that BDMC sensitizes gemcitabine by inducing mitochondrial dysfunctions and apoptosis in PANC-1 and MiaPaCa-2 pancreatic cancer cells. Utilizing two-dimensional gel electrophoresis and mass spectrometry, we identify 13 essential proteins with significantly altered expressions in response to gemcitabine alone or combined with BDMC. Protein-protein interaction network analysis pinpoints glucose-regulated protein 78 (GRP78) as the key hub activated by BDMC. We then reveal that BDMC upregulates GRP78 and facilitates apoptosis through eIF2α/CHOP pathway. Moreover, DJ-1 and prohibitin, two identified markers of chemoresistance, are increased by gemcitabine in PANC-1 cells. This could be meaningfully reversed by BDMC, suggesting that BDMC partially offsets the chemoresistance induced by gemcitabine. In summary, these findings show that BDMC promotes apoptosis through a GRP78-dependent pathway and mitochondrial dysfunctions, and potentiates the antitumor effect of gemcitabine in human pancreatic cancer cells.
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http://dx.doi.org/10.18632/oncotarget.13272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347794PMC
December 2016

KIAA0101 is associated with human renal cell carcinoma proliferation and migration induced by erythropoietin.

Oncotarget 2016 Mar;7(12):13520-37

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, China.

Erythropoietin (EPO) is a frequently prescribed anti-anemic drug for patients with advanced renal carcinoma. However, recent evidence from clinical studies suggested that EPO accelerated tumor progression and jeopardized the 5-year survival. Herein, we show, starting from the in silico microarray bioinformatics analysis, that activation of Erythropoietin signaling pathway enhanced renal clear carcinoma (RCC) progression. EPO accelerated the proliferative and migratory ability in 786-O and Caki-2 cells. Moreover, comparative proteomics expression profiling suggested that exogenous EPO stimulated RCC progression via up-regulation of KIAA0101 expression. Loss of KIAA0101 impeded the undesirable propensity of EPO in RCC. Finally, low expression of KIAA0101 was associated with the excellent prognosis and prognosticated a higher 5-year survival in human patients with renal carcinoma. Overall, KIAA0101 appears to be a key promoter of RCC malignancy induced by EPO, which provide mechanistic insights into KIAA0101 functions, and pave the road to develop new therapeutics for treatment of cancer-related and chemotherapy-induced anemia in patients with RCC.
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http://dx.doi.org/10.18632/oncotarget.5876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924658PMC
March 2016

Curcumin attenuates palmitate-induced apoptosis in MIN6 pancreatic β-cells through PI3K/Akt/FoxO1 and mitochondrial survival pathways.

Apoptosis 2015 Nov;20(11):1420-32

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems Biology, Peking University, 38 Xueyuan Road, Beijing, 100191, People's Republic of China.

Lipotoxicity plays a vital role in development and progression of type 2 diabetes. Prolonged elevation of free fatty acids especially the palmitate leads to pancreatic β-cell dysfunction and apoptosis. Curcumin (diferuloylmethane), a polyphenol from the curry spice turmeric, is considered to be a broadly cytoprotective agent. The present study was designed to determine the protective effect of curcumin on palmitate-induced apoptosis in β-cells and investigate underlying mechanisms. Our results showed that curcumin improved cell viability and enhanced glucose-induced insulin secretory function in MIN6 pancreatic β-cells. Palmitate incubation evoked chromatin condensation, DNA nick end labeling and activation of caspase-3 and -9. Curcumin treatment inhibited palmitate-induced apoptosis, relieved mitochondrial depolarization and up-regulated Bcl-2/Bax ratio. Palmitate induced the generation of reactive oxygen species and inhibited activities of antioxidant enzymes, which could be neutralized by curcumin treatment. Moreover, curcumin could promote rapid phosphorylation of Akt and nuclear exclusion of FoxO1 in MIN6 cells under lipotoxic condition. Phosphatidylinositol 3-kinase and Akt specific inhibitors abolished the anti-lipotoxic effect of curcumin and stimulated FoxO1 nuclear translocation. These findings suggested that curcumin protected MIN6 pancreatic β-Cells against apoptosis through activation of Akt, inhibition of nuclear translocation of FoxO1 and mitochondrial survival pathway.
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http://dx.doi.org/10.1007/s10495-015-1150-0DOI Listing
November 2015

Enoxaparin sensitizes human non-small-cell lung carcinomas to gefitinib by inhibiting DOCK1 expression, vimentin phosphorylation, and Akt activation.

