Co-reporter:Zhenzhen Wang, Chunming Wang, Shang Liu, Wei He, Lintao Wang, JingJing Gan, Zhen Huang, Zhenheng Wang, Haoyang Wei, Junfeng Zhang, and Lei Dong
ACS Nano 2017 Volume 11(Issue 2) pp:
Publication Date(Web):January 13, 2017
DOI:10.1021/acsnano.6b07461
A corona is a layer of macromolecules formed on a nanoparticle surface in vivo. It can substantially change the biological identity of nanomaterials and possibly trigger adverse responses from the body tissues. Dissecting the role of the corona in the development of a particular disease may provide profound insights for understanding toxicity of nanomaterials in general. In our present study, we explored the capability of different silica nanoparticles (SiNPs) to induce silicosis in the mouse lung and analyzed the composition of coronas formed on these particles. We found that SiNPs of certain size and surface chemistry could specifically recruit transforming growth factor β1 (TGF-β1) into their corona, which subsequently induces the development of lung fibrosis. Once embedded into the corona on SiNPs, TGF-β1 was remarkably more stable than in its free form, and its fibrosis-triggering activity was significantly prolonged. Our study meaningfully demonstrates that a specific corona component on a certain nanoparticle could initiate a particular pathogenic process in a clinically relevant disease model. Our findings may shed light on the understanding of molecular mechanisms of human health risks correlated with exposure to small-scale substances.Keywords: corona; lung fibrosis; nano−bio interface; silica nanoparticles; TGF-β1;
Co-reporter:Chen Wang, Xing Zhou, Wentao Li, Mingyue Li, Tingyue Tu, Ximing Ba, Yinyu Wu, Zhen Huang, Gentao Fan, Guangxin Zhou, Sujia Wu, Jianning Zhao, Junfeng Zhang, Jiangning Chen
Cancer Letters 2017 Volume 403(Volume 403) pp:
Publication Date(Web):10 September 2017
DOI:10.1016/j.canlet.2017.06.011
•MIF is up-regulated in both tissue and serum samples of OS patients.•Increased MIF is associated with three-year survival rate of OS patients.•MIF promotes OS cell proliferation and migration by activating the RAS/MAPK pathway.•MIF silencing significantly inhibits OS growth and lung metastasis.•Inhibition of MIF represents a feasible and promising approach for OS therapy.Emerging evidence suggests that the tumour microenvironment plays a critical role in osteosarcoma (OS) development. Thus, cytokine immunotherapy could be a novel strategy for OS treatment. In this study, we explored the role of macrophage migration inhibitory factor (MIF), an important cytokine in OS progression, and investigated the anti-tumour effects of targeting MIF in OS. The results showed that MIF significantly increased in the tissue and serum samples of OS patients and was associated with tumour size, pulmonary metastasis and the survival rate of OS patients. We verified a positive correlation between MIF and p-ERK1/2 in OS patients. The in vitro results indicated that MIF could activate the RAS/MAPK pathway in a time- and dose-dependent manner, thereby promoting cell proliferation and migration. Furthermore, shRNA targeting MIF significantly inhibited tumour growth and lung metastasis in a mouse xenograft model and orthotopic model of OS. Additionally, inhibition of MIF significantly enhanced the sensitivity of OS cells to cisplatin and doxorubicin. Our findings suggest that immunotherapy targeting MIF to block the RAS/MAPK kinase cascade may represent a feasible and promising approach for OS treatment.
Co-reporter:Gang Zhou;Naicheng Liu;Zhenheng Wang;Tongguo Shi
Journal of Nanoparticle Research 2017 Volume 19( Issue 2) pp:
Publication Date(Web):2017 February
DOI:10.1007/s11051-017-3787-9
Nanoparticle-based applications for diagnostics and therapeutics have been extensively studied. These applications require a profound understanding of the fate of nanoparticles (NPs) in cellular environments. However, until now, few analytical methods are available and most of them rely on fluorescent properties or special elements of NPs; therefore, for NPs without observable optical properties or special elements, the existing methods are hardly applicable. In this study, we introduce a flow cytometry light scattering (FCLS)-based approach that quantifies in situ NPs accurately in mammalian cells. Continuous cells of heterogeneous human epithelial colorectal adenocarcinoma (Caco-2 cells), mouse peritoneal macrophages (MPM), and human adenocarcinomic alveolar basal epithelia (A549 cells) were cultured with NPs with certain concentrations and size. The intensity of the flow cytometric side scattered light, which indicates the quantity of NPs in the cells, was analyzed. The result shows an accurate size- and dose-dependent uptake of Au NPs (5, 30, 250 nm) in Caco-2 cells. The size- and dose- dependence of Au NPs (5, 30, 250 nm) and carbon NPs (50, 500 nm) in cells was validated by transmission electron microscope (TEM). This paper demonstrates the great potential of flow cytometry light scattering in the quantitative study of the size and dose effect on in situ metallic or non-metallic NPs in mammalian cells.
Co-reporter:Yuanyuan Gu;Shuoxin Liu;Xiaodan Zhang;Guimin Chen;Hongwei Liang
Protein & Cell 2017 Volume 8( Issue 6) pp:455-466
Publication Date(Web):31 March 2017
DOI:10.1007/s13238-017-0393-7
MTUS1 (microtubule-associated tumor suppressor 1) has been identified that can function as a tumor suppressor gene in many malignant tumors. However, the function and mechanisms underlying the regulation of MTUS1 are unclear. In the present study, we reported that miR-19a and miR-19b (miR-19a/b) promote proliferation and migration of lung cancer cells by targeting MTUS1. First, MTUS1 was proved to function as a tumor suppressor in lung cancer and was linked to cell proliferation and migration promotion. Second, an inverse correlation between miR-19a/b expression and MTUS1 mRNA/protein expression was noted in human lung cancer tissues. Third, MTUS1 was appraised as a direct target of miR-19a/b by bioinformatics analysis. Fourth, direct MTUS1 regulation by miR-19a/b in lung cancer cells was experimentally affirmed by cell transfection assay and luciferase reporter assay. Finally, miR-19a/b were shown to cooperatively repress MTUS1 expression and synergistically regulate MTUS1 expression to promote lung cancer cell proliferation and migration. In conclusion, our findings have provided the first clues regarding the roles of miR-19a/b, which appear to function as oncomirs in lung cancer by downregulating MTUS1.
Co-reporter:Guoyin Liu;Naicheng Liu;Yuansheng Xu;Yunfan Ti
Cell and Tissue Research 2016 Volume 363( Issue 2) pp:427-447
Publication Date(Web):2016 February
DOI:10.1007/s00441-015-2205-9
Aseptic loosening secondary to periprosthetic inflammatory osteolysis results from the biological response to wear particles and is a leading cause of arthroplasty failure. The origin of this inflammatory response remains unclear. We aim to validate the definite link between endoplasmic reticulum (ER) stress and particle-induced inflammatory signaling pathways in periprosthetic osteolysis. We examine the histopathologic changes of osteolysis and the expression of specific biomarkers for ER-stress-mediated inflammatory signaling pathways (IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca2+). Moreover, pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and osteoclastogenic molecules (VEGF, OPG, RANKL and M-CSF) were assessed in clinical interface membranes and murine periosteum tissues. We found wear particles to be capable of inducing ER stress in macrophages within clinical osteolytic interface membranes and murine osteolytic periosteum tissues and to be associated with the inflammatory response and osteoclastogenesis. Blocking ER stress with sodium 4-phenylbutyrate (4-PBA) results in a dramatic amelioration of particle-induced osteolysis and a significant reduction of ER-stress intensity. Simultaneously, this ER-stress blocker also lessens inflammatory cell infiltration, diminishes the capability of osteoclastogenesis and reduces the inflammatory response by lowering IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca2+ levels. Thus, ER stress plays an important role in particle-induced inflammatory osteolysis and osteoclastogenic reactions. The pharmacological targeting of ER-stress-mediated inflammatory signaling pathways might be an appealing approach for alleviating or preventing particle-induced osteolysis in at-risk patients.
