Gaoxian Chen

All Publications

• Generation of two induced pluripotent stem cell lines from patients suffering from pulmonary hypertension. Stem cell research Chen, G., Orozco, L., Parmisano, S., Jahng, J. W., Vera, C. D., Zhuge, Y., Wu, J. C., Obal, D. 2023; 72: 103218

  Abstract

  Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease, with an estimated 500-1000 new cases diagnosed every year. A portion of these cases may be caused by mutations in the BMPR2 gene, suggesting a possible genetic component in the development of the disease. Here, we report two human induced pluripotent stem cell (iPSC) lines generated from IPAH patients. Both cell lines provide valuable insight into the molecular and cellular mechanisms of IPAH and can be used to further understand the disease.

  View details for DOI 10.1016/j.scr.2023.103218

  View details for PubMedID 37804546

• Detecting and measuring of GPCR signaling - comparison of human induced pluripotent stem cells and immortal cell lines. Frontiers in endocrinology Chen, G., Obal, D. 2023; 14: 1179600

  Abstract

  G protein-coupled receptors (GPCRs) are a large family of transmembrane proteins that play a major role in many physiological processes, and thus GPCR-targeted drug development has been widely promoted. Although research findings generated in immortal cell lines have contributed to the advancement of the GPCR field, the homogenous genetic backgrounds, and the overexpression of GPCRs in these cell lines make it difficult to correlate the results with clinical patients. Human induced pluripotent stem cells (hiPSCs) have the potential to overcome these limitations, because they contain patient specific genetic information and can differentiate into numerous cell types. To detect GPCRs in hiPSCs, highly selective labeling and sensitive imaging techniques are required. This review summarizes existing resonance energy transfer and protein complementation assay technologies, as well as existing and new labeling methods. The difficulties of extending existing detection methods to hiPSCs are discussed, as well as the potential of hiPSCs to expand GPCR research towards personalized medicine.

  View details for DOI 10.3389/fendo.2023.1179600

  View details for PubMedID 37293485

  View details for PubMedCentralID PMC10244570

• DNA-modularized construction of bivalent ligands precisely regulates receptor binding and activation CHEM Zhao, N., Wu, W., Wang, Y., Song, K., Chen, G., Chen, Y., Wang, R., Xu, J., Cui, K., Chen, H., Tan, W., Zhang, J., Xiao, Z. 2023; 9 (4): 901-923

  View details for DOI 10.1016/j.chempr.2022.12.002

  View details for Web of Science ID 000983646000001

• Balancing Microthrombosis and Inflammation via Injectable Protein Hydrogel for Inflammatory Bowel Disease ADVANCED SCIENCE Hong, L., Chen, G., Cai, Z., Liu, H., Zhang, C., Wang, F., Xiao, Z., Zhong, J., Wang, L., Wang, Z., Cui, W. 2022; 9 (20): e2200281

  Abstract

  Emerging evidence indicates that a vicious cycle between inflammation and microthrombosis catalyzes the pathogenesis of inflammatory bowel disease (IBD). Over-stimulated inflammation triggers a coagulation cascade and leads to microthrombosis, which further complicates the injury through tissue hypoxia and ischemia. Herein, an injectable protein hydrogel with anti-thrombosis and anti-inflammation competency is developed to impede this cycle, cross-linked by silver ion mediated metal-ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin, respectively. The ex vivo experiments show that the hydrogel, HEP-Ag-BSA, exhibits excellent self-healing ability, injectability, biocompatibility, and sustained drug release. HEP-Ag-BSA also demonstrates anti-coagulation and anti-inflammation abilities via coagulation analysis and lipopolysaccharide stimulation assay. The in vivo imaging confirms the longer retention time of HEP-Ag-BSA at inflammatory sites than in normal mucosa owing to electrostatic interactions. The in vivo study applying a mouse model with colitis also reveals that HEP-Ag-BSA can robustly inhibit inflammatory microthrombosis with reduced bleeding risk. This versatile protein hydrogel platform can definitively hinder the "inflammation and microthrombosis" cycle, providing a novel integrated approach against IBD.