Mol Pharmacol 2015 8;87(3):378-90. Epub 2014 Dec 8.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Health Science Center and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, People's Republic of China (Y.P., X.L., J.D., S.F., J.F., Y.X., H.Y., Y.W., X.L.); and Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing, People's Republic of China (L.Y.)

Gefitinib is widely used for the treatment of lung cancer in patients with sensitizing epidermal growth factor receptor mutations, but patients tend to develop resistance after an average of 10 months. Low molecular weight heparins, such as enoxaparin, potently inhibit experimental metastasis. This study aimed to determine the potential of combined enoxaparin and gefitinib (enoxaparin + gefitinib) treatment to inhibit tumor resistance to gefitinib both in vitro and in vivo. A549 and H1975 cell migration was analyzed in wound closure and Transwell assays. Akt and extracellular signal-related kinase 1/2 signaling pathways were identified, and a proteomics analysis was conducted using SDS-PAGE/liquid chromatography-tandem mass spectrometry analysis. Molecular interaction networks were visualized using the Cytoscape bioinformatics platform. Protein expression of dedicator of cytokinesis 1 (DOCK1) and cytoskeleton intermediate filament vimentin were identified using an enzyme-linked immunosorbent assay, Western blot, and small interfering RNA transfection of A549 cells. In xenograft A549-luc-C8 tumors in nude mice, enoxaparin + gefitinib inhibited tumor growth and reduced lung colony formation compared with gefitinib alone. Furthermore, the combination had stronger inhibitory effects on cell migration than either agent used individually. Additional enoxaparin administration resulted in better effective inhibition of Akt activity compared with gefitinib alone. Proteomics and network analysis implicated DOCK1 as the key node molecule. Western blot verified the effective inhibition of the expression of DOCK1 and vimentin phosphorylation by enoxaparin + gefitinib compared with gefitinib alone. DOCK1 knockdown confirmed its role in cell migration, Akt expression, and vimentin phosphorylation. Our data indicate that enoxaparin sensitizes gefitinib antitumor and antimigration activity in lung cancer by suppressing DOCK1 expression, Akt activity, and vimentin phosphorylation.
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http://dx.doi.org/10.1124/mol.114.094425DOI Listing
March 2015

Microarray gene expression profiling and bioinformatics analysis of premature ovarian failure in a rat model.

Exp Mol Pathol 2014 Dec 4;97(3):535-41. Epub 2014 Nov 4.

Department of Pharmacology, School of Basic Medical Sciences, Heilongjinag University of Chinese Medicine, Harbin 150040, China; The Key Laboratory of Myocardial Ischemia (Harbin Medical University) of Chinese Ministry of Education, Harbin 150086, China. Electronic address:

Premature ovarian failure (POF) remains one of the major gynecological problems worldwide which affected 1% of women. Even though tremendous achievements had been acquired as opposed to years past, molecular pathogenesis associated with POF is still unclear and needs to be well-defined. The aim of this study was to analyze the gene expression profiles in the POF rat model. To predict potential regulating factors, we firstly treated female Sprague Dawley (SD) rat with 4-vinylcyclohexene diepoxide (VCD). Total RNA from ovarian tissue was converted to cDNA and hybridized to mRNA Chip array. The differentially expressed genes (DEGs) were identified by two-sample t test and assessed using hierarchical clustering and Principal Component Analysis methods. Potential regulatory targets associated with these DEGs were constructed using BisoGenet in Cytoscape. Gene Ontology (GO) and functional enrichment analysis were performed using BiNGO and DAVID, respectively. As the results, 25 DEGs were found to be closely associated with POF initiation. Hierarchical clustering and Principal Component Analysis on the transcriptional profiles revealed an excellent separation of the vehicle and POF compartments. Pathway enrichment analysis based on the disease-gene interaction network analysis led to the identification of two core signaling pathways that were strongly affected during POF initiation and progression: immune response and cardiovascular disorders. In conclusion, we constructed a gene regulatory network associated with POF using the microarray gene expression profiling, and screened out some genes or transcription factors that may be used as potential molecular therapeutic targets for POF.
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http://dx.doi.org/10.1016/j.yexmp.2014.10.015DOI Listing
December 2014

Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models: in silico, in vitro and in vivo studies.