Co-reporter:Zhen Zhou, Xihan Li, Jinxiong Liu, Lei Dong, Qun Chen, Jialing Liu, Huihui Kong, Qianyi Zhang, Xian Qi, Dongxia Hou, Lin Zhang, Guoquan Zhang, Yuchen Liu, Yujing Zhang, Jing Li, Jin Wang, Xi Chen, Hua Wang, Junfeng Zhang, Hualan Chen, Ke Zen and Chen-Yu Zhang
Cell Research 2015 25(1) pp:39-49
Publication Date(Web):October 7, 2014
DOI:10.1038/cr.2014.130
Influenza A viruses (IAVs), particularly H1N1, H5N1 and H7N9, pose a substantial threat to public health worldwide. Here, we report that MIR2911, a honeysuckle (HS)-encoded atypical microRNA, directly targets IAVs with a broad spectrum. MIR2911 is highly stable in HS decoction, and continuous drinking or gavage feeding of HS decoction leads to a significant elevation of the MIR2911 level in mouse peripheral blood and lung. Bioinformatics prediction and a luciferase reporter assay showed that MIR2911 could target various IAVs, including H1N1, H5N1 and H7N9. Synthetic MIR2911 significantly inhibited H1N1-encoded PB2 and NS1 protein expression, but did not affect mutants in which the MIR2911-binding nucleotide sequences were altered. Synthetic MIR2911, extracted RNA from HS decoction and HS decoction all significantly inhibited H1N1 viral replication and rescued viral infection-induced mouse weight loss, but did not affect infection with a mutant virus in which the MIR2911-binding nucleotide sequences of PB2 and NS1 were altered. Importantly, the inhibitory effect of HS decoction on viral replication was abolished by an anti-MIR2911 antagomir, indicating that the physiological concentration of MIR2911 in HS decoction could directly and sufficiently suppress H1N1 viral replication. MIR2911 also inhibited H5N1 and H7N9 viral replication in vitro and in vivo. Strikingly, administration of MIR2911 or HS decoction dramatically reduced mouse mortality caused by H5N1 infection. Our results demonstrate that MIR2911 is the first active component identified in Traditional Chinese Medicine to directly target various IAVs and may represent a novel type of natural product that effectively suppresses viral infection.
Co-reporter:Zhenheng Wang, Zhen Huang, Jingjing Gan, Naicheng Liu, Gang Zhou, Tongguo Shi, Zhenzhen Wang, Rui Wang, Nirong Bao, Ting Guo, Jiangning Chen, Junfeng Zhang, Lei Dong, Jianning Zhao
Acta Biomaterialia 2015 Volume 24() pp:352-360
Publication Date(Web):15 September 2015
DOI:10.1016/j.actbio.2015.06.024
Abstract
Particle-induced osteolysis is a major cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure and revision surgery. Although existing studies suggest that synovial fibroblasts present in the interfacial membrane are important targets of wear particles during bone resorption, the interaction mechanisms between the particles and fibroblasts remains elusive. In the present study, we investigated the effect of ER stress induced by CoCrMo particles (CoPs) in fibroblasts, calvarial resorption animal models and aseptic loosening clinical samples and its role in the stimulation of the RANKL expression. Our study further demonstrated that CoPs could induce significant ER stress in fibroblasts. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of RANKL in vitro and in vivo. Furthermore, in fibroblasts, downregulation of the expression of XBP1s, a signaling molecule of ER stress, significantly reduced the expression of RANKL induced by wear particles. Moreover, inhibition of ER stress or XBP1s both ameliorated the CoPs-induced osteolysis in animal models. Collectively, these results suggested that in particle-induced osteolysis, CoPs could stimulate fibroblasts to secret RANKL through ER stress and the signaling molecule XBP1s. Therefore, downregulating ER stress or the signaling molecule XBP1s of fibroblasts represents a potential therapeutic approach for treating particle-induced peri-implant osteolysis.
Statement of Significance
For the first time, our study demonstrated that ER stress mediated the induction of RANKL expression by CoPs in fibroblasts and promoted particle-induced osteolysis. Furthermore, the upregulation of RANKL by CoPs in fibroblasts was mediated by the ER stress signaling molecule XBP1s. Both blocking ER stress and inhibiting the protein XBP1s by specific inhibitors resulted in downregulation of the expression of RANKL and amelioration of osteolysis induced by the implanted particles. Collectively, these findings suggest a possible mechanism underlying the RANKL expression induced by wear particles in fibroblasts, and downregulating ER stress and the XBP1s expression of fibroblasts represents a potential therapeutic approach for treating aseptic loosening.
Co-reporter:Zhengping Zhang, Chunming Wang, Yinhe Zha, Wei Hu, Zhongfei Gao, Yuhui Zang, Jiangning Chen, Junfeng Zhang, and Lei Dong
ACS Nano 2015 Volume 9(Issue 3) pp:2405
Publication Date(Web):January 14, 2015
DOI:10.1021/nn505166x
Strategies to modify nanoparticles with biological ligands for targeted drug delivery in vivo have been widely studied but met with limited clinical success. A possible reason is that, in the blood circulation, serum proteins could rapidly form a layer of protein “corona” on the vehicle surface, which might block the modified ligands and hamper their targeting functions. We speculate that strategies for drug delivery can be designed based upon elegant control of the corona formation on the vehicle surfaces. In this study, we demonstrate a retinol-conjugated polyetherimine (RcP) nanoparticle system that selectively recruited the retinol binding protein 4 (RBP) in its corona components. RBP was found to bind retinol, and direct the antisense oligonucleotide (ASO)-laden RcP carrier to hepatic stellate cells (HSC), which play essential roles in the progression of hepatic fibrosis. In both mouse fibrosis models, induced by carbon tetrachloride (CCl4) and bile duct ligation (BDL), respectively, the ASO-laden RcP particles effectively suppressed the expression of type I collagen (collagen I), and consequently ameliorated hepatic fibrosis. Such findings suggest that this delivery system, designed to exploit the power of corona proteins, can serve as a promising tool for targeted delivery of therapeutic agents for the treatment of hepatic fibrosis.Keywords: drug nanocarriers; hepatic fibrosis; protein corona; retinol; targeted delivery;
Co-reporter:Zhen Huang, Jingjing Gan, Lixin Jia, Guangxing Guo, Chunming Wang, Yuhui Zang, Zhi Ding, Jiangning Chen, Junfeng Zhang, Lei Dong
Biomaterials 2015 48() pp: 26-36
Publication Date(Web):
DOI:10.1016/j.biomaterials.2015.01.013
Co-reporter:Yuan Yin, Xing Cai, Xi Chen, Hongwei Liang, Yujing Zhang, Jing Li, Zuoyun Wang, Xiulan Chen, Wen Zhang, Seiji Yokoyama, Cheng Wang, Liang Li, Limin Li, Dongxia Hou, Lei Dong, Tao Xu, Takachika Hiroi, Fuquan Yang, Hongbin Ji, Junfeng Zhang, Ke Zen and Chen-Yu Zhang
Cell Research 2014 24(10) pp:1164-1180
Publication Date(Web):September 16, 2014
DOI:10.1038/cr.2014.121
An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion.
