Co-reporter:Rui Ding, Chao Zhang, Xiaoxia Zhu, Han Cheng, ... Jiyu Cao
Free Radical Biology and Medicine 2017 Volume 113(Volume 113) pp:
Publication Date(Web):1 December 2017
DOI:10.1016/j.freeradbiomed.2017.10.386
•COFs-derived PM2.5 reduced cell viability and induced reactive oxygen species (ROS).•COFs-derived PM2.5 induced autophagy via the PI3K/AKT/mTOR pathway.•The autophagy induced by COFs-derived PM2.5 is triggered by ROS.Cooking oil fumes-derived PM2.5 (COFs-derived PM2.5) exposure can induce oxidative stress and cytotoxic effects. Here we investigated the role of ROS-AKT-mTOR axis in COFs-derived PM2.5-induced autophagy in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with different concentrations of COFs-derived PM2.5, together with or without N-acetyl-L-cysteine (NAC, a radical scavenger) or 3-methyladenine (3-MA, an autophagy inhibitor). Cell viability was assessed with MTT assay, and ROS level was measured with DCFH-DA assay after the treatment. Transmission electron microscopy (TEM) was used to evaluate the formation of autophagosomes, while immunofluorescent assay and western blot were used to assess the expression of LC3-I/II and beclin 1. Proteins involved in the PI3K-AKT-mTOR signaling pathway were measured with western blot. The results showed that the treatment of COFs-derived PM2.5 dose-dependently reduced the viability of HUVECs and increased the ROS levels in the cells. Both immunofluorescent assay and western blot showed that treatment with COFs-derived PM2.5 significantly increased LC3-II and beclin 1 levels, as well as the ratio of LC3-II/LC3-I, which could be rescued by the co-incubation with NAC or 3-MA. TEM also confirmed the increased formation of autophagosomes in the cells treated with COFs-derived PM2.5, while co-treatment with NAC evidently decreased autophagosomes formation. In addition, western blot also showed that the phosphorylation of PI3K, AKT, and mTOR all decreased by the treatment of COFs-derived PM2.5, which was effectively rescued by the co-treatment with NAC. These findings demonstrate ROS-AKT-mTOR axis plays a critical role in HUVECs autophagy induced by COFs-derived PM2.5.Download high-res image (153KB)Download full-size image
Co-reporter:Chang Guo, Jingfan Ma, Qionghong Zhong, Mengyuan Zhao, Tianxing Hu, Tong Chen, Longxin Qiu, Longping Wen
Toxicology and Applied Pharmacology 2017 Volume 328(Volume 328) pp:
Publication Date(Web):1 August 2017
DOI:10.1016/j.taap.2017.05.001
•Hematoxylin and eosin stains showed curcumin improved ethanol-induced steatosis.•Metabolomics analysis identified forty-seven and thirty-three metabolites associated with ethanol and curcumin, respectively.•Coordinated pathway alteration in ethanol group•Ethanol-induced fatty acid biosynthesis was suppressed by curcumin.Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy.Download high-res image (499KB)Download full-size image
Co-reporter:Changli Wang; Renquan Ruan; Li Zhang; Yunjiao Zhang; Wei Zhou; Jun Lin; Weiping Ding;Longping Wen
Molecular Pharmaceutics 2015 Volume 12(Issue 4) pp:1259-1267
Publication Date(Web):March 3, 2015
DOI:10.1021/mp500789h
In this work, we discovered that the Na+/K+-ATPase beta-subunit (ATP1B1) on epidermal cells plays a key role in the peptide-mediated transdermal delivery of macromolecular drugs. First, using a yeast two-hybrid assay, we screened candidate proteins that have specific affinity for the short peptide TD1 (ACSSSPSKHCG) identified in our previous work. Then, we verified the specific binding of TD1 to ATP1B1 in yeast and mammalian cells by a pull-down ELISA and an immunoprecipitation assay. Finally, we confirmed that TD1 mainly interacted with the C-terminus of ATP1B1. Our results showed that the interaction between TD1 and ATP1B1 affected not only the expression and localization of ATP1B1, but also the epidermal structure. In addition, this interaction could be antagonized by the exogenous competitor ATP1B1 or be inhibited by ouabain, which results in the decreased delivery of macromolecular drugs across the skin. The discovery of a critical role of ATP1B1 in the peptide-mediated transdermal drug delivery is of great significance for the future development of new transdermal peptide enhancers.