Biochim Biophys Acta 2014 Sep 23;1842(9):1742-54. Epub 2014 Jun 23.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China. Electronic address:

The aim of this study was to investigate the angiogenic effects of curcumin on an ischemia and lung cancer model. To induce ischemia combined with lung cancer models, unilateral femoral arteries of C57BL/6 mice were disconnected on one side of the mouse and Lewis lung carcinoma (LLC) cells were xenografted on the opposite side. Angiogenic effects and underlying mechanisms associated with curcumin were investigated. Molecular target(s), signaling cascades and binding affinities were detected by Western blot, two-dimensional gel electrophoresis (2-DE), computer simulations and surface plasmon resonance (SPR) techniques. Curcumin promoted post-ischemic blood recirculation and suppressed lung cancer progression in inbred C57BL/6 mice via regulation of the HIF1α/mTOR/VEGF/VEGFR cascade oppositely. Inflammatory stimulation induced by neutrophil elastase (NE) promoted angiogenesis in lung cancer tissues, but these changes were reversed by curcumin through directly reducing NE secretion and stimulating α1-antitrypsin (α1-AT) and insulin receptor substrate-1 (IRS-1) production. Meanwhile, curcumin dose-dependently influenced endothelial cells (EC) tube formation and chicken embryo chorioallantoic membrane (CAM) neovascularization. Curcumin had opposite effects on blood vessel regeneration under physiological and pathological angiogenesis, which was effected through negative or positive regulation of the HIF1α/mTOR/VEGF/VEGFR cascade. Curcumin had the promise as a new treatment modality for both ischemic conditions and lung cancer simultaneously in the clinic.
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http://dx.doi.org/10.1016/j.bbadis.2014.06.019DOI Listing
September 2014

Layered signaling regulatory networks analysis of gene expression involved in malignant tumorigenesis of non-resolving ulcerative colitis via integration of cross-study microarray profiles.

PLoS One 2013 25;8(6):e67142. Epub 2013 Jun 25.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, China.

Background: Ulcerative colitis (UC) was the most frequently diagnosed inflammatory bowel disease (IBD) and closely linked to colorectal carcinogenesis. By far, the underlying mechanisms associated with the disease are still unclear. With the increasing accumulation of microarray gene expression profiles, it is profitable to gain a systematic perspective based on gene regulatory networks to better elucidate the roles of genes associated with disorders. However, a major challenge for microarray data analysis is the integration of multiple-studies generated by different groups.

Methodology/principal Findings: In this study, firstly, we modeled a signaling regulatory network associated with colorectal cancer (CRC) initiation via integration of cross-study microarray expression data sets using Empirical Bayes (EB) algorithm. Secondly, a manually curated human cancer signaling map was established via comprehensive retrieval of the publicly available repositories. Finally, the co-differently-expressed genes were manually curated to portray the layered signaling regulatory networks.

Results: Overall, the remodeled signaling regulatory networks were separated into four major layers including extracellular, membrane, cytoplasm and nucleus, which led to the identification of five core biological processes and four signaling pathways associated with colorectal carcinogenesis. As a result, our biological interpretation highlighted the importance of EGF/EGFR signaling pathway, EPO signaling pathway, T cell signal transduction and members of the BCR signaling pathway, which were responsible for the malignant transition of CRC from the benign UC to the aggressive one.

Conclusions: The present study illustrated a standardized normalization approach for cross-study microarray expression data sets. Our model for signaling networks construction was based on the experimentally-supported interaction and microarray co-expression modeling. Pathway-based signaling regulatory networks analysis sketched a directive insight into colorectal carcinogenesis, which was of significant importance to monitor disease progression and improve therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067142PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692446PMC
February 2014

Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach.

