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53. Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice

Author

Jin, Wang, Liang, Xiaowen, Brooks, Anastasia, Futrega, Kathryn, Liu, Xin, Doran, Michael R., Simpson, Matthew J., Roberts, Michael S., Wang, Haolu, Jin, Wang, Liang, Xiaowen, Brooks, Anastasia, Futrega, Kathryn, Liu, Xin, Doran, Michael R., Simpson, Matthew J., Roberts, Michael S., and Wang, Haolu

Abstract

Background: Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. Methods: A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA using droplet digital PCR (ddPCR) allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. Results: Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1 level in the I/R injured liver than that in the control. Correspondingly, the ddPCR results illustrate a higher MSC concentration in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ddPCR results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. Discussion: The modelling results suggest that SDF-1 in organs is an effective

Published
2018

55. Identification of hub genes and construction of transcriptional regulatory network for the progression of colon adenocarcinoma hub genes and TF regulatory network of colon adenocarcinoma.

Author

Wei, Shuxun, Chen, Jinshui, Huang, Yu, Sun, Qiang, Wang, Haolu, Liang, Xiaowen, Hu, Zhiqian, and Li, Xinxing

Subjects
NETWORK hubs, GENE regulatory networks, COLON (Anatomy), GENES, ONLINE databases, GENE ontology, TRANSCRIPTION factors
Abstract

The aim of this study was to identify key genes related to the progression of colon adenocarcinoma (COAD), and to investigate the regulatory network of hub genes and transcription factors (TFs). Dataset GSE20916 including 44 normal colon, 55 adenoma, and 36 adenocarcinoma tissue samples was used to construct co‐expression networks via weighted gene co‐expression network. Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis for the objective module were performed using the online Database for Annotation, Visualization and Integrated Discovery. Hub genes were identified by taking the intersection of differentially expressed genes between dataset GSE20916 and GSE39582 and validated using The Cancer Genome Atlas (TCGA) database. The correlations between microRNA (miRNA) and hub genes were analyzed using the online website StarBase. Cytoscape was used to establish a regulatory network of TF‐miRNA‐target gene. We found that the orange module was a key module related to the tumor progression in COAD. In datasets GSE20916 and GSE39582, a total of eight genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) were selected, which were closely related with patients' survivals in TCGA database and dataset GSE20916. COAD patients with higher expressions of each hub gene had a worse prognosis than those with lower expressions. A regulatory network of TF‐miRNA‐target gene with 144 TFs, 26 miRNAs, and 7 hub genes was established, including model KLF11‐miR149‐BGN, TCEAL6‐miR29B2‐COL1A1, and TCEAL6‐miR29B2‐COL1A2. In conclusion, during the progression of COAD, eight core genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) play vital roles. Regulatory networks of TF‐miRNA‐target gene can help to understand the disease progression and optimize treatment strategy. [ABSTRACT FROM AUTHOR]

Published
2020
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60. A Water-Soluble, Green-Light Triggered, and Photo-Calibrated Nitric Oxide Donor for Biological Applications

Author

He, Haihong, primary, Xia, Yang, additional, Qi, Yingxue, additional, Wang, Hong-Yin, additional, Wang, Zhuang, additional, Bao, Jianming, additional, Zhang, Ziqian, additional, Wu, Fu-Gen, additional, Wang, Haolu, additional, Chen, Daijie, additional, Yang, Dahai, additional, Liang, Xiaowen, additional, Chen, Jinquan, additional, Zhou, Shengmin, additional, Liang, Xin, additional, Qian, Xuhong, additional, and Yang, Youjun, additional

Published
2018
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61. Indocyanine green-incorporating nanoparticles for cancer theranostics

Author

Wang, Haolu, primary, Li, Xinxing, additional, Tse, Brian Wan-Chi, additional, Yang, Haotian, additional, Thorling, Camilla A., additional, Liu, Yuxin, additional, Touraud, Margaux, additional, Chouane, Jean Batiste, additional, Liu, Xin, additional, Roberts, Michael S., additional, and Liang, Xiaowen, additional

Published
2018
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71. Multiphoton imaging for assessing renal disposition in acute kidney injury

Author

Liu, Xin, Liang, Xiaowen, Wang, Haolu, Roberts, Darren, Roberts, Michael S., Liu, Xin, Liang, Xiaowen, Wang, Haolu, Roberts, Darren, and Roberts, Michael S.

