Publications by authors named "Bolei Cai"

16 Publications

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Multifunctional hierarchical nanohybrids perform triple antitumor theranostics in a cascaded manner for effective tumor treatment.

Acta Biomater 2021 Apr 18. Epub 2021 Apr 18.

School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Shenzhen Research Institute, Xi'an Jiao Tong University, Xi'an, 714049, China. Electronic address:

Gene therapy based on transfection of RNAs/DNAs offers tremendous promise for tumor treatment. However, the relatively weak therapeutic efficiency of current genetic nanohybrids in vivo has limited the application of this strategy. Herein, we fabricated multifunctional core-shell-corona nanohybrids by combining cascaded theranostics for enhanced gene therapy. The nanohybrids consist of polydopamine-modified FeO nanoparticles as core, anti-miRNA-21 oligonucleotides (anti-miRNA) strands as shell, and doxorubicin (DOX)-conjugated DNA-8pb (DOX-DNA-8bp) as corona. The polydopamine/FeO core not only serves as an active agent for local photothermal therapy under NIR irradiation, but it also provides magnetic targeting to tumor tissue for accurate treatment, which could enhance the therapeutic effect and reduce the undesired side effects to healthy tissues. The DOX-DNA-8bp corona was grafted on the anti-miRNA shell through base pairing, which could be replaced by overexpressed miRNA-21 in tumor cells due to the strong interaction between miRNA-21 and anti-miRNA, resulting in tumor-specific gene therapy through tumorigenic miRNA-21 consumption and tumor selective chemotherapy through miRNA-21-triggered DOX-DNA-8bp release in tumor cells. Moreover, the intelligent controlled release system can gradually stop the release of DOX to prevent side effects caused by drug overdose, once sufficient damage of tumor cells has occurred, due to the downregulation of miRNA-21. The results of both in vitro and in vivo analyses showed that the nanohybrids combining cascaded chemo-photo-gene therapy could effectively inhibit tumor growth, promote the survival of tumor-bearing mice, and show no visible adverse effects on these mice, resulting in a promising nanoplatform for tumor treatment. STATEMENT OF SIGNIFICANCE: Gene therapy based on transfection of RNAs/DNAs offers tremendous promise for cancer treatment. However, the relatively weak therapeutic efficiency of current genetic nanovectors in vivo that results in insufficient tumor targeting and easy decomposition/elimination of RNAs/DNAs during therapy has limited its application. Although some approaches have combined photothermal agents or antitumor drugs with RNA/DNA nanocarriers to achieve better treatment, the spatiotemporal differences in photothermal therapy, chemotherapy, and gene therapy using current nanohybrids may hinder their synergistic effect. In the present study, we fabricated multifunctional core-shell-corona nanohybrids (FeO@PDA@anti-miRNA/DNA) to simultaneously perform on-demand photothermal therapy, miR-21-triggered chemotherapy, and miR-21-dependent gene therapy at the same location, which can achieve an efficient synergistic effect for precise and effective tumor treatment.
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http://dx.doi.org/10.1016/j.actbio.2021.04.019DOI Listing
April 2021

Optimized BMSC-derived osteoinductive exosomes immobilized in hierarchical scaffold via lyophilization for bone repair through Bmpr2/Acvr2b competitive receptor-activated Smad pathway.

Biomaterials 2021 May 27;272:120718. Epub 2021 Mar 27.

Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, PR China; Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China. Electronic address:

Mesenchymal stem cell-derived exosomes (MSC-exos), with its inherent capacity to modulate cellular behavior, are emerging as a novel cell-free therapy for bone regeneration. Herein, focusing on practical applying problems, the osteoinductivity of MSC-exos produced by different stem cell sources (rBMSCs/rASCs) and culture conditions (osteoinductive/common) were systematically compared to screen out an optimized osteogenic exosome (BMSC-OI-exo). Via bioinformatic analyses by miRNA microarray and in vitro pathway verification by gene silencing and miRNA transfection, we first revealed that the osteoinductivity of BMSC-OI-exo was attributed to multi-component exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p and miR-31a-5p). These miRNAs targeted Acvr2b/Acvr1 and regulated the competitive balance of Bmpr2/Acvr2b toward Bmpr-elicited Smad1/5/9 phosphorylation. On these bases, lyophilized delivery of BMSC-OI-exo on hierarchical mesoporous bioactive glass (MBG) scaffold was developed to realize bioactivity maintenance and sustained release by entrapment in the surface microporosity of the scaffold. In a rat cranial defect model, the loading of BMSC-OI-exo efficiently enhanced the bone forming capacity of the scaffold and induced rapid initiation of bone regeneration. This paper could provide empirical bases of MSC-exo-based therapy for bone regeneration and theoretical bases of MSC-exo-induced osteogenesis mechanism. The BMSC-OI-exo-loaded MBG scaffold developed here represented a promising bone repairing strategy for future clinical application.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120718DOI Listing
May 2021

Injectable hydrogel with MSNs/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in pigs.

Sci Adv 2021 Feb 24;7(9). Epub 2021 Feb 24.

National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Current therapeutic strategies such as angiogenic therapy and anti-inflammatory therapy for treating myocardial infarction have limited success. An effective approach may benefit from resolution of excessive inflammation combined with enhancement of angiogenesis. Here, we developed a microRNA-21-5p delivery system using functionalized mesoporous silica nanoparticles (MSNs) with additional intrinsic therapeutic effects. These nanocarriers were encapsulated into an injectable hydrogel matrix (Gel@MSN/miR-21-5p) to enable controlled on-demand microRNA-21 delivery triggered by the local acidic microenvironment. In a porcine model of myocardial infarction, we demonstrated that the released MSN complexes notably inhibited the inflammatory response by inhibiting the polarization of M1 macrophage within the infarcted myocardium, while further microRNA-21-5p delivery by MSNs to endothelial cells markedly promoted local neovascularization and rescued at-risk cardiomyocytes. The synergy of anti-inflammatory and proangiogenic effects effectively reduced infarct size in a porcine model of myocardial infarction.
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http://dx.doi.org/10.1126/sciadv.abd6740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904259PMC
February 2021

Corrigendum to "A viscoelastic PEGylated poly(glycerol sebacate)-based bilayer scaffold for cartilage regeneration in full-thickness osteochondral defect" [Biomaterials 253 (2020) 120095].

Biomaterials 2021 Feb 10;269:120618. Epub 2021 Jan 10.

Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, PR China; Shanghai University of Medicine and Health Sciences, Shanghai, 201318, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.biomaterials.2020.120618DOI Listing
February 2021

NDRG2 ablation reprograms metastatic cancer cells towards glutamine dependence the induction of ASCT2.

Int J Biol Sci 2020 16;16(16):3100-3115. Epub 2020 Oct 16.

The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.

Metastasis is the most common cause of lethal outcome in various types of cancers. Although the cell proliferation related metabolism rewiring has been well characterized, less is known about the association of metabolic changes with tumor metastasis. Herein, we demonstrate that metastatic tumor obtained a mesenchymal phenotype, which is obtained by the loss of tumor suppressor NDRG2 triggered metabolic switch to glutamine metabolism. mRNA-seq and gene expression profile analysis were performed to define the differential gene expressions in primary MEC1 and metastatic MC3 cells and the downstream pathways of NDRG2. NDRG2 regulation of Fbw7-dependent c-Myc stability were determined by immunoprecipitation and protein half-life assay. Luciferase reporter and ChIP assays were used to determine the roles of Akt and c-Myc in mediating NDRG2-dependent regulation of ASCT2 in in both tumor and NDRG2-knockout MEF cells. Finally, the effect of the NDRG2/Akt/c-Myc/ASCT2 signaling on glutaminolysis and tumor metastasis were evaluated by functional experiments and clinical samples. Based on the gene expression profile analysis, we identified metastatic tumor cells acquired the mesenchymal-like characteristics and displayed the increased dependency on glutamine utilization. Further, the gain of NDRG2 function blocked epithelial-mesenchymal transition (EMT) and glutaminolysis, potentially through suppression of glutamine transporter ASCT2 expression. The ASCT2 restoration reversed NDRG2 inhibitory effect on EMT program and tumor metastasis. Mechanistic study indicates that NDRG2 promoted Fbw7-dependent c-Myc degradation by inhibiting Akt activation, and subsequently decreased c-Myc-mediated ASCT2 transcription, in both tumor and NDRG2-knockout MEF cells. Supporting the biological significance, the reciprocal relationship between NDRG2 and ASCT2 were observed in multiple types of tumor tissues, and associated with tumor malignancy. NDRG2-dependent repression of ASCT2 presumably is the predominant route by which NDRG2 rewires glutaminolysis and blocks metastatic tumor survival. Targeting glutaminolytic pathway may provide a new strategy for the treatment of metastatic tumors.
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http://dx.doi.org/10.7150/ijbs.48066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645990PMC
October 2020