Co-reporter:Qian Zhu, Lixin Jia, Zhongfei Gao, Chunming Wang, Haoyang Jiang, Junfeng Zhang, and Lei Dong
Molecular Pharmaceutics 2014 Volume 11(Issue 10) pp:3269-3278
Publication Date(Web):April 15, 2014
DOI:10.1021/mp4007776
Doxorubicin (DOX) is a potent cancer chemotherapeutic agent, but its clinical use is severely limited by potentially lethal cardiotoxicity. Delivery of DOX by particulate carriers can be an effective way to reduce its distribution in cardiac tissue. In the present study, we developed a self-assembled, tumor-microenvironment-responsive delivery system for DOX. The core of the carrier was built upon the DOX/DNA intercalation, which was further combined with cationic gelatin (C-gel) to form the complex GDD. GDD was then packaged into a complex, namely, HDD, based on the electrostatic interactions between the positively charged C-gel and negatively charged human serum albumin (HSA). The HSA molecules on the surface of the complex HDD effectively helped the particle evade the filtration of the body when injected into the circulation and passively accumulate into the tumor sites. After entering the tumor tissue, where albumin is rapidly consumed, GDD was release from HDD and the C-gel was then digested by the tumor-specific matrix metalloproteinase (MMPs) to free the DOX/DNA intercalation. Deoxyribonucleases (DNases) in the tissue could completely destroy the DNA molecules to release DOX into the microenvironments. After a series of in vitro optimization tests, we evaluated the anticancer capacity and cardiac toxicity of HDD in two animal models with cancer. The results suggested that HDD had a higher anticancer efficacy and a significantly lower cardiotoxicity than free DOX. Additionally, the main components of the carrier are all clinically approved materials. Taken together, our present delivery system is safe and efficient and has high potential for further clinical trials.Keywords: albumin encapsulated nanoparticle; doxorubicin; tumor environment responsive;
Co-reporter:Zhen Huang, Zhenzhen Wang, Shanshan Long, Haoyang Jiang, Jiangning Chen, Junfeng Zhang, and Lei Dong
Molecular Pharmaceutics 2014 Volume 11(Issue 7) pp:2051-2061
Publication Date(Web):January 23, 2014
DOI:10.1021/mp400723j
Functional engineered nanoparticles are promising drug delivery carriers. As the construction of a functional nanocarrier always needs the optimization of multiple technical variables, efficient in vitro high-throughput evaluation methods would help to shorten the development cycle. In the present study, we generated a tissue mimic of the colon of inflammatory bowel disease (IBD) patients. Generally, Caco-2 cells and THP-1 cells were grown in a 3-D matrix with different number, spatial distribution and specific extracellular cell matrix (ECM) composition according to real healthy and inflamed animal colon tissues. After interlerukin-1β/lipopolysaccharide (LPS) stimulation, the artificial model closely resembled the pathological features of IBD patient’s colon, including massive cytokines and mucus production, epithelium defect and leukocytic infiltration. The tissue and cellular uptake of three different nanoparticles in the artificial model was similar to that in 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitic mice. Most importantly, our artificial tissue can be placed into 96-well plates for high-throughput screening of drug delivery carriers for the treatment of IBD. Our study suggested a readily achievable way to improve current methodologies for the development of colon targeted drug delivery systems.Keywords: artificial model; drug delivery; inflammatory bowel disease; nanoparticle;
Co-reporter:Zhengping Zhang;Zhongfei Gao;Wei Hu;Shan Yin;Chunming Wang;Yuhui Zang;Jiangning Chen;Lei Dong
British Journal of Pharmacology 2013 Volume 170( Issue 3) pp:649-660
Publication Date(Web):
DOI:10.1111/bph.12323
Background and Purpose
Hepatic fibrosis is a type of liver disease characterized by excessive collagen deposition produced by activated hepatic stellate cells (HSCs), and no appropriate drug treatment is available clinically. The microRNA, miR-21 exhibits an important role in the pathogenesis and progression of hepatic fibrosis. 3,3′-Diindolylmethane (DIM) is a natural autolytic product in plants and can down-regulate miR-21 expression. Here we have assessed the therapeutic effects of DIM against hepatic fibrosis and investigated the underlying mechanisms.
Experimental Approach
The effects of DIM on HSC activation were measured by analysing the expression of α-smooth muscle actin and collagen I in both HSC-T6 cell line and primary HSCs. Expression of miR-21 was also measured after DIM treatment and the therapeutic effect of DIM was further studied in vivo, using the model of hepatic fibrosis induced by thioacetamide in mice. The antagonist oligonucleotide, antagomir-21, was also used to suppress the effects of miR-21.
Key Results
DIM suppressed the central TGF-β signalling pathway underlying HSC activation by down-regulating the expression of miR-21. The decreased miR-21 expression was achieved by inhibiting the activity of the transcription factor, AP-1. Moreover, DIM blunted the activation phenotype of primary HSCs. Administration of DIM in vivo attenuated liver fibrosis induced by thioacetamide, as assessed by collagen deposition and profiles of profibrogenic markers.
Conclusions and Implications
DIM shows potential as a therapeutic agent for the treatment of hepatic fibrosis.
Co-reporter:Rui Wang, Zhenheng Wang, Yutao Ma, Guoyin Liu, Hao Shi, Jiangning Chen, Lei Dong, Jianning Zhao, Junfeng Zhang
Biomaterials 2013 34(11) pp: 2611-2623
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.01.025
Co-reporter:Zhen Huang, Yang Yang, Yucui Jiang, Juan Shao, Xulun Sun, Jiangning Chen, Lei Dong, Junfeng Zhang
Biomaterials 2013 34(3) pp: 746-755
Publication Date(Web):
DOI:10.1016/j.biomaterials.2012.09.062
Co-reporter:Lin Zhang, Dongxia Hou, Xi Chen, Donghai Li, Lingyun Zhu, Yujing Zhang, Jing Li, Zhen Bian, Xiangying Liang, Xing Cai, Yuan Yin, Cheng Wang, Tianfu Zhang, Dihan Zhu, Dianmu Zhang, Jie Xu, Qun Chen, Yi Ba, Jing Liu, Qiang Wang, Jianqun Chen, Jin Wang, Meng Wang, Qipeng Zhang, Junfeng Zhang, Ke Zen and Chen-Yu Zhang
Cell Research 2012 22(1) pp:107-126
Publication Date(Web):September 20, 2011
DOI:10.1038/cr.2011.158
Our previous studies have demonstrated that stable microRNAs (miRNAs) in mammalian serum and plasma are actively secreted from tissues and cells and can serve as a novel class of biomarkers for diseases, and act as signaling molecules in intercellular communication. Here, we report the surprising finding that exogenous plant miRNAs are present in the sera and tissues of various animals and that these exogenous plant miRNAs are primarily acquired orally, through food intake. MIR168a is abundant in rice and is one of the most highly enriched exogenous plant miRNAs in the sera of Chinese subjects. Functional studies in vitro and in vivo demonstrated that MIR168a could bind to the human/mouse low-density lipoprotein receptor adapter protein 1 (LDLRAP1) mRNA, inhibit LDLRAP1 expression in liver, and consequently decrease LDL removal from mouse plasma. These findings demonstrate that exogenous plant miRNAs in food can regulate the expression of target genes in mammals.
