Publications by authors named "Fangrong Zhang"

24 Publications

  • Page 1 of 1

ATP regulates RNA-driven cold inducible RNA binding protein phase separation.

Protein Sci 2021 Jul 22;30(7):1438-1453. Epub 2021 May 22.

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology & Biochemistry, Medical University of Graz, Graz, Austria.

Intrinsically disordered proteins and proteins containing intrinsically disordered regions are highly abundant in the proteome of eukaryotes and are extensively involved in essential biological functions. More recently, their role in the organization of biomolecular condensates has become evident and along with their misregulation in several neurologic disorders. Currently, most studies involving these proteins are carried out in vitro and using purified proteins. Given that in cells, condensate-forming proteins are exposed to high, millimolar concentrations of cellular metabolites, we aimed to reveal the interactions of cellular metabolites and a representative condensate-forming protein. Here, using the arginine-glycine/arginine-glycine-glycine (RG/RGG)-rich cold inducible RNA binding protein (CIRBP) as paradigm, we studied binding of the cellular metabolome to CIRBP. We found that most of the highly abundant cellular metabolites, except nucleotides, do not directly bind to CIRBP. ATP, ADP, and AMP as well as NAD , NADH, NADP , and NADPH directly interact with CIRBP, involving both the folded RNA-recognition motif and the disordered RG/RGG region. ATP binding inhibited RNA-driven phase separation of CIRBP. Thus, it might be beneficial to include cellular metabolites in in vitro liquid-liquid phase separation studies of RG/RGG and other condensate-forming proteins in order to better mimic the cellular environment in the future.
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http://dx.doi.org/10.1002/pro.4123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197425PMC
July 2021

tRNA-derived fragments as novel potential biomarkers for relapsed/refractory multiple myeloma.

BMC Bioinformatics 2021 May 11;22(1):238. Epub 2021 May 11.

Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha, 410000, China.

Background: tRNA-derived fragments have been reported to be key regulatory factors in human tumors. However, their roles in the progression of multiple myeloma remain unknown.

Results: This study employed RNA-sequencing to explore the expression profiles of tRFs/tiRNAs in new diagnosed MM and relapsed/refractory MM samples. The expression of selected tRFs/tiRNAs were further validated in clinical specimens and myeloma cell lines by qPCR. Bioinformatic analysis was performed to predict their roles in multiple myeloma progression.We identified 10 upregulated tRFs/tiRNAs and 16 downregulated tRFs/tiRNAs. GO enrichment and KEGG pathway analysis were performed to analyse the functions of 1 significantly up-regulated and 1 significantly down-regulated tRNA-derived fragments. tRFs/tiRNAs may be involved in MM progression and drug-resistance.

Conclusion: tRFs/tiRNAs were dysregulated and could be potential biomarkers for relapsed/refractory MM.
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http://dx.doi.org/10.1186/s12859-021-04167-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111751PMC
May 2021

Growing Human Hepatocellular Tumors Undergo a Global Metabolic Reprogramming.

Cancers (Basel) 2021 Apr 20;13(8). Epub 2021 Apr 20.

Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.

Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis, high morbidity and mortality concerning with lack of effective diagnosis and high postoperative recurrence. Similar with other cancers, HCC cancer cells have to alter their metabolism to adapt to the changing requirements imposed by the environment of the growing tumor. In less vascularized regions of tumor, cancer cells experience hypoxia and nutrient starvation. Here, we show that HCC undergoes a global metabolic reprogramming during tumor growth. A combined proteomics and metabolomics analysis of paired peritumoral and tumor tissues from 200 HCC patients revealed liver-specific metabolic reprogramming and metabolic alterations with increasing tumor sizes. Several proteins and metabolites associated with glycolysis, the tricarboxylic acid cycle and pyrimidine synthesis were found to be differentially regulated in serum, tumor and peritumoral tissue with increased tumor sizes. Several prognostic metabolite biomarkers involved in HCC metabolic reprogramming were identified and integrated with clinical and pathological data. We built and validated this combined model to discriminate against patients with different recurrence risks. An integrated and comprehensive metabolomic analysis of HCC is provided by our present work. Metabolomic alterations associated with the advanced stage of the disease and poor clinical outcomes, were revealed. Targeting cancer metabolism may deliver effective therapies for HCC.
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http://dx.doi.org/10.3390/cancers13081980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074141PMC
April 2021

Efficacy and Safety of CAR-T Therapy for Relapse or Refractory Multiple Myeloma: A systematic review and meta-analysis.

Int J Med Sci 2021 18;18(8):1786-1797. Epub 2021 Feb 18.

Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.