Co-reporter:Ying Liu;Yan-Yan Chen;Ji-Yu Cao
Environmental Science and Pollution Research 2015 Volume 22( Issue 13) pp:9728-9741
Publication Date(Web):2015 July
DOI:10.1007/s11356-015-4140-4
Epidemiological studies demonstrate a linkage between morbidity and mortality and particulate matter (PM), particularly fine particulate matter (PM2.5) that can readily penetrate into the lungs and are therefore more likely to increase the incidence of respiratory and cardiovascular diseases. The present study investigated the compositions of cooking oil fume (COF)-derived PM2.5, which is the major source of indoor pollution in China. Furthermore, oxidative stress, cytotoxicity, apoptosis, and cell cycle arrest induced by COF-derived PM2.5 in primary fetal alveolar type II epithelial cells (AEC II cells) were also detected. N-acetyl-l-cysteine (NAC), a radical scavenger, was used to identify the role of oxidative stress in the abovementioned processes. Our results suggested that compositions of COF-derived PM2.5 are obviously different to PM2.5 derived from other sources, and COF-derived PM2.5 led to cell death, oxidative stress, apoptosis, and G0/G1 cell arrest in primary fetal AEC II cells. Furthermore, the results also showed that COF-derived PM2.5 induced apoptosis through the endoplasmic reticulum (ER) stress pathway, which is indicated by the increased expression of ER stress-related apoptotic markers, namely GRP78 and caspase-12. Besides, the induction of oxidative stress, cytotoxicity, apoptosis, and cell cycle arrest was reversed by pretreatment with NAC. These findings strongly suggested that COF-derived PM2.5-induced toxicity in primary fetal AEC II cells is mediated by increased oxidative stress, accompanied by ER stress which results in apoptosis.
Co-reporter:Hao Wu, Jun Lin, Peidang Liu, Zhihai Huang, Peng Zhao, Haizhen Jin, Cailian Wang, Longping Wen, Ning Gu
Biomaterials 2015 62() pp: 47-57
Publication Date(Web):
DOI:10.1016/j.biomaterials.2015.05.033
Co-reporter:Renquan Ruan, Peipei Jin, Li Zhang, Changli Wang, Chuanjun Chen, Weiping Ding, and Longping Wen
Molecular Pharmaceutics 2014 Volume 11(Issue 11) pp:4015-4022
Publication Date(Web):September 30, 2014
DOI:10.1021/mp500277g
The biologically inspired transdermal enhanced peptide TD1 has been discovered to specifically facilitate transdermal delivery of biological macromolecules. However, the biological behavior of TD1 has not been fully defined. In this study, we find that energy is required for the TD1-mediated transdermal protein delivery through rat and human skins. Our results show that the permeation activity of TD1-hEGF, a fusion protein composed of human epidermal growth factor (hEGF) and the TD1 sequence connected with a glycine-serine linker (GGGGS), can be inhibited by the energy inhibitor, rotenone or oligomycin. In addition, adenosine triphosphate (ATP), the essential energetic molecule in organic systems, can effectively facilitate the TD1 directed permeation of the protein-based drug into the skin in a dose-dependent fashion. Our results here demonstrate a novel energy-dependent permeation process during the TD1-mediated transdermal protein delivery that could be valuable for the future development of promising new transdermal drugs.Keywords: ATP; energy; peptide chaperon; transdermal drug delivery; transdermal peptide;
Co-reporter:Peng-Fei Wei, Li Zhang, Susheel Kumar Nethi, Ayan Kumar Barui, Jun Lin, Wei Zhou, Yi Shen, Na Man, Yun-Jiao Zhang, Jing Xu, Chitta Ranjan Patra, Long-Ping Wen
Biomaterials 2014 35(3) pp: 899-907
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.10.024
Co-reporter:Liang Chen, Yanyan Miao, Lin Chen, Jing Xu, Xinxing Wang, Han Zhao, Yi Shen, Yi Hu, Yunpeng Bian, Yuanyuan Shen, Jutao Chen, Yingying Zha, Long-Ping Wen, Ming Wang
Biomaterials 2014 35(34) pp: 9269-9279
Publication Date(Web):
DOI:10.1016/j.biomaterials.2014.07.030