Co-reporter:Zhen Huang, Zhengping Zhang, Yinhe Zha, Jialin Liu, Yucui Jiang, Yang Yang, Juan Shao, Xulun Sun, Xin Cai, Yuan Yin, Jiangning Chen, Lei Dong, Junfeng Zhang
Biomaterials 2012 33(30) pp: 7605-7612
Publication Date(Web):
DOI:10.1016/j.biomaterials.2012.06.074
Co-reporter:Xi Chen;Hongwei Liang;Ke Zen;Chen-Yu Zhang
Protein & Cell 2012 Volume 3( Issue 1) pp:28-37
Publication Date(Web):2012 January
DOI:10.1007/s13238-012-2003-z
A new class of RNA regulatory genes known as microRNAs (miRNAs) has been found to introduce a whole new layer of gene regulation in eukaryotes. The intensive studies of the past several years have demonstrated that miRNAs are not only found intracellularly, but are also detectable outside cells, including in various body fluids (e.g. serum, plasma, saliva, urine and milk). This phenomenon raises questions about the biological function of such extracellular miRNAs. Substantial amounts of extracellular miRNAs are enclosed in small membranous vesicles (e.g. exosomes, shedding vesicles and apoptotic bodies) or packaged with RNA-binding proteins (e.g. high-density lipoprotein, Argonaute 2 and nucleophosmin 1). These miRNAs may function as secreted signaling molecules to influence the recipient cell phenotypes. Furthermore, secreted extracellular miRNAs may reflect molecular changes in the cells from which they are derived and can therefore potentially serve as diagnostic indicators of disease. Several studies also point to the potential application of siRNA/miRNA delivery as a new therapeutic strategy for treating diseases. In this review, we summarize what is known about the mechanism of miRNA secretion. In addition, we describe the pathophysiological roles of secreted miRNAs and their clinical potential as diagnostic biomarkers and therapeutic drugs. We believe that miRNA transfer between cells will have a significant impact on biological research in the coming years.
Co-reporter:Jiangning Chen, Huan Chen, Pei Li, Huajia Diao, Shiyu Zhu, Lei Dong, Rui Wang, Ting Guo, Jianning Zhao, Junfeng Zhang
Biomaterials 2011 32(21) pp: 4793-4805
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.03.041
Co-reporter:Lei Dong;Zhen Huang;Xing Cai;Jiawei Xiang;Yi-An Zhu
Pharmaceutical Research 2011 Volume 28( Issue 6) pp:1349-1356
Publication Date(Web):2011 June
DOI:10.1007/s11095-010-0334-0
To investigate the possibility of using localized nucleic drug delivery methods for the treatment of osteolysis-related bone disease.A bio-degradable cationic hydrogel composed of gelatin and chitosan was used to deliver an antisense oligonucleotide (ASO) targeting murine TNF-α for the treatment of endotoxin-induced osteolysis.ASO combined with this hydrogel was released when it was digested by adhering cells. The released ASO was efficiently delivered into contacted cells and tissues in vitro and in vivo. When tested in animal models of edotoxin-induced bone resorption, ASO delivered by such means effectively suppressed the expression of TNF-α and subsequently the osteoclastogenesis in vivo. Osteolysis in the edotoxin-induced bone resorption animal models was blocked by the treatment.This is a successful attempt to apply localized gene delivery method to treat inflammatory diseases in vivo.
Co-reporter:Xi Chen, Chao Gao, Haijin Li, Lei Huang, Qi Sun, Yanye Dong, Chunliang Tian, Shengpu Gao, Hailin Dong, Danping Guan, Xiaoyun Hu, Shujian Zhao, Liang Li, Lin Zhu, Qiao Yan, Junfeng Zhang, Ke Zen and Chen-Yu Zhang
Cell Research 2010 20(10) pp:1128-1137
Publication Date(Web):June 15, 2010
DOI:10.1038/cr.2010.80
Recent baby formula milk powder contamination incidents have shown that the classic markers or standards in milk quality control are insufficient in identifying “manipulated” poor-quality milk. In the present study, we demonstrated for the first time that cow milk contains large amounts of microRNAs (miRNAs) and that the unique expression profile of milk-specific miRNAs can serve as a novel indicator and possible new standard for the quality control of raw milk and milk-related commercial products, such as fluid milk and powdered formula milk. First, using Solexa sequencing, we systematically screened miRNA expression in raw milk and identified a total of 245 miRNAs in raw milk. Unlike other classic biomarkers whose expression levels are nearly identical at different periods of lactation, individual miRNAs can be significantly altered during lactation process, implicating that miRNAs may be a more accurate indicator to reflect the quality alteration of milk. Second, using TaqMan probe-based miRNA quantitative RT-PCR, we further identified seven miRNAs that have a relatively consistent expression throughout the lactation process, and more importantly, the expression profile of these seven milk-specific miRNAs can serve as an ideal biomarker for discriminating poor-quality or “manipulated” milk from pure raw milk, as well as for the quality control of commercial milk products, such as fluid milk and powdered formula milk. Together, our findings provide a basis for understanding the physiological role of milk miRNAs and a new potential standard for determining the quality of raw milk or milk-related commercial products.
Co-reporter:Lei Dong;Suhua Xia;Huan Chen;Jiangning Chen
Journal of Cellular and Molecular Medicine 2010 Volume 14( Issue 7) pp:2015-2024
Publication Date(Web):
DOI:10.1111/j.1582-4934.2009.00806.x
Abstract
Cationic materials exhibit remarkable anti-inflammatory activity in experimental arthritis models. Our aim was to confirm this character of cationic materials and investigate its possible mechanism. Adjuvant-induced arthritis (AIA) models were used to test cationic materials for their anti-inflammatory activity. Cationic dextran (C-dextran) with different cationic degrees was used to investigate the influence of the cationic elements of materials on their anti-inflammatory ability. Peritoneal macrophages and spleen cells were used to test the expression of cytokines stimulated by cationic materials. Interferon (IFN)-γ receptor-deficient mice and macrophage-depleted rats were used to examine the possible mechanisms of the anti-inflammatory activity of cationic materials. In AIA models, different cationic materials shared similar anti-inflammatory characters. The anti-inflammatory activity of C-dextran increased with as the cationic degree increased. Cationic materials stimulated interleukin (IL)-12 expression in peritoneal macrophages, and strong stimulation of IFN-γ secretion was subsequently observed in spleen cells. In vivo experiments revealed that circulating IL-12 and IFN-γ were enhanced by the cationic materials. Using IFN-γ receptor knockout mice and macrophage-depleted rats, we found that IFN-γ and macrophages played key roles in the anti-inflammatory activity of the materials towards cells. We also found that neutrophil infiltration at inflammatory sites was reduced when AIA animals were treated with C-dextran. We propose that cationic signals act through an unknown receptor on macrophages to induce IL-12 secretion, and that IL-12 promotes the expression of IFN-γ by natural killer cells (or T cells). The resulting elevated systemic levels of IFN-γ inhibit arthritis development by preventing neutrophil recruitment to inflammatory sites.