A viscoelastic PEGylated poly(glycerol sebacate)-based bilayer scaffold for cartilage regeneration in full-thickness osteochondral defect.

Biomaterials 2020 09 6;253:120095. Epub 2020 May 6.

Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, PR China; Shanghai University of Medicine and Health Sciences, Shanghai, 201318, PR China. Electronic address:

Defects of either articular cartilage or subchondral bone would destroy the structural integrity and functionality of the joint. Reconstruction of osteochondral defects requires difunctional scaffolds that simultaneously induce cartilage and subchondral bone morphogenesis, however, high-performance cartilage reconstructive scaffolds remain a considerable challenge. In this study, a solvent-free urethane crosslinking and spontaneous pore-forming procedure under room temperature was proposed and optimized to produce PEGylated poly(glycerol sebacate) (PEGS) scaffolds with controllable crosslinking degrees and hierarchical macro-/micro-porosities. Based on the economical and feasible preparative approach, the viscoelastic PEGS-12h with low crosslinking degree was demonstrated to significantly stimulate chondrogenic differentiation, maintain chondrocyte phenotype and enhance cartilage matrix secretion compared to elastic polymer with high crosslinking degree, emphasizing the importance of matrix viscoelasticity in cartilage regeneration. On this basis, the viscoelastic low-crosslinked PEGS-12h was combined with the well-acknowledged osteoinductive mesoporous bioactive glass (MBG) to construct a difunctional PEGS/MBG bilayer scaffold, and evaluated in a full-thickness osteochondral defect model in vivo. The PEGS/MBG bilayer scaffold successfully reconstructed well-integrated articular hyaline cartilage and its subchondral bone in 12 weeks, exhibiting extraordinary regenerative efficiency. The results indicated that the viscoelastic PEGS scaffold and PEGS/MBG bilayer scaffold proposed in this study made an excellent candidate for cartilage and osteochondral regeneration, and was expected for clinical translation in the future.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120095DOI Listing
September 2020

Tumor-specific nanomedicine via sequential catalytic reactions for accurate tumor therapy.

J Mater Chem B 2020 08 5;8(31):6857-6865. Epub 2020 Feb 5.

Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiao Tong University, Xi'an, 710049, China.

Catalytic medicine based on various catalysts has attracted increasing interest for the treatment of tumors. However, the direct application of conventional catalysts may cause serious side effects to healthy tissue and low therapeutic efficiency against tumor tissue, due to their weak specificity for the tumor microenvironment (TME). Herein, a tumor-targeting and TME-responsive nanoreactor containing ferroferric oxide nanoparticles (FeO NPs) and glucose oxidase (GOD) was developed to perform hyaluronidase (HAase) and glutathione (GSH)-triggered chain catalytic reactions in tumor tissue. This nanoreactor was designed to take advantage of the unique biological molecules in tumors and several therapeutic agents to adjust the local microenvironments, and achieved satisfactory and accurate tumor therapy. The reactions started with the consumption of intratumoral glucose to inhibit tumor growth, and simultaneously produced hydrogen peroxide (HO) to make up for the deficiency of HO in the original tumor microenvironment, resulting in the generation of a high quantity of hydroxyl radicals as a result of the catalysis of FeO NPs to further eliminate tumor tissue. The tumor-specific catalytic medicine formed by our nanocomposite guaranteed both therapeutic efficiency and accuracy, avoiding potential risks to healthy tissue and leading to a four-fold improvement in the cytotoxicity against tumor cells compared with normal cells after incubations of 48 h. In vivo data from mouse models provided further evidence for its therapeutic efficacy: the tumor growth was completely inhibited after two weeks of the synergistic therapy, which indicated the promise of our nanocomposite for tumor treatment.
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http://dx.doi.org/10.1039/c9tb02812aDOI Listing
August 2020

A tumor-targeted nanoplatform with stimuli-responsive cascaded activities for multiple model tumor therapy.