Abstract

Estimation of renal function and drug renal disposition in acute kidney injury (AKI), is important for appropriate dosing of drugs and adjustment of therapeutic strategies, but is challenging due to fluctuations in kidney function. Multiphoton microscopy has been shown to be a useful tool in studying drug disposition in liver and can reflect dynamic changes of liver function. We extend this imaging technique to investigate glomerular filtration rate (GFR) and tubular transporter functional change in various animal models of AKI, which mimic a broad range of causes of AKI such as hypoxia (renal ischemia- reperfusion), therapeutic drugs (e.g. cisplatin), rhabdomyolysis (e.g. glycerol-induced) and sepsis (e.g. LPSinduced). The MPM images revealed acute injury of tubular cells as indicated by reduced autofluorescence and cellular vacuolation in AKI groups compared to control group. In control animal, systemically injected FITC-labelled inulin was rapidly cleared from glomerulus, while the clearance of FITC-inulin was significantly delayed in most of animals in AKI group, which may reflect the reduced GFR in AKI. Following intravenous injection, rhodamine 123, a fluorescent substrate of p-glycoprotein (one of tubular transporter), was excreted into urine in proximal tubule via p-glycoprotein; in response to AKI, rhodamine 123 was retained in tubular cells as revealed by slower decay of fluorescence intensity, indicating P-gp transporter dysfunction in AKI. Thus, real-time changes in GFR and transporter function can be imaged in rodent kidney with AKI using multiphoton excitation of exogenously injected fluorescent markers.

Published
2016

81. Extracellular vesicles secreted by highly metastatic clonal variants of osteosarcoma preferentially localize to the lungs and induce metastatic behaviour in poorly metastatic clones

Author

Macklin, Rebecca, primary, Wang, Haolu, additional, Loo, Dorothy, additional, Martin, Sally, additional, Cumming, Andrew, additional, Cai, Na, additional, Lane, Rebecca, additional, Ponce, Natalia Saenz, additional, Topkas, Eleni, additional, Inder, Kerry, additional, Saunders, Nicholas A, additional, and Endo-Munoz, Liliana, additional

Published
2016
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90. Negative lymph node count is an independent prognostic factor for patients with rectal cancer who received preoperative radiotherapy.

Author

Xinxing Li, Hao Lu, Kai Xu, Haolu Wang, Xiaowen Liang, Zhiqian Hu, Li, Xinxing, Lu, Hao, Xu, Kai, Wang, Haolu, Liang, Xiaowen, and Hu, Zhiqian

Subjects
RECTAL cancer treatment, RECTAL cancer, LYMPH node cancer, CANCER radiotherapy, SURVIVAL analysis (Biometry), MULTIVARIATE analysis, PROGNOSIS, ADENOCARCINOMA, REPORTING of diseases, LONGITUDINAL method, LYMPH nodes, METASTASIS, PREOPERATIVE care, RADIOTHERAPY, RECTUM tumors, SURVIVAL, TUMORS, TUMOR classification, TUMOR grading
Abstract

Background: Negative lymph node (NLN) count has been reported to provide more accurate prognostic information than the N stage alone in patients with rectal cancer (RC). Since preoperative radiotherapy (Pre-RT) can significantly affect the LN status, it is unclear whether NLN count still has prognostic value count on survival of patients with RC who received Pre-RT.Methods: In this study, clinicopathological characteristics, number of positive LNs and survival time were collected from Surveillance, Epidemiology, and End Results Program (SEER)-registered RC patients. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors for survival.Results: X-tile plots identified 9 (P < 0.001) as the optimal cutoff NLN value to divide the patients into high and low risk subsets in terms of cause specific survival (CSS). NLN count was validated as independently prognostic factor in univariate and multivariate analysis (P < 0.001). Subgroup analysis showed that NLN count was an independently prognostic factor for patients with stage ypII (P = 0.002) and ypIII (P < 0.001).Conclusions: Our results firmly demonstrated that NLN count provides accurate prognostic information for RC patients with Pre-RT. [ABSTRACT FROM AUTHOR]

Published
2017
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91. Visualizing liver anatomy, physiology and pharmacology using multiphoton microscopy.

Author

Wang, Haolu, Liang, Xiaowen, Gravot, Germain, Thorling, Camilla A., Crawford, Darrell H. G., Xu, Zhi Ping, Liu, Xin, and Roberts, Michael S.

Abstract

Multiphoton microscopy (MPM) has become increasingly popular and widely used in both basic and clinical liver studies over the past few years. This technology provides insights into deep live tissues with less photobleaching and phototoxicity, which helps us to better understand the cellular morphology, microenvironment, immune responses and spatiotemporal dynamics of drugs and therapeutic cells in the healthy and diseased liver. This review summarizes the principles, opportunities, applications and limitations of MPM in hepatology. A key emphasis is on the use of fluorescence lifetime imaging (FLIM) to add additional quantification and specificity to the detection of endogenous fluorescent species in the liver as well as exogenous molecules and nanoparticles that are applied to the liver in vivo. We anticipate that in the near future MPM-FLIM will advance our understanding of the cellular and molecular mechanisms of liver diseases, and will be evaluated from bench to bedside, leading to real-time histology of human liver diseases. [ABSTRACT FROM AUTHOR]

Published
2017
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94. Emodin enhances cisplatin-induced cytotoxicity in human bladder cancer cells through ROS elevation and MRP1 downregulation.