Co-reporter:C Zhang, W Peng, M Wang, J Zhu, Y Zang, W Shi, J Zhang and J Qin
Gene Therapy 2010 17(5) pp:626-633
Publication Date(Web):February 25, 2010
DOI:10.1038/gt.2010.11
Paraoxonase (PON) possesses antiatherogenic potentials, but the distinct functions of PON members in alleviating atherosclerosis are not yet clear. This study aimed to evaluate the protective effects of hPON1 and hPON3 against atherosclerosis, and thereby exploring their synergistic mechanism in atherosclerosis development. We generated the recombinant adenovirus AdPON1 and AdPON3, which were capable of expressing hPON1 and hPON3. After AdPON1 and AdPON3 were injected intravenously into 5-week-old apolipoprotein E knockout mice, abundant hPON1 and hPON3 mRNA expression levels were detected. However, increase in serum lactonase activity was detected only in AdPON1-treated mice. Serum antioxidation and anti-inflammation capabilities in AdPON1-treated mice, reflected by malondialdehyde, total antioxidant capability and tumor necrosis factor-α levels, were greatly enhanced, whereas those in AdPON3-treated mice were not significantly affected. Nevertheless, histological analysis revealed that adenovirus-mediated expression of hPON1, hPON3 or both of them reduced atherosclerotic plaque area to a similar extent. Although no synergistic mechanism was detected in reducing arterial lesion size, hPON1 and hPON3 showed synergistic effects on promoting macrophage cholesterol efflux. In conclusion, hPON1 and hPON3 exhibited similar potentials in reducing arterial lesion size, but they exerted antiatherogenic effects in distinct ways.
Co-reporter:Lei Dong, Suhua Xia, Ke Wu, Zhen Huang, Huan Chen, Jiangning Chen, Junfeng Zhang
Biomaterials 2010 31(24) pp: 6309-6316
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.04.049
Co-reporter:Huan Chen, Pei Li, Yuan Yin, Xing Cai, Zhen Huang, Jiangning Chen, Lei Dong, Junfeng Zhang
Biomaterials 2010 31(32) pp: 8172-8180
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.07.056
Co-reporter:Lei Dong, Suhua Xia, Yi Luo, Huajia Diao, Jiani Zhang, Jiangning Chen, Junfeng Zhang
Journal of Controlled Release 2009 Volume 134(Issue 3) pp:214-220
Publication Date(Web):19 March 2009
DOI:10.1016/j.jconrel.2008.11.013
Competent vehicles based on natural biopolymers are highly demanded in the practice of gene-assisted cell therapy. In this study, a novel gene carrier was developed based on a bioactive glucomannan that was a polysaccharide isolated from an herb Bletilla striata (BSP) and modified with N, N′-carbonyldiimidazole (CDI)/ethylenediamine in order to acquire nucleic acid binding affinity. Particle size observation and electrophoretic mobility tests indicated that the cationized BSP (cBSP) could efficiently combine DNA to form nano-scaled compact and stable complexes and promote the transfection of oligodeoxynucleotide (ODN). Specifically, cBSP exhibited significantly high affinity to macrophages, as evidenced by transfection examination on multiple cell types and competitive test with mannose/glucomannan. In addition, the efficacy of the delivered ODN by cBSP was evaluated by the quantification of gene expression and a dramatic enhancement in suppressing target gene expression was observed. All the findings suggested the possible existence of interaction between cBSP ligand and receptor on macrophage surface. In this way, the ubiquitous mannose receptors and β-glucan receptors on macrophage could recognize the mannose and β-glucose residues in BSP framework, thus further mediated the oriented ODN delivery. We expect cBSP to be capable of conveying antisense nucleotides (e.g., oligodeoxynucleotide and small interference RNA) for the practical anti-inflammatory therapy.Cationic polysaccharide from Bletilla striata containing α-Mannose and β-Glucose monosaccharide contents exhibits high transfection effects and specificity to macrophage cell lines.
Co-reporter:X Chen;X Guo;H Zhang;5];Y Xiang;J Chen;Y Yin;X Cai;K Wang;G Wang;Y Ba;L Zhu;J Wang;R Yang;Y Zhang;Z Ren;K Zen;J Zhang;C-Y Zhang
Oncogene 2009 28(10) pp:1385-1392
Publication Date(Web):2009-01-12
DOI:10.1038/onc.2008.474
Dysregulated expression of microRNAs (miRNAs) is associated with a variety of diseases, including colorectal cancer. By comparing more than 200 miRNAs in 13 pairs of matched colorectal cancer and normal adjacent tissue samples through qRT-PCR and microarray analysis, we found a widespread disruption of miRNA expression during colorectal tumorigenesis. In particular, among a panel of presumed targets generated by in silico analysis that may interact with these aberrantly expressed miRNAs, KRAS oncogene has been further experimentally validated as the target of miR-143. First, an inverse correlation between KRAS protein and miR-143 in vivo was found. Second, KRAS expression in Lovo cells was significantly abolished by treatment with miR-143 mimic, whereas miR-143 inhibitor increased KRAS protein level. Third, luciferase reporter assay confirmed that miR-143 directly recognize the 3′-untranslated region of KRAS transcripts. Four, Lovo cells treated with miR-143 inhibitor showed a stimulated cell proliferation, whereas miR-143 overexpression had an opposite effect. Finally, inhibition of KRAS expression by miR-143 inhibits constitutive phosphorylation of ERK1/2. Taken together, the present study provides the first evidences that miR-143 is significant in suppressing colorectal cancer cell growth through inhibition of KRAS translation.
Co-reporter:Xi Chen, Yi Ba, Lijia Ma, Xing Cai, Yuan Yin, Kehui Wang, Jigang Guo, Yujing Zhang, Jiangning Chen, Xing Guo, Qibin Li, Xiaoying Li, Wenjing Wang, Yan Zhang, Jin Wang, Xueyuan Jiang, Yang Xiang, Chen Xu, Pingping Zheng, Juanbin Zhang, Ruiqiang Li, Hongjie Zhang, Xiaobin Shang, Ting Gong, Guang Ning, Jun Wang, Ke Zen, Junfeng Zhang and Chen-Yu Zhang
Cell Research 2008 18(10) pp:997-1006
Publication Date(Web):September 2, 2008
DOI:10.1038/cr.2008.282
Dysregulated expression of microRNAs (miRNAs) in various tissues has been associated with a variety of diseases, including cancers. Here we demonstrate that miRNAs are present in the serum and plasma of humans and other animals such as mice, rats, bovine fetuses, calves, and horses. The levels of miRNAs in serum are stable, reproducible, and consistent among individuals of the same species. Employing Solexa, we sequenced all serum miRNAs of healthy Chinese subjects and found over 100 and 91 serum miRNAs in male and female subjects, respectively. We also identified specific expression patterns of serum miRNAs for lung cancer, colorectal cancer, and diabetes, providing evidence that serum miRNAs contain fingerprints for various diseases. Two non-small cell lung cancer-specific serum miRNAs obtained by Solexa were further validated in an independent trial of 75 healthy donors and 152 cancer patients, using quantitative reverse transcription polymerase chain reaction assays. Through these analyses, we conclude that serum miRNAs can serve as potential biomarkers for the detection of various cancers and other diseases.