Co-reporter:Yanyan Miao, Jing Xu, Yi Shen, Liang Chen, Yunpeng Bian, Yi Hu, Wei Zhou, Fang Zheng, Na Man, Yuanyuan Shen, Yunjiao Zhang, Ming Wang, and Longping Wen
ACS Nano 2014 Volume 8(Issue 6) pp:6131
Publication Date(Web):May 26, 2014
DOI:10.1021/nn501495a
In a biological environment, nanoparticles encounter and interact with thousands of proteins, forming a protein corona on the surface of the nanoparticles, but these interactions are oftentimes perceived as nonspecific protein adsorption, with protein unfolding and deactivation as the most likely consequences. The potential of a nanoparticle–protein interaction to mimic a protein–protein interaction in a cellular signaling process, characterized by stringent binding specificity and robust functional modulation for the interacting protein, has not been adequately demonstrated. Here, we show that water-suspended fullerene C60 nanocrystals (nano-C60) interact with and modulate the function of the Ca2+/calmodulin-dependent protein kinase II (CaMKII), a multimeric intracellular serine/threonine kinase central to Ca2+ signal transduction, in a fashion that rivals the well-documented interaction between the NMDA (N-methyl-d-aspartate) receptor subunit NR2B protein and CaMKII. The stable high-affinity binding of CaMKII to distinct sites on nano-C60, mediated by amino acid residues D246 and K250 within the catalytic domain of CaMKIIα, but not the nonspecific adsorption of CaMKII to diamond nanoparticles, leads to functional consequences reminiscent of the NR2B–CaMKII interaction, including generation of autonomous CaMKII activity after Ca2+ withdrawal, calmodulin trapping and CaMKII translocation to postsynaptic sites. Our results underscore the critical importance of specific interactions between nanoparticles and cellular signaling proteins, and the ability of nano-C60 to sustain the autonomous kinase activity of CaMKII may have significant implications for both the biosafety and the potential therapeutic applications of fullerene C60.Keywords: amino acid residues; autonomous activity; Ca2+/CaM-dependent protein kinase II; fullerene C60 nanocrystals; NMDA receptor subunit NR2B protein; specific interaction; T286 autophosphorylation
Co-reporter:Liang Dong;Yun Liu;Yang Lu;Li Zhang;Na Man;Liang Cao;Kai Ma;Duo An;Jun Lin;Yun-Jun Xu;Wei-Ping Xu;Wen-Bin Wu;Shu-Hong Yu
Advanced Functional Materials 2013 Volume 23( Issue 47) pp:5930-5940
Publication Date(Web):
DOI:10.1002/adfm.201203767
Abstract
Induction of autophagy is a common response of cells upon exposure to nanomaterials and represents both a safety concern and an application niche for engineered nanomaterials. Herein, it is reported that the magnetic property and the autophagy-inducing activity for Ni–Co alloy nanocrystal (NC) assemblies can be differentially “tuned” through altering the material composition. A series of Ni–Co alloy NC assemblies, composed of nanoparticles (NPs) with a size of about 30 nm, can be quickly synthesized under microwave irradiation in aqueous solution. A controllable self-assembling effect is observed due to the strong magnetic moment of NPs and external magnetic field. Interestingly, the saturation magnetization (Ms) shows a ‘roller coaster’ effect with varying component molar ratio, while the autophagy-inducing activity and toxicity of these alloy NCs presents an elevated tendency with the increase of nickel component. The autophagic response partly contributes to the observed cellular toxicity of the NC assemblies, as inhibition of autophagy partially but significantly reduces toxicity. Therefore, through tuning the composition of the alloy, optimal Ni–Co NCs satisfying the needs of different applications such as diagnostic imaging (maximum magnetization and low autophagic response) or magnetically-directed cancer cell killing (maximum autophagic response and sufficient magnetization) may be designed and developed.