  View details for DOI 10.1002/advs.202200281

  View details for Web of Science ID 000791692000001

  View details for PubMedID 35524641

  View details for PubMedCentralID PMC9284187

• Molecular Regulation of Polymeric Raman Probes for Ultrasensitive Microtumor Diagnosis and Noninvasive Microvessle Imaging SMALL Cui, K., Zhang, Y., Chen, G., Cui, Y., Wu, W., Zhao, N., Liu, T., Xiao, Z. 2022; 18 (12): e2106925

  Abstract

  Raman imaging is a powerful tool for the diagnosis of cancers and visualization of various biological processes. Polymers possessing excellent biocompatibility are promising probes for Raman imaging. However, few polymers are reported to serve as Raman probes for in vivo imaging, mainly due to the intrinsic weak Raman signal intensity and fluorescence interference of these polymers. Herein, a poly(indacenodithiophene-benzothiadiazole) (IDT-BT) polymer is presented, which emits unprecedentedly strong Raman signals under the near-infrared wavelength (785 nm) excitation, thus functioning as a Raman probe for ultrasensitive in vivo Raman imaging. Further mechanistic studies unveil that the unique Raman feature of the IDT-BT polymer relies on molecularly regulating its absorbance edge adjacent to the desired excitation wavelength, thus avoiding fluorescence interference and simultaneously emitting strong Raman scattering under preresonant excitation. Taking advantage of this discipline, the IDT-BT polymeric probe successfully realizes intraoperative Raman imaging of micrometastasis as small as 0.3 mm × 0.3 mm, comparable to the most sensitive Raman probes currently reported. Impressively, the IDT-BT enables noninvasive microvascular imaging, which is not achieved using other Raman probes. This work opens a new avenue toward the development of polymeric Raman probes for in vivo Raman imaging.

  View details for DOI 10.1002/smll.202106925

  View details for Web of Science ID 000748236300001

  View details for PubMedID 35092156

• Ultrasensitive Exosome Detection by Modularized SERS Labeling for Postoperative Recurrence Surveillance ACS SENSORS Fan, C., Zhao, N., Cui, K., Chen, G., Chen, Y., Wu, W., Li, Q., Cui, Y., Li, R., Xiao, Z. 2021; 6 (9): 3234-3241

  Abstract

  Exosome-based liquid biopsy holds great potential in monitoring tumor progression. Current exosome detection biosensors rely on signal amplification strategies to improve sensitivity; however, these strategies pay little attention to manipulating the number of signal reporters, limiting the rational optimization of the biosensors. Here, we have developed a modularized surface-enhanced Raman spectroscopy (SERS) labeling strategy, where each Raman reporter is coupled with lysine as a signal-lysine module, and thus the number of Raman reporters can be precisely controlled by the modularized solid-phase peptide synthesis. Using this strategy, we screened out an optimum Raman biosensor for ultrasensitive exosome detection, with the limit of detection of 2.4 particles per microliter. This biosensor enables a successful detection of the tumor with an average diameter of approximately 3.55 mm, and thus enables successful surveillance of the postoperative tumor recurrence in mice models and distinguishing cancer patients from healthy subjects. Our work provides a de novo strategy to precisely amplify signals toward a myriad of biosensor-related medical applications.

  View details for DOI 10.1021/acssensors.1c00890

  View details for Web of Science ID 000702090500011

  View details for PubMedID 34472832

• Copper Sulfide Nanoparticle-Redirected Macrophages for Adoptive Transfer Therapy of Melanoma ADVANCED FUNCTIONAL MATERIALS Xu, J., Zheng, B., Zhang, S., Liao, X., Tong, Q., Wei, G., Yu, S., Chen, G., Wu, A., Gao, S., Qian, Y., Xiao, Z., Lu, W. 2021; 31 (11)

  View details for DOI 10.1002/adfm.202008022

  View details for Web of Science ID 000606958000001

• Artificial Cells Based on DNA Nanotechnology ACS APPLIED BIO MATERIALS Zhao, N., Chen, Y., Chen, G., Xiao, Z. 2020; 3 (7): 3928-3934