Co-reporter:Lei Dong;Shuying Gao;Huajia Diao;Jiangning Chen
Journal of Biomedical Materials Research Part A 2008 Volume 84A( Issue 3) pp:777-784
Publication Date(Web):
DOI:10.1002/jbm.a.31328
Abstract
The in vivo cellular localization of oligodeoxynucleotides (ODNs) delivered by galactosylated low molecular weight chitosan (gal-LMWC) was investigated. The gal-LMWCs preference for Kupffer cells was confirmed by in vivo and in vitro experiments. Furthermore, asialoglycoprotein receptor (ASGPr) was studied as a possible surface lectin which may involved in the endocytosis of the gal-LMWC/ODN complexes. Results showed that the gal-LMWC/ODN complex accumulated in liver when injected intravenously (i.v.). Further studies revealed that 50.6% of the complex was taken up by Kupffer cells in liver, 33.2% was taken up by endothelial cells, and only 16.2% of the complex was taken up by parenchymal cells. In vitro results also confirmed the affinity of gal-LMWC to murine Kupffer cells. Inhibition of the transfection by lactose and N-acetyl galactosamine (GalNAc) suggested that the particles might enter macrophages via ASGPr and the inhibition by LMWC implied that there might be other lectins involved in the endocytosis. In summary, our studies revealed that gal-LMWC/ODN complex is inclined to enter into Kupffer cells rather than into liver parenchymal cells in vivo. Galactosylation may not be a proper means for targeting chitosan/DNA nanoparticles to hepatocytes but it does have the potential to be a Kupffer cells targeting strategy especially for delivering drugs for antiinflammation. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2008
Co-reporter:Ting Guo, Jianning Zhao, Jianbin Chang, Zhi Ding, Hao Hong, Jiangning Chen, Junfeng Zhang
Biomaterials 2006 Volume 27(Issue 7) pp:1095-1103
Publication Date(Web):March 2006
DOI:10.1016/j.biomaterials.2005.08.015
Cartilage defects as a result of disease or injury have a very limited ability to heal spontaneously. Recently, tissue engineering and local therapeutic gene delivery systems have been paid much attention in the cartilage natural healing process. Gene-activated matrix (GAM) blends these two strategies, serving as local bioreactor with therapeutic agents expression and also providing a structural template to fill the lesion defects for cell adhesion, proliferation and synthesis of extracellular matrix (ECM). In the current study, we used chitosan-gelatin complex as biomaterials to fabricate three-dimensional scaffolds and plasmid DNA were entrapped in the scaffolds encoding transforming growth factor-β1 (TGF-β1), which has been proposed as a promoter of cartilage regeneration for its effect on the synthesis of matrix molecules and cell proliferation. The plasmid DNA incorporated in the scaffolds showed a burst release in the first week and a sustained release for the other 2 weeks. The gene transfectd into chondrocytes expresses TGF-β1 protein stably in 3 weeks. The histological and immunohistochemical results confirmed that the primary chondrocytes cultured into the chitosan-gelatin scaffold maintained round and owned characters of high secretion of specific ECM. From this study, it can be concluded that this gene-activated chitosan-gelatins matrix has a potential in the application of cartilage defects regeneration.
Co-reporter:Zhi Ding, Jiangning Chen, Shuying Gao, Jianbing Chang, Junfeng Zhang, E.T. Kang
Biomaterials 2004 Volume 25(Issue 6) pp:1059-1067
Publication Date(Web):March 2004
DOI:10.1016/S0142-9612(03)00615-X
Surface functionalization of biodegradable poly-l-lactic acid (PLLA) was achieved by plasma coupling reaction of chitosan. The structure of modified PLLA surfaces was characterized by contact angle measurements and X-ray photoelectron spectroscopy. Two cell lines, L929 (mouse fibroblasts) and L02 (human hepatocytes), were cultured on the modified PLLA surface. It was found that cells cultured on this film could hardly spread and tend to become round, and the film was demonstrated to be a poorly adhering substrate. However, cells grown on this substrate can proliferate at almost the same speed as cultured on a glass surface. These results suggest that the new substrate can be used to control the morphology of cells, and has potential applications in tissue engineering. It may be helpful in understanding the mechanism of the switch between cell phases of growth and differentiation, which is necessary for the design of tissue regeneration biomaterials.
Co-reporter:Junfeng Zhang, Xuerong Xu, Jiangning Chen, En-tang Kang
Thin Solid Films 2002 Volume 413(1–2) pp:76-84
Publication Date(Web):24 June 2002
DOI:10.1016/S0040-6090(02)00345-0
Graft polymerization of functional monomers onto self-assembled monolayers (SAMs) on gold via argon plasma treatment and then UV irradiation has been carried out. Two alkanethiols, viz., 3-mercaptopropionic acid and 3-mercaptopropionic acid-2-ethylhexyl ester, were employed for the deposition of SAMs from ethanol solutions onto gold surfaces. The monomers used for graft polymerization were water-soluble acrylic acid (AAc) and hydrophobic allylpentafluorobenzene. Angle-resolved X-ray photoelectron spectroscopy (XPS) and contact angle measurements were used to investigate the surface chemical composition, surface coverage, film thickness, and wettablity. XPS results suggest that mild and brief plasma treatments can be employed to generate sufficient peroxides and hydroperoxides on the SAMs for the subsequent UV-induced graft polymerization while maintaining the SAMs intact. For all the cases investigated, XPS results reveal that the graft polymer forms a thin layer of 6–7 nm in thickness on the SAM surfaces. Contact angle measurements indicate that the SAM-modified Au surfaces could be selectively made hydrophilic or hydrophobic through the graft copolymerization with an appropriate monomer. It was also demonstrated that the AAc graft polymerized SAMs selectively adsorbed Fe3+ ions via coordination complexation.
Co-reporter:Yun Luo, Jingwei Li, Junfeng Zhang, Yun Xu
International Journal of Developmental Neuroscience (November 2013) Volume 31(Issue 7) pp:634-638
Publication Date(Web):1 November 2013
DOI:10.1016/j.ijdevneu.2013.08.002
BackgroundOur previous study demonstrated that the level of serum bilirubin after acute ischemic stroke (AIS) was correlated to the severity of stroke, also there has the evidence of hyperbilirubinemia prevalent in AIS. We aimed to identify the exact change of bilirubin in the early phase of AIS, and study if this kind of change linked to the severity of stroke.MethodsBilirubin and other biochemical indexes were measured in 608 AIS patients and 188 transient ischemic attack (TIA) patients which set as the control group. National Institutes of Health Stroke Scale (NIHSS) scores were assessed simultaneously with blood collection. First, the level of bilirubin and its distribution were compared between the AIS and control group. According to a cut-off point, we next analyzed the impacted factors of elevated bilirubin including the direct bilirubin (Dbil) and total bilirubin (Tbil), especially the correlation between elevated bilirubin and the severity of stroke. Finally, we compared the difference of concentration and percent of elevated bilirubin among the Oxford Community Stroke Project (OCSP) subtypes.ResultsThe level of serum Dbil and Tbil was significantly higher in the AIS group than that in the TIA group. Different distribution was observed between the two groups, which manifested as the percent of low bilirubin level group was lower while high level group was higher in AIS than that in TIA, the p value were 0.043 and 0.078 in Dbil and Tbil, respectively. When the cut-off point of elevated bilirubin was selected as Dbil ≥ 6.84 μmol/L and Tbil ≥ 22.2 μmol/L, we found that both NIHSS score and relative severity of AIS were significantly associated with elevated bilirubin whenever in Dbil or Tbil, so did the OCSP subtypes. This trend was still maintained by multivariable logistic regression analysis adjust for relative influence factors. In regard of OCSP subtypes, the highest level of bilirubin was found in TACI, so did the highest rate of elevated bilirubin.ConclusionThe serum levels of Dbil and Tbil were increased after AIS, which linked to the severity of stroke.