Multiple myeloma (MM) is incurable in spite of recent treatment improvements, highlighting the development of new therapies. Chimeric antigen receptor (CAR) T-cell therapy has dramatically changed the therapeutic effectiveness in high-risk B-cell malignancies. For relapsed/refractory multiple myeloma (RRMM), preclinical evaluations of CAR-T therapy have shown promising efficacy, thus various active clinical trials are under way. Herein, we conducted this review to summarize efficacy and safety of CAR-T therapy and provide more evidence to guide clinical treatments. We systematically searched literature based on databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials), and conference abstracts reported from American Society of Hematology (ASH), European Hematology Association (EHA) and American Society of Clinical Oncology (ASCO), in addition to other sources (www.clinicaltrials.gov, article citations). Data assessed efficacy and safety of CAR-T therapy in patients with RRMM were extracted and evaluated, and then systematically analyzed by Comprehensive Meta-analysis 3.0 (CMA 3.0). A total of 23 studies including 350 participants from different countries, diagnosed as RRMM and treated with CAR-T therapy (containing 7 antigens targeted by CARs) were combined. In summary, we discovered the pooled overall response rate (77%), complete response rate (37%) and minimal residual disease (MRD) negativity rate within responders (78%). Furthermore, the pooled relapse rate of responders was 38% and median progression-free survival was 8 months. The pooled survival rate was 87% at last follow-up (median, 12 months). In addition, the pooled grade 3-4 rates of cytokine release syndrome (CRS) and neurologic toxicities (NT) were 14% and 13%, respectively. Our study suggests that CAR-T therapy has demonstrated efficacy and safety in RRMM patients. BCMA-targeted CAR-T and anti-BCMA contained regimen have shown better efficacy.
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http://dx.doi.org/10.7150/ijms.46811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976586PMC
February 2021

Tissue-Specific Landscape of Metabolic Dysregulation during Ageing.

Biomolecules 2021 02 7;11(2). Epub 2021 Feb 7.

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.

The dysregulation of cellular metabolism is a hallmark of ageing. To understand the metabolic changes that occur as a consequence of the ageing process and to find biomarkers for age-related diseases, we conducted metabolomic analyses of the brain, heart, kidney, liver, lung and spleen in young (9-10 weeks) and old (96-104 weeks) wild-type mice [mixed genetic background of 129/J and C57BL/6] using NMR spectroscopy. We found differences in the metabolic fingerprints of all tissues and distinguished several metabolites to be altered in most tissues, suggesting that they may be universal biomarkers of ageing. In addition, we found distinct tissue-clustered sets of metabolites throughout the organism. The associated metabolic changes may reveal novel therapeutic targets for the treatment of ageing and age-related diseases. Moreover, the identified metabolite biomarkers could provide a sensitive molecular read-out to determine the age of biologic tissues and organs and to validate the effectiveness and potential off-target effects of senolytic drug candidates on both a systemic and tissue-specific level.
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http://dx.doi.org/10.3390/biom11020235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914945PMC
February 2021

Endothelial lipase increases antioxidative capacity of high-density lipoprotein.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 10 17;1864(10):1363-1374. Epub 2019 Jun 17.

Otto Loewi Research Center, Division of Physiological Chemistry, Medical University of Graz, Neue Stiftingtalstraße 6/3, 8010 Graz, Austria.

Endothelial lipase (EL) is a strong determinant of structural and functional properties of high-density lipoprotein (HDL). We examined whether the antioxidative capacity of HDL is affected by EL. EL-modified HDL (EL-HDL) and control EV-HDL were generated by incubation of HDL with EL- overexpressing or control HepG2 cells. As determined by native gradient gel electrophoresis, electron microscopy, and small-angle X-ray scattering EL-HDL is smaller than EV-HDL. Mass spectrometry revealed an enrichment of EL-HDL with lipolytic products and depletion of phospholipids and triacylglycerol. Kinetics of conjugated diene formation and HPLC-based malondialdehyde quantification revealed that EL-HDL exhibited a significantly higher resistance to copper ion-induced oxidation and a significantly higher capacity to protect low-density lipoprotein (LDL) from copper ion-induced oxidation when compared to EV-HDL. Depletion of the lipolytic products from EL-HDL abolished the capacity of EL-HDL to protect LDL from copper ion-induced oxidation, which could be partially restored by lysophosphatidylcholine enrichment. Proteomics of HDL incubated with oxidized LDL revealed significantly higher levels of methionine 136 sulfoxide in EL-HDL compared to EV-HDL. Chloramine T (oxidizes methionines and modifies free thiols), diminished the difference between EL-HDL and EV-HDL regarding the capacity to protect LDL from oxidation. In absence of LDL small EV-HDL and EL-HDL exhibited higher resistance to copper ion-induced oxidation when compared to respective large particles. In conclusion, the augmented antioxidative capacity of EL-HDL is primarily determined by the enrichment of HDL with EL-generated lipolytic products and to a lesser extent by the decreased HDL particle size and the increased activity of chloramine T-sensitive mechanisms.
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http://dx.doi.org/10.1016/j.bbalip.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699986PMC
October 2019

Bortezomib-inducible long non-coding RNA myocardial infarction associated transcript is an oncogene in multiple myeloma that suppresses miR-29b.

Cell Death Dis 2019 04 9;10(4):319. Epub 2019 Apr 9.