Biomater Sci 2020 Mar;8(7):1865-1874

School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an, 710049, China.

Herein, a rambutan-like nanocomplex (PDA-SNO-GA-HA-DOX, PSGHD for short) was designed to enable effective and accurate tumor therapy. The PSGHD nanocomplex consists of an S-nitrosothiol-functionalized polydopamine (PDA-SNO) core and a gambogic acid-derivatized hyaluronic acid (HA-GA) shell with doxorubicin (DOX) as the cargo. Due to the HA section, the PSGHD nanocomplex can be rapidly and selectively internalized by tumor cells instead of healthy cells in 12 h of co-incubation. After that, the internalized PSGHD nanocomplex is able to gradually release both DOX (agent for chemotherapy) and GA (agent for enhancing thermal damage) under different tumor-specific physiological conditions (low pH and rich HAase). When 808 nm NIR radiation was employed, the PSGHD nanocomplex further demonstrated excellent photothermal conversion to increase the local temperature over 43 °C and convert SNO to nitric oxide (NO, an agent for decreasing drug-efflux). Based on the synergistic effects of NO/DOX and GA/heat, the PSGHD nanocomplex simultaneously achieved tumor-specific low-drug-efflux chemotherapy and low-temperature photothermal therapy, resulting in an eight-fold apoptosis of tumor cells over normal cells under NIR radiation. In vivo data from mouse models further showed that the PSGHD nanocomplex can completely inhibit tumor growth and significantly prolong the survival rate of tumor bearing mice in 50 days, demonstrating the high efficiency of the PSGHD nanocomplex for tumor therapy.
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http://dx.doi.org/10.1039/c9bm01992hDOI Listing
March 2020

c-Myc Overexpression Promotes Oral Cancer Cell Proliferation and Migration by Enhancing Glutaminase and Glutamine Synthetase Activity.

Am J Med Sci 2019 09 7;358(3):235-242. Epub 2019 Jun 7.

State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Shaanxi Province, China. Electronic address:

Background: This study aimed to investigate whether glutaminase (GLS) and glutamine synthetase (GS) are involved in c-Myc-mediated tumor development in oral cancer.

Methods: The correlation between the expressions of c-Myc, GLS, and GS in clinical samples and the clinicopathologic features of oral cancer were examined using immunohistochemistry and quantitative real-time polymerase chain reaction. After overexpressing the c-Myc gene and using an inhibitor of GLS or GS, functional experiments were performed to confirm the effects of c-Myc, GLS and GS on proliferation, cell cycle and migration in KB oral cancer cells. The expressions of E-cadherin and N-cadherin were determined by immunofluorescence assays in KB cells overexpressing c-Myc in the presence of GLS or GS inhibitors.

Results: The protein expression of GS was correlated with the Tumor, Lymph Node, and Metastasis (TNM) stage. In addition, c-Myc mRNA levels were positively correlated with GS mRNA levels. Overexpression of c-Myc increased the colonies derived from oral cancer cells and caused more cells to be in S phase compared with the mock-vehicle group. The migratory speed of KB cells was promoted by overexpression of c-Myc compared to the mock-vehicle group. However, these effects were effectively reversed in the presence of GLS or GS inhibitor. Furthermore, c-Myc could inhibit E-cadherin protein expression while promoting N-cadherin expression by enhancing the activity of GLS and GS.

Conclusions: c-Myc overexpression promotes oral cancer cell proliferation and migration by enhancing GLS and GS activity. Our findings are beneficial for the identification of novel molecular targets for the prevention and treatment of oral cancer.
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http://dx.doi.org/10.1016/j.amjms.2019.05.014DOI Listing
September 2019

Intracellular Enzyme-Triggered Assembly of Amino Acid-Modified Gold Nanoparticles for Accurate Cancer Therapy with Multimode.