Co-reporter:Xi Chen, Hongwei Liang, Junfeng Zhang, Ke Zen, Chen-Yu Zhang
Trends in Cell Biology (March 2012) Volume 22(Issue 3) pp:125-132
Publication Date(Web):1 March 2012
DOI:10.1016/j.tcb.2011.12.001
In multicellular organisms, cell-to-cell communication is of particular importance for the proper development and function of the organism as a whole. Intensive studies over the past three years suggesting horizontal transfer of secreted microRNAs (miRNAs) between cells point to a potentially novel role for these molecules in intercellular communication. Using a microvesicle-dependent, or RNA-binding protein-associated, active trafficking system, secreted miRNAs can be delivered into recipient cells where they function as endogenous miRNAs, simultaneously regulating multiple target genes or signaling events. In this Opinion, we summarize recent literature on the biogenesis and uptake of secreted miRNAs, propose a possible working model for how secreted miRNAs might be sorted and transferred between cells and speculate on their biological significance.
Co-reporter:Zhen Huang, Jingjing Gan, Ziyan Long, Guangxing Guo, Xiafei Shi, Chunming Wang, Yuhui Zang, Zhi Ding, Jiangning Chen, Junfeng Zhang, Lei Dong
Biomaterials (June 2016) Volume 90() pp:72-84
Publication Date(Web):June 2016
DOI:10.1016/j.biomaterials.2016.03.009
Co-reporter:Haixia Ding, Zhen Huang, Mengjie Chen, Cheng Wang, Xi Chen, Jiangning Chen, Junfeng Zhang
Parkinsonism & Related Disorders (January 2016) Volume 22() pp:68-73
Publication Date(Web):1 January 2016
DOI:10.1016/j.parkreldis.2015.11.014
•PD patients exhibit a distinctive serum miRNA profile from healthy controls.•Five miRNA were identified to be differently expressed in PD patients' serum.•The 5-member serum miRNA panel can distinguish PD patients from health individuals.Background and objectiveParkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease. The aim of this work was to determine whether the differences of serum miRNAs profiling could distinguish PD patients from healthy individuals.MethodsWe collected serum samples from 106 sporadic PD patients and 91 age/gender-matched healthy controls. Serum miRNAs were analysed by Solexa sequencing followed by a qRT-PCR examination. The qRT-PCR assay, which was divided into two phases, was used to validate the expression of miRNAs screened by Solexa sequencing. Receiver operating characteristic (ROC) curve analysis and clustering analysis were performed to determine the diagnostic usefulness of the selected miRNAs for PD.ResultsIn this study, we generated a profile of 5 serum miRNAs: miR-195 was up-regulated, and miR-185, miR-15b, miR-221 and miR-181a were down-regulated.ConclusionThis group of five miRNAs can precisely distinguish PD patients from health individuals and may be used as a potential serum-based biomarker for the diagnosis of PD.
Co-reporter:Jie Ouyang, Hao Hong, Yong Zhao, Hongqin Shen, Chao Shen, Chenyu Zhang, Junfeng Zhang
Nitric Oxide (August 2008) Volume 19(Issue 1) pp:42-49
Publication Date(Web):1 August 2008
DOI:10.1016/j.niox.2008.03.003
Nitric oxide (NO) serves as a messenger for cellular signaling and physiological reactions such as inflammatory responses in vivo. Fluorescent bioimaging of nitric oxide is a very useful tool in NO functional research. Although many encouraging results have been achieved in the field of NO fluorescent detection, there is rarely satisfying result in inflammatory NO imaging in vivo. Here we report that fluorescent 5′-chloro-2-(2′-hydroxyphenyl)-1H-naphtho[2,3-d]imidazol can coordinate with Cu(II) to form a non-fluorescent coordination compound, which is able to directly and quickly image NO in cellular system or in vivo inflammation system with a turn-on fluorescence, based on a redox action of Cu(II). It was used to image NO produced by inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS) activated murine macrophages. More importantly, it could image the NO production in an acute severe hepatic injury (ASHI) model of BALB/c mice induced by integrative LPS and d-galactosamine (GalN) treatment. The results prove that the 5′-chloro-2-(2′-hydroxyphenyl)-1H-naphtho[2,3-d]imidazol coordinated with cupric ions can serve as an excellent NO bioimaging agent in different biological systems especially in inflammation related systems, and it may be valuable for diagnostic and pathological studies of NO related diseases.
Co-reporter:Zhen Huang, Yucui Jiang, Yang Yang, Juan Shao, Xulun Sun, Jiangning Chen, Lei Dong, Junfeng Zhang
Molecular Immunology (April 2013) Volume 53(Issue 4) pp:335-344
Publication Date(Web):1 April 2013
DOI:10.1016/j.molimm.2012.09.007
The T cell is pivotal in orchestrating and promoting an immune response during ulcerative colitis (UC). The aryl hydrocarbon receptor (AhR) is involved in the regulation of T cell responses, and 3,3′-diindolylmethane (DIM) is a known ligand of AhR. The aim of this study was to examine the therapeutic effects of DIM in experimental colitis and to investigate the possible mechanisms underlying its effects on mucosal T cell responses. The therapeutic effects of DIM were studied in an oxazolone-induced colitis model. The pathologic markers of colitis were measured, moreover, T-helper cell (Th)- and regulatory T cell (Treg)-related transcription factor expression and associated colonic cytokine production were determined. The impact of DIM on T cell differentiation was further investigated in cultures of naive Th cells that were stimulated with anti-CD3/CD28 monoclonal antibodies (mAbs). The administration of DIM attenuated experimental colitis, as determined by pathological indices. DIM may affect signaling pathways downstream of AhR, leading to decreased Th2/Th17 cells and increased Tregs. Ultimately, this could result in the alleviation of experimental colitis. DIM has shown anti-UC activity in animal models via inhibition of Th2/Th17 cells and promotion of Tregs and may thus offer potential treatments for UC patients.Highlights► DIM inhibited Th2 responses in naive T cells via AhR signaling. ► DIM mediated reciprocal regulation of Th17 and Treg in naive T cells is AhR dependent. ► DIM attenuated oxazolone-induced colitis via regulating mucosal T cell responses.