  Abstract

  Artificial cells have led to many potential applications in synthetic biology and served as useful platforms to study biological phenomena. With increasing development of DNA nanotechnology, DNA-based nanostructures with various morphologies have been constructed for protein mimicking. These biomimicking elements can be assembled on cell membrane involved in various cellular activities, as well as be constructed as signaling networks inside cells. DNA nanotechnology provides an efficient approach to accomplish multiple functions, including signal recognition, transduction, and output. Here, we review a myriad of predominant studies on the construction of artificial cells based on DNA nanotechnology, including the morphological and functional mimic of membrane proteins, biosensors for monitoring the cellular microenvironment, and construction of DNA-based signal feedback networks. We also provide a comprehensive insight into DNA-based artificial cells, on the basis of current challenges and scientific requirements, which will prompt their reasonable designs in the future.

  View details for DOI 10.1021/acsabm.0c00149

  View details for Web of Science ID 000604597100002

  View details for PubMedID 35025469

• Bacterium-Mimicking Vector with Enhanced Adjuvanticity for Cancer Immunotherapy and Minimized Toxicity ADVANCED FUNCTIONAL MATERIALS Zheng, B., Xu, J., Chen, G., Zhang, S., Xiao, Z., Lu, W. 2019; 29 (33)

  View details for DOI 10.1002/adfm.201901437

  View details for Web of Science ID 000482137900022

• Photodegradable CuS SERS Probes for lntraoperative Residual Tumor Detection, Ablation, and Self-Clearance ACS APPLIED MATERIALS & INTERFACES Qiu, Y., Lin, M., Chen, G., Fang, C., Li, M., Gu, X., Cong, S., Zhao, Z., Fu, L., Fang, X., Xiao, Z. 2019; 11 (26): 23436-23444

  Abstract

  Surface-enhanced Raman scattering (SERS) probes have exhibited great potential in biomedical applications. However, currently reported SERS probes are mainly fabricated by nondegradable Au or Ag nanostructures, which are not favorably cleared from the imaged tissues. This bottleneck hinders their in vivo applications. We herein explore a degradable SERS probe consisting of hollow CuS nanoparticles (NPs) to circumvent the current limitation. We identify, for the first time, the Raman enhancement effects of hollow CuS NPs as a SERS probe for Raman imaging of residual tumor lesions. Uniquely, CuS SERS probes are degradable, which stems from laser-induced photothermal effects of CuS NPs, leading to their disintegration from shell structures into individual crystals, thus facilitating their self-clearance from imaged tissues. This novel CuS SERS probe with photodegradation characteristics opens avenues for applying Raman imaging toward a myriad of biomedical applications.

  View details for DOI 10.1021/acsami.9b00469

  View details for Web of Science ID 000474670100059

  View details for PubMedID 31252485

• Albumin tailoring fluorescence and photothermal conversion effect of near-infrared-II fluorophore with aggregation-induced emission characteristics NATURE COMMUNICATIONS Gao, S., Wei, G., Zhang, S., Zheng, B., Xu, J., Chen, G., Li, M., Song, S., Fu, W., Xiao, Z., Lu, W. 2019; 10: 2206

  Abstract

  Fluorophores with donor-acceptor-donor groups with the emission spanning the second near-infrared window (NIR-II) have recently received great attention for biomedical application. Yet, the mechanism underlying the equilibrium between fluorescence (radiative decay) and photothermal effect (non-radiative decay) of these fluorophores remains elusive. Here, we demonstrate that a lipophilic NIR-II fluorophore, BPBBT, possesses both twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) characteristics. Human serum albumin (HSA) binds to BPBBT, which changes the planarity of the fluorophore and restricts its intramolecular rotation. The binding results in alteration to the equilibrium between AIE and TICT state of BPBBT, tailoring its fluorescence and photothermal efficiency. Under the guidance of intraoperative NIR-II fluorescence image, the prepared HSA-bound BPBBT nanoparticles delineate primary orthotopic mouse colon tumor and metastatic lesions with dimensions as small as 0.5 mm × 0.3 mm, and offer photothermal ablation therapy with optimized timing, dosing and area of the laser irradiation.