ACS Appl Mater Interfaces 2019 Aug 31;11(32):28621-28630. Epub 2019 Jul 31.

Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology , Xi'an Jiao Tong University , Xi'an 710049 , P. R. China.

Multiple amino acid (glutamine and lysine)-modified gold nanoparticles a with pH-switchable zwitterionic surface were fabricated through coordination bonds using ferrous iron (Fe) as bridge ions, which are able to spontaneously and selectively assemble in tumor cells for accurate tumor therapy combining enzyme-triggered photothermal therapy and HO-dependent catalytic medicine. These gold nanoparticles showed electric neutrality at pH 7.4 (hematological system) to prevent endocytosis of normal cells, which could be positively charged at pH 6.8 (tumor microenvironment) to promote the endocytosis of tumor cells to these nanoparticles, performing great tumor selectivity. After cell uptake, the specific enzyme (transglutaminase) in tumor cells would catalyze the polymerization of glutamine and lysine to cause the intracellular assembly of these gold nanoparticles, resulting in an excellent photothermal property for accurate tumor therapy. Moreover, the Fe ion could decompose excess hydrogen peroxide (HO) in tumor cells via the Fenton reaction, resulting in a large amount of hydroxyl radicals (·OH). These radicals would also cause tumor cell damage. This synergetic therapy associating with high tumor selectivity generated an 8-fold in vitro cytotoxicity against tumor cells compared with normal cells under 48 h incubation with 10 min NIR irradiation. Moreover, in vivo data from tumor-bearing nude mice models showed that tumors can be completely inhibited and gradually eliminated after multimode treatment combining catalytic medicine and photothermal therapy for 3 weeks. This system takes advantage of three tumor microenvironment conditions (low pH, enzyme, and HO) to trigger the therapeutic actions, which is a promising platform for cancer therapy that achieved prolonged circulation time in the blood system, selective cellular uptake, and accurate tumor therapy in multiple models.
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http://dx.doi.org/10.1021/acsami.9b05943DOI Listing
August 2019

Biological role of metabolic reprogramming of cancer cells during epithelial‑mesenchymal transition (Review).

Oncol Rep 2019 Feb 23;41(2):727-741. Epub 2018 Nov 23.

The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

Epithelial‑mesenchymal transition (EMT) is required for the distant metastasis of tumors. The degree of tumor malignancy increases as EMT progresses. Notably, the biology of tumor cells differs from that of normal cells, with regards to characteristics and energy metabolism mechanisms; abnormal glucose metabolism, excessive accumulation of fatty acids and other metabolic disorders occur in metastatic tumors. Previous studies have confirmed that the regulation of tumor cell metabolism can affect tumor metastasis and some findings have resulted in novel clinical applications. The present review aimed to provide a basis for treatments targeting the tumor EMT process and metabolic reprogramming.
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http://dx.doi.org/10.3892/or.2018.6882DOI Listing
February 2019

Changes of disc status in adult patients with condylar head fracture who did or did not undergo disc anchoring operation.

J Craniomaxillofac Surg 2018 Dec 10;46(12):2248-2255. Epub 2018 Oct 10.

Department of Oral & Craniomaxillofacial Science, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China. Electronic address:

Purpose: Views on treatment procedures for condylar head fractures (CHFs) are far from reaching a consensus. The aim of this study was to evaluate the changes in disc status for anteromedial disc displacement with anchorage (AMDDwA) and without anchorage (AMDDwoA - just suturing to the adjacent TMJ soft tissue) in adult CHFs, to get a better understanding of this very complex process and to show that rigid disc anchorage is an essential technique for the treatment of CHF during the open reduction and internal fixation (ORIF).

