Co-reporter:Hui Gao, Ying Bi, Xin Wang, Miao Wang, Mengxue Zhou, Huiru Lu, Jimin Gao, Jun Chen, and Yi Hu
ACS Biomaterials Science & Engineering December 11, 2017 Volume 3(Issue 12) pp:3628-3628
Publication Date(Web):October 20, 2017
DOI:10.1021/acsbiomaterials.7b00405
Nanomedicines have shown great promise in increasing the efficacy and preventing adverse effects of drugs for bladder cancer. Here we sought to examine the effect of chemo-photothermal therapy on an orthotopic mouse model of superficial bladder cancer. Doxorubicin (DOX) was encapsulated in CS/PNIPAAm@SWCNTs nanoparticles. The biodistribution and antitumor effects of DOX-loaded nanoparticles were analyzed. DOX-loaded nanoparticles were accumulated in tumor cells upon near-infrared (NIR) irradiation and exhibited strong antitumor activity in mice bearing orthotopic bladder tumors. In addition, NIR-induced hyperthermia enhanced the permeability of tumor blood vessels, which presumably accounted for specific targeting of the nanomedicines to tumors. These results suggest that NIR-guided thermal-responsive nanomedicines are potentially applicable for chemo-photothermal therapy against orthotopic bladder tumors.Keywords: chemo-photothermal therapy; near-infrared; orthotopic bladder tumor; targeted drug delivery; tumor vasculature;
Co-reporter:Ai-ping Lan;Jun Chen;Yuliang Zhao;Zhifang Chai
NeuroMolecular Medicine 2017 Volume 19( Issue 1) pp:1-10
Publication Date(Web):2017 March
DOI:10.1007/s12017-016-8417-7
As a key regulator of cell metabolism and survival, mechanistic target of rapamycin (mTOR) emerges as a novel therapeutic target for Parkinson’s disease (PD). A growing body of research indicates that restoring perturbed mTOR signaling in PD models can prevent neuronal cell death. Nevertheless, molecular mechanisms underlying mTOR-mediated effects in PD have not been fully understood yet. Here, we review recent progress in characterizing the association of mTOR signaling with PD risk factors and further discuss the potential roles of mTOR in PD.
Co-reporter:Yi Tan, Ling Zhang, Ka Ho Man, Raoul Peltier, Ganchao Chen, Huatang Zhang, Liyi Zhou, Feng WangDerek Ho, Shao Q. Yao, Yi Hu, Hongyan Sun
ACS Applied Materials & Interfaces 2017 Volume 9(Issue 8) pp:
Publication Date(Web):January 31, 2017
DOI:10.1021/acsami.6b14176
Alkaline phosphatases are a group of enzymes that play important roles in regulating diverse cellular functions and disease pathogenesis. Hence, developing fluorescent probes for in vivo detection of alkaline phosphatase activity is highly desirable for studying the dynamic phosphorylation in living organisms. Here, we developed the very first reaction-based near-infrared (NIR) probe (DHXP) for sensitive detection of alkaline phosphatase activity both in vitro and in vivo. Our studies demonstrated that the probe displayed an up to 66-fold fluorescence increment upon incubation with alkaline phosphatases, and the detection limit of our probe was determined to be 0.07 U/L, which is lower than that of most of alkaline phosphatase probes reported in literature. Furthermore, we demonstrated that the probe can be applied to detecting alkaline phosphatase activity in cells and mice. In addition, our probe possesses excellent biocompatibility and rapid cell-internalization ability. In light of these prominent properties, we envision that DHXP will add useful tools for investigating alkaline phosphatase activity in biomedical research.Keywords: alkaline phosphatase; bioimaging; fluorescent probe; mice; near-infrared;
Co-reporter:Hui Huang;Jun Chen;Huiru Lu;Mengxue Zhou;Zhifang Chai
BioMetals 2017 Volume 30( Issue 6) pp:975-980
Publication Date(Web):23 October 2017
DOI:10.1007/s10534-017-0059-1
It is generally believed that gene-environment interaction may contribute to neurodegeneration. Of particular note is that iron overload may be one of the risk factors for neurodegeneration. However, the mechanisms underlying iron-associated neurotoxicity are not fully understood. Here we explored the effects of mechanistic target of rapamycin (mTOR) inhibition in iron-stressed human neuroblastoma cells. Two mTOR inhibitors, rapamycin and Torin 1, had similar effects in cells exposed to a relatively low concentration of iron. At a higher concentration of iron, Torin 1, instead of rapamycin, could further aggravate iron-induced cytotoxicity, and mitochondrial ROS levels were significantly higher in Torin 1-treated cells. These results suggest that mTOR inhibition may not be able to alleviate iron-induced neurotoxicity.