Author

Xinxing Li, Haolu Wang, Juan Wang, Yuying Chen, Xiaobin Yin, Guiying Shi, Hui Li, Zhiqian Hu, Xiaowen Liang, Li, Xinxing, Wang, Haolu, Wang, Juan, Chen, Yuying, Yin, Xiaobin, Shi, Guiying, Li, Hui, Hu, Zhiqian, and Liang, Xiaowen

Subjects
BLADDER cancer treatment, CELL-mediated cytotoxicity, CISPLATIN, EMODIN, DRUG side effects, DOWNREGULATION, REACTIVE oxygen species, CANCER invasiveness, ANIMAL experimentation, ANIMALS, BIOCHEMISTRY, BLADDER tumors, CARRIER proteins, CELL lines, CELL physiology, DRUG synergism, GENES, PHENOMENOLOGY, MICE, CASCARA sagrada
Abstract

Background: Chemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer. Reactive oxygen species (ROS) plays a key role in the chemosensitivity of cancer cells. In the present study, emodin (1,3,8-trihydroxy-6-methylanthraquinone) was applied as a ROS generator in combination with cisplatin in T24 and J82 human bladder cancer cells.Methods: Cell viability and apoptosis rate of different treatment groups were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM). The expression of transporters was measured at both the transcription and translation levels using PCR and western blotting. In vitro findings were confirmed by in vivo experiments using tumor-bearing mice. The expression of multidrug resistance-associated protein 1 (MRP1) in tumour tissue was measured using immunohistochemistry and side effects of the emodin/cisplatin co-treatment were investigated by histological examination.Results: Emodin increased the cellular ROS level and effectively enhanced the cisplatin-induced cytotoxicity of T24 and J82 human bladder cancer cells through decreasing glutathione-cisplatin (GSH-cisplatin) conjugates. It blocked the chemoresistance of T24 and J82 cells to cisplatin through suppressing the expression of MRP1. This effect was specific in T24 and J82 cells but not in HCV-29 normal bladder epithelial cells. Consistent with in vitro experiments, emodin/cisplatin co-treatment increased the cell apoptosis and repressed the MRP1 expression in xenograft tumors, and without obvious systemic toxicity.Conclusions: This study revealed that emodin could increase the cisplatin-induced cytotoxicity against T24 and J82 cells via elevating the cellular ROS level and downregulating MRP1 expression. We suggest that emodin could serve as an effective adjuvant agent for the cisplatin-based chemotherapy of bladder cancer. [ABSTRACT FROM AUTHOR]

Published
2016
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96. Visualization and Modeling of the In VivoDistribution of Mesenchymal Stem Cells

Author

Wang, Haolu, Thorling, Camilla A., Xu, Zhi Ping, Crawford, Darrell H. G., Liang, Xiaowen, Liu, Xin, and Roberts, Michael S.

Abstract

This unit describes a protocol for elucidating the in vivodisposition of administered mesenchymal stem cells (MSCs). Specifically, direct visualization of donor cell spatiotemporal distribution and assessment of donor cell quantity in recipient organs are described. Protocols for data analysis are suggested, with the goal of developing a model to characterize and predict the physiological kinetics of administered MSCs. The use of this model is described, suggesting that it can be applied to abnormal conditions and has potential interspecies and inter‐route predictive capability. These universal methods can be employed, regardless of the type of stem cell or disease, to guide future experiments and design treatment protocols. © 2017 by John Wiley & Sons, Inc.

Published
2017
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98. Diagnostic imaging and therapeutic application of nanoparticles targeting the liver.

Author

Thorling, Camilla A., Liang, Xiaowen, Grice, Jeffrey E., Liu, Xin, Wang, Haolu, Roberts, Michael S., Bridle, Kim R., Crawford, Darrell H. G., Zhu, Yian, and Xu, Zhi Ping

Abstract

Liver diseases, particularly viral hepatitis, cirrhosis and hepatocellular carcinoma, are common in clinical practice with high morbidity and mortality worldwide. Many substances for diagnostic imaging and therapy of liver diseases may have either severe adverse effects or insufficient effectiveness in vivo because of their nonspecific uptake. Therefore, by targeting the delivery of drugs into the liver or specific liver cells, drug efficiency may be largely improved. This review summarizes the up-to-date research progress focusing on nanoparticles targeting the liver for both diagnostic and therapeutic purposes. Targeting strategies, mechanisms of enhanced effects, and clinical applications of nanoparticles are discussed specifically. We believe that new targeting nanotechnology such as nanoprobes for multi-modality imaging and multifunctional nanoparticles would facilitate significant advancements in this active research area in the near future. [ABSTRACT FROM AUTHOR]

Published
2015
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