Patients And Methods: 144 temporomandibular joints (TMJ) in 95 patients were included in this retrospective study, and were divided into an AMDDwA group (50 TMJs in 38 patients) and an AMDDwoA group (94 TMJs in 57 patients) based on the different surgical procedures. The joints were quantitatively and qualitatively assessed for disc length and disc morphology preoperatively and at follow-up visits. Other variables, such as disc position, joint effusion, retrodiscal tear and lateral capsular tear, were also evaluated. Paired t-tests, Wilcoxon signed rank tests, independent t-tests and χ tests were used to assess intragroup and intergroup differences.

Results: The results showed that discs became shorter, moved further forward and distorted more seriously in the AMDDwoA group. In contrast, discs became longer, maintained a normal disc-condyle relationship in the AMDDwA group. Joint effusion, retrodiscal tear, and lateral capsular tear healed well in both groups.

Conclusion: Taking these findings together suggests that the rigid disc anchorage is an alternative technique for the treatment of CHF.
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http://dx.doi.org/10.1016/j.jcms.2018.10.001DOI Listing
December 2018

MiRNA-29b suppresses tumor growth through simultaneously inhibiting angiogenesis and tumorigenesis by targeting Akt3.

Cancer Lett 2017 07 29;397:111-119. Epub 2017 Mar 29.

State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China. Electronic address:

The traditional anti-angiogenic cancer therapy could trigger hypoxia induced factor (HIF) response, leading to "reactive resistance" to chemotherapy. Simultaneously inhibiting both angiogenesis and tumorigenesis would be ideal to overcome this limitation. MicroRNAs (miRNAs) are increasingly explored as new agents for cancer therapy. In the present study, we identified a microRNA (miR-29b) with the ability of simultaneously inhibiting angiogenesis and tumorigenesis. Ectopic expression of miR-29b inhibits HUVECs formed three-dimensional capillary-like tubular structures, tumor cell proliferation, migration and tumor formation. Systemic administration of miR-29b potently suppressed tumor vascularization and cancer cell activity in vivo, resulting in dramatic suppression of tumor growth without toxicity. Moreover, we demonstrated the role of miR-29b in anti-angiogenesis and anti-tumorigenesis is through targeting Akt3 and inducing VEGF and C-myc arrest in breast cancer cells. These findings indicate that this single miRNA could be used as an efficient anti-cancer therapeutic agent to address a critical challenge in cancer therapy.
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http://dx.doi.org/10.1016/j.canlet.2017.03.032DOI Listing
July 2017

The role of myofibroblasts in the development of osteoradionecrosis in a newly established rabbit model.

J Craniomaxillofac Surg 2016 Jun 19;44(6):725-33. Epub 2016 Mar 19.

Department of Cranio-facial Trauma and Orthognathic Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, China; The State Key Laboratory of Military Stomatology, School of Stomatology, Fourth Military Medical University, Xi'an, China. Electronic address:

This study aimed to establish a proper animal model of osteoradionecrosis of jaws (ORNJ) and to observe preliminarily the characteristics of myofibroblasts, the key effector cell of fibrosis, in ORNJ. Rabbit mandibles were irradiated at three different doses based on a human equivalent radiation schedule, and examined by gross manifestation, single-photon emission computed tomography (SPECT), micro-computed tomography, sequential fluorochrome labeling, and histology. Immunohistochemistry staining of α-SMA was applied to detect the existence of myofibroblasts. The exposed necrotic bone, which is the main indication of ORNJ, started to be observed at all rabbits at 9 Gy. With the radiation dose increasing, the microarchitecture of the irradiated mandibles was more destroyed, the metabolism and mineralization of the irradiated mandibles diminished, the osteocytes number decreased, and more mature bones were substituted by fibrosis in the irradiated mandibles. In addition, as the radiation dose increased, the myofibroblast number increased and collected around the separated sequestrum, which indicated that myofibroblasts might relate to the pathogenesis of ORNJ. In summary, a clinically translational ORNJ model was successfully established in our study, and the role of myofibroblasts in the pathogenesis of ORNJ is described for the first time.
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http://dx.doi.org/10.1016/j.jcms.2016.03.002DOI Listing
June 2016

Nuclear multidrug-resistance related protein 1 contributes to multidrug-resistance of mucoepidermoid carcinoma mainly via regulating multidrug-resistance protein 1: a human mucoepidermoid carcinoma cells model and Spearman's rank correlation analysis.