Co-reporter:Huiru Lu;Jun Chen;Hui Huang;Mengxue Zhou;Qing Zhu;Shao Q. Yao
BioMetals 2017 Volume 30( Issue 4) pp:599-607
Publication Date(Web):30 June 2017
DOI:10.1007/s10534-017-0030-1
Both monoamine oxidase B (MAO-B) and iron accumulation are associated with neurologic diseases including Parkinson’s disease. However, the association of iron with MAO-B activity was poorly understood. Here we took advantage of highly sensitive and specific fluorescence probes to examine the change in MAO-B activity in human dopaminergic neuroblastoma (SH-SY5Y) cells upon iron exposure. Both ferric and ferrous ions could significantly enhance the activity of MAO-B, instead of MAO-A, in SH-SY5Y cells. In addition, iron-induced increase in MAO-B probe fluorescence could be prevented by pargyline and other newly developed MAO-B inhibitors, suggesting that it was MAO-B activity-dependent. These findings may suggest MAO-B is an important sensor in iron-stressed neuronal cells.
Co-reporter:Hui Huang;Jun Chen;Huiru Lu;Mengxue Zhou;Zhifang Chai
BioMetals 2017 Volume 30( Issue 4) pp:623-628
Publication Date(Web):12 June 2017
DOI:10.1007/s10534-017-0023-0
Deregulated iron homeostasis is generally believed to be implicated in neurodegenerative diseases, including Parkinson’s disease. Nevertheless, it is not fully understood how iron overload can elicit neuronal cell damage. Here we examined mitochondrial reactive oxygen species (ROS) levels in human dopaminergic neuroblastoma SH-SY5Y cells upon iron exposure. A relatively high concentration of iron could significantly increase mitochondrial ROS levels in SH-SY5Y cells. Pharmacological activation of AMP-activated protein kinase (AMPK) almost completely inhibited the effect of iron on mitochondrial ROS. By contrast, AMPK inhibition aggravated the neurotoxicity of iron and enhanced the production of mitochondrial ROS. Collectively, these findings suggested that excess iron may be able to perturb mitochondrial function, and AMPK activity is important for the association of iron and mitochondria.
Co-reporter:Yi Liu;Heping Li;Jin Xie;Mengxue Zhou;Hui Huang;Huiru Lu;Zhifang Chai;Jun Chen
Biomaterials Science (2013-Present) 2017 vol. 5(Issue 5) pp:1022-1031
Publication Date(Web):2017/05/02
DOI:10.1039/C6BM00878J
Phototherapy, as a noninvasive therapeutic procedure, has been applied to treat tumors. However, the application of phototherapy is often compromised by its low efficiency. Herein, we developed a novel nanoplatform based on cationic amphiphilic polymer-wrapped carbon nanotubes (rPAA@SWCNTs) with a photosensitizer, indocyanine green (ICG), for phototherapy. The as-prepared nanoparticles exhibited excellent mitochondria targeting due to the synergistic properties of highly positive charges from the polycations on the corona and the high hydrophobicity from the carbon nanotubes in the core. Moreover, the high buffer capacity of the polycations facilitated the endosomal escape of nanoparticles via a proton-sponge effect. When irradiated with an 808 nm NIR laser, ICG/rPAA@SWCNTs could precisely damage mitochondria with high efficiency and produce reactive oxygen species (ROS) and hyperthermia, which further induced the ROS burst from damaged mitochondria. The overproduced ROS accumulated in mitochondria ultimately resulted in mitochondrial damage and cell death. Therefore ICG/rPAA@SWCNTs may be able to achieve an amplifying phototherapeutic effect.