The Third Xiangya Hospital of Central South University, Changsha, 410013, China.

Clinical outcomes of patients with multiple myeloma (MM) have almost doubled the overall survival over the last decade owing to the use of proteasome inhibitor such as bortezomib (BTZ). However, some patients with MM develop primary resistance to BTZ, whereas others develop resistance after treatment. In this study, we investigated relationships between BTZ resistance and dysfunction of long non-coding RNAs (lncRNAs) in patients with MM. Bone marrow samples were collected from patients with MM and healthy donors for lncRNA microarray and survival analyses. To investigate functions and underlying mechanisms of lncRNA-mediated BTZ resistance in MM, we performed CCK-8 assays, flow cytometry analyses, dual luciferase report gene assays, and RNA pulldown assays with samples from nude mice carrying tumor xenografts and in clinical samples. Differentially expressed lncRNA myocardial infarction associated transcripts (MIAT) were highly expressed in patients with MM compared with healthy controls, and were predictive of poor survival outcomes. Moreover, MIAT expression was significantly increased in BTZ-resistant patients with MM compared with newly diagnosed patients with MM, and was identified as a BTZ-inducible lncRNA. Specifically, BTZ upregulated MIAT expression through increased stat1 phosphorylation. Silencing of MIAT inhibited MM cell growth and sensitized MM cells to BTZ by negatively regulating miR-29b. Our data demonstrated the utility of MIAT as a tool for overcoming BTZ resistance in patients with MM.
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http://dx.doi.org/10.1038/s41419-019-1551-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456577PMC
April 2019

Polydopamine doped reduced graphene oxide/mesoporous silica nanosheets for chemo-photothermal and enhanced photothermal therapy.

Mater Sci Eng C Mater Biol Appl 2019 Mar 1;96:138-145. Epub 2018 Nov 1.

Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361021, People's Republic of China; Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, People's Republic of China. Electronic address:

The nanoplatform of synergistic chemo-photothermal therapy has superior advantages on antitumor. It is urgently needed to explore novel nanocarrier for improving photothermal performance in drug delivery process. Herein, we synthesized polydopamine doped mesoporous silica-coated reduced graphene oxide (rGO/MSN/PDA) by simply adding dopamine hydrochloride into the oil-water biphasic reaction system as a multifunctional drug carrier for anticancer treatment, which combines chemotherapy and photothermal therapy. The rGO/MSN/PDA showed nearly twice the photothermal conversion efficiency of mesoporous silica-coated graphene oxide (GO/MSN) due to the reduction of GO and doping with PDA. In addition, the rGO/MSN/PDA showed pH-response DOX release abilities, which means higher release of DOX in tumor cells. The cell experiments in vitro proved that rGO/MSN/PDA with better biocompatibility compare to GO/MSN might offer a promising tool for improving the therapeutic effects of hepatocellular carcinoma cells through synergistic chemo-photothermal therapy.
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http://dx.doi.org/10.1016/j.msec.2018.10.093DOI Listing
March 2019

A dual-targeting reconstituted high density lipoprotein leveraging the synergy of sorafenib and antimiRNA21 for enhanced hepatocellular carcinoma therapy.

Acta Biomater 2018 07 31;75:413-426. Epub 2018 May 31.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address:

Sorafenib (So) is a multi-target kinase inhibitor extensively used in clinic for hepatocellular carcinoma therapy. It demonstrated strong inhibition both in tumor proliferation and tumor angiogenesis, while hampered by associated cutaneous side-effect and drug resistance. The knockdown of miR-21 with antisense oligonucleotides (antimiRNA21) was regarded as an efficient strategy for increasing tumor sensibility to chemotherapy, which could be employed to appreciate the efficacy of So. Herein, we successfully formulated a dual-targeting delivery system for enhanced hepatocellular carcinoma therapy by encapsulating So and antimiRNA21 in RGD pentapeptide-modified reconstituted high-density lipoprotein (RGD-rHDL/So/antimiRNA21). The RGD and apolipoprotein A-I (ApoA-I) on nanoparticles (NPs) could drive the system simultaneously to tumor neovascular and parenchyma by binding to the overexpressed ανβ3-integrin and SR-B1 receptors, achieving precise delivery of therapeutics to maximize the efficacy. A series in vitro and in vivo experiments revealed that co-delivery of So and antimiRNA21 by RGD-rHDL significantly strengthened the anti-tumor and anti-angiogenic effect of So with negligible toxicity towards major organs, reversed drug-resistance and was capable of remodeling tumor environments. The constructed RGD-rHDL/So/antimiRNA21 with improved efficacy and excellent tumor targeting ability provided new idea for chemo-gene combined therapy in hepatocellular carcinoma.