Co-reporter:Yang Lu;Li Zhang;Jing Li;Yu-De Su;Yun Liu;Yun-Jun Xu;Liang Dong;Huai-Ling Gao;Jun Lin;Na Man;Peng-Fei Wei;Wei-Ping Xu;Shu-Hong Yu
Advanced Functional Materials 2013 Volume 23( Issue 12) pp:1534-1546
Publication Date(Web):
DOI:10.1002/adfm.201202233
Abstract
Herein, a kind of novel monocomponent hydrophilic and paramagnetic manganese(II) oxide nanocrystal is prepared in polar solution by a one-pot microwave-assisted synthesis. This kind of nanocrystal can be taken up efficiently to serve as an excellent T1 magnetic resonance imaging (MRI) contrast agent with an enhanced r1 value of 0.81 mM−1 s−1. The key to the success of this method is that no additional capping agents are required for coating onto the surface via ligand exchange, facilitating research of their intrinsic biological activities. Furthermore, multiple lines of convincing evidence are presented to prove that MnO nanocrystals (NCs) elicit p53-activation-independent and authentic functional autophagy via inducing autophagosome formation. Notably, there are very few reports so far of the autophagy phenomenon induced by magnetic nanocrystals. Moreover, these results offer an indication for cancer therapy that MnO NCs combined with doxorubicin at a nontoxic concentration can have a definite synergistic effect, which is mediated through the genuine autophagy induction, on killing cancer cells in vitro and in vivo.
Co-reporter:Liang Chen, Yanyan Miao, Lin Chen, Peipei Jin, Yingying Zha, Yuming Chai, Fang Zheng, Yunjiao Zhang, Wei Zhou, Jigui Zhang, Longping Wen, Ming Wang
Biomaterials 2013 34(38) pp: 10172-10181
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.09.048
Co-reporter:Jingwei Li, Liang Feng, Li Fan, Yuan Zha, Liangran Guo, Qizhi Zhang, Jun Chen, Zhiqing Pang, Yuchen Wang, Xinguo Jiang, Victor C. Yang, Longping Wen
Biomaterials 2011 32(21) pp: 4943-4950
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.03.031
Co-reporter:GuanYi Huang;Ying Zhang;Qiang Zhang;Bin Zhang;LongPing Wen
Science China Chemistry 2010 Volume 53( Issue 11) pp:2272-2278
Publication Date(Web):2010 November
DOI:10.1007/s11426-010-4116-7
Selenium (Se), a potential drug candidate for cancer prevention, has a special property: Its nutritional dosage and tolerable upper intake level appear in a narrow range, while the therapeutic use of this mineral may depend on a higher body intake level. Nano-selenium (nano-Se) particles, however, preserve the selenium element’s low toxicity characteristic but give a high biochemical activity effect of selenium compounds. In the present study different morphologies of synthesized nano-Se were evaluated concerning its anti-proliferation and apoptosis-inducing effect. Then nano-Se (sphere) were picked out to investigate its influence on two significant events involved in apoptosis, cell cycle arrest and mitochondrial membrane potential disruption. Furthermore, massive vacuolization of HeLa cells treated by nano-Se (sphere) was observed and more methods were used to measure the level of vacuolization. Such vacuolization needs energy supply and has been demonstrated to be related to Se endocytosis. These results suggest a possible mechanism to trigger apoptosis initiation.