Co-reporter:Ganchao Chen, Yusheng Xie, Raoul Peltier, Haipeng Lei, Ping Wang, Jun Chen, Yi Hu, Feng Wang, Xi Yao, and Hongyan Sun
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 18) pp:11204
Publication Date(Web):April 22, 2016
DOI:10.1021/acsami.6b02594
A stimuli-responsive drug delivery system (DDS) with bioactive surface is constructed by end-capping mesoporous silica nanoparticles (MSNs) with functional peptide-coated gold nanoparticles (GNPs). MSNs are first functionalized with acid-labile α-amide-β-carboxyl groups to carry negative charges, and then capped with positively charged GNPs that are decorated with oligo-lysine-containing peptide. The resulting hybrid delivery system exhibits endo/lysosomal pH triggered drug release, and the incorporation of RGD peptide facilitates targeting delivery to αvβ3 integrin overexpressing cancer cells. The system can serve as a platform for preparing diversified multifunctional nanocomposites using various functional inorganic nanoparticles and bioactive peptides.Keywords: charge reversal; controlled release; gold nanoparticles; peptides; targeted delivery
Co-reporter:Hui Gao, Ying Bi, Jun Chen, Lirong Peng, Kaikai Wen, Pan Ji, Weifeng Ren, Xiaoqing Li, Ning Zhang, Jimin Gao, Zhifang Chai, and Yi Hu
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 24) pp:15103-15112
Publication Date(Web):May 26, 2016
DOI:10.1021/acsami.6b03905
Accumulation of nanoparticles in solid tumors depends on their extravasation, but their efficacy is often compromised by intrinsic physiological heterogeneity in tumors. The conventional solutions to circumvent this problem are size control of nanoparticles or increasing the vascular permeability. The aim of this study is to investigate the combination effect of size variation of stimuli-responsive nanoparticles and improved vascular permeability triggered by near-infrared (NIR) light irradiation. Doxorubicin (DOX), a clinically proven drug for bladder cancer, was encapsulated in the nanocomposites with high loading content up to 45%. We show that NIR light-responsive size-switchable nanocarriers could considerably enhance the tumor-targeting of DOX in bladder tumor-bearing mice. Moreover, a combination of NIR-induced hyperthermia and DOX-mediated chemotherapy resulted in remarkable inhibition of tumor growth in mice. Histological results suggest that the change in morphology of tumor microvasculature may account for enhanced extravasation and accumulation of the nanodrugs upon NIR irradiation. Together, these data suggest that external stimuli-responsive drug delivery system offers a safe and effective means of targeted chemo/photothermal therapy.
Co-reporter:A. P. Lan;J. Chen;Z. F. Chai;Y. Hu
BioMetals 2016 Volume 29( Issue 4) pp:665-678
Publication Date(Web):2016 August
DOI:10.1007/s10534-016-9942-4
Parkinson’s disease (PD) is the second most common neurodegenerative disease with gradual loss of dopaminergic neurons. Despite extensive research in the past decades, the etiology of PD remains elusive. Nevertheless, multiple lines of evidence suggest that oxidative stress is one of the common causes in the pathogenesis of PD. It has also been suggested that heavy metal-associated oxidative stress may be implicated in the etiology and pathogenesis of PD. Here we review the roles of redox metals, including iron, copper and cobalt, in PD. Iron is a highly reactive element and deregulation of iron homeostasis is accompanied by concomitant oxidation processes in PD. Copper is a key metal in cell division process, and it has been shown to have an important role in neurodegenerative diseases such as PD. Cobalt induces the generation of reactive oxygen species (ROS) and DNA damage in brain tissues.
Co-reporter:Ai-ping Lan;Xian-jia Xiong;Jun Chen;Xi Wang;Zhi-fang Chai
Neurotoxicity Research 2016 Volume 30( Issue 3) pp:499-509
Publication Date(Web):2016 October
DOI:10.1007/s12640-016-9651-3
The involvement of copper in the pathophysiology of neurodegenerative disorders has been documented but remains poorly understood. This study aimed at investigating the molecular mechanism underlying copper-induced neurotoxicity. Human neuroblastoma SH-SY5Y cells were treated with different concentrations of Cu(II) (25–800 μM). The relative levels of AMPKα, phosphorylated (p)-AMPKα were examined by western blotting. The results showed that copper reduced cell viability and enhanced apoptosis of SH-SY5Y cells. Pretreatment with N-acetyl-l-cysteine, a common ROS scavenger, decreased copper-induced cytotoxicity. Furthermore, the levels of p-AMPKα in SH-SY5Y cells were increased by a relatively low concentration of copper and decreased by a relatively high concentration of copper at 24 h. Moreover, inhibition of AMPK with compound C or RNA interference aggravated concentration-dependent cytotoxicity of Cu(II). Taken together, these results indicated that AMPK activity might be important for the neurotoxicity of Cu(II).