BMC Syst Biol 2012 Dec 10;6:152. Epub 2012 Dec 10.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.

Background: Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor which raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol level, has been documented to increase mortality and cardiac events associated with adverse effects. However, it is still unclear the underlying mechanisms of the off-target effects of torcetrapib.

Results: In the present study, we developed a systems biology approach by combining a human reassembled signaling network with the publicly available microarray gene expression data to provide unique insights into the off-target adverse effects for torcetrapib. Cytoscape with three plugins including BisoGenet, NetworkAnalyzer and ClusterONE was utilized to establish a context-specific drug-gene interaction network. The DAVID functional annotation tool was applied for gene ontology (GO) analysis, while pathway enrichment analysis was clustered by ToppFun. Furthermore, potential off-targets of torcetrapib were predicted by a reverse docking approach. In general, 10503 nodes were retrieved from the integrative signaling network and 47660 inter-connected relations were obtained from the BisoGenet plugin. In addition, 388 significantly up-regulated genes were detected by Significance Analysis of Microarray (SAM) in adrenal carcinoma cells treated with torcetrapib. After constructing the human signaling network, the over-expressed microarray genes were mapped to illustrate the context-specific network. Subsequently, three conspicuous gene regulatory networks (GRNs) modules were unearthed, which contributed to the off-target effects of torcetrapib. GO analysis reflected dramatically over-represented biological processes associated with torcetrapib including activation of cell death, apoptosis and regulation of RNA metabolic process. Enriched signaling pathways uncovered that IL-2 Receptor Beta Chain in T cell Activation, Platelet-Derived Growth Factor Receptor (PDGFR) beta signaling pathway, IL2-mediated signaling events, ErbB signaling pathway and signaling events mediated by Hepatocyte Growth Factor Receptor (HGFR, c-Met) might play decisive characters in the adverse cardiovascular effects associated with torcetrapib. Finally, a reverse docking algorithm in silico between torcetrapib and transmembrane receptors was conducted to identify the potential off-targets. This screening was carried out based on the enriched signaling network analysis.

Conclusions: Our study provided unique insights into the biological processes of torcetrapib-associated off-target adverse effects in a systems biology visual angle. In particular, we highlighted the importance of PDGFR, HGFR, IL-2 Receptor and ErbB1tyrosine kinase might be direct off-targets, which were highly related to the unfavorable adverse effects of torcetrapib and worthy of further experimental validation.
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http://dx.doi.org/10.1186/1752-0509-6-152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547811PMC
December 2012

Genistein accelerates refractory wound healing by suppressing superoxide and FoxO1/iNOS pathway in type 1 diabetes.

J Nutr Biochem 2013 Jan 20;24(1):88-96. Epub 2012 Jul 20.

State Key Laboratory of Natural & Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, and Institute of System Biomedicine, Peking University, Beijing 100191, China.

Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the protective effect of the soy isoflavone genistein on diabetic wound healing and investigate underlying mechanisms. Streptozotocin (STZ)-induced type 1 diabetic mice with full-thickness excisional wounds received 0.2, 1 or 5mg/kg/day of genistein via subcutaneous injection. Genistein dose-dependently rescued the delay of wound closure in diabetic mice. A dose of 5 mg/kg/day of genistein treatment significantly increased the mean perfusion rate, and in vitro treatment with genistein protected against high glucose-induced impairment of capillary tube formation in cultured endothelial cells. Diabetic conditions significantly increased superoxide anion (O(2)·(-)) production and nitrotyrosine formation, and decreased nitrite levels in wound tissues. Genistein treatment at all doses normalized the elevated O(2)·(-) production and nitrotyrosine formation, and reversed the attenuated nitrite level. In diabetic wound tissues, the inducible nitric oxide synthase (iNOS) was activated, and genistein administration prevented increased iNOS activity. Moreover, genistein attenuated diabetic cutaneous silent information regulator 1 and forkhead box O transcription factor 1 (FoxO1) levels and potentiated ac-FoxO1 in a dose-dependent manner. Genistein rescued the delayed wound healing and improved wound angiogenesis in STZ-induced type 1 diabetes in mice, at least in part, by suppression of FoxO1, iNOS activity and oxidative stress.
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http://dx.doi.org/10.1016/j.jnutbio.2012.02.011DOI Listing
January 2013

[Determination of mangiferin in rat plasma and aqueous humor by HPLC].