Statement Of Significance: Sorafenib (So) is a multi-target kinase inhibitor which was approved by FDA as first-line drug for hepatocellular carcinoma (HCC) therapy. However, long term application of So in clinic was hampered by serious dermal toxicity and drug resistance. Although numerous researchers were devoted to finding alternatives or therapies as combination treatments with So to reach more desired therapeutic efficacy, the therapeutic options were still limited. The present study prepares RGD pentapeptide decorated biomimic reconstituted high-density lipoprotein (rHDL) loaded with So and antimiRNA21 (RGD-rHDL/So/antimiRNA21) for enhanced HCC therapy. The RGD-rHDL/So/antimiRNA21 NPs offer an effective platform for anti-tumor and anti-angiogenesis therapy in HCC and provide new approach to reverse drug-resistance of So for feasible clinical application.
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http://dx.doi.org/10.1016/j.actbio.2018.05.049DOI Listing
July 2018

Nanoparticles designed to regulate tumor microenvironment for cancer therapy.

Life Sci 2018 May 22;201:37-44. Epub 2018 Mar 22.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address:

Increasing understanding in tumor pathology reveals that tumor microenvironment (TME), which supports tumor progression and poses barriers for available therapies, takes a great responsibility in inefficient treatment and poor prognosis. In recent years, the versatile nanotechnology employed in TME regulation has made great progress. The nanoparticles (NPs) can be tailored as needed to accurately target TME components by distinguishing healthy tissues from malignancy, and to regulate TME to promote tumor regression. Meanwhile, the emerging microRNAs (miRNAs) demonstrate great potentials for TME regulation, but are regrettably restricted by quick degradation. NPs systems enable the successful delivery of miRNA to TME without the limitation, expanding the application of nucleic acid drug. In this review, we summarized recent NPs-based strategies aiming at regulating TME in different ways, including anti-angiogenesis, extracellular matrix (ECM) remodeling, tumor-associated fibroblasts (TAFs) treatment and tumor-associated macrophages (TAMs) treatment, along with the miRNAs-loaded NPs for TME regulation. Catching and utilizing the features of TME for NPs design can contribute to reversing drug-resistance, optimized drug distribution, and eventually more efficient cancer therapy.
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http://dx.doi.org/10.1016/j.lfs.2018.03.044DOI Listing
May 2018

Enhanced antibacterial activity of silver-decorated sandwich-like mesoporous silica/reduced graphene oxide nanosheets through photothermal effect.

Nanotechnology 2018 Mar;29(10):105704

Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361021, People's Republic of China. Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, People's Republic of China.

Drug resistance of bacteria has become a global health problem, as it makes conventional antibiotics less efficient. It is urgently needed to explore novel antibacterial materials and develop effective treatment strategies to overcome the drug resistance of antibiotics. Herein, we successfully synthesized silver decorated sandwich-like mesoporous silica/reduced graphene oxide nanosheets (rGO/MSN/Ag) as a novel antibacterial material through facile method. The rGO and Ag nanoparticles can be reduced in the reaction system without adding any other reductants. In addition, the rGO/MSN/Ag showed higher photothermal conversion capacity due to the modification of silver nanoparticles and exhibited excellent antibacterial activities against Pseudomonas putida, Escherichia coli and Rhodococcus at relatively low dosages, which was confirmed by the minimum inhibitory concentration (MIC) test. Meanwhile, the E. coli with a high concentration was selected for exposure using an 808 nm laser, and the antibacterial effect was obviously enhanced by the near-infrared irradiation induced photothermal effect. Moreover, the hepatocyte LO2 were used for the cytotoxicity evaluation, and the rGO/MSN/Ag showed low toxicity and were without detectable cytotoxicity at the antimicrobial dose. As the prepared rGO/MSN/Ag nanosheets have the advantages of low-cost and high antibacterial activity, they might be of promising and useful antibacterial agents for different applications.
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http://dx.doi.org/10.1088/1361-6528/aaa624DOI Listing
March 2018

Synergistic Suppression of Tumor Angiogenesis by the Co-delivering of Vascular Endothelial Growth Factor Targeted siRNA and Candesartan Mediated by Functionalized Carbon Nanovectors.

ACS Appl Mater Interfaces 2017 Jul 5;9(28):23353-23369. Epub 2017 Jul 5.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.

Single-walled carbon nanotubes (SWNTs) with unique physicochemical properties have exhibited promising biomedical applications as drug and gene carriers. In this study, polyethylenimine (PEI)-modified SWNT conjugates linked with candesartan (CD) were developed to deliver vascular endothelial growth factor (VEGF)-targeted siRNA (siVEGF) for the synergistic and targeted treatment of tumor angiogenesis. The characterization results revealed that SWNT-PEI-CD conjugates were successfully synthesized and exhibited desirable dispersibility and superior stability. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) results showed that SWNT-PEI-CD/siVEGF complexes could achieve high cellular uptake and specific intracellular distribution of siRNA in ATR overexpressed PANC-1 cells. Strong down-regulation of VEGF was also verified by qualitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot in complex-treated PANC-1 cells. The in vitro angiogenesis assay showed that SWNT-PEI-CD/siVEGF complexes highly inhibited tube formation of human umbilical vein endothelial cells. Furthermore, in vivo observation in PANC-1 xenografted nude mice demonstrated that SWNT-PEI-CD/siVEGF complexes exhibited significant distribution at tumor sites and caused obvious inhibition of tumor growth and tumor-associated angiogenesis repression induced by the drug combination of CD and siVEGF. Finally, a WST-1 assay indicated that SWNT-PEI-CD possessed low cytotoxicity, and a hemolysis test showed good biocompatibility of SWNT-PEI-CD. Hematological and histological analyses confirmed that SWNT-PEI-CD/siVEGF complexes did not cause any obvious toxic effects to blood and major organs. These findings suggested that the SWNT-PEI-CD/siVEGF co-delivery system with tumor-targeting specificity, improved endosomal escaping properties, and collaboration of angiogenesis inhibition could be a prospective method for efficient tumor antiangiogenic therapy.
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http://dx.doi.org/10.1021/acsami.7b04971DOI Listing
July 2017