Co-reporter:Huiru Lu, Huatang Zhang, Jun Chen, Jinchao Zhang, Ruochuan Liu, Hongyan Sun, Yuliang Zhao, Zhifang Chai, Yi Hu
Talanta 2016 Volume 146() pp:477-482
Publication Date(Web):1 January 2016
DOI:10.1016/j.talanta.2015.09.014
•We reported that a fluorescent probe could detect Cu(II) at subnanomolar concentrations.•Cu(II) is a specific and potent inhibitor of cysteine.•Cu(II) can differentially modulate the reactivity of cysteinyl thiol.•Cell imaging experiments confirmed the inhibitory effects of Cu(II) on Cys's reactivity.In this study, Cu(II)-mediated differential alteration of cysteine (Cys) reactivity is reported by using a Cys-specific fluorescent probe. The probe could react with Cys to give out strong fluorescence. When Cys was preincubated with Cu(II), the fluorescence of the probe was decreased due to the inhibition of Cys's reactivity by Cu(II). Remarkably, experimental results reveal that the probe could detect Cu(II) at subnanomolar concentrations. In contrast, Cu(II) could only partially inhibit the reaction between Cys and Ellman's reagent (DTNB). Furthermore, selectivity experiments show that Cu(II) is a much more potent inhibitor for Cys compared to other metal ions. Cell imaging experiments also confirm the inhibitory effects of Cu(II) on Cys's reactivity in living cells. We envision that the probe could add a useful tool for sensitive and selective detection of Cu(II) for biomedical research.
Co-reporter:Yanping Qin, Jun Chen, Ying Bi, Xiaohan Xu, Hui Zhou, Jimin Gao, Yi Hu, Yuliang Zhao, Zhifang Chai
Acta Biomaterialia 2015 Volume 17() pp:201-209
Publication Date(Web):15 April 2015
DOI:10.1016/j.actbio.2015.01.026
Abstract
Stimuli-responsive drug delivery systems have been developed to enhance the tumor-targeting drug transportation and minimize the severe side effects along with the chemotherapy. In this study, a near-infrared (NIR) light triggered drug delivery system was developed based on the amphiphilic chitosan derivative-coated single-wall carbon nanotubes (CNT) encapsulated in the thermo/pH sensitive nanogel (CS/PNIPAAm@CNT). The PEG diacrylate (Mw = 250 Da) was applied in the present work to tune the nanoparticles with the phase transition temperature at ∼38 °C, which was an attempt to match the prerequisite for the in vivo applications. Owing to the π–π stacking, hydrophobic interaction and the opportunity of Schiff-base formation between chitosan and doxorubicin (DOX), the nanoparticles possessed a relative high drug loading capacity (∼43%). The DOX loaded CS/PNIPAAm@CNT released DOX faster at 40 °C than at 25 °C, meanwhile faster at pH 5.0 in comparison with that at pH 7.4. Moreover, the rapid and repetitive release of DOX was observed when the DOX-loaded CS/PNIPAAm@CNT was irradiated under NIR light. Furthermore, DOX-loaded CS/PNIPAAm@CNT upon NIR irradiation showed significantly greater cytotoxicity in HeLa cells owing to NIR-triggered increase in temperature and enhanced DOX release. Confocal laser scanning microscopy (CLSM) was utilized to demonstrate the enhanced cell uptake of the as prepared nanoparticles and the faster drug release under the NIR irradiation and lower pH. All the results suggest that multifunctional DOX-loaded CS/PNIPAAm@CNT nanocomposite is a promising therapeutic nanocarrier for intracellular drug delivery with great potential for targeted cancer therapy.