Co-reporter:Qi-Hong Zhao;Ying Zhang;Yun Liu;Wen-Jun Yang;Hui-Li Wang;Yuan-Yuan Shen;Long-Ping Wen
Medical Oncology 2010 Volume 27( Issue 2) pp:
Publication Date(Web):2010/06/01
DOI:10.1007/s12032-009-9192-1
Realgar has been used successfully to treat diseases for thousands of years, but its poor water solubility and high toxicity hampered its further medical uses. Here, we first applied transdermal drug delivery system to deliver realgar nanoparticles to investigate its anticancer effect and toxicity in vivo. In this study, MTT assay and flow cytometry analysis demonstrated that realgar significantly suppressed the proliferation and induced apoptosis of B16 melanoma cells in a dose-dependent manner. Transdermal penetration studies in vitro showed realgar nanoparticles could be delivered efficiently through skin. Tests on tumor-bearing C57BL/6 mice displayed that realgar could decrease the tumor volume markedly via transdermal drug delivery compared with the intraperitoneal administration and the control. Hematoxylin–eosin and immunohistochemical staining revealed that it could inhibit angiogenesis. The monitoring of the hepatic injury, body weight, feeding behavior, motor activity, and skin irritation of each animal indicated little toxicity of realgar to mice. The results demonstrated that realgar nanoparticles can be dermally delivered to achieve high efficacy against menaloma in vivo with low toxicity.
Co-reporter:Wenjun Yang, Yiyun Cheng, Tongwen Xu, Xueyuan Wang, Long-ping Wen
European Journal of Medicinal Chemistry 2009 Volume 44(Issue 2) pp:862-868
Publication Date(Web):February 2009
DOI:10.1016/j.ejmech.2008.04.021
Star-burst dendrimers represent a superior carrier platform for targeted drug delivery. Partially acetylated generation 5 (G5) polyamidoamine (PAMAM) dendrimer was conjugated with the targeting moiety (biotin) and the imaging moiety (fluoresceinisothiocyanate, FITC), and the resulting dendrimer–biotin conjugate was characterized by 1H NMR, UV–vis spectrum. As revealed by flow cytometry and confocal microscopy, the bifunctional conjugate (dendrimer–biotin–FITC) exhibited much higher cellular uptake into HeLa cells than the conjugate without biotin. The uptake was energy-dependent, dose-dependent, and could be effectively blocked by dendrimer-conjugated biotin. Our results indicated that the biocompatible biotin–dendrimer conjugate might be a promising nano-platform for cancer therapy and cancer diagnosis.Schematic representation of the reactions involved in the synthesis of multi-functional nanodevices based on PAMAM dendrimers for cancer cell targeting and imaging.
Co-reporter:Minglu Ma, Yiyun Cheng, Zhenhua Xu, Peng Xu, Haiou Qu, Yujie Fang, Tongwen Xu, Longping Wen
European Journal of Medicinal Chemistry 2007 Volume 42(Issue 1) pp:93-98
Publication Date(Web):January 2007
DOI:10.1016/j.ejmech.2006.07.015
Sulfamethoxazole (SMZ), a sulfonamide with well-known anti-bacterial properties, is not freely soluble in water and causes problems in its clinical applications. In the present study we investigated the potential of ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimers as drug carriers of SMZ by aqueous solubility, in vitro release as well as anti-bacterial activity studies. Results showed that the aqueous solubility of SMZ was approximately proportional to dendrimer concentration (a 40-fold increase in solubility in 10 mg/ml G3 PAMAM dendrimer solutions compared with that in double-distilled water at 37 °C). The in vitro release of SMZ in the presence of PAMAM dendrimers was significantly slower compared to pure SMZ dissolved in ethanol. Microbiology studies showed that PAMAM dendrimers could increase the anti-bacterial activity of SMZ (a 4- or 8-fold increase in the anti-bacterial activity of SMZ in dendrimer solution compared to pure SMZ dissolved in dimethylsulfoxide (DMSO) or 0.01 M NaOH solution). The in vitro release behavior and anti-bacterial activity studies indicated that PAMAM dendrimers might be considered as potential drug carriers of sulfonamides with a sustained release behavior under suitable conditions.Solubility of SMZ can be greatly enhanced by PAMAM dendrimers.