A precision-guided MWNT mediated reawakening the sunk synergy in RAS for anti-angiogenesis lung cancer therapy.

Biomaterials 2017 Sep 31;139:75-90. Epub 2017 May 31.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address:

Multi-walled carbon nanotube (MWNT) with its versatility has exhibited tremendous superiority in drug delivery. Despite plenty of researches on MWNT based delivery systems, precision-guided assistances to maximize their profitable properties are still lacking in substantive progress. We developed here a dual-targeting and co-delivery system based on MWNT for antiangiogenesis therapy in lung cancer which aimed at renin-angiotensin system (RAS) dysregulation by synergistically conducting angiotensin II type 1 receptor (ATR) and type 2 receptor (ATR) pathway. In this work, iRGD peptide connected to polyethyleneimine (PEI) was linked to MWNT skeleton, accompanying with candesartan (CD) conjugated to MWNT mediated by cystamine (SS). The functionalized MWNT is assembled with plasmid AT (pAT) to form iRGD-PEI-MWNT-SS-CD/pAT complexes. iRGD and CD act as pilots for complexes to dually target symbolic ανβ3-integrin and ATR both overexpressed on tumor angiogenic endothelium and lung cancer cell. CD as chemotherapy showed synergistic downregulation of VEGF when combining of pAT and efficiently inhibited angiogenesis. iRGD-PEI-MWNT-SS-CD/pAT complexes greatly appreciated drug activities by changing drug distribution and exhibited remarkable tumor growth suppression in A549 xenograft nude mice. Our work presents that such dual-targeting strategy highly improves the delivery performance of MWNT and open a new avenue for RAS related lung cancer therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2017.05.046DOI Listing
September 2017

Overcoming multidrug resistance by a combination of chemotherapy and photothermal therapy mediated by carbon nanohorns.

J Mater Chem B 2016 Sep 26;4(36):6043-6051. Epub 2016 Aug 26.

Department of analytical chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China.

Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy due to the overexpression of P-glycoprotein (P-gp). Herein, etoposide (ETO) was loaded onto oxidized carbon nanohorns (oxCNHs), which were modified by polyethylene glycol (PEG) and further functionalized with the targeting ligand P-gp monoclonal antibody (PA) in an attempt to overcome MDR. The obtained drug delivery system ([email protected]/PEG-PA) showed high drug loading efficiency, enhanced drug release under laser irradiation, improved cellular uptake and increased therapeutic effect both in vitro and in vivo. In addition, NIR laser irradiation had a synergistic effect on overcoming MDR. The MDR-overcoming mechanism could be the efficient cellular uptake, enhanced drug release and reduced drug efflux by P-gp. These results demonstrated that [email protected]/PEG-PA could be a promising drug delivery system for cancer MDR reversion.
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http://dx.doi.org/10.1039/c6tb01469kDOI Listing
September 2016

Reconstituted high density lipoprotein mediated targeted co-delivery of HZ08 and paclitaxel enhances the efficacy of paclitaxel in multidrug-resistant MCF-7 breast cancer cells.

Eur J Pharm Sci 2016 Sep 23;92:11-21. Epub 2016 Jun 23.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address:

In the past decades, reconstituted high density lipoprotein (rHDL) has been successfully developed as a drug carrier since the enhanced HDL-lipids uptake is demonstrated in several human cancers. In this paper, rHDL, for the first time, was utilized to co-encapsulate two hydrophobic drugs: an anticancer drug, paclitaxel (PTX), and a new reversal agent for P-gp (P-glycoprotein)-mediated multidrug resistance (MDR) of cancer, N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide (HZ08). We proposed this drug co-delivery strategy to reverse PTX resistance. The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted PTX-HZ08 delivery for cancer therapy. Using sodium cholate dialysis method, we successfully formulated dual-agent co-delivering rHDL nanoparticles (PTX-HZ08-rHDL NPs) with a typical spherical morphology, well-distributed size (~100nm), high drug encapsulation efficiency (approximately 90%), sustained drug release properties and exceptional stability even after storage for 1month or incubation in 10% fetal bovine serum (FBS) DMEM for up to 2days. Results demonstrated that PTX-HZ08-rHDL NPs significantly enhanced anticancer efficacy in vitro, including higher cytotoxicity and better ability to induce cell apoptosis against both PTX-sensitive and -resistant MCF-7 human breast cancer cell lines (MCF-7 and MCF-7/PTX cells). Mechanism studies demonstrated that these improvements could be correlated with increased cellular uptake of PTX mediated by scavenger receptor class B type I (SR-BI) as well as prolonged intracellular retention of PTX due to the HZ08 mediated drug-efflux inhibition. In addition, in vivo investigation showed that the PTX-HZ08-rHDL NPs were substantially safer, have higher tumor-targeted capacity and have stronger antitumor activity than the corresponding dosage of paclitaxel injection. These findings suggested that rHDL NPs could be an ideal tumor-targeted nanovector for simultaneous transfer of insoluble anticancer drug and drug resistance reversal agents. The PTX-HZ08-rHDL NPs co-delivery system might be a new promising strategy to overcome tumor drug resistance.
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http://dx.doi.org/10.1016/j.ejps.2016.06.017DOI Listing
September 2016

Metabolism and bioactivation of the tricyclic antidepressant amitriptyline in human liver microsomes and human urine.

Bioanalysis 2016 Jul 9;8(13):1365-81. Epub 2016 Jun 9.

Tongji School of Pharmacy, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan 430030, Hubei, China.

Aim: Amitriptyline is a widely used tricyclic antidepressant, but the metabolic studies were conducted almost 20 years ago using high-performance liquid chromatography coupled with ultraviolet detector or radiolabeled methods.

Results: First, multiple ion monitoring (MIM)- enhanced product ion (EPI) scan was used to obtain the diagnostic ions or neutral losses in human liver microsome incubations with amitriptyline. Subsequently, predicted multiple reaction monitoring (MRM)-EPI scan was used to identify the metabolites in human urine with the diagnostic ions or neutral losses. Finally, product ion filtering and neutral loss filtering were used as the data mining tools to screen metabolites. Consequently, a total of 28 metabolites were identified in human urine after an oral administration using LC-MS/MS.

Conclusion: An integrated workflow using LC-MS/MS was developed to comprehensively profile the metabolites of amitriptyline in human urine, in which five N-acetyl-l-cysteine conjugates were characterized as tentative biomarkers for idiosyncratic toxicity.
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http://dx.doi.org/10.4155/bio-2016-0025DOI Listing
July 2016

Impact of curcumin on the pharmacokinetics of rosuvastatin in rats and dogs based on the conjugated metabolites.

Xenobiotica 2017 Mar 13;47(3):267-275. Epub 2016 May 13.

a Tongji School of Pharmacy, Huazhong University of Science & Technology , Wuhan , P.R. China.

1. Plasma concentrations of curcumin-O-glucuronide (COG) and curcumin-O-sulfate (COS) significantly increased after Sprague-Dawley rats dealt with the Oatp inhibitor rifampicin, with the C ascending 2.9 and 6.7 times, and the AUC ascending 4.4 and 10.8 times, respectively. When pretreated with the Oat inhibitor probenecid, the C increased 4.4 and 20 times, and the AUC increased 3.2 and 13.9 times, respectively. The results suggested that COG and COS may be the substrates of Oatp and Oat. 2. The accumulation of curcumin significantly increased in organic anion transporting polypeptide (OATP)- and organic anion transporter (OAT)-transfected human embryonic kidney (HEK) 293 systems, which suggested that curcumin was a substrate of OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT3; and COG was a substrate of OATP1B1, OATP1B3, and OAT3. 3. Inhibition study using rosuvastatin as the substrate in OATP1B1- and OATP1B3-transfected cells indicated that curcumin was an OATP1B1 and 1B3 inhibitor, with IC at 5.19 ± 0.05 and 3.68 ± 0.05 μM, respectively; the data for COG were 1.04 ± 0.01 and 1.08 ± 0.02 μM, respectively. COS was speculated to be an inhibitor of hepatic OATP1B1 as calculated using the ADMET Predictor. 4. COG and COS are substrates and inhibitors of OATP/Oatp. Co-administration of curcumin significantly increased rosuvastatin concentration in rat and dog plasma.
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http://dx.doi.org/10.1080/00498254.2016.1183060DOI Listing
March 2017

A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy.

Mater Sci Eng C Mater Biol Appl 2016 Jul 5;64:208-218. Epub 2016 Apr 5.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address:

Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers, and chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor, without apparent toxicity in normal tissues. Combining DCA and p53 gene could be an effective way to treat tumors. The progress towards broad applications of DCA/p53 combination requires the development of safe and efficient vectors that target to specific cells. In this study, we developed a DSPE-PEG-AA (1,2-distearoryl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide) modified reconstituted high-density lipoprotein-based DCA/p53-loaded nanoparticles (DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes), which was fabricated as a drug/gene dual-targeting co-delivery system for potential cancer therapy. Here, DCA-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL and to act as an antitumor drug to inhibit tumor cell growth. The DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge and low cytotoxicity for normal cells in vitro. The results of confocal laser scanning microscopy (CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug delivery and gene transfection in human lung adenocarcinoma cell line A549. And in vivo investigation on nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes possessed specific tumor targeting and strong antitumor activity. The work described here demonstrated that the DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes might offer a promising tool for effective cancer therapy.
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http://dx.doi.org/10.1016/j.msec.2016.03.083DOI Listing
July 2016

Finding New Tricks for Old Drugs: Tumoricidal Activity of Non-Traditional Antitumor Drugs.