Co-reporter:Huiru Lu, Shenghui Li, Jun Chen, Jing Xia, Jinchao Zhang, Yan Huang, Xiaoxiao Liu, Hai-chen Wu, Yuliang Zhao, Zhifang Chai and Yi Hu
Metallomics 2015 vol. 7(Issue 11) pp:1508-1514
Publication Date(Web):08 Sep 2015
DOI:10.1039/C5MT00188A
Small-molecule ligands for stabilizing the G-quadruplex in telomeres are promising chemotherapeutic agents. Despite extensive research, few G-quadruplex-stabilizing ligands have been clinically approved to date. We hypothesized that metal ions may be able to interfere with the ligand-mediated stabilization of the G-quadruplex. Here we found that several metal ions could interfere with the Na+-induced G-quadruplex conformation even in the presence of a ligand. The destabilizing effects of metal ions may not be negligible as most of them are essential elements in organisms. In contrast, Ba2+ was found to be a potent stabilizing cation, which could compete with other destabilizing cations to modulate the stability of the G-quadruplex. Moreover, the destabilizing effects of divalent or trivalent cations were considerably inhibited when a metal chelator was used. These data suggested that the unfavorable effects of destabilizing cations must be minimized for enhancing the ligand-mediated stabilization of the G-quadruplex.
Co-reporter:Yuxi Gao, Xiaomin Peng, Jinchao Zhang, Jiating Zhao, Yunyun Li, Yufeng Li, Bai Li, Yi Hu and Zhifang Chai
Metallomics 2013 vol. 5(Issue 7) pp:913-919
Publication Date(Web):24 May 2013
DOI:10.1039/C3MT20279H
The response of E. coli to Hg2+ exposure was investigated using proteomic and metalloproteomic approaches. E. coli was cultured in the LB medium containing HgCl2 and/or selenomethionine. The growth curve of E. coli was measured to estimate the toxicity of Hg2+ or selenomethionine. After two-dimensional gel electrophoresis (2-DE), distribution of Hg in 2-DE gel was detected with synchrotron radiation X-ray fluorescence (SRXRF) at 4W1B, Beijing Synchrotron Radiation Facility. The proteins with differential expression and those containing Hg were identified with electrospray ionization tandem mass spectrometry (ESI-MS/MS) and peptide mass fingerprinting analysis. The results showed that Hg2+ can inhibit the growth of E. coli, while supplement of selenomethionine can shorten the lag period induced by Hg2+, indicating an antagonistic effect of selenomethionine against Hg2+ toxicity. Mechanistically, Hg was observed to be able to bind pyruvate kinase, a glycolytic enzyme, and modulate the expression of five other proteins, including down-regulation of outer membrane protein W and up-regulation of transcription termination factor rho, cysteine synthase, transaldolase A and alkyl hydroperoxide reductase subunit C. Therefore, our results indicated that mercury may influence osmosis of plasma membrane, antioxidant defense, and glycometabolism of the microorganism. This study demonstrates the high sensitivity of SRXRF in identifying metal-associated proteins compared to conventional proteomic approaches.
Co-reporter:Yi Liu, Heping Li, Jin Xie, Mengxue Zhou, Hui Huang, Huiru Lu, Zhifang Chai, Jun Chen and Yi Hu
Biomaterials Science (2013-Present) 2017 - vol. 5(Issue 5) pp:NaN1031-1031
Publication Date(Web):2017/03/20
DOI:10.1039/C6BM00878J
Phototherapy, as a noninvasive therapeutic procedure, has been applied to treat tumors. However, the application of phototherapy is often compromised by its low efficiency. Herein, we developed a novel nanoplatform based on cationic amphiphilic polymer-wrapped carbon nanotubes (rPAA@SWCNTs) with a photosensitizer, indocyanine green (ICG), for phototherapy. The as-prepared nanoparticles exhibited excellent mitochondria targeting due to the synergistic properties of highly positive charges from the polycations on the corona and the high hydrophobicity from the carbon nanotubes in the core. Moreover, the high buffer capacity of the polycations facilitated the endosomal escape of nanoparticles via a proton-sponge effect. When irradiated with an 808 nm NIR laser, ICG/rPAA@SWCNTs could precisely damage mitochondria with high efficiency and produce reactive oxygen species (ROS) and hyperthermia, which further induced the ROS burst from damaged mitochondria. The overproduced ROS accumulated in mitochondria ultimately resulted in mitochondrial damage and cell death. Therefore ICG/rPAA@SWCNTs may be able to achieve an amplifying phototherapeutic effect.
![3',6'-Dihydroxy-3H-spiro[isobenzofuran-1,9'-xanthen]-3-one](http://img.cochemist.com/ccimg/2400/2321-07-5.png)
![3',6'-Dihydroxy-3H-spiro[isobenzofuran-1,9'-xanthen]-3-one](http://img.cochemist.com/ccimg/2400/2321-07-5_b.png)