PLoS One 2013 27;8(8):e69611. Epub 2013 Aug 27.

Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, Xi'an, China.

Background: Multidrug resistance-related protein 1 (MRP1/ABCC1) and multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1) are both membrane-bound drug transporters. In contrast to MDR1, MRP1 also transports glutathione (GSH) and drugs conjugated to GSH. Due to its extraordinary transport properties, MRP1/ABCC1 contributes to several physiological functions and pathophysiological incidents. We previously found that nuclear translocation of MRP1 contributes to multidrug-resistance (MDR) of mucoepidermoid carcinoma (MEC). The present study investigated how MRP1 contributes to MDR in the nuclei of MEC cells.

Methods: Western blot and RT-PCR was carried out to investigate the change of multidrug-resistance protein 1 (MDR1) in MC3/5FU cells after MRP1 was downregulated through RNA interference (RNAi). Immunohistochemistry (IHC) staining of 127 cases of MEC tissues was scored with the expression index (EI). The EI of MDR1 and MRP1 (or nuclear MRP1) was analyzed with Spearman's rank correlation analysis. Using multiple tumor tissue assays, the location of MRP1 in other tissues was checked by HIC. Luciferase reporter assays of MDR1 promoter was carried out to check the connection between MRP1 and MDR1 promoter.

Results: MRP1 downregulation led to a decreased MDR1 expression in MC3/5FU cells which was caused by decreased activity of MDR1 promoter. IHC study of 127 cases of MEC tissues demonstrated a strong positive correlation between nuclear MRP1 expression and MDR1 expression. Furthermore, IHC study of multiple tumor tissue array sections showed that although nuclear MRP1 widely existed in MEC tissues, it was not found in normal tissues or other tumor tissues.

Conclusions: Our findings indicate that nuclear MRP1 contributes to MDR mainly through regulating MDR1 expression in MEC. And the unique location of MRP1 made it an available target in identifying MEC from other tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754958PMC
May 2014

Cell bricks-enriched platelet-rich plasma gel for injectable cartilage engineering - an in vivo experiment in nude mice.

J Tissue Eng Regen Med 2013 Oct 21;7(10):819-30. Epub 2012 Mar 21.

Rege Laboratory of Tissue Engineering, College of Life Science, Northwest University, Xi'an, People's Republic of China.

Clinical application of platelet-rich plasma (PRP)-based injectable tissue engineering is limited by weak mechanical properties and a rapid fibrinolytic rate. We proposed a new strategy, a cell bricks-stabilized PRP injectable system, to engineer and regenerate cartilage with stable morphology and structure in vivo. Chondrocytes from the auricular cartilage of rabbits were isolated and cultured to form cell bricks (fragmented cell sheet) or cell expansions. Fifteen nude mice were divided evenly (n = 5) into cells-PRP (C-P), cell bricks-PRP (CB-P) and cell bricks-cells-PRP (CB-C-P) groups. Cells, cell bricks or a cell bricks/cells mixture were suspended in PRP and were injected subcutaneously in animals. After 8 weeks, all the constructs were replaced by white resilient tissue; however, specimens from the CB-P and CB-C-P groups were well maintained in shape, while the C-P group appeared distorted, with a compressed outline. Histologically, all groups presented lacuna-like structures, glycosaminoglycan-enriched matrices and positive immunostaining of collagen type II. Different from the uniform structure presented in CB-C-P samples, CB-P presented interrupted, island-like chondrogenesis and contracted structure; fibrous interruption was shown in the C-P group. The highest percentage of matrix was presented in CB-C-P samples. Collagen and sGAG quantification confirmed that the CB-C-P constructs had statistically higher amounts than the C-P and CB-P groups; statistical differences were also found among the groups in terms of biomechanical properties and gene expression. We concluded that cell bricks-enriched PRP gel sufficiently enhanced the morphological stability of the constructs, maintained chondrocyte phenotypes and favoured chondrogenesis in vivo, which suggests that such an injectable, completely biological system is a suitable cell carrier for cell-based cartilage repair.
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http://dx.doi.org/10.1002/term.1475DOI Listing
October 2013