AAPS PharmSciTech 2016 Jun 31;17(3):539-52. Epub 2016 Mar 31.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.

Chemotherapy, a traditional method, plays an important role in tumor therapy. Currently, common clinical antitumor drugs have several defects like poor efficacy, side effects, etc. Furthermore, developing new antitumor drugs takes a long time and requires many resources. Recent studies have found that oldies are newbies for the oncologist, such as flavonoid, metformin, aspirin, etc. These non-traditional antitumor drugs (NTADs) are widely used in management of non-cancer diseases, which gained FDA approval for treatment of patients. Increasingly, studies about antitumor action of NTADs have attracted many researchers' interests. A giant amount of studies showed a decrease in cancer incidence in NTAD-treated patients. Several reports outlined a direct inhibitory effect of NTADs on cancer cell growth and antitumoral actions. This review summarized the research progress on antitumor effects of ten NTADs. Retrospective and meta-analyses of trials also showed that these NTADs had preventive effects against cancer in vitro and in vivo. These drugs represent a promising option for cancer treatment, which have clear benefits including clinical safety, obvious curative effect, and saving medical and health resources. Judged from previous reports, future studies will yield valuable data about the profitable effects of these drugs. With a better understanding of its mechanisms of antitumor activity, NTADs may become available for combination with chemotherapy or targeted therapy in clinic.
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http://dx.doi.org/10.1208/s12249-016-0518-yDOI Listing
June 2016

Development and validation of an LC-MS/MS method for simultaneous quantification of levodopa and MD01 in rat plasma and its application to a pharmacokinetic study of mucuna pruriens extract.

Biomed Chromatogr 2016 Sep 22;30(9):1506-14. Epub 2016 Mar 22.

Tongji School of Pharmacy, Huazhong University of Scinence and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.

Mucuna pruriens, an ancient Indian herbal medicine containing levodopa, is widely used for Parkinson's disease. In order to simultaneously determine levodopa and 1,1-dimethyl-3-carboxy-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (MD01) in rat plasma, an improved LC-MS/MS method was developed and validated for a pharmacokinetic study in rats orally administered levodopa or Mucuna pruriens extract (MPE). Elimination of matrix effect and improvement of extraction recovery were achieved through systematic optimization of reversed-phase and hydrophilic interaction chromatographic conditions together with sample clean-up procedures. A satisfactory chromatographic performance was obtained with a Thermo Aquasil C18 column (50 × 2.1 mm, 3 µm) using acetonitrile and water containing 0.2% formic acid as mobile phases. Futhermore, sodium metabisulfite and formic acid were used as stabilizers in neat solutions as well as rat plasma. The method was validated in a dynamic range of 20.0-10,000 ng/mL for levodopa and MD01; the intra- and inter-day precision and accuracy were acceptable. The method was successfully utilized to determine the levodopa level in plasma samples of rats administered levodopa or MPE. Pharmacokinetic results showed that an increase in the AUC of levodopa was observed in rats following oral administration of multiple doses of MPE. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/bmc.3714DOI Listing
September 2016

Up-regulation of serum miR-744 predicts poor prognosis in patients with nasopharyngeal carcinoma.

Int J Clin Exp Med 2015 15;8(8):13296-302. Epub 2015 Aug 15.

College of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.

Background: MiRNAs has been shown to be implicated in the pathogenesis of many human diseases including cancer. Dysregulation of miR-744 is common in a number of cancers, indicating miR-774 might be closely correlated with the tumorigenesis process. However, the role and clinical significance of miR-774 in nasopharyngeal carcinoma (NPC) is poorly known. Thus the aim of this study is to investigate whether there was any clinical value of serum miR-744 in detecting and predicting the prognosis of NPC.

Materials And Methods: Real-time PCR was used to examine the expression level of serum miR-744 in patients with NPC and the healthy volunteers. The changes in serum miR-744 expression level of NPC patients after receiving chemo-radiotherapy were also evaluated. The association between pre-treatment serum miR-744 expression level and NPC clinicopathological parameters was investigated. Finally we employed Kaplan-Meier method and Cox proportional hazards model to evaluate the clinical value of serum miR-744 in predicting the prognosis of NPC.