  View details for DOI 10.1038/s41467-019-10056-9

  View details for Web of Science ID 000468174600006

  View details for PubMedID 31101816

  View details for PubMedCentralID PMC6525245

• CuS Nanoparticles as a Photodynamic Nanoswitch for Abrogating Bypass Signaling To Overcome Gefitinib Resistance NANO LETTERS Gu, X., Qiu, Y., Lin, M., Cui, K., Chen, G., Chen, Y., Fan, C., Zhang, Y., Xu, L., Chen, H., Wan, J., Lu, W., Xiao, Z. 2019; 19 (5): 3344-3352

  Abstract

  Bypass signaling activation plays a crucial role in the acquired resistance of gefitinib, the first targeted drug in the clinic to treat advanced non-small cell lung cancer. Although the inactivation of bypass signaling by small-molecule inhibitors or monoclonal antibodies may overcome gefitinib resistance, their clinical use has been limited by the complex production process and off-target toxicity. Here we show CuS nanoparticles (NPs) behaved as a photodynamic nanoswitch to specifically abrogate overactive bypass signaling in resistant tumor cells without interfering with the same signal pathways in normal cells. In representative insulin growth factor-1 receptor (IGF1R) bypass activation-induced gefitinib resistant tumors, CuS NPs upon near-infrared laser irradiation locally elevated reactive oxygen species (ROS) level in tumor cells, leading to the blockage of bypass IGF1R and its downstream AKT/ERK/NF-κB signaling cascades. Consequently, laser-irradiated CuS NPs sensitized tumors to gefitinib treatment and prolonged the survival of mice with no obvious toxicity. Laser-irradiated CuS NPs may serve as a simple and safe nanomedicine strategy to overcome bypass activation-induced gefitinib resistance in a specific and controllable manner and provide insights into the treatment of a myriad of other resistant tumors in the field of cancer therapy.

  View details for DOI 10.1021/acs.nanolett.9b01065

  View details for Web of Science ID 000467781900074

  View details for PubMedID 30974946

• <i>para</i>-Aminothiophenol Radical Reaction-Functionalized Gold Nanoprobe for One-to-All Detection of Five Reactive Oxygen Species In Vivo ANALYTICAL CHEMISTRY Cui, K., Fan, C., Chen, G., Qiu, Y., Li, M., Lin, M., Wan, J., Cai, C., Xiao, Z. 2018; 90 (20): 12137-12144

  Abstract

  Five major reactive oxygen species (ROS) are generated in diseases including H2O2, •OH, O2•-, ROO•, and 1O2. Simultaneous detection of the five ROS with a single probe is crucial for a comprehensive understanding of the development and progression of many diseases, such as cancer and inflammatory diseases. However, currently reported detection systems are limited by targeting one ROS with one probe. This one-to-one detection mode may fail to sufficiently unveil the diseased state. In this study, we achieved simultaneous detection of all the five ROS with one probe (i.e., one-to-all detection), by designing a novel para-aminothiophenol (PATP) and hemin-decorated gold (Au/PATP/Hemin) nanoprobe. The design is principled by our discovery that PATP can react with •OH, O2•-, ROO•, and 1O2 by a radical oxidative coupling mechanism to form 4,4'-dimercaptoazobenzene (DMAB). The DMAB then elicited strong characteristic surface-enhanced Raman scattering (SERS) peaks at 1142, 1386, and 1432 cm-1; which in turn enables direct detection of •OH, O2•-, ROO•, and 1O2 and indirect detection of H2O2 by hemin-catalyzed fenton reaction to convert H2O2 into •OH. In two representative ROS-elevated mice models of tumors and allergic dermatitis, the Au/PATP/Hemin nanoprobe demonstrated its robust performance of monitoring tumor development and inflammation progression in a highly sensitive and quantitative manner.