Co-reporter:Cheng Yiyun;Man Na;Xu Tongwen;Fu Rongqiang;Wang Xueyuan;Wang Xiaomin;Wen Longping
Journal of Pharmaceutical Sciences 2007 Volume 96(Issue 3) pp:595-602
Publication Date(Web):8 NOV 2006
DOI:10.1002/jps.20745
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs in the world, primarily for symptoms associated with osteoarthritis and other chronic musculoskeletal conditions. However, adverse effects caused by oral administration, such as local or systemic disturbance in the gastrointestinal tract, have limited the clinical applications of these drugs. In the present study we have assessed the ability of polyamidoamine (PAMAM) dendrimers to facilitate transdermal delivery of NSAIDs, using Ketoprofen and Diflunisal as model drugs. In vitro permeation studies with excised rat skins indicated that PAMAM dendrimers significantly enhanced the accumulative permeated amount of both drugs after 24 h, as compared to drug suspensions without PAMAM dendrimers. Similarly, anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic profile for the NSAIDs–PAMAM dendrimer complex after transdermal administration. In addition, blood drug level studies revealed that the bioavailability was 2.73 times higher for the Ketoprofen–PAMAM dendrimer complex and 2.48 times higher for the Diflunisal–PAMAM dendrimer complex, respectively, than the pure drug suspensions. These results demonstrated that PAMAM dendrimers can effectively facilitate skin penetration of NSAIDs and may have the potential applications for the development of new transdermal formulations. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci
Co-reporter:Man Na, Cheng Yiyun, Xu Tongwen, Ding Yang, Wang Xiaomin, Li Zhenwei, Chen Zhichao, Huang Guanyi, Shi Yunyu, Wen Longping
European Journal of Medicinal Chemistry 2006 Volume 41(Issue 5) pp:670-674
Publication Date(Web):May 2006
DOI:10.1016/j.ejmech.2006.01.001
Ketoprofen, a non-steroidal anti-inflammatory drug with well-known anti-inflammatory, antipyretic and analgesic properties, has low solubility in water and causes local or systemic disturbance in the gastrointestinal tract. In the present study we investigated the potential of polyamidoamine (PAMAM) dendrimers as drug carriers of ketoprofen by in vitro and in vivo studies. The in vitro release of ketoprofen from the drug–dendrimer complex is significantly slower compared to pure ketoprofen. Anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic behavior for the ketoprofen–PAMAM dendrimer complex. Also, the blood level studies were investigated. We concluded that PAMAM dendrimers might be considered as a potential drug carrier of ketoprofen with a sustained release behavior under suitable conditions.Anti-nociceptive pharmcodynamic of pure ketoprofen and ketoprofen–PAMAM dendrimer complex in an acetic acid-induced writhing model. Mean ± S.E.M. (*P < 0.05; **P < 0.01, compared to the control).
Co-reporter:Yuanyuan Shen;Xin Guo;Yongping Chen;Caoshou Zhang;Wenjuan Yang;Maobin Zhang;Minglu Ma;Shu Liu
Nature Biotechnology 2006 Volume 24(Issue 4) pp:455-460
Publication Date(Web):2006-03-26
DOI:10.1038/nbt1193
Efficient transdermal drug delivery of large hydrophilic drugs is challenging. Here we report that the short synthetic peptide, ACSSSPSKHCG, identified by in vivo phage display, facilitated efficient transdermal protein drug delivery through intact skin. Coadministration of the peptide and insulin to the abdominal skin of diabetic rats resulted in elevated systemic levels of insulin and suppressed serum glucose levels for at least 11 h. Significant systemic bioavailability of human growth hormone was also achieved when topically coadministered with the peptide. The transdermal-enhancing activity of the peptide was sequence specific and dose dependent, did not involve direct interaction with insulin and enabled penetration of insulin into hair follicles beyond a depth of 600 m. Time-lapse studies suggested that the peptide creates a transient opening in the skin barrier to enable macromolecular drugs to reach systemic circulation.