Results: Our study showed the expression level of serum miR-744 was significant higher in patients with NPC in comparison with healthy controls (P<0.01). The serum miR-744 expression level was down-regulated significantly in NPC patients after receiving chemo-radiotherapy (P<0.01). The Pre-treatment Serum miR-744 expression level was correlated with various important NPC clinicopathological parameters including N stage, clinical stage and grade. In addition, NPC patients with higher serum miR-744 expression had poorer 5 year overall survival rate and relapse-free survival rate. What was more, serum miR-744 was showed to be an independent factor for predicting the prognosis of NPC.

Conclusion: Serum miR-744 was up-regulated in NPC patients. Higher expression level of serum miR-744 was closely correlated with was associated with poor prognosis in NPC and it might be employed as a potential biomarker for predicting the clinical outcome of NPC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612941PMC
November 2015

Versatile reticular polyethylenimine derivative-mediated targeted drug and gene codelivery for tumor therapy.

Mol Pharm 2014 Oct 1;11(10):3307-21. Epub 2014 Aug 1.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.

The study is aimed to develop a versatile reticular polyethylenimine (PEI) derivative eprosartan-g-PEI (ESP) conjugate-mediated targeted drug and gene codelivery system for tumor therapy. Eprosartan (ES), an angiotensin II type 1 receptor blocker (ARB), which has been proven to exert beneficial effects on tumor progression, vascularization, and metastasis as the conventional antihypertensive drug, was conjugated with PEI-1.8K chains into ESP via a bis-amide bond of pH-sensitivity to overcome high cytotoxicity and nontargeted gene delivery of PEI-25K. P53 gene was encapsulated in the ESP to form the codelivery system of ESP/p53 complexes, and this system was comprehensively characterized. In vitro ESP/p53 complexes had a significant effect on inhibiting angiogenesis by reducing the expression and secretion of VEGF. In vivo the effective antitumor activity of ESP/p53 complexes was observed on nude mice bearing PANC-1 xenografts, and the microvessel density (MVD) examination demonstrated that ESP/p53 complex-produced antitumor efficacy was closely correlated with the efficient angiogenesis repression. These findings disclosed that the multifunctional ESP/p53 complexes might be a promising dual anticancer drug and gene codelivery system.
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http://dx.doi.org/10.1021/mp5001263DOI Listing
October 2014

Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling.

Blood 2006 Jul 28;108(1):305-10. Epub 2006 Feb 28.

Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Overexpression of intracellular Notch plays an important role in the generation of human acute lymphoblastic T cell leukemia (T-ALL). In mouse models, it was shown that Notch-dependent T-ALL required pre-TCR signaling. Here we show that pre-TCR signaling is required to condition mice for Notch-dependent transformation but that it is not required to sustain malignant growth of T-ALL. In contrast to previous studies, we found that disease development does not require pre-TCR but that it can be accelerated in Rag2(-/-) mice by transient mimicking of pre-TCR signals.
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http://dx.doi.org/10.1182/blood-2006-01-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895839PMC
July 2006

Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality.

J Biol Chem 2006 Mar 8;281(9):5916-27. Epub 2005 Dec 8.

Glycobiology and Carbohydrate Chemistry Program, Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

MPI encodes phosphomannose isomerase, which interconverts fructose 6-phosphate and mannose 6-phosphate (Man-6-P), used for glycoconjugate biosynthesis. MPI mutations in humans impair protein glycosylation causing congenital disorder of glycosylation Ib (CDG-Ib), but oral mannose supplements normalize glycosylation. To establish a mannose-responsive mouse model for CDG-Ib, we ablated Mpi and provided dams with mannose to rescue the anticipated defective glycosylation. Surprisingly, although glycosylation was normal, Mpi(-/-) embryos died around E11.5. Mannose supplementation even hastened their death, suggesting that man-nose was toxic. Mpi(-/-) embryos showed growth retardation and placental hyperplasia. More than 90% of Mpi(-/-) embryos failed to form yolk sac vasculature, and 35% failed chorioallantoic fusion. We generated primary embryonic fibroblasts to investigate the mechanisms leading to embryonic lethality and found that mannose caused a concentration- and time-dependent accumulation of Man 6-P in Mpi(-/-) fibroblasts. In parallel, ATP decreased by more than 70% after 24 h compared with Mpi(+/+) controls. In cell lysates, Man-6-P inhibited hexokinase (70%), phosphoglucose isomerase (65%), and glucose-6-phosphate dehydrogenase (85%), but not phosphofructokinase. Incubating intact Mpi(-/-) fibroblasts with 2-[(3)H]deoxyglucose confirmed mannose-dependent hexokinase inhibition. Our results in vitro suggest that mannose toxicity in Mpi(-/-) embryos is caused by Man-6-P accumulation, which inhibits glucose metabolism and depletes intracellular ATP. This was confirmed in E10.5 Mpi(-/-) embryos where Man-6-P increased more than 10 times, and ATP decreased by 50% compared with Mpi(+/+) littermates. Because Mpi ablation is embryonic lethal, a murine CDG-Ib model will require hypomorphic Mpi alleles.
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http://dx.doi.org/10.1074/jbc.M511982200DOI Listing
March 2006