  View details for DOI 10.1021/acs.analchem.8b03116

  View details for Web of Science ID 000447816400055

  View details for PubMedID 30207154

• Intraoperative Detection and Eradication of Residual Microtumors with Gap-Enhanced Raman Tags ACS NANO Qiu, Y., Zhang, Y., Li, M., Chen, G., Fan, C., Cui, K., Wan, J., Han, A., Ye, J., Xiao, Z. 2018; 12 (8): 7974-7985

  Abstract

  The inability to intraoperatively diagnose and eliminate microscopic residual tumors represents a significant challenge in cancer surgery. These residual microtumors cause lethal recurrence and metastasis. Herein, we show a crucial example of Raman imaging with gap-enhanced Raman tags (GERTs) to serve as a robust platform for intraoperative detection and eradication of residual microscopic foci, which exist in surgical margins, tumor invasion, and multifocal tumor spread. The GERTs feature gap-enhanced gold core-shell nanostructures, with Raman reporters embedding inside the interior gap junction. This nanostructure elicits highly sensitive and photostable Raman signals for microtumor detection by applying a 785 nm, low-energy laser and produces hyperthermia effects for microtumor ablation upon switching a 808 nm, high-power laser. In the orthotopic prostate metastasis tumor model, systematic delivery of GERTs enabled precise imaging and real-time ablation of macroscopic malignant lesions around the surgical bed without damaging normal tissues. Consequently, the GERTs-based surgery prevented local recurrence and delivered 100% tumor-free survival. These results suggest the efficiency of theranostic GERTs for precise detection and removal of residual miroctumors, broadening the avenues to apply Raman-based imaging for theranostic precision medicine.

  View details for DOI 10.1021/acsnano.8b02681

  View details for Web of Science ID 000443525600049

  View details for PubMedID 30080395

• The potassium channel KCa3.1 constitutes a pharmacological target for astrogliosis associated with ischemia stroke JOURNAL OF NEUROINFLAMMATION Yi, M., Wei, T., Wang, Y., Lu, Q., Chen, G., Gao, X., Geller, H. M., Chen, H., Yu, Z. 2017; 14: 203

  Abstract

  Reactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease.Wild type mice and KCa3.1-/- mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro.Immunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1-/- mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1-/- pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis.Our data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.

  View details for DOI 10.1186/s12974-017-0973-8

  View details for Web of Science ID 000412977700001

  View details for PubMedID 29037241

  View details for PubMedCentralID PMC5644250

• Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction INTERNATIONAL JOURNAL OF NANOMEDICINE Qi, Q., Lu, L., Li, H., Yuan, Z., Chen, G., Lin, M., Ruan, Z., Ye, X., Xiao, Z., Zhao, Q. 2017; 12: 4835-4848

  Abstract

  The local, intramyocardial injection of proteins into the infarcted heart is an attractive option to initiate cardiac regeneration after myocardial infarction (MI). Liraglutide, which was developed as a treatment for type 2 diabetes, has been implicated as one of the most promising protein candidates in cardiac regeneration. A significant challenge to the therapeutic use of this protein is its short half-life in vivo. In this study, we evaluated the therapeutic effects and long-term retention of liraglutide loaded in poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NP-liraglutide) on experimental MI. PLGA-PEG nanoparticles (NPs) have been shown to efficiently load liraglutide and release bioactive liraglutide in a sustained manner. For in vitro test, the released liraglutide retained bioactivity, as measured by its ability to activate liraglutide signaling pathways. Next, we compared the effects of an intramyocardial injection of saline, empty NPs, free liraglutide and NP-liraglutide in a rat model of MI. NPs were detected in the myocardium for up to 4 weeks. More importantly, an intramyocardial injection of NP-liraglutide was sufficient to improve cardiac function (P<0.05), attenuate the infarct size (P<0.05), preserve wall thickness (P<0.05), promote angiogenesis (P<0.05) and prevent cardiomyocyte apoptosis (P<0.05) at 4 weeks after injection without affecting glucose levels. The local, controlled, intramyocardial delivery of NP-liraglutide represents an effective and promising strategy for the treatment of MI.

  View details for DOI 10.2147/IJN.S132064

  View details for Web of Science ID 000405175700001

  View details for PubMedID 28744119

  View details for PubMedCentralID PMC5511023

• Nanoparticle-based oral delivery systems for colon targeting: principles and design strategies SCIENCE BULLETIN Lu, L., Chen, G., Qiu, Y., Li, M., Liu, D., Hu, D., Gu, X., Xiao, Z. 2016; 61 (9): 670-681

  View details for DOI 10.1007/s11434-016-1056-4

  View details for Web of Science ID 000375234000002