Co-reporter:Zhengwei Yao, Wei Hu, Shan Yin, Zhen Huang, Qian Zhu, Jiangning Chen, Yuhui Zang, Lei Dong, Junfeng Zhang
Pharmacological Research (April 2013) Volume 70(Issue 1) pp:139-146
Publication Date(Web):1 April 2013
DOI:10.1016/j.phrs.2013.01.006
The cardiotoxicity of adriamycin greatly limits its application in the treatment of cancer. Heart failure that is caused by adriamycin-treatment induced cardiac fibrosis is a major cause of death in patients who are treated with this medication. The severe oxidative stress that is induced by adriamycin is considered to be one of the primary mechanisms by which fibrogenesis of cardiac tissue occurs. In the present study, we demonstrate that 3,3′-diindolymethane (DIM) exhibits a significant anti-fibrosis effect on cardiac tissue in an animal model of adriamycin-induced cardiac fibrosis (AICF). Further studies demonstrated that DIM is able to dramatically up-regulate the expression of breast cancer type 1 susceptibility protein (BRCA1) in cardiac tissue and fibroblast, which subsequently activate the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The upregulation of this transcription factor resulted in the expression of several anti-oxidant genes in the cell. Because DIM is a safe food additive that has been used for decades, our findings suggest that there is a great potential for this chemical to be developed into a clinical medication for the treatment of adriamycin-induced heart failure during cancer therapy.Download high-res image (112KB)Download full-size image
Co-reporter:Yujing Zhang, Danqing Liu, Xi Chen, Jing Li, ... Chen-Yu Zhang
Molecular Cell (9 July 2010) Volume 39(Issue 1) pp:133-144
Publication Date(Web):9 July 2010
DOI:10.1016/j.molcel.2010.06.010
MicroRNAs (miRNAs) are a class of noncoding RNAs that regulate target gene expression at the posttranscriptional level. Here, we report that secreted miRNAs can serve as signaling molecules mediating intercellular communication. In human blood cells and cultured THP-1 cells, miR-150 was selectively packaged into microvesicles (MVs) and actively secreted. THP-1-derived MVs can enter and deliver miR-150 into human HMEC-1 cells, and elevated exogenous miR-150 effectively reduced c-Myb expression and enhanced cell migration in HMEC-1 cells. In vivo studies confirmed that intravenous injection of THP-1 MVs significantly increased the level of miR-150 in mouse blood vessels. MVs isolated from the plasma of patients with atherosclerosis contained higher levels of miR-150, and they more effectively promoted HMEC-1 cell migration than MVs from healthy donors. These results demonstrate that cells can secrete miRNAs and deliver them into recipient cells where the exogenous miRNAs can regulate target gene expression and recipient cell function.Highlights► MVs derived from plasma and cultured cell medium are carriers of secreted miRNAs ► Cells selectively secrete miRNAs via MVs in response to stimuli ► Secreted miRNAs serve as signaling molecules mediating intercellular communication ► Secreted monocytic miR-150 modulates targeted endothelial cell function
Co-reporter:Jie Ouyang, Hao Hong, Chao Shen, Yong Zhao, ... Junfeng Zhang
Free Radical Biology and Medicine (15 November 2008) Volume 45(Issue 10) pp:1426-1436
Publication Date(Web):15 November 2008
DOI:10.1016/j.freeradbiomed.2008.08.016
Fluorescence imaging of nitric oxide (NO) in vitro and in vivo is essential to developing our understanding of the role of nitric oxide in biology and medicine. Current probes such as diaminofluorescein depend on reactions with oxidized NO products, but not with nitric oxide directly, and this limits their applicability. Here we report the formation of an imaging probe for nitric oxide by coordinating the highly fluorescent chemical 4-methoxy-2-(1H-naphtho[2,3-d]imidazol-2-yl)phenol (MNIP) with Cu(II). The coordination compound MNIP–Cu reacts rapidly and specifically with nitric oxide to generate a product with blue fluorescence that can be used in vitro and in vivo. In the present study MNIP–Cu was used to reveal nitric oxide produced by inducible nitric oxide synthase in lipopolysaccharide (LPS)-activated macrophages (Raw 264.7 cells) and by endothelial nitric oxide synthase in endothelial cells (HUVEC). MNIP–Cu was also used to evaluate the distribution of nitric oxide synthesis in a model of acute liver injury induced by LPS and d-galactosamine in mice. The results demonstrate that MNIP–Cu can act as a novel fluorescent probe for nitric oxide and has many potential applications in biomedical research.
Co-reporter:Zhen Huang, Longsheng Zuo, Zhengping Zhang, Jialin Liu, ... Junfeng Zhang
Free Radical Biology and Medicine (15 January 2011) Volume 50(Issue 2) pp:228-236
Publication Date(Web):15 January 2011
DOI:10.1016/j.freeradbiomed.2010.10.703
Reactive oxygen species (ROS) exhibit a key role in the pathogenesis of inflammatory bowel disease (IBD). 3,3′-Diindolylmethane (DIM) can protect against oxidative stress in a breast cancer susceptibility gene 1 (BRCA1)-dependent manner. The aim of this study was to examine the therapeutic effects of DIM in experimental colitis and investigate the possible mechanisms underlying its effects on intestinal inflammation. The therapeutic effects of DIM were studied in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Pathological markers of colitis severity, antioxidant activity, and ROS generation in colonic tissue were measured. The impact of DIM on ROS-induced endothelial vascular cell adhesion molecule 1 (VCAM-1) expression and leukocyte–endothelial cell interaction was further investigated in cultures of endothelial cells and in the TNBS-induced colitis model. Administration of DIM was demonstrated to attenuate experimental colitis, as judged by pathological indices. DIM could effectively stimulate the expression of BRCA1 in vitro and in vivo and reduce ROS generation, leading to the inhibition of VCAM-1 expression and leukocyte–endothelial cell adhesion, and finally resulted in an alleviation of experimental colitis. DIM has shown anti-IBD activity in animal models by inhibiting ROS-induced VCAM-1 expression and leukocyte recruitment via a BRCA1-dependent antioxidant pathway and thus may offer potential treatments for IBD patients.
Co-reporter:Zhen Huang, Lei Dong, Jijun Chen, Fengbo Gao, Zhengping Zhang, Jiangning Chen, Junfeng Zhang
Life Sciences (10 December 2012) Volume 91(Issues 23–24) pp:1207-1215
Publication Date(Web):10 December 2012
DOI:10.1016/j.lfs.2012.09.015
AimsVascular endothelial growth factor (VEGF) has been shown to be a key driving force for angiogenesis and tumor growth in hepatocellular carcinoma (HCC). As an emerging approach to block this angiogenic stimulator, the RNA interference (RNAi) technique has rapidly developed but is hindered for in vivo applications due to low cellular uptake and poor stability of small RNA. Based on low molecular weight chitosan (LMWC), a gene delivery system of short hairpin RNA (shRNA) directed against VEGF was constructed. The objective of this study was to investigate whether LMWC/shRNA nano-complexes can effectively inhibit VEGF expression in cancer cells and tumor tissues and suppress tumor growth in different HCC models.Main methodsThe transfection experiment and Real-time qPCR assay were used to evaluate the transfection efficiency and gene suppression activity of LMWC/shRNA complexes in Hepa 1–6 murine hepatocarcinoma cells. The therapeutic effect of LMWC/ VEGF shRNA was further tested in ectopic and orthotopic liver cancer models.Key findingsLMWC/VEGF shRNA complexes significantly inhibited VEGF expression of HCC cells and liver tumor tissues. LMWC obviously enhanced and prolonged the deposition of shRNA at the tumor site when LMWC/shRNA complexes were intravenously injected into orthotopic allograft liver tumor-bearing mice. The administration of LMWC/VEGF shRNA complexes by intratumoral or intravenous injection demonstrated more effective suppression of tumor angiogenesis and tumor growth in different HCC models compared with naked shRNA.SignificanceThis study demonstrated the feasibility of using LMWC as a potential carrier for RNA interference drugs in liver cancer therapy.
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![(3s,5s,8r,9s,10s,13r,14s,17r)-3,5,14-trihydroxy-13-methyl-17-(6-oxopyran-3-yl)-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene-10-carbaldehyde](http://img.cochemist.com/ccimg/500/465-90-7_b.png)
![N-phenyl-n-[1-(2-phenylethyl)piperidin-4-yl]propanamide](http://img.cochemist.com/ccimg/500/437-38-7.png)
![N-phenyl-n-[1-(2-phenylethyl)piperidin-4-yl]propanamide](http://img.cochemist.com/ccimg/500/437-38-7_b.png)