Zhongguo Zhong Yao Za Zhi 2011 Mar;36(5):598-602

Department of Pharmacology, Harbin Medical University, Harbin 150086, China.

A HPLC method was developed for the determination of mangiferin in rat plasma and aqueous humor. 4-Nitrophenol was used as internal standard. Analysis was performed on a Cosmosil ODS C18 analytical column (4.6 mm x 250 mm, 5 microm) with mobile phase consisting of methanol-water (40: 60) with 2% glacial acetic acid at a flow rate of 1.0 mL x min(-1). The calibration curve of mangiferin in rat plasma and aqueous humor showed excellent linear behaviors over the investigated concentration of 0. 50-250.00 mg x L(-1) in plasma and 0.10-10.00 mg x L(-1) in aqueous humor, respectively, and the correlation coefficients were all above 0.995 4. The intra-day and inter-day precisions for all samples were measured to be below 12%. The limit of quantitation was 0.10 mg x L(-1) and low enough for the determination of mangiferin in all samples. The validated method has been successfully applied to preliminary pharmacokinetics study of mangiferin in rat plasma and aqueous humor.
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March 2011

[Determination of magnoflorine in Coptidis Rhizoma and Phellodendri Chinensis Cortex by LC-MS].

Zhongguo Zhong Yao Za Zhi 2010 Dec;35(24):3322-4

Department of Pharmacology, Harbin Medical University, Harbin 150086, China.

A rapid and specific high performance liquid chromatography-mass spectrometric method was developed for determination of magnoflorine in Rhizoma Coptidis and Cortex Phellodendri Chinensis. Samples were extracted by methanol. Agilent Eclipse XDB-C18 ODS column (4.6 mm x 150 mm, 5 microm) was used, and mobile phase was methanol-water (60:40) at a flow rate of 0.8 mL x min(-1). Electrospray ionization model (ESI), and MRM model were used for quantification. The linear range of magnoflorine was 4.352-2720 microg x L(-1). The average recovery was above 98%. The method is simple, sensitive and accurate, it can be used for determination of magnoflorine in Rhizoma Coptidis and Cortex Phellodendri Chinensis.
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December 2010

Pharmacokinetic study of mangiferin in rat plasma and retina using high-performance liquid chromatography.

Mol Vis 2010 Aug 17;16:1659-68. Epub 2010 Aug 17.

Department of Pharmacology, Harbin Medical University, Harbin, PR China.

Purpose: Although the naturally occurring antioxidant mangiferin has been widely used, it is not yet known whether it can cross the blood-retina barrier (BRB) and enter the eye. The purpose of this experiment was to investigate the ability of mangiferin to pass the blood-retina barrier.

Methods: Sprague-Dawley rats were used for biologic fluid sampling after intravenous administration of mangiferin at doses of 10, 25, and 50 mg/kg. Blood and retina samples were collected at different time points post-dose. High-performance liquid chromatography (HPLC) separation was conducted on a COSMOSIL 5C(18)-MS-II column (4.6 mm x 250 mm, 5 microm) with a flow rate of 1.0 ml/min using a mobile phase comprised of methanol -2% glacial acetic acid (40:60 v:v).

Results: The HPLC method has proven suitable to determine the presence of mangiferin in the eye. The plasma concentration of mangiferin was dose dependent. Pharmacokinetic parameters of mangiferin in plasma after intravenous administration were fitted to the two-compartment model with the first-order elimination and first-order transfer between central and peripheral compartments. The concentration of mangiferin in the retina goes with that in the blood. Mangiferin concentrations in the retina reached 5.69+/-1.48 microg/ml 0.5 h after intravenous administration (50 mg/kg) and then dropped gradually to 0.30+/-0.02 microg/ml 5.0 h later. The eye-to-plasma concentration ratio was 2.80%.

Conclusions: Mangiferin can pass the blood-retina barrier after a single intravenous administration and may be a potential natural antioxidant in treating eye diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927378PMC
August 2010