Co-reporter:Hao Wu, Jun Lin, Peidang Liu, Zhihai Huang, Peng Zhao, Haizhen Jin, Jun Ma, Longping Wen, Ning Gu
Biomaterials (September 2016) Volume 101() pp:1-9
Publication Date(Web):September 2016
DOI:10.1016/j.biomaterials.2016.05.031
Malignant glioma is one of the most common intracranial tumor with a dismal prognosis. The radiosensitizing effect of silver nanoparticles (AgNPs) on glioma both in vitro and in vivo were demonstrated in the previous studies of our group. However, the underlying mechanism is still unclear. In this present study, the use of antioxidants is employed for the regulating of reactive oxygen species (ROS) in U251 cells treated with various agents, and the results shows that ROS played an essential role in the autophagy inducing and radiosensitization effect of AgNPs. Moreover, the inhibition of protective autophagy with 3-MA is another way to increase ROS, resulting in the increasing of cell death and apoptosis. Taken together, understanding the relationship between the elevated ROS and autophagy and the effect of ROS should be useful to the clinical applications of AgNPs. These findings could potentially be exploited for new therapeutic strategies in glioma radiotherapy.
Co-reporter:Hao Wu, Jun Lin, Peidang Liu, Zhihai Huang, Peng Zhao, Haizhen Jin, Jun Ma, Longping Wen, Ning Gu
Biomaterials (September 2016) Volume 101() pp:1-9
Publication Date(Web):September 2016
DOI:10.1016/j.biomaterials.2016.05.031
Co-reporter:Han Yao, Yunjiao Zhang, Liu Liu, Youcui Xu, Xi Liu, Jun Lin, Wei Zhou, Pengfei Wei, Peipei Jin, Long-Ping Wen
Biomaterials (November 2016) Volume 108() pp:143-156
Publication Date(Web):November 2016
DOI:10.1016/j.biomaterials.2016.08.036
Co-reporter:Han Yao, Yunjiao Zhang, Liu Liu, Youcui Xu, Xi Liu, Jun Lin, Wei Zhou, Pengfei Wei, Peipei Jin, Long-Ping Wen
Biomaterials (November 2016) Volume 108() pp:143-156
Publication Date(Web):November 2016
DOI:10.1016/j.biomaterials.2016.08.036
Lanthanide-based nanoparticles (LNs) hold great promise in medicine. A variety of nanocrystals, including LNs, elicits potent inflammatory response through activation of NLRP3 inflammasome. We have previously identified an LNs-specific surface coating peptide RE-1, with the sequence of ‘ACTARSPWICG’, which reduced nanocrystal-cell interaction and abrogated LNs-induced autophagy and toxicity in both HeLa cells and liver hepatocytes. Here we show that RE-1 coating effectively inhibited LNs-induced inflammasome activation, mostly mediated by NLRP3, in mouse bone marrow derived macrophage (BMDM) cells, human THP-1 cells and mouse peritoneal macrophages and also reduced LNs-elicited inflammatory response in vivo. RE-1 coating had no effect on cellular internalization of LNs in BMDM cells, in contrast to the situation in HeLa cells where cell uptake of LNs was significantly inhibited by RE-1. To elucidate the molecular mechanism underlying the inflammasome-inhibiting effect of RE-1, we assessed several parameters known to influence nanocrystal-induced NLRP3 inflammasome activation. RE-1 coating did not reduce potassium efflux, which occurred after LNs treatment in BMDM cells and was necessary but insufficient for LNs-induced inflammasome activation. RE-1 did decrease lysosomal damage induced by LNs, but the inhibitor of cathepsin B did not affect LNs-elicited caspase 1 activation and IL-1β release, suggesting that lysosomal damage was not critically important for LNs-induced inflammasome activation. On the other hand, LNs-induced elevation of intracellular reactive oxygen species (ROS), critically important for inflammasome activation, was largely abolished by RE-1 coating, with the reduction on NADPH oxidase-generated ROS playing a more prominent role for RE-1's inflammasome-inhibiting effect than the reduction on mitochondria-generated ROS. ROS generation further triggered Ca2+ influx, an event that was mediated by Transient Receptor Potential M2 (TRPM2) and was necessary for inflammasome activation, and this event was completely inhibited by RE-1 coating. We conclude from these studies that inhibition of ROS production, and the subsequent abrogation of TRPM2-mediated Ca2+ influx, is the primary mechanism underlying RE-1's inhibitory effect on LNs-induced inflammasome activation. The ability of regulating the inflammatory response of nanocrystals through peptide surface coating may be of great value for in vivo applications of LNs and other engineered nanomaterials.
